Common fixed points in best approximation for Banach operator pairs with Ciric type I-contractions

NASA Astrophysics Data System (ADS)

Hussain, N.

2008-02-01

The common fixed point theorems, similar to those of Ciric [Lj.B. Ciric, On a common fixed point theorem of a Gregus type, Publ. Inst. Math. (Beograd) (N.S.) 49 (1991) 174-178; Lj.B. Ciric, On Diviccaro, Fisher and Sessa open questions, Arch. Math. (Brno) 29 (1993) 145-152; Lj.B. Ciric, On a generalization of Gregus fixed point theorem, Czechoslovak Math. J. 50 (2000) 449-458], Fisher and Sessa [B. Fisher, S. Sessa, On a fixed point theorem of Gregus, Internat. J. Math. Math. Sci. 9 (1986) 23-28], Jungck [G. Jungck, On a fixed point theorem of Fisher and Sessa, Internat. J. Math. Math. Sci. 13 (1990) 497-500] and Mukherjee and Verma [R.N. Mukherjee, V. Verma, A note on fixed point theorem of Gregus, Math. Japon. 33 (1988) 745-749], are proved for a Banach operator pair. As applications, common fixed point and approximation results for Banach operator pair satisfying Ciric type contractive conditions are obtained without the assumption of linearity or affinity of either T or I. Our results unify and generalize various known results to a more general class of noncommuting mappings.

Viagra warning re "poppers" and notice re protease inhibitors.

PubMed

James, J S

1998-05-01

Pfizer, Inc., manufacturer of Viagra (sildenafil), is warning patients that Viagra is contraindicated with nitrate inhalers (poppers). Nitrates in any form or nitric oxide donors can potentially cause hypotension. Pfizer also recommends that patients using protease inhibitors, particularly ritonavir, use a lower dose of Viagra (25 mg) because they interfere with the elimination of Viagra. This interaction does not pose a significant risk to the patient.

The accuracies of DNA-based estimates of genetic merit derived from Angus or multibreed beef cattle training populations.

PubMed

Weber, K L; Drake, D J; Taylor, J F; Garrick, D J; Kuehn, L A; Thallman, R M; Schnabel, R D; Snelling, W M; Pollak, E J; Van Eenennaam, A L

2012-12-01

Several organizations have developed prediction models for molecular breeding values (MBV) for quantitative growth and carcass traits in beef cattle using Bovine SNP50 genotypes and phenotypic or EBV data. Molecular breeding values for Angus cattle have been developed by IGENITY, Pfizer Animal Genetics, and a collaboration between researchers from Iowa State University and the University of Missouri-Columbia (ISU/UMC). The U.S. Meat Animal Research Center (USMARC; Clay Center, NE) has also developed MBV for 16 cattle breeds using 2 multibreed populations, the Germplasm Evaluation (GPE) Program and the 2,000 Bull Project (2K(ALL)), and 2 single breed subpopulations of the 2,000 Bull Project, Angus (2K(AN)) and Hereford (2K(HH)). In this study, these MBV were assessed relative to commercial ranch EBV estimated from the progeny phenotypes of Angus bulls naturally mated in multisire breeding pastures to commercial cows: 121 for USMARC MBV, 99 for ISU/UMC MBV, and 29 for IGENITY and Pfizer MBV (selected based on number of progeny carcass records). Five traits were analyzed: weaning weight (WW), HCW, marbling score (MS), rib-eye muscle area (RE), and, for IGENITY and Pfizer only, feedlot ADG. The average accuracies of MBV across traits were 0.38 ± 0.05 for IGENITY, 0.61 ± 0.12 for Pfizer, 0.46 ± 0.12 for ISU/UMC, 0.16 ± 0.04 for GPE, 0.26 ± 0.05 for 2K(ALL), 0.24 ± 0.04 for 2K(AN), and 0.02 ± 0.12 for 2K(HH). Angus-based MBV (IGENITY, Pfizer, ISU/UMC, and 2K(AN)) explained larger proportions of genetic variance in this population than GPE, 2K(ALL), or 2K(HH) MBV for the same traits. In this data set, IGENITY, Pfizer, and ISU/UMC MBV were predictive of realized performance of progeny, and incorporation of that information into national genetic evaluations would be expected to improve EPD accuracy, particularly for young animals.

Analysis of Pfizer compounds in EPA's ToxCast chemicals-assay space.

PubMed

Shah, Falgun; Greene, Nigel

2014-01-21

The U.S. Environmental Protection Agency (EPA) launched the ToxCast program in 2007 with the goal of evaluating high-throughput in vitro assays to prioritize chemicals that need toxicity testing. Their goal was to develop predictive bioactivity signatures for toxic compounds using a set of in vitro assays and/or in silico properties. In 2009, Pfizer joined the ToxCast initiative by contributing 52 compounds with preclinical and clinical data for profiling across the multiple assay platforms available. Here, we describe the initial analysis of the Pfizer subset of compounds within the ToxCast chemical (n = 1814) and in vitro assay (n = 486) space. An analysis of the hit rate of Pfizer compounds in the ToxCast assay panel allowed us to focus our mining of assays potentially most relevant to the attrition of our compounds. We compared the bioactivity profile of Pfizer compounds to other compounds in the ToxCast chemical space to gain insights into common toxicity pathways. Additionally, we explored the similarity in the chemical and biological spaces between drug-like compounds and environmental chemicals in ToxCast and compared the in vivo profiles of a subset of failed pharmaceuticals having high similarity in both spaces. We found differences in the chemical and biological spaces of pharmaceuticals compared to environmental chemicals, which may question the applicability of bioactivity signatures developed exclusively based on the latter to drug-like compounds if used without prior validation with the ToxCast Phase-II chemicals. Finally, our analysis has allowed us to identify novel interactions for our compounds in particular with multiple nuclear receptors that were previously not known. This insight may help us to identify potential liabilities with future novel compounds.

Experiences in implementing uHTS--cutting edge technology meets the real world.

PubMed

Gribbon, Philip; Schaertl, Sabine; Wickenden, Malcolm; Williams, Gareth; Grimley, Rachel; Stuhmeier, Frank; Preckel, Hartwig; Eggeling, Christian; Kraemer, Joachim; Everett, Jeremy; Keighley, Wilma W; Sewing, Andreas

2004-01-01

Driven by growing corporate compound files, the demands of target biology, and attempts to cut cost, the number of solutions to HTS has spiralled. In quick succession new assay technologies and screening platforms are appearing on the market, with the promise of screening faster than ever in low volume high density formats whilst providing high quality data. Within this world of rapid change, Pfizer has applied cutting edge technology to HTS by introducing screening in 1 microl formats utilising single molecule detection technology. Instead of resource intensive in-house development, Pfizer entered into a collaboration with Evotec OAI / Evotec Technologies and introduced their Mark-II EVOscreen platform. In this article we will outline the benefits of the approach taken at Pfizer, Sandwich, and introduce the Mark-II EVOscreen platform, illustrating the potential but also possible pitfalls of HTS miniaturisation.

A Converse of the Mean Value Theorem Made Easy

ERIC Educational Resources Information Center

Mortici, Cristinel

2011-01-01

The aim of this article is to discuss some results about the converse mean value theorem stated by Tong and Braza [J. Tong and P. Braza, "A converse of the mean value theorem", Amer. Math. Monthly 104(10), (1997), pp. 939-942] and Almeida [R. Almeida, "An elementary proof of a converse mean-value theorem", Internat. J. Math. Ed. Sci. Tech. 39(8)…

Infectious Disease in the Twenty-First Century: The Need for a Comprehensive Strategy

DTIC Science & Technology

1999-04-26

diseases also’appeared within the U.S., Including Lyme disease , Legionnaires disease , and hantavlrus pulmonary syndrome, and Ebola bneflv reappeared in...response mechanisms. U.S. support for further I8 U S Department of Health & Human Services, Centers for Disease Control and Prevention Preventzng Enzergzng...the strategy calls for strengthening the Infectious disease surveillance and response capabilities In the U S and InternatIonally. Surveillance data

The National Security Doctrine and Policies of the Brazilian Government.

DTIC Science & Technology

1977-07-15

Studies (1970) and Brazil’s Future Role In Internat ional Politics (1973), and has written articles for professional journals . - S...Considering such an “audit” of their internal political affairs an ~ front to sovereignty, they turned to their own arms industry and West European suppliers...ideologies and empty nationalism such as Mussolini’s and realj power based on technology, industrialization , and organization, and to avoid the

Advanced Distributed Simulation Technology II (ADST-II) Dismounted Warrior Network Front End Analysis Experiments

DTIC Science & Technology

1997-12-19

Resource Consultants Inc. (RCI) Science Applications InternatT Corp (SAIC) Veda Inc. Virtual Space Devices (VSD) 1.1 Background The Land Warrior...network. The VICs included: • VIC Alpha - a fully immersive Dismounted Soldier System developed by Veda under a STRICOM applied research effort...consists of the Dismounted Soldier System (DSS), which is characterized as follows: • Developed by Veda under a STRICOM applied research effort

Bibliography of Ticks and Tickborne Diseases from Homer (About 800 B.C.) to 31 December 1981. Volume 7.

DTIC Science & Technology

1982-05-01

Oklahoma. Brt. J.". Nu-tr..-f Arch. Pediat., Barcelona Brit. J. Nutr. BRITISH JOURNAL OF NUTRITION . ARCHIVOS DE PEDIATRIA. BARCELONA. London. Arh. Biol...INTERNATIONAL. The CEUTICAL CHEMISTRY. Nw York, Journal of Stock Breeding, Animal London Health, Nutrition and Husbandry. Surrey. J. Neurocyt. Med...INSTITUT. Tiflis. J. Therm. Biol. Nutr. Rep. Internat. JOURNAL OF THERMAL BIOLOGY. NUTRITION REPORTS INTERNATIONAL. Sutton Bonington, England. Los

Acquiring Pharmaceutical Industry Assets in the UK: 1 + 1 = 1?

PubMed

Kanavos, Panos; Angelis, Aris

2014-01-01

The recent AstraZeneca takeover bid from Pfizer puts pharmaceutical R&D once again on the public agenda. Three pertinent questions are (a) what can be expected from this acquisition, (b) what are the implications for the UK economy and science base, and (c) whether such a deal should go ahead. Although the key driver behind this acquisition would be an improvement in company performance and shareholder value, past evidence suggests that mergers and acquisitions (M&A) of large pharmaceutical companies imply a neutral net effect on productivity, if not a decline, with employment decreasing and R&D spend following a similar trend. Similarities between the two companies include dropping sales; however, relative to its size, AstraZeneca has a more promising R&D pipeline, especially in therapeutic areas where Pfizer's strength is currently limited (e.g. oncology). Ensuring a portfolio diversification would make Pfizer's takeover proposal a knight's one, but history points towards a knave-like behavior.

canvasDesigner: A versatile interactive high-resolution scientific multi-panel visualization toolkit.

PubMed

Zhang, Baohong; Zhao, Shanrong; Neuhaus, Isaac

2018-05-03

We present a bioinformatics and systems biology visualization toolkit harmonizing real time interactive exploring and analyzing of big data, full-fledged customizing of look-n-feel, and producing multi-panel publication-ready figures in PDF format simultaneously. Source code and detailed user guides are available at http://canvasxpress.org, https://baohongz.github.io/canvasDesigner, and https://baohongz.github.io/canvasDesigner/demo_video.html. isaac.neuhaus@bms.com, baohong.zhang@pfizer.com, shanrong.zhao@pfizer.com. Supplementary materials are available at https://goo.gl/1uQygs.

Cross-sectional study of Pfizer-sponsored clinical trials: assessment of time to publication and publication history.

PubMed

Mooney, LaVerne A; Fay, Lorna

2016-07-18

To estimate the proportion of Pfizer-sponsored clinical trials that completed in 2010 and are published as manuscripts in the peer-reviewed literature, and to assess the manuscript development history. Retrospective, cross-sectional analysis. Clinical trials registered in ClinicalTrials.gov that completed in 2010 for approved, Pfizer prescription products in patients or vaccines in healthy participants. The proportion of studies for which the primary outcome(s) was published and the median time from study completion to publication. The manuscript development history included the number of times a manuscript was submitted before it was accepted for publication. Among registered clinical trials for which Pfizer was the sponsor that completed in 2010, 76 met all inclusion criteria. The primary outcome(s) for 65 (85%) studies was published in 71 manuscripts; the median time to publication was 31 months (range 3-63 months). Of the remaining 11 studies, 2 had been submitted to at least one journal, 2 had not yet been submitted and 7 had no plans to publish because the study had terminated early due to recruitment challenges. Manuscripts accepted at the first choice journal were published at median time of 28 months (range 8-63, n=31), those accepted at second choice journal were published at 32 months (3-45, n=19), and for those accepted at third choice journal, it was 40 months (range 24-53, n=13). The publication rate and median time to publication from study completion for Pfizer-sponsored studies were comparable to those previously reported for combined analyses of industry and non-industry sectors. Opportunities exist for sponsors, authors and journals to explore ideas that would facilitate more timely publication for clinical trial results. However, to be effective, such changes may need to revisit the entire publication process. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Implementation of a publication strategy in the context of reporting biases. A case study based on new documents from Neurontin litigation.

PubMed

Vedula, S Swaroop; Goldman, Palko S; Rona, Ilyas J; Greene, Thomas M; Dickersin, Kay

2012-08-13

Previous studies have documented strategies to promote off-label use of drugs using journal publications and other means. Few studies have presented internal company communications that discussed financial reasons for manipulating the scholarly record related to off-label indications. The objective of this study was to build on previous studies to illustrate implementation of a publication strategy by the drug manufacturer for four off-label uses of gabapentin (Neurontin, Pfizer, Inc.): migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. We included in this study internal company documents, email correspondence, memoranda, study protocols and reports that were made publicly available in 2008 as part of litigation brought by consumers and health insurers against Pfizer for fraudulent sales practices in its marketing of gabapentin (see http://pacer.mad.uscourts.gov/dc/cgi-bin/recentops.pl?filename=saris/pdf/ucl%20opinion.pdf for the Court's findings).We reviewed documents pertaining to 20 clinical trials, 12 of which were published. We categorized our observations related to reporting biases and linked them with topics covered in internal documents, that is, deciding what should and should not be published and how to spin the study findings (re-framing study results to explain away unfavorable findings or to emphasize favorable findings); and where and when findings should be published and by whom. We present extracts from internal company marketing assessments recommending that Pfizer and Parke-Davis (Pfizer acquired Parke-Davis in 2000) adopt a publication strategy to conduct trials and disseminate trial findings for unapproved uses rather than an indication strategy to obtain regulatory approval. We show internal company email correspondence and documents revealing how publication content was influenced and spin was applied; how the company selected where trial findings would be presented or published; how publication of study results was delayed; and the role of ghost authorship. Taken together, the extracts we present from internal company documents illustrate implementation of a strategy at odds with unbiased study conduct and dissemination. Our findings suggest that Pfizer and Parke-Davis's publication strategy had the potential to distort the scientific literature, and thus misinform healthcare decision-makers.

Prediction of Ship Roll Damping. A State of the Art

DTIC Science & Technology

1981-09-01

Armin W. Troesch and Mr. John P. Hackett for their valuable advice, discussions and encouragement. The author also feels grateful to Professor Norio...Hadd- . (60], and Lewison [61] have proposed expressing the roll damping in a cubi orm without quadratic term, B 1 +B 3 0 , for con- venience in the...34 Internat. Shipbuildin; Progress, Vo.l. 20 (1973). 61. Lewison , G.R.G.: "Optimum Design of Passive Roll Stabilizer Tanks," The Naval Architect (1976). Ij t

Instrumentation Automation for Concrete Structures; Report 1: Instrumentation Automation Techniques

DTIC Science & Technology

1986-12-01

The internat.i..onal measuring system sets up independent standards for t:hese fundamental quanti ties. All other quanti ties (force, acceleration...measurement systems are typically composed of several fundamental performing a special function (Figure 1). 3 accuracy of a quantitative measurement is...equiJ2.ID_g_:)1t 2 J, A fundament ’’ J function of ~" i1 ’r. ’’i::rumentation system is to prese~t desired measurement data to Lne user in a form that

Driving external chemistry optimization via operations management principles.

PubMed

Bi, F Christopher; Frost, Heather N; Ling, Xiaolan; Perry, David A; Sakata, Sylvie K; Bailey, Simon; Fobian, Yvette M; Sloan, Leslie; Wood, Anthony

2014-03-01

Confronted with the need to significantly raise the productivity of remotely located chemistry CROs Pfizer embraced a commitment to continuous improvement which leveraged the tools from both Lean Six Sigma and queue management theory to deliver positive measurable outcomes. During 2012 cycle times were reduced by 48% by optimization of the work in progress and conducting a detailed workflow analysis to identify and address pinch points. Compound flow was increased by 29% by optimizing the request process and de-risking the chemistry. Underpinning both achievements was the development of close working relationships and productive communications between Pfizer and CRO chemists. Copyright © 2013 Elsevier Ltd. All rights reserved.

Implementation of a publication strategy in the context of reporting biases. A case study based on new documents from Neurontin® litigation

PubMed Central

2012-01-01

Background Previous studies have documented strategies to promote off-label use of drugs using journal publications and other means. Few studies have presented internal company communications that discussed financial reasons for manipulating the scholarly record related to off-label indications. The objective of this study was to build on previous studies to illustrate implementation of a publication strategy by the drug manufacturer for four off-label uses of gabapentin (Neurontin®, Pfizer, Inc.): migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. Methods We included in this study internal company documents, email correspondence, memoranda, study protocols and reports that were made publicly available in 2008 as part of litigation brought by consumers and health insurers against Pfizer for fraudulent sales practices in its marketing of gabapentin (see http://pacer.mad.uscourts.gov/dc/cgi-bin/recentops.pl?filename=saris/pdf/ucl%20opinion.pdf for the Court’s findings). We reviewed documents pertaining to 20 clinical trials, 12 of which were published. We categorized our observations related to reporting biases and linked them with topics covered in internal documents, that is, deciding what should and should not be published and how to spin the study findings (re-framing study results to explain away unfavorable findings or to emphasize favorable findings); and where and when findings should be published and by whom. Results We present extracts from internal company marketing assessments recommending that Pfizer and Parke-Davis (Pfizer acquired Parke-Davis in 2000) adopt a publication strategy to conduct trials and disseminate trial findings for unapproved uses rather than an indication strategy to obtain regulatory approval. We show internal company email correspondence and documents revealing how publication content was influenced and spin was applied; how the company selected where trial findings would be presented or published; how publication of study results was delayed; and the role of ghost authorship. Conclusions Taken together, the extracts we present from internal company documents illustrate implementation of a strategy at odds with unbiased study conduct and dissemination. Our findings suggest that Pfizer and Parke-Davis’s publication strategy had the potential to distort the scientific literature, and thus misinform healthcare decision-makers. PMID:22888801

Expression and purification of myristoylated matrix protein of Mason-Pfizer monkey virus for NMR and MS measurements.

PubMed

Prchal, Jan; Junkova, Petra; Strmiskova, Miroslava; Lipov, Jan; Hynek, Radovan; Ruml, Tomas; Hrabal, Richard

2011-09-01

Matrix proteins play multiple roles both in early and late stages of the viral replication cycle. Their N-terminal myristoylation is important for interaction with the host cell membrane during virus budding. We used Escherichia coli, carrying N-myristoyltransferase gene, for the expression of the myristoylated His-tagged matrix protein of Mason-Pfizer monkey virus. An efficient, single-step purification procedure eliminating all contaminating proteins including, importantly, the non-myristoylated matrix protein was designed. The comparison of NMR spectra of matrix protein with its myristoylated form revealed substantial structural changes induced by this fatty acid modification. Copyright © 2011 Elsevier Inc. All rights reserved.

Ketamine: stimulating antidepressant treatment?

PubMed

Malhi, Gin S; Byrow, Yulisha; Cassidy, Frederick; Cipriani, Andrea; Demyttenaere, Koen; Frye, Mark A; Gitlin, Michael; Kennedy, Sidney H; Ketter, Terence A; Lam, Raymond W; McShane, Rupert; Mitchell, Alex J; Ostacher, Michael J; Rizvi, Sakina J; Thase, Michael E; Tohen, Mauricio

2016-05-01

The appeal of ketamine - in promptly ameliorating depressive symptoms even in those with non-response - has led to a dramatic increase in its off-label use. Initial promising results await robust corroboration and key questions remain, particularly concerning its long-term administration. It is, therefore, timely to review the opinions of mood disorder experts worldwide pertaining to ketamine's potential as an option for treating depression and provide a synthesis of perspectives - derived from evidence and clinical experience - and to consider strategies for future investigations. G.S.M. Grant/research support: National Health Medical Research Council, NSW Health, Ramsay Health, American Foundation for Suicide Prevention, AstraZeneca, Eli Lilly & Co, Organon, Pfizer, Servier, and Wyeth; has been a speaker for Abbott, AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, Pfizer, Ranbaxy, Servier, and Wyeth; consultant: AstraZeneca, Eli Lilly & Co, Janssen Cilag, Lundbeck, and Servier. M.A.F. Grant support: AssureRx, Janssen Research & Development, Mayo Foundation, Myriad, National Institute of Alcohol Abuse and Alcoholism (NIAAA), National Institute of Mental Health (NIMH), Pfizer. Consultant (Mayo): Janssen Research & Development, LLC, Mitsubishi Tanabe Pharma Corporation, Myriad Genetics, Neuralstem Inc., Sunovion, Supernus Pharmaceuticals, Teva Pharmaceuticals. CME/travel support: American Physician Institute, CME Outfitters. Financial interest/Mayo Clinic 2016: AssureRx. S.H.K. Grant/research support: Brain Canada, Bristol Meyer Squibb, CIHR, Janssen, Johnson & Johnson, Lundbeck, Ontario Brain Institute, Pfizer, Servier, St. Jude Medical, Sunovion. T.A.K. Grant/research support (through Stanford University): Sunovion Pharmaceuticals and Merck & Co., Inc.; consultant/advisory board bember: Allergan, Inc., Janssen Pharmaceuticals, Myriad Genetic Laboratories, Inc., and Sunovion Pharmaceuticals; lecture honoraria (not Speaker's Bureau payments): GlaxoSmithKline, and Sunovion Pharmaceuticals; royalties from American Psychiatric Publishing, Inc. Also, AstraZeneca Pharmaceuticals LP provided publication support to Parexel for preparation of a manuscript. Spouse employee and stockholder of Janssen Pharmaceuticals. R.W.L. Honoraria for speaking/advising/consulting, and/or received research funds: AstraZeneca, Brain Canada, Bristol Myers Squibb, Canadian Institutes of Health Research, Canadian Depression Research and Intervention Network, Canadian Network for Mood and Anxiety Treatments, Canadian Psychiatric Association, Coast Capital Savings, Johnson and Johnson, Lundbeck, Lundbeck Institute, Pfizer, Servier, St. Jude Medical, Takeda University, Health Network Foundation, and Vancouver Coastal Health Research Institute. R.M. Investigator Janssen trials of esketamine; 'paid-for' ketamine clinic operated by Oxford Health NHS Foundation Trust - fees used to support the Trust. M.J.O. Consultant: Sunovion and Acadia Pharmaceuticals. Full-time employee of U.S. Department of Veterans Affairs. M.E.T. Advisory/Consultant: Alkermes, Allergan, AstraZeneca, Bristol-Myers Squibb Company, Cerecor inc., Eli Lilly & Co., Forest Laboratories, Gerson Lehrman Group, Fabre-Kramer Pharmaceuticals, Inc., GlaxoSmithKline, Guidepoint Global, H. Lundbeck A/S, MedAvante Inc., Merck and Co. Inc. (formerly Schering Plough and Organon), Moksha8, Naurex Inc., Neuronetics Inc., Novartis, Ortho-McNeil Pharmaceuticals (Johnson & Johnson; Janssen), Otsuka, Pamlab, L.L.C. (Nestle), Pfizer (formerly Wyeth Ayerst Pharmaceuticals), Shire US Inc., Sunovion Pharmaceuticals Inc., Trius Therapeutical Inc. and Takeda. Grant support: Agency for Healthcare Research and Quality, Alkermes, AssureRx, Avanir, Forest Pharmaceuticals, Janssen, National Institute of Mental Health, and Otsuka Pharmaceuticals. Speakers Bureau: None since June, 2010. Equity Holdings: MedAvante, Inc. Royalties: American Psychiatric Foundation, Guilford Publications, Herald House, W.W. Norton & Company, Inc. Spouse's employment: Peloton Advantage, which does business with Pfizer. M.T. Full-time employee at Lilly 1997 to 2008. Honoraria/consulted: Abbott, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Johnson & Johnson, Allergan, Otsuka, Merck, Sunovion, Forest, Geodon Richter Plc, Roche, Elan, Alkermes, Lundbeck, Teva, Pamlab, Minerva, Wyeth and Wiley Publishing. Spouse was full time-employee at Lilly 1998-2013. © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Crystallization and preliminary X-ray studies of dUTPase from Mason–Pfizer monkey retrovirus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barabás, Orsolya; Németh, Veronika; Vértessy, Beáta G., E-mail: vertessy@enzim.hu

2006-04-01

Deoxyuridine 5′-triphosphate nucleotidohydrolase from Mason–Pfizer monkey retrovirus (M-PMV dUTPase) is a betaretroviral member of the dUTPase enzyme family. The nucleocapsid-free dUTPase (48426 Da) was co-crystallized with a dUTP substrate analogue using the hanging-drop vapour-diffusion method. Deoxyuridine 5′-triphosphate nucleotidohydrolase from Mason–Pfizer monkey retrovirus (M-PMV dUTPase) is a betaretroviral member of the dUTPase enzyme family. In the mature M-PMV virion, this enzyme is present as the C-terminal domain of the fusion protein nucleocapsid-dUTPase. The homotrimeric organization characteristic of dUTPases is retained in this bifunctional fusion protein. The fusion protein supposedly plays a role in adequate localization of dUTPase activity in the vicinitymore » of nucleic acids during reverse transcription and integration. Here, the nucleocapsid-free dUTPase (48 426 Da) was cocrystallized with a dUTP substrate analogue using the hanging-drop vapour-diffusion method. The obtained crystals belong to the primitive hexagonal space group P6{sub 3}, with unit-cell parameters a = 60.6, b = 60.6, c = 63.6 Å, α = 90, β = 90, γ = 120°. Native and PtCl{sub 4}-derivative data sets were collected using synchrotron radiation to 1.75 and 2.3 Å, respectively. Phasing was successfully performed by isomorphous replacement combined with anomalous scattering.« less

A Riemann-Hilbert approach to asymptotic questions for orthogonal polynomials

NASA Astrophysics Data System (ADS)

Deift, P.; Kriecherbauer, T.; McLaughlin, K. T.-R.; Venakides, S.; Zhou, X.

2001-08-01

A few years ago the authors introduced a new approach to study asymptotic questions for orthogonal polynomials. In this paper we give an overview of our method and review the results which have been obtained in Deift et al. (Internat. Math. Res. Notices (1997) 759, Comm. Pure Appl. Math. 52 (1999) 1491, 1335), Deift (Orthogonal Polynomials and Random Matrices: A Riemann-Hilbert Approach, Courant Lecture Notes, Vol. 3, New York University, 1999), Kriecherbauer and McLaughlin (Internat. Math. Res. Notices (1999) 299) and Baik et al. (J. Amer. Math. Soc. 12 (1999) 1119). We mainly consider orthogonal polynomials with respect to weights on the real line which are either (1) Freud-type weights d[alpha](x)=e-Q(x) dx (Q polynomial or Q(x)=x[beta], [beta]>0), or (2) varying weights d[alpha]n(x)=e-nV(x) dx (V analytic, limx-->[infinity] V(x)/logx=[infinity]). We obtain Plancherel-Rotach-type asymptotics in the entire complex plane as well as asymptotic formulae with error estimates for the leading coefficients, for the recurrence coefficients, and for the zeros of the orthogonal polynomials. Our proof starts from an observation of Fokas et al. (Comm. Math. Phys. 142 (1991) 313) that the orthogonal polynomials can be determined as solutions of certain matrix valued Riemann-Hilbert problems. We analyze the Riemann-Hilbert problems by a steepest descent type method introduced by Deift and Zhou (Ann. Math. 137 (1993) 295) and further developed in Deift and Zhou (Comm. Pure Appl. Math. 48 (1995) 277) and Deift et al. (Proc. Nat. Acad. Sci. USA 95 (1998) 450). A crucial step in our analysis is the use of the well-known equilibrium measure which describes the asymptotic distribution of the zeros of the orthogonal polynomials.

SFC/MS in drug discovery at Pfizer, La Jolla

NASA Astrophysics Data System (ADS)

Bolaños, Ben; Greig, Michael; Ventura, Manuel; Farrell, William; Aurigemma, Christine M.; Li, Haitao; Quenzer, Terri L.; Tivel, Kathleen; Bylund, Jessica M. R.; Tran, Phuong; Pham, Catherine; Phillipson, Doug

2004-11-01

We report the use of supercritical fluid chromatography/mass spectrometry (SFC/MS) for numerous applications in drug discovery at Pfizer, La Jolla. Namely, SFC/MS has been heavily relied upon for analysis and purification of a diverse set of compounds from the in-house chemical library. Supporting high-speed SFC/MS quality control of the purified compounds is made possible at high flow rate SFC along with time-of-flight mass detection. The flexibility of SFC/MS systems has been extended with the integration of an atmospheric pressure photoionization source (APPI) for use with more non-polar compounds and enhancements in signal to noise. Further SFC/MS applications of note include chiral analysis for purification and assessment of enantiomers and SFC/MS analysis of difficult to separate hydrophobic peptides.

Flaws in design, analysis and interpretation of Pfizer's antifungal trials of voriconazole and uncritical subsequent quotations.

PubMed

Jørgensen, Karsten J; Johansen, Helle Krogh; Gøtzsche, Peter C

2006-01-19

We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison. In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial. We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.

Presidential Green Chemistry Challenge: 2002 Greener Synthetic Pathways Award

EPA Pesticide Factsheets

Presidential Green Chemistry Challenge 2002 award winner, Pfizer, improved its synthesis of sertraline, the active ingredient in its drug, Zoloft, to double the yield and reduce the use of raw materials, energy, and water.

Viagra selfhood: pharmaceutical advertising and the visual formation of Swedish masculinity.

PubMed

Asberg, Cecilia; Johnson, Ericka

2009-06-01

Using material from the Pfizer sponsored website providing health information on erectile dysfunction to potential Swedish Viagra customers (www.potenslinjen.se), this article explores the public image of masculinity in relation to sexual health and the cultural techniques for creating pharmaceutical appeal. We zoom in on the targeted ideal users of Viagra, and the nationalized, racialized and sexualized identities they are assigned. As part of Pfizer's marketing strategy of adjustments to fit the local consumer base, the ways in which Viagra is promoted for the Swedish setting is telling of what concepts of masculinity are so stable and unassailable that they can withstand the association with a drug that is, in essence, an acknowledgement of 'failed' masculinity and 'dysfunctional' sexuality. With comparative national examples, this study presents an interdisciplinary take on the 'glocalized' cultural imaginary of Viagra, and the masculine subject positions it engenders.

Conformational changes of the N-terminal part of Mason-Pfizer monkey virus p12 protein during multimerization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knejzlik, Zdenek; Ulbrich, Pavel; Strohalm, Martin

2009-10-10

The Mason-Pfizer monkey virus is a prototype Betaretrovirus with the defining characteristic that it assembles spherical immature particles from Gag-related polyprotein precursors within the cytoplasm of the infected cell. It was shown previously that the N-terminal part of the Gag p12 domain (wt-Np12) is required for efficient assembly. However, the precise role for p12 in mediating Gag-Gag interaction is still poorly understood. In this study we employed detailed circular dichroism spectroscopy, electron microscopy and ultracentrifugation analyses of recombinant wt-Np12 prepared by in vitro transcription and translation. The wt-Np12 domain fragment forms fibrillar structures in a concentration-dependent manner. Assembly into fibersmore » is linked to a conformational transition from unfolded or another non-periodical state to alpha-helix during multimerization.« less

International Conference on Numerical Ship Hydrodynamics (2nd) Held in Berkeley, California on 19-21 September 1977

DTIC Science & Technology

1977-09-01

ORDERING INFORMATION Sec d Internat nal Contere ce on Nu erical Ship ydro nermics ay be order by mallin a req~uest the folio ng ad ess: Firt ilererin I...f(x)dx - 0 (f ’ J d Gd(x’,X 3) dx’ -D0 (jx) 0 d.’ d’U is a closed subspacs of aUoxV ’XT,. hence I O Gde Loach space. d o l , Aw D(4 (x U ’!’ ) Proofs...crest of unbro- domain as an initial-value problem advancing in Ken waves. The inception of wave breaking is time until a steady-state condition has

Identifying the Right Disease Targets to Develop Better Drugs, Faster | NIH MedlinePlus the Magazine

MedlinePlus

... Association Foundation for the NIH Rheumatoid Arthritis and Lupus The Partners Government NIH Industry AbbVie Bristol-Myers ... Pfizer Sanofi Takeda Non-Profit Organizations Alliance for Lupus Research Foundation for HIH Lupus Research Institute Rheumatology ...

A CTD-Pfizer collaboration: manual curation of 88,000 scientific articles text mined for drug-disease and drug-phenotype interactions.

PubMed

Davis, Allan Peter; Wiegers, Thomas C; Roberts, Phoebe M; King, Benjamin L; Lay, Jean M; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J; Enayetallah, Ahmed E; Mattingly, Carolyn J

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88,629 articles relating over 1,200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 254,173 toxicogenomic interactions (152,173 chemical-disease, 58,572 chemical-gene, 5,345 gene-disease and 38,083 phenotype interactions). All chemical-gene-disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer's text-mining process to collate the articles, and CTD's curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug-disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades' worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/

How much cash does your company need?

PubMed

Passov, Richard

2003-11-01

In late 2001, the directors of Pfizer asked that very question. And with good reason. After its 2000 merger with rival Warner-Lambert, the New York-based pharmaceutical giant found itself sitting on a net cash position of $8 billion, which seemed extraordinarily conservative for a company whose products generated $30 billion in revenues. Most large companies with revenues that healthy would increase leverage, thereby unlocking tremendous value for shareholders. But knowledge-intensive companies like Pfizer, this author argues, are in a class apart. Because their largely intangible assets (like R&D) are highly volatile and cannot easily be valued, they are more vulnerable to financial distress than are firms with a preponderance of tangible assets. To insure against that risk, they need to maintain large positive cash balances. These companies' decisions to run large cash balances is one of the key reasons their shares sustain consistent premiums. Only by investing in their intangible assets can knowledge-based companies hope to preserve the value of those assets. A company that finds itself unable to do so because unfavorable market conditions reduce its operating cash flows will see its share price suffer almost as much as if it were to default on its debts. By the same token, with the right balance sheet, knowledge companies can profitably insure against the risk of failing to sustain value-added investments in difficult times. An optimal capital structure that calls for significant cash balances is certainly at odds with the results of a traditional capital structure analysis, the author demonstrates, but it explains the financial policies of many well-run companies, from Pfizer to Intel to ChevronTexaco.

Measurement of the Lamb shift in the hydrogen atom (n = 2)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sokolov, Y.L.; Yakovlev, V.P.

1982-07-01

A principle is proposed for the observation of the stationary interference pattern of two phase-shifted components of the 2p (or 2s) state of the hydrogen atom (Yu. L. Sokolov, Sov. Phys. JETP 36, 243 (1973)); (Proc. 6-th Internat. Conf. on Atomic Phys., Riga, 1978, p. 207). An atomic interferometer, a device analogous in principle to a two-channel optical (such as Michelson's) interferometer, is used to measure the frequency of the (2s/sub 1/2/, F = 0)--(2p/sub 1/2/, F = 0) transition in the hydrogen atom, which is found to equal 909.9014 +- 0.0019 MHz. The corresponding Lamb shift is delta(H, nmore » = 2) = 1057.8594 +- 0.0019 MHz.« less

Polypodium sp. (Coelenterata) infection of paddlefish (Polyodon spathula) eggs

USGS Publications Warehouse

Suppes, V. Charles; Meyer, Fred P.

1975-01-01

Parasitism of fish by coelenterates is rare and the first North American infection was reported in sturgeon (Hoffman et al., 1974, J Parasitol 60: 548-550). In the USSR parasitism of sturgeon (Acipenser sp.) eggs by the coelenterate Polypodium hydriforme Ussov 1885 has long been reported and investigated [Raikova, 1959, in Parasites of Freshwater Fish and the Biological Basis for their Control. Bull State Sci Res Inst Lake and River Fish. XLIX. Eng. transl. No. TT61-31056, O. T. S., U. S. Dep. Commerce, Washington, D. C., 1962, 235 p.: Raikova, 1973, (Proc Second Internat Symp on Cnidaria), Seto Marine Biological Laboratory 20: 165-173]. This report represents the first known infection of Polypodium in the paddlefish (Polyodon spathula).

75 FR 24719 - Withdrawal of Approval of New Animal Drug Applications; Coumaphos; Novobiocin; Buquinolate and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-05

... NADA 13-467/ALBAMIX Not codified Co., a Division of Susceptibility Disks Pfizer, Inc., 235 (novobiocin... approval of application (21 CFR 514.116), notice is given that approval of NADAs 13-467, 42-117, and 45-738...

Evaluation of Pfizer selective enterococcus and KF media for recovery of fecal streptococci from water by membrane filtration.

PubMed Central

Brodsky, M H; Schiemann, D A

1976-01-01

Pfizer selective enterococcus (PSE) and KF agars were compared for their recovery of fecal streptococci from sewage effluent on membrane filters. The results showed that PSE agar is highly selective for the enterococci. The tan color resulting from esculin hydrolysis, which was not always visible on the surfaces of the colonies, is not considered a necessary differential characteristic on PSE agar since more than 90% of all colonies recovered on membrane filters were confirmed as fecal streptococci and 86% were confirmed as enterococci. The detection of esculin hydrolysis on membrane filters was not improved by using the new Millipore type HC filter. KF agar recovered significantly greater numbers of organisms but was not as selective, with 83% of the typical colonies being confirmed as fecal streptococci and 54% as enterococci. An attempt to improve the selectivity of KF agar while retaining its inclusiveness by incubation at 45 C was not successful. PMID:818956

Plate-based diversity subset screening: an efficient paradigm for high throughput screening of a large screening file.

PubMed

Bell, Andrew S; Bradley, Joseph; Everett, Jeremy R; Knight, Michelle; Loesel, Jens; Mathias, John; McLoughlin, David; Mills, James; Sharp, Robert E; Williams, Christine; Wood, Terence P

2013-05-01

The screening files of many large companies, including Pfizer, have grown considerably due to internal chemistry efforts, company mergers and acquisitions, external contracted synthesis, or compound purchase schemes. In order to screen the targets of interest in a cost-effective fashion, we devised an easy-to-assemble, plate-based diversity subset (PBDS) that represents almost the entire computed chemical space of the screening file whilst comprising only a fraction of the plates in the collection. In order to create this file, we developed new design principles for the quality assessment of screening plates: the Rule of 40 (Ro40) and a plate selection process that insured excellent coverage of both library chemistry and legacy chemistry space. This paper describes the rationale, design, construction, and performance of the PBDS, that has evolved into the standard paradigm for singleton (one compound per well) high-throughput screening in Pfizer since its introduction in 2006.

Interspecies radioimmunoassay for the major structural proteins of primate type-D retroviruses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Colcher, D.; Teramoto, Y.A.; Schlom, J.

1977-12-01

A competition radioimmunoassay has been developed in which type-D retroviruses from three primate species compete. The assay utilizes the major structural protein (36,000 daltons) of the endogenous squirrel monkey retrovirus and antisera directed against the major structural protein (27,000 daltons) of the Mason-Pfizer monkey virus isolated from rhesus monkeys. Purified preparations of both viruses grown in heterologous cells, as well as extracts of heterologous cells infected with squirrel monkey retrovirus or Mason-Pfizer monkey virus, compete completely in the assay. Addition of an endogenous virus of the langur monkey also results in complete blocking. No blocking in the assay is observedmore » with type-C baboon viruses, woolly monkey virus, and gibbon virus. Various other type-C and type-B viruses also showed no reactivity. An interspecies assay has thus been developed that recognizes the type-D retroviruses from both Old World monkey (rhesus and langur) and New World monkey (squirrel) species.« less

Business Process Flow Diagrams in Tissue Bank Informatics System Design, and Identification and Communication of Best Practices: The Pharmaceutical Industry Experience.

PubMed

McDonald, Sandra A; Velasco, Elizabeth; Ilasi, Nicholas T

2010-12-01

Pfizer, Inc.'s Tissue Bank, in conjunction with Pfizer's BioBank (biofluid repository), endeavored to create an overarching internal software package to cover all general functions of both research facilities, including sample receipt, reconciliation, processing, storage, and ordering. Business process flow diagrams were developed by the Tissue Bank and Informatics teams as a way of characterizing best practices both within the Bank and in its interactions with key internal and external stakeholders. Besides serving as a first step for the software development, such formalized process maps greatly assisted the identification and communication of best practices and the optimization of current procedures. The diagrams shared here could assist other biospecimen research repositories (both pharmaceutical and other settings) for comparative purposes or as a guide to successful informatics design. Therefore, it is recommended that biorepositories consider establishing formalized business process flow diagrams for their laboratories, to address these objectives of communication and strategy.

76 FR 17927 - Withdrawal of Approval of New Animal Drug Applications; Chorionic Gonadotropin; Cuprimyxin...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-31

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0151] Withdrawal of Approval of New Animal Drug Applications; Chorionic Gonadotropin; Cuprimyxin... wholly owned TRAMISOL-10% Pig Wormer....... (000856) subsidiary of Pfizer, Inc., 235 East (levamisole...

The preconditioned Gauss-Seidel method faster than the SOR method

NASA Astrophysics Data System (ADS)

Niki, Hiroshi; Kohno, Toshiyuki; Morimoto, Munenori

2008-09-01

In recent years, a number of preconditioners have been applied to linear systems [A.D. Gunawardena, S.K. Jain, L. Snyder, Modified iterative methods for consistent linear systems, Linear Algebra Appl. 154-156 (1991) 123-143; T. Kohno, H. Kotakemori, H. Niki, M. Usui, Improving modified Gauss-Seidel method for Z-matrices, Linear Algebra Appl. 267 (1997) 113-123; H. Kotakemori, K. Harada, M. Morimoto, H. Niki, A comparison theorem for the iterative method with the preconditioner (I+Smax), J. Comput. Appl. Math. 145 (2002) 373-378; H. Kotakemori, H. Niki, N. Okamoto, Accelerated iteration method for Z-matrices, J. Comput. Appl. Math. 75 (1996) 87-97; M. Usui, H. Niki, T.Kohno, Adaptive Gauss-Seidel method for linear systems, Internat. J. Comput. Math. 51(1994)119-125 [10

75 FR 17803 - Self-Regulatory Organizations; NASDAQ OMX PHLX, Inc.; Notice of Filing and Immediate...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-07

.... The text of the proposed rule change is available on the Exchange's Web site at http://nasdaqtrader... and discussed any comments it received on the proposed rule change. The text of these statements may... Mining Corporation (``NEM''); Palm, Inc. (``PALM''); Pfizer, Inc. (``PFE''); ''); Potash Corp...

75 FR 6386 - Pesticide Products; Registration Applications for a New Active Ingredient Chemical; Demiditraz

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-09

... decision by the Agency on these applications. 1. File Symbol: 1007-OL. Applicant: Pfizer, Inc., 7000...: Insecticide and Demiditraz at 100%. Proposed classification/Use: None. 2. File Symbol: 1007-OA. Applicant..., Director, Registration Division, Office of Pesticide Programs. [FR Doc. 2010-2826 Filed 2-8-10; 8:45 am...

75 FR 60308 - New Animal Drugs for Use in Animal Feeds; Melengestrol

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-30

.... FDA-2010-N-0002] New Animal Drugs for Use in Animal Feeds; Melengestrol AGENCY: Food and Drug... amending the animal drug regulations to more accurately reflect the recent approval of two supplemental new animal drug applications (NADAs) filed by Pharmacia & Upjohn Co., a Division of Pfizer, Inc. The...

The accuracies of DNA-based estimates of genetic merit derived from Angus or multibreed beef cattle training populations

USDA-ARS?s Scientific Manuscript database

Several organizations have developed prediction models for molecular breeding values (MBV) for quantitative growth and carcass traits in beef cattle using BovineSNP50 genotypes and phenotypic or EBV data. MBV for Angus cattle have been developed by IGENITY, Pfizer Animal Genetics, and a collaboratio...

77 FR 34052 - Pfizer, Inc.; Withdrawal of Approval of Familial Adenomatous Polyposis Indication for CELEBREX

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-08

... withdrawing approval of the familial adenomatous polyposis (FAP) indication for CELEBREX (celecoxib) Capsules... Spring, MD 20993-0002, 301- 796-3601. SUPPLEMENTARY INFORMATION: FDA approved the FAP indication for..., subpart H. In addition to FAP, CELEBREX is indicated for the relief of the signs and symptoms of...

Public-private partnerships to build human capacity in low income countries: findings from the Pfizer program

PubMed Central

Vian, Taryn; Richards, Sarah C; McCoy, Kelly; Connelly, Patrick; Feeley, Frank

2007-01-01

Background The ability of health organizations in developing countries to expand access to quality services depends in large part on organizational and human capacity. Capacity building includes professional development of staff, as well as efforts to create working environments conducive to high levels of performance. The current study evaluated an approach to public-private partnership where corporate volunteers give technical assistance to improve organizational and staff performance. From 2003 to 2005, the Pfizer Global Health Fellows program sent 72 employees to work with organizations in 19 countries. This evaluation was designed to assess program impact. Methods The researchers administered a survey to 60 Fellows and 48 Pfizer Supervisors. In addition, the team conducted over 100 interviews with partner organization staff and other key informants during site visits in Uganda, Kenya, Ghana, South Africa and India, the five countries where 60% of Fellows were placed. Results Over three-quarters of Fellowships appear to have imparted skills or enhanced operations of NGOs in HIV/AIDS and other health programs. Overall, 79% of Fellows reported meeting all or most technical assistance goals. Partner organization staff reported that the Fellows provided training to clinical and research personnel; strengthened laboratory, pharmacy, financial control, and human resource management systems; and helped expand Partner organization networks. Local staff also reported the Program changed their work habits and attitudes. The evaluation identified problems in defining goals of Fellowships and matching Organizations with Fellows. Capacity building success also appears related to size and sophistication of partner organization. Conclusion Public expectations have grown regarding the role corporations should play in improving health systems in developing countries. Corporate philanthropy programs based on "donations" of personnel can help build the organizational and human capacity of frontline agencies delivering health services. More attention is needed to measure and compare outcomes of international volunteering programs, and to identify appropriate strategies for expansion. PMID:17335578

Mobile App Usage Patterns of Patients Prescribed a Smoking Cessation Medicine: Prospective Observational Study

PubMed Central

2018-01-01

Background Cigarette smoking is the leading preventable cause of death and is responsible for more than 480,000 deaths per year in the United States. Smoking cessation is challenging for many patients. Regardless of available treatment options, most quit attempts are unaided, and it takes multiple attempts before a patient is successful. With the ever-increasing use of smartphones, mobile apps hold promise in supporting cessation efforts. This study evaluates the ease of use and user satisfaction with the Pfizer Meds app to support smoking cessation among patients prescribed varenicline (Chantix). Objective Study participants included varenicline users who downloaded and used the app on their personal smartphone. The main objectives were to report mobile app download frequency and usage details and to describe the participant-reported satisfaction with and usefulness of the app over the 14-week follow-up study period. Methods Adults aged 18 years or older who had been prescribed varenicline were identified from the Express Scripts Incorporated pharmacy claims database. After meeting privacy restrictions, subjects were sent an invitation letter and second reminder letter with instructions on how to download the Pfizer Meds mobile app. Participants received a push notification to complete a smartphone-enabled survey regarding the utility of the app 12 weeks after downloading the app. Descriptive statistics summarized sociodemographics, use of varenicline, and details of use and satisfaction with the mobile app. Results Of the 38,129 varenicline users who were sent invitation letters, 1281 participants (3.35%) downloaded the Pfizer Meds app. Of the 1032 users with demographic and other data, 585 (56.68%) were females, and 446 (43.22%) were males; mean age was 46.4 years (SD 10.8). The mean number of app sessions per participant was 4.0 (SD 6.8). The end-of-study survey was completed by 131 survey respondents (10.23%, 131/1281); a large number of participants (117/131, 89.3%) reported being extremely, very, or moderately satisfied with the app. A total of 97 survey respondents (97/131, 74.0%) reported setting up a quit date in the app. Of those, 74 (74/97, 76%) reported quitting on their quit date. Conclusions Positive patient engagement was observed in this study based on app download and usage. This study quantified how the Pfizer Meds app performed in an observational real-world data setting. The findings demonstrate the willingness of participants to set a quit date and use the app for support in medication adherence, refill reminders, and information regarding how to take the medication. This study provides real-world evidence of the contribution apps can make to the continued encouragement of smokers to improve their health by smoking cessation. PMID:29666043

Training Top 10 Hall of Fame

ERIC Educational Resources Information Center

Training, 2012

2012-01-01

Microsoft Corporation and SCC Soft Computer are the newest inductees into the Training Top 10 Hall of Fame, joining the ranks of the 11 companies named to the hall since its inception in 2008 (Wyeth Pharmaceuticals subsequently was acquired by Pfizer Inc. in 2009). These 11 companies held Top 10 spots in the Training Top 50, Top 100, and now Top…

Correction to the gas phase pressure term in the continuum model for partially saturated granular media presented by Pietruszczak and co-workers

NASA Astrophysics Data System (ADS)

Iveson, Simon M.

2003-06-01

Pietruszczak and coworkers (Internat. J. Numer. Anal. Methods Geomech. 1994; 18(2):93-105; Comput. Geotech. 1991; 12( ):55-71) have presented a continuum-based model for predicting the dynamic mechanical response of partially saturated granular media with viscous interstitial liquids. In their model they assume that the gas phase is distributed uniformly throughout the medium as discrete spherical air bubbles occupying the voids between the particles. However, their derivation of the air pressure inside these gas bubbles is inconsistent with their stated assumptions. In addition the resultant dependence of gas pressure on liquid saturation lies outside of the plausible range of possible values for discrete air bubbles. This results in an over-prediction of the average bulk modulus of the void phase. Corrected equations are presented.

75 FR 76490 - Investigations Regarding Certifications of Eligibility To Apply for Worker Adjustment Assistance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-08

...... 11/23/10 11/18/10 Plastics (Union). 74909 Heritage Valley Health Moon Township, PA..... 11/23/10 11... 11/20/10 Technologies, Inc. (Union). 74927 Pfizer, Inc. (Union)....... Pearl River, NY....... 11/26... Adjustment Assistance. APPENDIX TAA Petitions Instituted between 11/22/10 and 11/26/10 Date of Date of TA-W...

76 FR 49649 - Oral Dosage Form New Animal Drugs; Change of Sponsor; Chlortetracycline; Sulfamethazine

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-11

...;Prices of new books are listed in the first FEDERAL REGISTER issue of each #0;week. #0; #0; #0; #0;#0... wholly owned subsidiary of Pfizer, Inc., 235 East 42d St., New York, NY 10017 has informed FDA that it...-0003] Oral Dosage Form New Animal Drugs; Change of Sponsor; Chlortetracycline; Sulfamethazine AGENCY...

The Effect of Two Different Oxytetracycline Treatments in Experimental Ehrlichia phagocytophila Infected Lambs

PubMed Central

Stuen, S; Bergström, K

2001-01-01

The effect of 2 different oxytetracycline treatments in acute E. phagocytophila infected lambs was investigated. Twenty 5-month-old lambs of the Dala and Rygja breeds were used. Ten lambs were inoculated intravenously with a stabilate of an ovine E. phagocytophila strain. On the third day of fever, 4 lambs were given long-acting oxytetracycline (Terramycin prolongatum vet®, Pfizer) (20 mg/kg) intramuscularly and another 4 lambs were given short-acting oxytetracycline (Terramycin vet®, Pfizer) (10 mg/kg) intravenously for 5 consecutive days. The lambs were examined for the presence of Ehrlichia infection by blood smear evaluation, polymerase chain reaction (PCR) and antibody titre against E. equi. One month after the last antibiotic treatment, 250 ml citrate blood from each of these lambs were inoculated into each of 10 susceptible lambs, which were observed during the following 6 weeks. The results indicate that oxytetracycline given in the acute stage of the infection may effectively teminate the development of fever, rickettsemia and weight reduction in E. phagocytophila infected lambs. No difference was observed between the 2 treatment groups. However, at least 3 of 8 antibiotic treated lambs (37.5%) were still infected with granulocytic Ehrlichia 3 months after treatment. PMID:11887394

Asbestos information clearinghouse. Hearing before the Subcommittee on Commerce, Transportation, and Tourism, Committee on Energy and Commerce, House of Representatives, Ninety-Ninth Congress, Second Session on H. R. 5078, July 17, 1986

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1986-01-01

Representatives of US Gypsum Co., Pfizer Inc., and the Environmental Protection Agency (EPA) testified on the Asbestos Information Clearinghouse Act of 1986 (H.R. 5078), which calls for an information center with samples of materials containing asbestos to simplify the task of identifying their characteristics. The goal of the bill is to make judiciary processes more efficient. EPA opposes the bill on the grounds that the rulemaking and collection of samples from building owners and asbestos manufacturers and processors for analysis would shift the inefficiency from the judiciary arena to EPA. EPA argued that the identification of defendants is a private-sectormore » issue, and that the activities that would be assigned to EPA would be outside its mission. Pfizer supported the legislation, while the spokesman for US Gypsum pointed out that if the purpose is to remove those defendants from litigation who are not involved, extensive sampling would be a waste of time. Additional material submitted for the record follows the text of H.R. 5078 and the testimony of four witnesses.« less

Atomic force microscopy investigation of Mason-Pfizer monkey virus and human immunodeficiency virus type 1 reassembled particles

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuznetsov, Yu. G.; Ulbrich, P.; Institute of Molecular Genetics, Czech Academy of Sciences, 166 10 Prague

2007-04-10

Particles of {delta}ProCANC, a fusion of capsid (Canada) and nucleocapsid (NC) protein of Mason-Pfizer monkey virus (M-PMV), which lacks the amino terminal proline, were reassembled in vitro and visualized by atomic force microscopy (AFM). The particles, of 83-84 nm diameter, exhibited ordered domains based on trigonal arrays of prominent rings with center to center distances of 8.7 nm. Imperfect closure of the lattice on the spherical surface was affected by formation of discontinuities. The lattice is consistent only with plane group p3 where one molecule is shared between contiguous rings. There are no pentameric clusters nor evidence that the particlesmore » are icosahedral. Tubular structures were also reassembled, in vitro, from two HIV fusion proteins, {delta}ProCANC and CANC. The tubes were uniform in diameter, 40 nm, but varied in length to a maximum of 600 nm. They exhibited left handed helical symmetry based on a p6 hexagonal net. The organization of HIV fusion proteins in the tubes is significantly different than for the protein units in the particles of M-PMV {delta}ProCANC.« less

Warfarin Management and Outcomes in Patients with Nonvalvular Atrial Fibrillation Within an Integrated Health Care System.

PubMed

An, JaeJin; Niu, Fang; Zheng, Chengyi; Rashid, Nazia; Mendes, Robert A; Dills, Diana; Vo, Lien; Singh, Prianka; Bruno, Amanda; Lang, Daniel T; Le, Paul T; Jazdzewski, Kristin P; Aranda, Gustavus

2017-06-01

Warfarin is a common treatment option to manage patients with nonvalvular atrial fibrillation (NVAF) in clinical practice. Understanding current pharmacist-led anticoagulation clinic management patterns and associated outcomes is important for quality improvement; however, currently little evidence associating outcomes with management patterns exists. To (a) describe warfarin management patterns and (b) evaluate associations between warfarin treatment and clinical outcomes for patients with NVAF in an integrated health care system. A retrospective cohort study was conducted among NVAF patients with warfarin therapy between January 1, 2006, and December 31, 2011, using Kaiser Permanente Southern California data, and followed until December 31, 2013. Management patterns related to international normalized ratio (INR) monitoring, anticoagulation clinic pharmacist intervention (consultation), and warfarin dose adjustments were investigated along with yearly attrition rates, time-in-therapeutic ranges (TTRs), and clinical outcomes (stroke or systemic embolism and major bleeding). Descriptive statistics and multivariable Cox proportional hazard models were used to determine associations between TTR and clinical outcomes. A total of 32,074 NVAF patients on warfarin treatment were identified and followed for a median of 3.8 years. About half (49%) of the patients were newly initiating warfarin therapy. INR monitoring and pharmacist interventions were conducted roughly every 3 weeks after 6 months of warfarin treatment. Sixty-three percent of the study population had ≥ 1 warfarin dose adjustments with a mean (SD) of 6.7 (6.3) annual dose adjustments. Warfarin dose adjustments occurred at a median of 1 day (interquartile ranges [IQR] 1-3) after the INR measurement. Yearly attrition rate was from 3.3% to 6.3% during the follow-up, and median (IQR) TTR was 61% (46%-73%). Patients who received frequent INR monitoring (≥ 27 times per year), pharmacist interventions (≥ 24 times per year), or frequently adjusted warfarin dose (≥ 11 times per year) consistently showed poor TTRs (mean TTR for the highest quartiles was 45.3%-48.3%). A higher TTR was associated with a lower risk of clinical outcomes regardless of frequency of INR monitoring, pharmacist interventions, or number of dose adjustments. Patients whose TTRs were < 65%, even with frequent pharmacist interventions, had similar stroke or systemic embolism event rates, as compared with patients with TTRs < 65% and less frequent interventions (1.88 vs. 1.54 stroke or systemic embolism rates per 100 person-years, respectively, P = 0.78). The lowest TTR quartile (< 46%) was associated with a 3 times higher risk of stroke or systemic embolism (hazard ratio [HR] = 3.19, 95% CI = 2.71-3.77) and a 2 times higher risk of major bleeding (HR = 2.10, 95% CI = 1.96-2.24) compared with the highest TTR quartile (≥ 73%). Despite close monitoring with timely warfarin dose adjustments, there were still a substantial number of challenging patients whose TTRs were suboptimal despite a higher number of pharmacist interventions. These patients eventually experienced more stroke or systemic embolism and bleeding events among NVAF patients managed by anticoagulation clinics. New individualized treatment or management strategies for patients who are not able to reach optimal therapeutic ranges are necessary to improve outcomes. This research and manuscript were funded by Bristol-Myers Squibb Company and Pfizer. Authors from Bristol-Myers Squibb Company and Pfizer participated in the design of the study, interpretation of the data, review/revision of the manuscript, and approval of the final version of the manuscript. An received a grant for research support from Bristol-Myers Squibb/Pfizer. Niu, Rashid, and Zheng received a grant from Bristol-Myers Squibb/Pfizer to their institutions for salary reimbursement. Vo, Singh, and Aranda are employed by Bristol-Myers Squibb; Bruno was employed by Bristol-Myers Squibb at the time of this study. Mendes and Dills are employed by Pfizer, and Mendes was a member of the Pfizer Cardiovascular and Metabolic Field Medical Team during the time of this study. Lang, Jazdzewski, and Le have no known conflicts of interest to report. Study concept and design were contributed primarily by An and Rashid, along with the other authors. Niu took the lead in data collection, along with Zheng, and data interpretation was performed by An, along with Mendes and Dills, with assistance from the other authors. The manuscript was written by An and revised by Mendes, Dills, Vo, Singh, Bruno, and Aranda, along with Lang, Le, and Jazdezewski. Part of this study's findings was presented at the CHEST 2015 Annual Meeting in Montreal, Canada, on October 28, 2015.

Convergence and conflict: anthropology, psychiatry and feminism in the early writings of Madeleine Pelletier (1874-1939).

PubMed

Gordon, Felicia

2008-06-01

This paper reviews the early career and psychiatric writings of Madeleine Pelletier (1874-1939), between 1901 and 1906. Pelletier, a committed feminist and socialist, was the first woman to remove the barriers to women entering the French psychiatric profession, successfully passing the examination for the l'internat des hôpitaux psychiatriques in 1903. Her involvement in La Société d'Anthropologie de Paris and the Institut Général de Psychologie provided a forum for her interest in psychology, both normal and abnormal. She turned increasingly to sociological explanations for mental illness, unwilling to accept the determinism inherent in degeneration theory. Although her career in psychiatry was cut short in 1906, her training and her debating skills, honed in the rationalism of the scientific and Free Masonic societies that she frequented, stood her in good stead in her subsequent career as a political militant.

NIC23

PubMed Central

Baxter, David; Guppy, Martin J.

2013-01-01

The 23rd National Immunization Conference for Health Care Workers was held on December 7th, 2012 at the Manchester Conference Centre. There were over 220 delegates for this event sponsored by educational grants from Crucell, Glaxo Smith Kline, Pfizer Vaccines and Sanofi Pasteur. A number of speakers took the opportunity kindly afforded by Human Vaccines and Immunotherapeutics to write up their conference presentation as a paper for this special supplement. PMID:23857271

Strengthening capacity for AIDS vaccine research: analysis of the Pfizer Global Health Fellows Program and the International AIDS Vaccine Initiative

PubMed Central

2013-01-01

Background Industry partnerships can help leverage resources to advance HIV/AIDS vaccine research, service delivery, and policy advocacy goals. This often involves capacity building for international and local non-governmental organizations (NGOs). International volunteering is increasingly being used as a capacity building strategy, yet little is known about how corporate volunteers help to improve performance of NGOs in the fight against HIV/AIDS. Methods This case study helps to extend our understanding by analyzing how the Pfizer Global Health Fellows (GHF) program helped develop capacity of the International AIDS Vaccine Initiative (IAVI), looking specifically at Fellowship activities in South Africa, Kenya, and Uganda. From 2005–2009, 8 Pfizer GHF worked with IAVI and local research centers to strengthen capacity to conduct and monitor vaccine trials to meet international standards and expand trial activities. Data collection for the case study included review of Fellow job descriptions, online journals, evaluation reports, and interviews with Fellows and IAVI staff. Qualitative methods were used to analyze factors which influenced the process and outcomes of capacity strengthening. Results Fellows filled critical short-term expert staffing needs at IAVI as well as providing technical assistance and staff development activities. Capacity building included assistance in establishing operating procedures for the start-up period of research centers; training staff in Good Clinical Practice (GCP); developing monitoring capacity (staff and systems) to assure that centers are audit-ready at all times; and strategic planning for data management systems. Factors key to the success of volunteering partnerships included similarities in mission between the corporate and NGO partners, expertise and experience of Fellows, and attitudes of partner organization staff. Conclusion By developing standard operating procedures, ensuring that monitoring and regulatory compliance systems were in place, training African investigators and community members, and engaging in other systems strengthening activities, the GHF program helped IAVI to accelerate vaccine development activities in the field, and to develop the organization’s capacity to manage change in the future. Our study suggests that a program of sustained corporate volunteering over several years may increase organizational learning and trust, leading to stronger capacity to advance and achieve NGO goals. PMID:24088300

Strengthening capacity for AIDS vaccine research: analysis of the Pfizer Global Health Fellows program and the International AIDS Vaccine Initiative.

PubMed

Vian, Taryn; Koseki, Sayaka; Feeley, Frank G; Beard, Jennifer

2013-10-02

Industry partnerships can help leverage resources to advance HIV/AIDS vaccine research, service delivery, and policy advocacy goals. This often involves capacity building for international and local non-governmental organizations (NGOs). International volunteering is increasingly being used as a capacity building strategy, yet little is known about how corporate volunteers help to improve performance of NGOs in the fight against HIV/AIDS. This case study helps to extend our understanding by analyzing how the Pfizer Global Health Fellows (GHF) program helped develop capacity of the International AIDS Vaccine Initiative (IAVI), looking specifically at Fellowship activities in South Africa, Kenya, and Uganda. From 2005-2009, 8 Pfizer GHF worked with IAVI and local research centers to strengthen capacity to conduct and monitor vaccine trials to meet international standards and expand trial activities. Data collection for the case study included review of Fellow job descriptions, online journals, evaluation reports, and interviews with Fellows and IAVI staff. Qualitative methods were used to analyze factors which influenced the process and outcomes of capacity strengthening. Fellows filled critical short-term expert staffing needs at IAVI as well as providing technical assistance and staff development activities. Capacity building included assistance in establishing operating procedures for the start-up period of research centers; training staff in Good Clinical Practice (GCP); developing monitoring capacity (staff and systems) to assure that centers are audit-ready at all times; and strategic planning for data management systems. Factors key to the success of volunteering partnerships included similarities in mission between the corporate and NGO partners, expertise and experience of Fellows, and attitudes of partner organization staff. By developing standard operating procedures, ensuring that monitoring and regulatory compliance systems were in place, training African investigators and community members, and engaging in other systems strengthening activities, the GHF program helped IAVI to accelerate vaccine development activities in the field, and to develop the organization's capacity to manage change in the future. Our study suggests that a program of sustained corporate volunteering over several years may increase organizational learning and trust, leading to stronger capacity to advance and achieve NGO goals.

The clinician impact and financial cost to the NHS of litigation over pregabalin: a cohort study in English primary care.

PubMed

Croker, Richard; Smyth, Darren; Walker, Alex J; Goldacre, Ben

2018-06-07

Following litigation over pregabalin's second-use medical patent for neuropathic pain, National Health Service (NHS) England was required by the court to instruct general practitioners (GPs) to prescribe the branded form (Lyrica) for pain. Pfizer's patent was found invalid in 2015, a ruling subject to ongoing appeals. If the Supreme Court appeal in February 2018, whose judgement is awaited, is unsuccessful, the NHS can seek to reclaim excess prescribing costs. We set out to describe the variation in prescribing of pregabalin as branded Lyrica, geographically and over time; to determine how clinicians responded to the NHS England instruction to GPs; and to model excess costs to the NHS attributable to the legal judgements. English primary care. English general practices. Variation in prescribing of branded Lyrica across the country before and after the NHS England instruction, by practice and by Clinical Commissioning Group; excess prescribing costs. The proportion of pregabalin prescribed as Lyrica increased from 0.3% over 6 months before the NHS England instruction (September 2014 to February 2015) to 25.7% afterwards (April to September 2015). Although 70% of pregabalin is estimated to be for pain, including neuropathic pain, only 11.6% of practices prescribed Lyrica at this level; the median proportion prescribed as Lyrica was 8.8% (IQR 1.1%-41.9%). If pregabalin had come entirely off patent in September 2015, and Pfizer had not appealed, we estimate the NHS would have spent £502 million less on pregabalin to July 2017. NHS England instructions to GPs regarding branded prescription of pregabalin were widely ignored and have created much debate around clinical independence in prescribing. Protecting revenue from 'skinny labels' will pose a challenge. If Pfizer's final appeal on the patent is unsuccessful, the NHS can seek reimbursement of excess pregabalin prescribing costs, potentially £502 million. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy

DTIC Science & Technology

2012-09-01

Cardiac Outcome Measures in Children with Muscular Dystrophy o Cardiac MRI Protocol: PITT0110 - Cardiac Magnetic Resonance: A Parallel Protocol...permitted during the study. Study drug. The study drug was PTX (Trental; Sanofi- Aventis U.S. LLC, Bridgewater, NJ) tablets , an FDA-approved pharmaceutical...that is available for oral administration as 400-mg oblong tablets . Both the study drug PTX and placebo were overencapsulated by Capsugel (Pfizer Inc

Clinical Microbiology Reviews. Volume 2, April 1989 Supplement. Perspectives on Pathogenic Neisseriae

DTIC Science & Technology

1989-04-01

Control; Emory University: National Irtitute of Allergy and Infectious Diseases; Food and Drug Administration; U.S. Army: Miles. Inc./ Bayer AG: SYVA...Pharmaceuticals Inc.; Marion Laboratories, Inc.; Roerig Division of Pfizer , Inc.: Lederle Laboratories: and F-istman Kodak Co. The Organizing Committee also wishes...expectations for these Management of Bacterial Enteric Infections drugs by researchers have been borne out by ( DuPont ) clinical studies published in the

The structure of myristoylated Mason-Pfizer monkey virus matrix protein and the role of phosphatidylinositol-(4,5)-bisphosphate in its membrane binding.

PubMed

Prchal, Jan; Srb, Pavel; Hunter, Eric; Ruml, Tomáš; Hrabal, Richard

2012-10-26

We determined the solution structure of myristoylated Mason-Pfizer monkey virus matrix protein by NMR spectroscopy. The myristoyl group is buried inside the protein and causes a slight reorientation of the helices. This reorientation leads to the creation of a binding site for phosphatidylinositols. The interaction between the matrix protein and phosphatidylinositols carrying C(8) fatty acid chains was monitored by observation of concentration-dependent chemical shift changes of the affected amino acid residues, a saturation transfer difference experiment and changes in (31)P chemical shifts. No differences in the binding mode or affinity were observed with differently phosphorylated phosphatidylinositols. The structure of the matrix protein-phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)] complex was then calculated with HADDOCK software based on the intermolecular nuclear Overhauser enhancement contacts between the ligand and the matrix protein obtained from a (13)C-filtered/(13)C-edited nuclear Overhauser enhancement spectroscopy experiment. PI(4,5)P(2) binding was not strong enough for triggering of the myristoyl-switch. The structural changes of the myristoylated matrix protein were also found to result in a drop in the oligomerization capacity of the protein. Copyright © 2012. Published by Elsevier Ltd.

Prebiotic Potential of Polydextrose

NASA Astrophysics Data System (ADS)

Stowell, Julian D.

Polydextrose is a randomly bonded polymer of glucose with some sorbitol end-groups. It was originally developed by scientists at Pfizer seeking a low calorie bulking agent to be used in conjunction with intense sweeteners. Polydextrose has been used for more than 25 years in human food and beverage products around the world. It is currently marketed by Danisco A/S as Litesse®Two and Litesse®UltraTM and by A E Staley as Sta-Lite III.

Nucleic Acid Binding by Mason-Pfizer Monkey Virus CA Promotes Virus Assembly and Genome Packaging

PubMed Central

Füzik, Tibor; Píchalová, Růžena; Schur, Florian K. M.; Strohalmová, Karolína; Křížová, Ivana; Hadravová, Romana; Rumlová, Michaela; Briggs, John A. G.

2016-01-01

ABSTRACT The Gag polyprotein of retroviruses drives immature virus assembly by forming hexameric protein lattices. The assembly is primarily mediated by protein-protein interactions between capsid (CA) domains and by interactions between nucleocapsid (NC) domains and RNA. Specific interactions between NC and the viral RNA are required for genome packaging. Previously reported cryoelectron microscopy analysis of immature Mason-Pfizer monkey virus (M-PMV) particles suggested that a basic region (residues RKK) in CA may serve as an additional binding site for nucleic acids. Here, we have introduced mutations into the RKK region in both bacterial and proviral M-PMV vectors and have assessed their impact on M-PMV assembly, structure, RNA binding, budding/release, nuclear trafficking, and infectivity using in vitro and in vivo systems. Our data indicate that the RKK region binds and structures nucleic acid that serves to promote virus particle assembly in the cytoplasm. Moreover, the RKK region appears to be important for recruitment of viral genomic RNA into Gag particles, and this function could be linked to changes in nuclear trafficking. Together these observations suggest that in M-PMV, direct interactions between CA and nucleic acid play important functions in the late stages of the viral life cycle. IMPORTANCE Assembly of retrovirus particles is driven by the Gag polyprotein, which can self-assemble to form virus particles and interact with RNA to recruit the viral genome into the particles. Generally, the capsid domains of Gag contribute to essential protein-protein interactions during assembly, while the nucleocapsid domain interacts with RNA. The interactions between the nucleocapsid domain and RNA are important both for identifying the genome and for self-assembly of Gag molecules. Here, we show that a region of basic residues in the capsid protein of the betaretrovirus Mason-Pfizer monkey virus (M-PMV) contributes to interaction of Gag with nucleic acid. This interaction appears to provide a critical scaffolding function that promotes assembly of virus particles in the cytoplasm. It is also crucial for packaging the viral genome and thus for infectivity. These data indicate that, surprisingly, interactions between the capsid domain and RNA play an important role in the assembly of M-PMV. PMID:26912613

Characterization and Targeting of the Aldehyde Dehydrogenase Subpopulation in Ovarian Cancer

DTIC Science & Technology

2015-07-01

Model in Cervical Cancer. Pilot Project, SPORE in Cervical Cancer. 9/1/2012 – 8/31/2013. $30,000. o Co-Principle Investigator. Predicting response of...and 1.5% for maintenance. Mice were administered carprofen (7mg/ kg, Pfizer) prior to incision to reduce post-operative pain . For injection into the...effects of chemotherapy), mice were euthanized by CO 2 asphyxiation and cervical dislocation. Samples of treated and mice treated with vehicle were

Research and Operational Support for the Study of Militarily Relevant Infectious Diseases of Interest to United States and Royal Thai Governments

DTIC Science & Technology

2004-01-01

resistance of exo-erythrocytic stage parasites to primaquine and tafenoquine ). B.2. Parasite Characterization: In the absence of an in vitro culture...Tropical Diseases, Mahidol University. Efforts are partnered with Pfizer and the NIH. Developed and approved a protocol to test tafenoquine (WR238605) in...completed by September 2004. Publication of previous dose-ranging studies of tafenoquine completed. Publication of prophylaxis study in the Royal

Partnerships in Pharma--An Economist Intelligence Unit Seminar--Building Innovation into Alliances and Business Models. 1 October 2010, London, UK.

PubMed

Kibble, Alexandra

2010-12-01

The Partnerships in Pharma seminar, held in London, included topics related to building innovation into alliances and business models within the pharmaceutical industry. This conference report highlights selected presentations on strategies for successful partnering, partnering alongside an evolving CRO industry, considering the pharma value chain, and partnerships between industry and academia. Approaches used by Ipsen, Merck Serono, Pfizer and ViiV Healthcare are also described.

Structure of the immature HIV-1 capsid in intact virus particles at 8.8 Å resolution

NASA Astrophysics Data System (ADS)

Schur, Florian K. M.; Hagen, Wim J. H.; Rumlová, Michaela; Ruml, Tomáš; Müller, Barbara; Kräusslich, Hans-Georg; Briggs, John A. G.

2015-01-01

Human immunodeficiency virus type 1 (HIV-1) assembly proceeds in two stages. First, the 55 kilodalton viral Gag polyprotein assembles into a hexameric protein lattice at the plasma membrane of the infected cell, inducing budding and release of an immature particle. Second, Gag is cleaved by the viral protease, leading to internal rearrangement of the virus into the mature, infectious form. Immature and mature HIV-1 particles are heterogeneous in size and morphology, preventing high-resolution analysis of their protein arrangement in situ by conventional structural biology methods. Here we apply cryo-electron tomography and sub-tomogram averaging methods to resolve the structure of the capsid lattice within intact immature HIV-1 particles at subnanometre resolution, allowing unambiguous positioning of all α-helices. The resulting model reveals tertiary and quaternary structural interactions that mediate HIV-1 assembly. Strikingly, these interactions differ from those predicted by the current model based on in vitro-assembled arrays of Gag-derived proteins from Mason-Pfizer monkey virus. To validate this difference, we solve the structure of the capsid lattice within intact immature Mason-Pfizer monkey virus particles. Comparison with the immature HIV-1 structure reveals that retroviral capsid proteins, while having conserved tertiary structures, adopt different quaternary arrangements during virus assembly. The approach demonstrated here should be applicable to determine structures of other proteins at subnanometre resolution within heterogeneous environments.

Vertex Algebras W(p)Am and W(p)Dm and Constant Term Identities

NASA Astrophysics Data System (ADS)

Adamović, Dražen; Lin, Xianzu; Milas, Antun

2015-03-01

We consider AD-type orbifolds of the triplet vertex algebras W(p) extending the well-known c=1 orbifolds of lattice vertex algebras. We study the structure of Zhu's algebras A(W(p)^{A_m}) and A(W(p)^{D_m}), where A_m and D_m are cyclic and dihedral groups, respectively. A combinatorial algorithm for classification of irreducible W(p)^Γ-modules is developed, which relies on a family of constant term identities and properties of certain polynomials based on constant terms. All these properties can be checked for small values of m and p with a computer software. As a result, we argue that if certain constant term properties hold, the irreducible modules constructed in [Commun. Contemp. Math. 15 (2013), 1350028, 30 pages; Internat. J. Math. 25 (2014), 1450001, 34 pages] provide a complete list of irreducible W(p)^{A_m} and W(p)^{D_m}-modules. This paper is a continuation of our previous work on the ADE subalgebras of the triplet vertex algebra W(p).

Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews.

PubMed

Levis, Brooke; Benedetti, Andrea; Riehm, Kira E; Saadat, Nazanin; Levis, Alexander W; Azar, Marleine; Rice, Danielle B; Chiovitti, Matthew J; Sanchez, Tatiana A; Cuijpers, Pim; Gilbody, Simon; Ioannidis, John P A; Kloda, Lorie A; McMillan, Dean; Patten, Scott B; Shrier, Ian; Steele, Russell J; Ziegelstein, Roy C; Akena, Dickens H; Arroll, Bruce; Ayalon, Liat; Baradaran, Hamid R; Baron, Murray; Beraldi, Anna; Bombardier, Charles H; Butterworth, Peter; Carter, Gregory; Chagas, Marcos H; Chan, Juliana C N; Cholera, Rushina; Chowdhary, Neerja; Clover, Kerrie; Conwell, Yeates; de Man-van Ginkel, Janneke M; Delgadillo, Jaime; Fann, Jesse R; Fischer, Felix H; Fischler, Benjamin; Fung, Daniel; Gelaye, Bizu; Goodyear-Smith, Felicity; Greeno, Catherine G; Hall, Brian J; Hambridge, John; Harrison, Patricia A; Hegerl, Ulrich; Hides, Leanne; Hobfoll, Stevan E; Hudson, Marie; Hyphantis, Thomas; Inagaki, Masatoshi; Ismail, Khalida; Jetté, Nathalie; Khamseh, Mohammad E; Kiely, Kim M; Lamers, Femke; Liu, Shen-Ing; Lotrakul, Manote; Loureiro, Sonia R; Löwe, Bernd; Marsh, Laura; McGuire, Anthony; Mohd Sidik, Sherina; Munhoz, Tiago N; Muramatsu, Kumiko; Osório, Flávia L; Patel, Vikram; Pence, Brian W; Persoons, Philippe; Picardi, Angelo; Rooney, Alasdair G; Santos, Iná S; Shaaban, Juwita; Sidebottom, Abbey; Simning, Adam; Stafford, Lesley; Sung, Sharon; Tan, Pei Lin Lynnette; Turner, Alyna; van der Feltz-Cornelis, Christina M; van Weert, Henk C; Vöhringer, Paul A; White, Jennifer; Whooley, Mary A; Winkley, Kirsty; Yamada, Mitsuhiko; Zhang, Yuying; Thombs, Brett D

2018-06-01

Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98-10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26-0.97). The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

[23 and Me: how to make (a lot of) money out of your customers].

PubMed

Jordan, Bertrand

2015-04-01

The announcement of several deals between the DTC genetics firm 23 and Me and Genentech, Pfizer and other corporations reveals the real business model of the company: selling access to sets of characterized patients for targeted drug development. This may be a useful strategy, but it raises a number of questions concerning the privacy of the company's customers and also of adequate compensation when they become valuable currency. © 2015 médecine/sciences – Inserm.

A Novel Strategy for Controlling the Metastatic Phenotype: Targeting the SNAG Repression Domain in the SNAIL Zinc-Finger Protein

DTIC Science & Technology

2007-07-01

interacts with nuclear receptors and can inhibit betaFTZ-F1-dependent transcription. Mol. Cell, 7, 753–765. 29. Dupont , S., Zacchigna, L., Cordenonsi, M...Washington University/ Pfizer Biomedical Research Program to GDL. GDL was an Established Investigator of the American Heart Association. 26...Cell 11, 1043-1054. Hecker, C. M., Rabiller, M., Haglund, K., Bayer , P., and Dikic, I. (2006). Specification of SUMO1- and SUMO2-interacting motifs. J

American Academy of Allergy, Asthma and Immunology (AAAAI)-2010 annual meeting. 26 February-2 March 2010, New Orleans, LA, USA.

PubMed

Bielory, Leonard

2010-05-01

The 2010 American Academy of Allergy, Asthma and Immunology (AAAAI) meeting, held in New Orleans, included topics covering new therapeutic developments in the fields of allergy, asthma and immunological diseases. This conference report highlights selected presentations on potential treatments for food and other allergies, as well as therapies for asthma and other immunological diseases. Investigational drugs discussed include Oralair Mites (Stallergenes SA/Paladin Labs Inc), PF-03654746 (Pfizer Inc) and AMG-853 (Amgen Inc).

High heterogeneity and low reliability in the diagnosis of major depression will impair the development of new drugs.

PubMed

Lieblich, Samuel M; Castle, David J; Pantelis, Christos; Hopwood, Malcolm; Young, Allan Hunter; Everall, Ian P

2015-10-01

Major depressive disorder is a common diagnosis associated with a high burden of disease that has proven to be highly heterogeneous and unreliable. Treatments currently available demonstrate limited efficacy and effectiveness. New drug development is urgently required but is likely to be hindered by diagnostic limitations. D.J.C. has received grants and personal fees from Eli Lilly, Janssen-Cilag, Roche, Allergen, Bristol-Myers Squibb, Pfizer, Lundbeck, AstraZeneca, Hospira, Organon, Sanofi-Aventis, and Wyeth during the writing of this review. C.P. has received grant support from Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, and received honoraria for consultancy to Janssen-Cilag, Eli Lilly, Hospira (Mayne), AstraZeneca, Pfizer, Schering Plough, and Lundbeck. Over the past 2 years he has participated on advisory boards for Janssen-Cilag and Lundbeck, and received honoraria for talks presented at educational meetings organised by AstraZeneca, Janssen-Cilag and Lundbeck. M.H. has received personal fees or grants from Lundbeck, AstraZeneca and Servier during the writing of this review. A.H.Y. reports personal fees from Lundbeck, Sunovion, AstraZeneca and Janssen outside the submitted work. I.P.E. has received personal fees or grants from Lundbeck, AstraZeneca, and Abbvie during the writing of this review. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Alterations in dorsal and ventral posterior cingulate connectivity in APOE ε4 carriers at risk of Alzheimer's disease.

PubMed

Kerestes, Rebecca; Phal, Pramit M; Steward, Chris; Moffat, Bradford A; Salinas, Simon; Cox, Kay L; Ellis, Kathryn A; Cyarto, Elizabeth V; Ames, David; Martins, Ralph N; Masters, Colin L; Rowe, Christopher C; Sharman, Matthew J; Salvado, Olivier; Szoeke, Cassandra; Lai, Michelle; Lautenschlager, Nicola T; Desmond, Patricia M

2015-10-01

Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE ε 4) allele. Participants were 22 SMC carrying the APOE ε 4 allele ( ε 4+; mean age 72.18 years) and 58 SMC non-carriers ( ε 4-; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. ε 4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC-SMA connectivity. The results provide the first evidence that ε 4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity. D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, Prana and Pfizer, and as Editor-in-Chief for International Psychogeriatrics; received speaker honoraria from Pfizer and Lundbeck, and research support from Eli Lilly, GlaxoSmithKline, Forest Laboratories, Novartis, and CSIRO. C.L.M. has received consulting fees from Eli Lilly and Prana Biotechnology, and has stock ownership in Prana Biotechnology. C.C.R. has received consultancy payments from Roche and Piramal, and research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Piramal and Navidea for amyloid imaging. C.S. has provided clinical consultancy and been on scientific advisory committees for the Australian CSIRO, Alzheimer's Australia, University of Melbourne and other relationships, which are subject to confidentiality clauses; she has been a named Chief Investigator on investigator-driven collaborative research projects in partnership with Pfizer, Merck, Piramal, Bayer and GE Healthcare. Her research programme has received support from the National Health and Medical Research Council Alzheimer's Association, Collier Trust, Scobie and Claire McKinnon Foundation, JO and JR Wicking Trust, Shepherd Foundation, Brain Foundation, Mason Foundation, Ramaciotti Foundation, Alzheimer's Australia and the Royal Australian College of Physicians. © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Alterations in dorsal and ventral posterior cingulate connectivity in APOE ε4 carriers at risk of Alzheimer's disease

PubMed Central

Phal, Pramit M.; Steward, Chris; Moffat, Bradford A.; Salinas, Simon; Cox, Kay L.; Ellis, Kathryn A.; Cyarto, Elizabeth V.; Ames, David; Martins, Ralph N.; Masters, Colin L.; Rowe, Christopher C.; Sharman, Matthew J.; Salvado, Olivier; Szoeke, Cassandra; Lai, Michelle; Lautenschlager, Nicola T.; Desmond, Patricia M.

2015-01-01

Background Recent evidence suggests that exercise plays a role in cognition and that the posterior cingulate cortex (PCC) can be divided into dorsal and ventral subregions based on distinct connectivity patterns. Aims To examine the effect of physical activity and division of the PCC on brain functional connectivity measures in subjective memory complainers (SMC) carrying the epsilon 4 allele of apolipoprotein E (APOE ε4) allele. Method Participants were 22 SMC carrying the APOE ε4 allele (ε4+; mean age 72.18 years) and 58 SMC non-carriers (ε4–; mean age 72.79 years). Connectivity of four dorsal and ventral seeds was examined. Relationships between PCC connectivity and physical activity measures were explored. Results ε4+ individuals showed increased connectivity between the dorsal PCC and dorsolateral prefrontal cortex, and the ventral PCC and supplementary motor area (SMA). Greater levels of physical activity correlated with the magnitude of ventral PCC–SMA connectivity. Conclusions The results provide the first evidence that ε4+ individuals at increased risk of cognitive decline show distinct alterations in dorsal and ventral PCC functional connectivity. Declaration of interest D.A. has served on scientific advisory boards for Novartis, Eli Lilly, Janssen, Prana and Pfizer, and as Editor-in-Chief for International Psychogeriatrics; received speaker honoraria from Pfizer and Lundbeck, and research support from Eli Lilly, GlaxoSmithKline, Forest Laboratories, Novartis, and CSIRO. C.L.M. has received consulting fees from Eli Lilly and Prana Biotechnology, and has stock ownership in Prana Biotechnology. C.C.R. has received consultancy payments from Roche and Piramal, and research support from Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Piramal and Navidea for amyloid imaging. C.S. has provided clinical consultancy and been on scientific advisory committees for the Australian CSIRO, Alzheimer's Australia, University of Melbourne and other relationships, which are subject to confidentiality clauses; she has been a named Chief Investigator on investigator-driven collaborative research projects in partnership with Pfizer, Merck, Piramal, Bayer and GE Healthcare. Her research programme has received support from the National Health and Medical Research Council Alzheimer's Association, Collier Trust, Scobie and Claire McKinnon Foundation, JO and JR Wicking Trust, Shepherd Foundation, Brain Foundation, Mason Foundation, Ramaciotti Foundation, Alzheimer's Australia and the Royal Australian College of Physicians. Copyright and usage © The Royal College of Psychiatrists 2015. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence. PMID:27703739

Safinamide for the treatment of Parkinson's disease, epilepsy and restless legs syndrome.

PubMed

Chazot, Paul L

2007-07-01

Merck Serono SA (formerly Serono), under license from Newron Pharmaceuticals SpA (following its acquisition of the rights from Pharmacia and Upjohn AB [now Pfizer Inc]), is developing the oral alpha-aminoamide derivative of milacemide, safinamide, a monoamine oxidase-B and glutamate release inhibitor, for the potential treatment of Parkinson's disease, epilepsy and restless legs syndrome. In March 2007, plans to develop the agent for the potential treatment of other cognitive disorders, such as Alzheimer's disease, were being finalized and testing was expected to begin before the end of that year.

Shaping a screening file for maximal lead discovery efficiency and effectiveness: elimination of molecular redundancy.

PubMed

Bakken, Gregory A; Bell, Andrew S; Boehm, Markus; Everett, Jeremy R; Gonzales, Rosalia; Hepworth, David; Klug-McLeod, Jacquelyn L; Lanfear, Jeremy; Loesel, Jens; Mathias, John; Wood, Terence P

2012-11-26

High Throughput Screening (HTS) is a successful strategy for finding hits and leads that have the opportunity to be converted into drugs. In this paper we highlight novel computational methods used to select compounds to build a new screening file at Pfizer and the analytical methods we used to assess their quality. We also introduce the novel concept of molecular redundancy to help decide on the density of compounds required in any region of chemical space in order to be confident of running successful HTS campaigns.

An extended GS method for dense linear systems

NASA Astrophysics Data System (ADS)

Niki, Hiroshi; Kohno, Toshiyuki; Abe, Kuniyoshi

2009-09-01

Davey and Rosindale [K. Davey, I. Rosindale, An iterative solution scheme for systems of boundary element equations, Internat. J. Numer. Methods Engrg. 37 (1994) 1399-1411] derived the GSOR method, which uses an upper triangular matrix [Omega] in order to solve dense linear systems. By applying functional analysis, the authors presented an expression for the optimum [Omega]. Moreover, Davey and Bounds [K. Davey, S. Bounds, A generalized SOR method for dense linear systems of boundary element equations, SIAM J. Comput. 19 (1998) 953-967] also introduced further interesting results. In this note, we employ a matrix analysis approach to investigate these schemes, and derive theorems that compare these schemes with existing preconditioners for dense linear systems. We show that the convergence rate of the Gauss-Seidel method with preconditioner PG is superior to that of the GSOR method. Moreover, we define some splittings associated with the iterative schemes. Some numerical examples are reported to confirm the theoretical analysis. We show that the EGS method with preconditioner produces an extremely small spectral radius in comparison with the other schemes considered.

Internet-ordered viagra (sildenafil citrate) is rarely genuine.

PubMed

Campbell, Neil; Clark, John P; Stecher, Vera J; Goldstein, Irwin

2012-11-01

Counterfeit medication is a growing problem. This study assessed the requirement for prescription, cost, origin, and content of medications sold via the Internet and purporting to be the phosphodiesterase type 5 inhibitor Viagra (sildenafil citrate). Pfizer monitored top search results for the query "buy Viagra" on the two leading Internet search engines in March 2011. Orders were placed from 22 unique Web sites claiming to sell Viagra manufactured by Pfizer. Tablets received were assessed for chemical composition. No Web site examined required a prescription for purchase or a health screening survey; 90% offered illegal "generic Viagra." Cost per tablet ranged from $3.28-$33.00. Shipment origins of purchases were Hong Kong (N = 11), the United States (N = 6), and the United Kingdom (N = 2) as well as Canada, China, and India (N = 1 each). Notably, the four Internet pharmacies claiming to be Canadian did not ship medication from a Canadian address. Of 22 sample tablets examined, 17 (77%) were counterfeit, 4 (18%) were authentic, and 1 (5%) was an illegal generic. Counterfeit tablets were analyzed for sildenafil citrate, the active pharmaceutical ingredient (API) of Viagra, and contents varied between 30% and 50% of the label claim. Counterfeits lacked product information leaflets, including appropriate safety warnings, and genuine Viagra formulations. Internet sites claiming to sell authentic Viagra shipped counterfeit medication 77% of the time; counterfeits usually came from non-U.S. addresses and had 30% to 50% of the labeled API claim. Caution is warranted when purchasing Viagra via the Internet. © 2012 International Society for Sexual Medicine.

Internet-based crowdsourcing and research ethics: the case for IRB review.

PubMed

Graber, Mark A; Graber, Abraham

2013-02-01

The recent success of Foldit in determining the structure of the Mason-Pfizer monkey virus (M-PMV) retroviral protease is suggestive of the power-solving potential of internet-facilitated game-like crowdsourcing. This research model is highly novel, however, and thus, deserves careful consideration of potential ethical issues. In this paper, we will demonstrate that the crowdsourcing model of research has the potential to cause harm to participants, manipulates the participant into continued participation, and uses participants as experimental subjects. We conclude that protocols relying on this model require institutional review board (IRB) scrutiny.

Mutations in the Basic Region of the Mason-Pfizer Monkey Virus Nucleocapsid Protein Affect Reverse Transcription, Genomic RNA Packaging, and the Virus Assembly Site.

PubMed

Dostálková, Alžběta; Kaufman, Filip; Křížová, Ivana; Kultová, Anna; Strohalmová, Karolína; Hadravová, Romana; Ruml, Tomáš; Rumlová, Michaela

2018-05-15

In addition to specific RNA-binding zinc finger domains, the retroviral Gag polyprotein contains clusters of basic amino acid residues that are thought to support Gag-viral genomic RNA (gRNA) interactions. One of these clusters is the basic K 16 NK 18 EK 20 region, located upstream of the first zinc finger of the Mason-Pfizer monkey virus (M-PMV) nucleocapsid (NC) protein. To investigate the role of this basic region in the M-PMV life cycle, we used a combination of in vivo and in vitro methods to study a series of mutants in which the overall charge of this region was more positive (RNRER), more negative (AEAEA), or neutral (AAAAA). The mutations markedly affected gRNA incorporation and the onset of reverse transcription. The introduction of a more negative charge (AEAEA) significantly reduced the incorporation of M-PMV gRNA into nascent particles. Moreover, the assembly of immature particles of the AEAEA Gag mutant was relocated from the perinuclear region to the plasma membrane. In contrast, an enhancement of the basicity of this region of M-PMV NC (RNRER) caused a substantially more efficient incorporation of gRNA, subsequently resulting in an increase in M-PMV RNRER infectivity. Nevertheless, despite the larger amount of gRNA packaged by the RNRER mutant, the onset of reverse transcription was delayed in comparison to that of the wild type. Our data clearly show the requirement for certain positively charged amino acid residues upstream of the first zinc finger for proper gRNA incorporation, assembly of immature particles, and proceeding of reverse transcription. IMPORTANCE We identified a short sequence within the Gag polyprotein that, together with the zinc finger domains and the previously identified RKK motif, contributes to the packaging of genomic RNA (gRNA) of Mason-Pfizer monkey virus (M-PMV). Importantly, in addition to gRNA incorporation, this basic region (KNKEK) at the N terminus of the nucleocapsid protein is crucial for the onset of reverse transcription. Mutations that change the positive charge of the region to a negative one significantly reduced specific gRNA packaging. The assembly of immature particles of this mutant was reoriented from the perinuclear region to the plasma membrane. On the contrary, an enhancement of the basic character of this region increased both the efficiency of gRNA packaging and the infectivity of the virus. However, the onset of reverse transcription was delayed even in this mutant. In summary, the basic region in M-PMV Gag plays a key role in the packaging of genomic RNA and, consequently, in assembly and reverse transcription. Copyright © 2018 American Society for Microbiology.

My thoughts on teaching.

PubMed

Smith, Bonnie J

2009-01-01

The Pfizer Distinguished Teacher Award, presented annually to a faculty member at each college or school of veterinary medicine in the United States, is the most prestigious teaching award in veterinary medicine. Originally this award was known as the Norden Award, named in honor of Carl J. Norden, founder of Norden Laboratories, but since 1963 it has been sponsored by Pfizer Animal Health. Awardees are selected by their individual colleges and schools based on the following criteria: teaching excellence in lectures, laboratories, and/or clinical settings; support of student learning and development outside of traditional venues, such as by counseling, advising of specialty clubs, and so on (extracurricular activities); and character and leadership. Students, peers, and administrators provide input into the various criteria. Each of the 28 colleges or schools of veterinary medicine in the United States is invited to submit the dossier of their awardee to a national selection committee sponsored by the Association of American Veterinary Medical Colleges (AAVMC). It gives me great pleasure to note that the committee has awarded the 2008 Pfizer Teaching Award to Dr. Bonnie Smith, Associate Professor of Anatomy, Embryology, and Physiology at the Virginia-Maryland Regional College of Veterinary Medicine (VMRCVM) at Virginia Tech. Dr. Smith began her faculty service at VMRCVM in 1991, and previous to that spent four years on the faculty at North Carolina State University. Her ability to make a positive impact in the lives of students and their learning has become legendary over the years. Likewise, as a member of the Curriculum Board (Committee) and serving on various course design teams, Dr. Smith has been a steadying force in guiding the curriculum through various iterations. Helping students and faculty keep a sense of balance throughout these changes has been one of her major contributions. As a testament to her long-term teaching excellence, Dr. Bonnie Smith has received at least 22 different awards and citations for teaching excellence, two of which came very early in her career while she was at North Carolina State University. Most notable among these many awards is the fact that she is now a three-time recipient of the Pfizer Teaching Award. Dr. Smith has also been nominated by Student AVMA for a Teaching Excellence Award in Basic Sciences and has received an Honorable Mention, Teacher of the Year Award from the AVMA. Additionally, she has received an Alumni Teaching Award and a University Award for Teaching Excellence, and she has been elected to the Virginia Tech Academy of Teaching Excellence. Each of these three awards recognizes the best educators on Virginia Tech's faculty. Students have been very articulate in their praise of Dr. Smith's teaching. The comments received include "She has developed a unique teaching style that infuses traditional lectures with her unrelenting energy while never sacrificing content or complexity" and "She approaches the material from many angles, with clear verbalization of concepts, creatively utilizing stories and metaphors for clarification." Finally, a very fitting comment that illustrates her impact on her students: "Outside the classroom, Dr. Smith also influences many of us by serving as a strong female role model. In the face of life's hardships, she perseveres with an unshakably positive spirit. She encourages us to excel in all we do within the walls of our school and in our own lives." Peers have likewise been most complimentary of Dr. Smith's abilities as an educator. Examples from her nomination packet include the following: "Dr. Smith is truly a Master Teacher of the college. She has consistently demonstrated exemplary qualities of teaching, dedication and work ethic. She has received every teaching award the College has to offer and is consistently recognized by students, peers and the University" and "She epitomizes the qualities we have come to associate with teaching excellence. First and foremost is her dedication and commitment to student learning. Second, Dr. Smith's rapport with her students is outstanding because she invests the time necessary to gain their trust so she knows exactly what they are struggling with in her course. Third, she has the uncommon ability and desire to reach into students' minds and hearts to tailor instruction to meet individual learning styles and needs. Indeed, Dr. Smith is extremely gifted in being able to take complex details and concepts, and simplify, organize and present them in a very clear, understandable fashion." Other peer comments include: "Dr. Smith's animated and enthusiastic style was very effective and well-received"; "She is commended for her very good use of metaphors, examples and humor"; and "We all agree that attending Dr. Smith's lectures was beneficial to us as well as to the students! Keep up the fine work." In summary, Dr. Smith is to be sincerely congratulated on receiving this prestigious award. It is well deserved, based on her long history of teaching excellence and on the positive impact she has had in the lives of her students. -J. Blair Meldrum, Professor of Toxicology, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, and Chair, VMRCVM Pfizer Teaching Award Selection Committee.

Worldwide, 3-Year, Post-Marketing Surveillance Experience with Tofacitinib in Rheumatoid Arthritis.

PubMed

Cohen, Stanley; Curtis, Jeffrey R; DeMasi, Ryan; Chen, Yan; Fan, Haiyun; Soonasra, Arif; Fleischmann, Roy

2018-06-01

Post-marketing surveillance (PMS) is an integral part of monitoring adverse events (AEs) following approval of new drugs. Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). An analysis of PMS reports was conducted to evaluate the safety of tofacitinib in a post-marketing setting. Worldwide tofacitinib PMS data received in the Pfizer safety database from November 6, 2012 (first marketing authorization of tofacitinib) to November 5, 2015 were analyzed. Serious AEs (SAEs) of interest were reviewed and reporting rates (RRs) were calculated by dividing the number of SAEs by the estimated 100 patient-years of exposure. Patient exposure was calculated based on estimated worldwide sales and an estimated daily regimen of tofacitinib 5 mg twice daily. During the 3-year reporting period, worldwide post-marketing exposure to tofacitinib since approval was estimated to be 34,223 patient-years. In total, 9291 case reports (82.9% non-serious) were received and 25,417 AEs, 102 fatal cases, and 4352 SAEs were reported. The RRs (per 100 patient-years) for SAEs of interest by Medical Dictionary for Regulatory Activities System Organ Class were 2.57 for infections, 0.91 for gastrointestinal disorders, 0.60 for respiratory disorders, 0.45 for neoplasms, 0.43 for cardiac disorders, and 0.12 for hepatobiliary disorders. Although there are limitations to these data, no new safety risks were revealed in this real-world setting compared with the safety profile identified in the tofacitinib RA clinical development program. Any risks identified through the tofacitinib development program and PMS will continue to be monitored through pharmacovigilance surveillance. Pfizer Inc.

A CTD–Pfizer collaboration: manual curation of 88 000 scientific articles text mined for drug–disease and drug–phenotype interactions

PubMed Central

Davis, Allan Peter; Wiegers, Thomas C.; Roberts, Phoebe M.; King, Benjamin L.; Lay, Jean M.; Lennon-Hopkins, Kelley; Sciaky, Daniela; Johnson, Robin; Keating, Heather; Greene, Nigel; Hernandez, Robert; McConnell, Kevin J.; Enayetallah, Ahmed E.; Mattingly, Carolyn J.

2013-01-01

Improving the prediction of chemical toxicity is a goal common to both environmental health research and pharmaceutical drug development. To improve safety detection assays, it is critical to have a reference set of molecules with well-defined toxicity annotations for training and validation purposes. Here, we describe a collaboration between safety researchers at Pfizer and the research team at the Comparative Toxicogenomics Database (CTD) to text mine and manually review a collection of 88 629 articles relating over 1 200 pharmaceutical drugs to their potential involvement in cardiovascular, neurological, renal and hepatic toxicity. In 1 year, CTD biocurators curated 2 54 173 toxicogenomic interactions (1 52 173 chemical–disease, 58 572 chemical–gene, 5 345 gene–disease and 38 083 phenotype interactions). All chemical–gene–disease interactions are fully integrated with public CTD, and phenotype interactions can be downloaded. We describe Pfizer’s text-mining process to collate the articles, and CTD’s curation strategy, performance metrics, enhanced data content and new module to curate phenotype information. As well, we show how data integration can connect phenotypes to diseases. This curation can be leveraged for information about toxic endpoints important to drug safety and help develop testable hypotheses for drug–disease events. The availability of these detailed, contextualized, high-quality annotations curated from seven decades’ worth of the scientific literature should help facilitate new mechanistic screening assays for pharmaceutical compound survival. This unique partnership demonstrates the importance of resource sharing and collaboration between public and private entities and underscores the complementary needs of the environmental health science and pharmaceutical communities. Database URL: http://ctdbase.org/ PMID:24288140

The concomitant use of fesoterodine and topical vaginal estrogen in the management of overactive bladder and sexual dysfunction in postmenopausal women.

PubMed

Chughtai, Bilal; Forde, James C; Buck, Jessica; Asfaw, Tirsit; Lee, Richard; Te, Alexis E; Kaplan, Steven A

2016-03-01

The objective of this study is to investigate the combination effect of anti-muscarinic medication and topical vaginal estrogen in the treatment of overactive bladder (OAB) and female sexual dysfunction in postmenopausal women. After IRB approval, 23 female subjects who met the entry criteria were randomized into two groups: (1) fesoterodine (Toviaz®, Pfizer, NY) with topical vaginal estrogen (Premarin®, Pfizer, NY) once daily or (2) fesoterodine once daily alone. If 4 mg fesoterodine was tolerated at 1-week, the dose was increased to 8 mg. Primary endpoints were improvement in OAB symptom severity (Overactive Bladder Questionnaire, OAB-Q SF), improvement in OAB health-related quality of life (HRQL) (OAB-Q SF), and sexual function (Sexual Quality of Life-Female, SQOL-F) after 12 weeks. Secondary endpoint was change in total number of micturitions. After 12-weeks, the combination group had a significant improvement in OAB symptom severity (p = 0.006), HRQL (p = 0.029), and SQOL-F (0.0003). The fesoterodine alone group also had significant improvement in OAB symptom severity (p < 0.0001), HRQL (p = 0.0002), and SQOL-F (p = 0.02). When compared directly to the fesoterodine alone group, the combination group after 12-weeks had a reduced OAB symptom severity (10 versus 23.3; p = 0.35), higher HRQL (96.9 versus 84.6; p = 0.75), and higher SQOL-F (99 versus 81; p = 0.098). The total number of micturitions over 3 d was significantly reduced in the combination group (45-26, p = 0.03) between baseline and 12-weeks. The combined effect of fesoterodine and topical vaginal estrogen improved OAB symptoms and sexual function in postmenopausal women. © The Author(s) 2016.

Safety and tolerability of varenicline tartrate (Champix(®)/Chantix(®)) for smoking cessation in HIV-infected subjects: a pilot open-label study.

PubMed

Cui, Qu; Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix(®), Pfizer, Saint-Laurent, QC, Canada or Chantix(®), Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p = 0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9-12 was 42% (95% confidence interval [CI]: 26-58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline.

Narrative review: the promotion of gabapentin: an analysis of internal industry documents.

PubMed

Steinman, Michael A; Bero, Lisa A; Chren, Mary-Margaret; Landefeld, C Seth

2006-08-15

Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity.

"Center punch" and "whole spot" bioanalysis of apixaban in human dried blood spot samples by UHPLC-MS/MS.

PubMed

Zheng, Naiyu; Yuan, Long; Ji, Qin C; Mangus, Heidi; Song, Yan; Frost, Charles; Zeng, Jianing; Aubry, Anne-Françoise; Arnold, Mark E

2015-04-15

Apixaban (Eliquis™) was developed by Bristol-Myers Squibb (BMS) and Pfizer to use as an antithrombotic/anticoagulant agent and has been recently approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. A clinical study of apixaban, sponsored by BMS and Pfizer, included a pilot exploratory portion to evaluate the potential for future drug concentration monitoring using dried blood spot (DBS) sample collection. For DBS sample collection, a fixed blood volume was dispensed onto a DBS card by either regular volumetric pipette (venous blood collection) or capillary dispenser (finger prick blood collection). A 96-well semi-automated liquid-liquid extraction sample preparation procedure was developed to provide clean extracts for UHPLC-MS/MS quantitation. Assays using both partial-spot center punch and whole spot punch were developed and validated. The linear dynamic ranges for all the analyses were from 0.5 to 500 ng/mL. The coefficient of determination (r(2)) values was >0.9944 for all the validation runs. For the center punch approach, the intra-assay precision (%CV) was within 4.4% and inter-assay precision was within 2.6%. The assay accuracy, expressed as %Dev., was within ± 5.4% of the nominal concentrations. One accuracy and precision run was performed using the whole spot approach, the intra-assay precision (%CV) was within 7.1% and the accuracy was within ± 8.0% of the nominal concentrations. In contrast to the center punch approach, the whole spot approach eliminated the effect of hematocrit and high lipids on the analysis of apixaban in human DBS when an accurate sample blood volume was collected on DBS cards. Copyright © 2015 Elsevier B.V. All rights reserved.

Seasonal affective disorder and non-seasonal affective disorders: results from the NESDA study

PubMed Central

Roest, Annelieke M.; Bos, Elisabeth H.; Meesters, Ybe; Penninx, Brenda W.J.H.; Nolen, Willem A.; de Jonge, Peter

2017-01-01

Background Seasonal affective disorder (SAD) is considered to be a subtype of depression. Aims To compare the clinical picture of SAD to non-seasonal affective disorders (non-SADs). Method Diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) were established in 2185 participants of the Netherlands Study of Depression and Anxiety. The Seasonal Pattern Assessment Questionnaire was administered to diagnose SAD. Symptoms of depression and anxiety were measured with the Inventory of Depressive Symptoms, the Beck Anxiety Inventory and the Fear Questionnaire. Results Participants with SAD, participants with a lifetime bipolar disorder and participants with a lifetime comorbid anxiety and depressive disorder scored highest in terms of psychopathology in the past year. The seasonal distribution of major depressive episodes was not different for participants with or without SAD. Conclusions SAD may be a measure of severity of depression with a subjectively perceived worsening of symptoms in the winter months. Declaration of interest Y.M. has received research funding and served as a consultant for Royal Philips Electronics NV and The Litebook Company Ltd. W.A.N. has received grants from the Netherlands Organization for Health Research and Development, the European Union, the Stanley Medical Research Institute, Astra Zeneca, Eli Lilly, GlaxoSmithKline and Wyeth; has received honoraria/speaker’s fees from Astra Zeneca, Pfizer, Servier and Wyeth; and has served in advisory boards for Astra Zeneca, Pfizer and Servier. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID:28904813

Safety and Tolerability of Varenicline Tartrate (Champix®/Chantix®) for Smoking Cessation in HIV-Infected Subjects: A Pilot Open-Label Study

PubMed Central

Robinson, Linda; Elston, Dawn; Smaill, Fiona; Cohen, Jeffrey; Quan, Corinna; McFarland, Nancy; Thabane, Lehana; McIvor, Andrew; Zeidler, Johannes; Smieja, Marek

2012-01-01

Abstract The prevalence of smoking in HIV-infected subjects is high. As a smoking cessation aid, varenicline (Champix®, Pfizer, Saint-Laurent, QC, Canada or Chantix®, Pfizer, Mission, KS) has not been previously evaluated in HIV-infected smokers. In this multicenter pilot open label study, varenicline 1.0 mg was used twice daily for 12 weeks with dose titration in the first week. Adverse events (AEs) during the treatment period were recorded. Changes from baseline in laboratory tests, vital signs, daily cigarette consumption, nicotine dependence, and withdrawal were measured through week 24. Self-reported abstinence was validated by serum cotinine at week 12. We enrolled 36 subjects with a mean of 29 pack-years of smoking and a minimum of 4 cigarettes per day. All but 1 were male, 33 (92%) were white. The most frequently reported AEs were nausea (33%), abnormal dreams (31%), affect lability (19%), and insomnia (19%). Six (17%) subjects discontinued varenicline due to AEs. No grade 3/4 laboratory abnormalities or serious AEs occurred during the study. There was no significant change in HIV viral load. CD4 counts increased by 69 cells/mm3 (p=0.001) at week 24. Serum cotinine-verified 4-week continuous abstinence rate through weeks 9–12 was 42% (95% confidence interval [CI]: 26–58%). AEs and abstinence rates were comparable to those in published randomized controlled trials conducted in generally healthy HIV-negative smokers. Varenicline was safe and appears effective among HIV-infected smokers in this exploratory study, although AEs were common. The most common AE was nausea, with no adverse effect on HIV treatment outcome. Close monitoring of liver enzymes and blood pressure is recommended for HIV-positive smokers taking varenicline. PMID:22007690

Interscience Conference on Antimicrobial Agents and Chemotherapy--49th annual meeting. Part 2. 12-15 September 2009, San Francisco, CA, USA.

PubMed

Turner, Ben; Murch, Lisa

2009-11-01

The Interscience Conference on Antimicrobial Agents and Chemotherapy held in San Francisco included topics covering new therapeutic developments for the treatment of infectious diseases. This conference report highlights selected presentations on several antibiotics in development including a broad-spectrum penem beta-lactam antibiotic, a novel siderophore monobactam, as well as other novel antibiotics. Investigational drugs discussed include sulopenem and sulopenem etzadroxil (both Pfizer Inc), BAL-30072 (Basilea Pharmaceutica International Ltd), TP-120 and TP-787 (both Tetraphase Pharmaceuticals Inc), NAI-107 (New Anti Infectives Consortium/NexThera Biosciences) and ABI-200 (AdRem Biotech/US Department of Agriculture).

Design of targeted libraries against the human Chk1 kinase using PGVL Hub.

PubMed

Peng, Zhengwei; Hu, Qiyue

2011-01-01

PGVL Hub is a Pfizer internal desktop tool for chemical library and singleton design. In this chapter, we give a short introduction to PGVL Hub, the core workflow it supports, and the rich design capabilities it provides. By re-creating two legacy targeted libraries against the human checkpoint kinase 1 (Chk1) as a showcase, we illustrate how PGVL Hub could be used to help library designers carry out the steps in library design and realize design objectives such as SAR expansion and improvement in both kinase selectivity and compound aqueous solubility. Finally we share several tips about library design and usage of PGVL Hub.

Coronary artery bypass grafting in a patient with hemophilia B: continuous recombinant factor IX infusion as per the Japanese guidelines for replacement therapy.

PubMed

Suzuki, Tomoyuki; Kawamoto, Shunsuke; Kumagai, Kiichiro; Adachi, Osamu; Kanda, Keisuke; Ishikawa, Masaaki; Okitsu, Yoko; Harigae, Hideo; Kurosawa, Shin; Saiki, Yoshikatsu

2016-08-01

We herein report our experience of successfully managing the hemostatic system by controlling serum factor IX levels throughout the perioperative period in a patient with hemophilia B. Coronary artery bypass grafting with cardiopulmonary bypass was planned for a 52-year-old man with moderate severity of hemophilia B. During surgery, recombinant factor IX (rFIX; BeneFIX(®) Pfizer Japan inc., Tokyo, Japan) was administered by bolus infusion followed by continuous infusion as per the guidelines of the Japanese Society on Thrombosis and Hemostasis. The operative course was uneventful without any considerable bleeding or complications.

Computer Models Simulate Fine Particle Dispersion

NASA Technical Reports Server (NTRS)

2010-01-01

Through a NASA Seed Fund partnership with DEM Solutions Inc., of Lebanon, New Hampshire, scientists at Kennedy Space Center refined existing software to study the electrostatic phenomena of granular and bulk materials as they apply to planetary surfaces. The software, EDEM, allows users to import particles and obtain accurate representations of their shapes for modeling purposes, such as simulating bulk solids behavior, and was enhanced to be able to more accurately model fine, abrasive, cohesive particles. These new EDEM capabilities can be applied in many industries unrelated to space exploration and have been adopted by several prominent U.S. companies, including John Deere, Pfizer, and Procter & Gamble.

Nucleic Acid-Induced Resistance to Viral Infection

PubMed Central

Takano, Kouichi; Warren, Joel; Jensen, Keith E.; Neal, Alan L.

1965-01-01

Takano, Kouichi (Chas. Pfizer & Co., Inc., Terre Haute, Ind.), Joel Warren, Keith E. Jensen, and Alan L. Neal. Nucleic acid resistance to viral infection. J. Bacteriol. 90:1542–1547. 1965.—Administration of nonviral nucleic acids to mice increased their resistance to a subsequent infection with influenza or encephalomyocarditis viruses. Injection of ribonucleic acid or deoxyribonucleic acid by peripheral routes did not modify susceptibility to intranasal infection. Lung tissue extracts from animals previously treated with yeast nucleic acid inhibited the growth of vaccinia and influenza viruses. The protective effect of exogenous nucleic acids persisted in mice for several days, but gradually diminished to undetectable levels. PMID:4285332

An Economic Evaluation of Tofacitinib Treatment in Rheumatoid Arthritis: Modeling the Cost of Treatment Strategies in the United States.

PubMed

Claxton, Lindsay; Jenks, Michelle; Taylor, Matthew; Wallenstein, Gene; Mendelsohn, Alan M; Bourret, Jeffrey A; Singh, Amitabh; Moynagh, Dermot; Gerber, Robert A

2016-09-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib is approved in the United States for use in adults with moderately to severely active RA and an inadequate response or intolerance to methotrexate. To (a) evaluate, using an economic model, the treatment costs of an RA strategy including tofacitinib, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic RA treatment strategies, which are commonly prescribed in the United States, and (b) assess the economic impact of monotherapy and combination therapy in patients who had an inadequate response to methotrexate therapy (MTX-IR analysis) and to combination therapy in patients who had an inadequate response to a tumor necrosis factor inhibitor (TNF-IR analysis). A transparent, Excel-based economic model with a decision-tree approach was developed to evaluate costs over a 1- and 2-year time horizon. The model compared tofacitinib 5 mg twice a day (BID) either as monotherapy or in combination with MTX with similarly labeled biologic therapies. Response to treatment was modeled as American College of Rheumatology (ACR) 20/50/70 response. ACR20 represented clinical response and determined whether patients continued therapy. ACR response rates at 6-month intervals were sourced from prescribing information and safety event rates from a published meta-analysis. Following an adverse event or a lack of response to treatment, it was assumed that 75% of patients switched to the next line of treatment (first to abatacept and then to rituximab). The perspective was that of a U.S. payer. Costs were reported in 2015 U.S. dollars and included drug wholesale acquisition costs, monitoring, drug administration, and treatment for minor and serious adverse events. The patient population eligible for treatment was based on the total number of members (i.e., RA and non-RA) in a payer organization; members with RA treated with biologic therapies were estimated using epidemiological data. Sensitivity analyses were conducted to explore the impact of varying key parameters, including treatment-switching probability, product rebate, major rates of adverse drug reaction, and ACR20 rates, on the model outcomes. Tofacitinib combination therapy after MTX failure was associated with the lowest cost per member per month (PMPM) over a 2-year time frame at $5.53, compared with $6.49 for adalimumab, $6.43 for etanercept, $5.95 for certolizumab, and $5.89 for tocilizumab. Similar savings were observed when all biologics were administered as monotherapy. Tofacitinib combination therapy was also associated with the lower PMPM cost compared with adalimumab combination therapy in the TNF-IR analysis. Tofacitinib was also among the lowest cost per ACR20 responder in each analysis. Sensitivity analyses demonstrated that tofacitinib would potentially be cost saving even in the least optimistic scenarios. This analysis suggests that tofacitinib 5 mg BID following MTX failure is a lower cost per patient treatment option when used either as monotherapy or combination therapy, compared with adalimumab, etanercept, certolizumab and tocilizumab biologic regimens. Tofacitinib + MTX in TNF-IR patients was also predicted to be a lower-cost treatment option compared with adalimumab+MTX and was associated with the lowest cost per ACR 20/50/70 responder. This study was funded by Pfizer, which determined the research topic and paid York Health Economics Consortium to develop the analysis and conduct the research. York Health Economics Consortium has received consultancy fees from Pfizer. Gerber, Wallenstein, Mendelsohn, Bourret, Singh, and Moynagh are employees and shareholders of Pfizer. Editorial support was funded by Pfizer and was provided by Claxton, Jenks, and Taylor, who are employees of York Health Economics Consortium. Study concept and design were contributed primarily by Taylor, Jenks, Gerber, and Singh, along with the other authors. Gerber, Moynagh, and Singh collected the data, assisted by Bouret and Mendelsohn; data interpretation was performed by Claxton, Gerber, Bouret, and Mendelsohn. The manuscript was written primarily by Claxton, with assistance from the other authors, and revised by Claxton, Gerber, Bouret, and Mendelsohn, with assistance from the other authors.

High levels of confusion for cholesterol awareness campaigns.

PubMed

Hall, Danika V

2008-09-15

Earlier this year, two industry-sponsored advertising campaigns for cholesterol awareness that target the general public were launched in Australia. These campaigns aimed to alert the public to the risks associated with having high cholesterol and encouraged cholesterol testing for wider groups than those specified by the National Heart Foundation. General practitioners should be aware of the potential for the two campaigns to confuse the general public as to who should be tested, and where. The campaign sponsors (Unilever Australasia and Pfizer) each have the potential to benefit by increased market share for their products, and increased profits. These disease awareness campaigns are examples of what is increasingly being termed "condition branding" by pharmaceutical marketing experts.

A review of the off-label use of selamectin (Stronghold®/Revolution®) in dogs and cats

PubMed Central

Fisher, Maggie A; Shanks, David J

2008-01-01

Since its introduction approximately seven years ago, selamectin (Stronghold®/Revolution®, Pfizer Inc.) has been used off-label to treat a number of ecto- and endoparasite conditions in dogs and cats. It has been used as a successful prophylactic against Dirofilaria repens and as a treatment for Aelurostrongylus abstrusus in cats. It has also been used to treat notoedric mange, infestation with the nasal mite Pneumonyssoides caninum, Cheyletiella spp. and Neotrombicula autumnalis infestations and larval Cordylobia anthropophaga infection. However, to date attempts to treat generalised canine demodicosis have not been successful. In all cases, treatment was apparently well tolerated by the host. PMID:19032763

Mild Bilateral Hemorrhagic Occlusive Retinal Vasculitis Following Intracameral Vancomycin Administration in Cataract Surgery.

PubMed

Arepalli, Sruthi; Modi, Yasha S; Deasy, Ryan; Srivastava, Sunil K

2018-05-01

A patient underwent cataract surgery with prophylactic intracameral vancomycin (Vancocin; Pfizer, New York City, NY) in each eye, 2 weeks apart. Four weeks after, the patient presented with a mild bilateral hemorrhagic occlusive retinal vasculitis (HORV). A systemic work-up was negative for syphilis, toxoplasmosis, Bartonella, tuberculosis, and sarcoidosis. The patient was treated with oral steroids and one intravitreal steroid injection in the left eye. Ten months after presentation, the patient's vasculitis was quiescent. Although the literature describes primarily severe forms of HORV, the authors' case describes bilateral, mild HORV and highlights the potential underreporting of these cases in the literature. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:369-373.]. Copyright 2018, SLACK Incorporated.

Results from an international multicenter trial evaluating the ease-of-use of and preference for a newly developed disposable injection pen for the treatment of growth hormone deficiency in treatment-naïve children and adults

PubMed Central

Pleil, Andreas M; Darendeliler, Feyza; Dörr, Helmuth G; Hutchinson, Katherine; Wollmann, Hartmut A

2014-01-01

Previous research has reported that ease of use of and preference for a delivery device are associated with greater patient compliance – an important factor in achieving optimal therapeutic results. The objective of this study was to assess the ease-of-use of a new disposable pen (GoQuick®, Pfizer, Inc.) versus the current reusable pen (GENOTROPIN Pen®, Pfizer, Inc.) to inject a daily dose of recombinant DNA origin human growth hormone, Genotropin® (somatropin) in standard practice. In this randomized, crossover, multicenter, multinational, open-label study, ease-of-use of and preference for the two pens were assessed in three treatment-naïve populations: 1) parents of very young children; 2) parent–child dyads; and 3) adults via use of a validated self-report Injection Pen Assessment Questionnaire (IPAQ) after 2 months of at-home-use experience. The primary endpoint was the proportion of participants who reported the new disposable pen to be no different from or easier to use than the current reusable pen. Safety was also assessed and reported according to local legal requirements. Of the 120 screened patients, 119 were included in the ease-of-use analysis and all were included in the safety analyses. In all, 67.2% found the new somatropin disposable pen to be no different from or easier to use than the reusable pen (95% confidence interval: 58.8–75.7). Most adverse events were mild or moderate. No deaths or device- or treatment-related serious adverse events were reported. These results suggest that improvements made to the reusable somatropin pen are tangible and recognizable to treatment-naïve patients and their caregivers, child–caregiver dyads, and adults, and may positively impact continued compliance with therapy. Registry information ClinicalTrials.gov identifier: NCT01112865. PMID:24748824

Instability of misoprostol tablets stored outside the blister: a potential serious concern for clinical outcome in medical abortion.

PubMed

Berard, Veronique; Fiala, Christian; Cameron, Sharon; Bombas, Teresa; Parachini, Mirella; Gemzell-Danielsson, Kristina

2014-01-01

Misoprostol (Cytotec) is recognised to be effective for many gynaecological indications including termination of pregnancy, management of miscarriage and postpartum haemorrhage. Although not licensed for such indications, it has been used for these purposes by millions of women throughout the world. Misoprostol tablets are most often packaged as multiple tablets within an aluminium strip, each within an individual alveolus. When an alveolus is opened, tablets will be exposed to atmospheric conditions. To compare the pharmaco technical characteristics (weight, friability), water content, misoprostol content and decomposition product content (type A misoprostol, type B misoprostol and 8-epi misoprostol) of misoprostol tablets Cytotec (Pfizer) exposed to air for periods of 1 hour to 720 hours (30 days), to those of identical non exposed tablets. Four hundred and twenty (420) tablets of Cytotec (Pfizer) were removed from their alveoli blister and stored at 25°C/60% relative humidity. Water content, and misoprostol degradation products were assayed in tablets exposed from 1 to 720 hours (30 days). Comparison was made with control tablets (N=60) from the same batch stored in non-damaged blisters. Statistical analyses were carried out using Fisher's exact test for small sample sizes. By 48 hours, exposed tablets demonstrated increased weight (+4.5%), friability (+1 300%), and water content (+80%) compared to controls. Exposed tablets also exhibited a decrease in Cytotec active ingredient dosage (-5.1% after 48 hours) and an increase in the inactive degradation products (+25% for type B, +50% for type A and +11% for 8-epi misoprostol after 48 hours) compared to controls. Exposure of Cytotec tablets to 'typical' European levels of air and humidity results in significant time-dependent changes in physical and biological composition that could impact adversely upon clinical efficacy. Health professionals should be made aware of the degradation of misoprostol with inappropriate storage of misoprostol tablets.

Instability of Misoprostol Tablets Stored Outside the Blister: A Potential Serious Concern for Clinical Outcome in Medical Abortion

PubMed Central

Berard, Veronique; Fiala, Christian; Cameron, Sharon; Bombas, Teresa; Parachini, Mirella; Gemzell-Danielsson, Kristina

2014-01-01

Introduction Misoprostol (Cytotec) is recognised to be effective for many gynaecological indications including termination of pregnancy, management of miscarriage and postpartum haemorrhage. Although not licensed for such indications, it has been used for these purposes by millions of women throughout the world. Misoprostol tablets are most often packaged as multiple tablets within an aluminium strip, each within an individual alveolus. When an alveolus is opened, tablets will be exposed to atmospheric conditions. Objective To compare the pharmaco technical characteristics (weight, friability), water content, misoprostol content and decomposition product content (type A misoprostol, type B misoprostol and 8-epi misoprostol) of misoprostol tablets Cytotec (Pfizer) exposed to air for periods of 1 hour to 720 hours (30 days), to those of identical non exposed tablets. Methods Four hundred and twenty (420) tablets of Cytotec (Pfizer) were removed from their alveoli blister and stored at 25°C/60% relative humidity. Water content, and misoprostol degradation products were assayed in tablets exposed from 1 to 720 hours (30 days). Comparison was made with control tablets (N = 60) from the same batch stored in non-damaged blisters. Statistical analyses were carried out using Fisher’s exact test for small sample sizes. Results By 48 hours, exposed tablets demonstrated increased weight (+4.5%), friability (+1 300%), and water content (+80%) compared to controls. Exposed tablets also exhibited a decrease in Cytotec active ingredient dosage (−5.1% after 48 hours) and an increase in the inactive degradation products (+25% for type B, +50% for type A and +11% for 8-epi misoprostol after 48 hours) compared to controls. Conclusion Exposure of Cytotec tablets to ‘typical’ European levels of air and humidity results in significant time-dependent changes in physical and biological composition that could impact adversely upon clinical efficacy. Health professionals should be made aware of the degradation of misoprostol with inappropriate storage of misoprostol tablets. PMID:25502819

Media coverage of off-label promotion: a content analysis of US newspapers.

PubMed

Joshi, Avani D; Patel, Dipen A; Holdford, David A

2011-09-01

Promotion of drugs for off-label use is newsworthy, because it is an illegal but all too common strategy used by pharmaceutical companies. The print media are an important source of information about coverage of off-label promotion of drugs and devices and can influence public perceptions of the practice. Print media coverage of off-label promotion during the years 1990-2008 were described and quantified. The primary themes and general tones relating to off-label promotion articles were evaluated. General concerns associated with off-label promotion and complaints about specific brand name drugs were also identified. Content analyses of the top 6 US newspapers were conducted over the period of 1990-2008 to analyze the media coverage given to off-label promotion of drugs and devices. Headlines and full text of articles were analyzed for primary themes and tones of the coverage. Intercoder reliability tests were performed on all the study variables. One hundred and one articles were identified meeting the study inclusion criteria. Coverage varied by newspaper. The Wall Street Journal had the most coverage on the topic (45%), and USA Today and Chicago Tribune had the least coverage (5%). Overall, most of the stories sampled were deemed to have a negative tone in coverage (77%), focusing mainly on lawsuits against drug companies for promoting their drugs for off-label uses. Pfizer's Neurontin(®) (Pfizer Inc., New York, NY 10017, USA) and Johnson & Johnson's Retin-A(®) (Orthoneutrogena, Los Angeles, CA 90045, USA) received the most media attention. The news media helps shape public understanding of promotional practices of pharmaceutical companies and their potential benefits and harms. This study suggests that print media coverage is generally negative about off-label promotion, focusing on legal actions taken against drug companies and the negative consequences of such promotional practices. Copyright © 2011 Elsevier Inc. All rights reserved.

High-resolution structure of a retroviral protease folded as a monomer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gilski, Miroslaw; Polish Academy of Sciences, 61-704 Poznan; Kazmierczyk, Maciej

2011-11-01

The crystal structure of Mason–Pfizer monkey virus protease folded as a monomer has been solved by molecular replacement using a model generated by players of the online game Foldit. The structure shows at high resolution the details of a retroviral protease folded as a monomer which can guide rational design of protease dimerization inhibitors as retroviral drugs. Mason–Pfizer monkey virus (M-PMV), a D-type retrovirus assembling in the cytoplasm, causes simian acquired immunodeficiency syndrome (SAIDS) in rhesus monkeys. Its pepsin-like aspartic protease (retropepsin) is an integral part of the expressed retroviral polyproteins. As in all retroviral life cycles, release and dimerizationmore » of the protease (PR) is strictly required for polyprotein processing and virion maturation. Biophysical and NMR studies have indicated that in the absence of substrates or inhibitors M-PMV PR should fold into a stable monomer, but the crystal structure of this protein could not be solved by molecular replacement despite countless attempts. Ultimately, a solution was obtained in mr-rosetta using a model constructed by players of the online protein-folding game Foldit. The structure indeed shows a monomeric protein, with the N- and C-termini completely disordered. On the other hand, the flap loop, which normally gates access to the active site of homodimeric retropepsins, is clearly traceable in the electron density. The flap has an unusual curled shape and a different orientation from both the open and closed states known from dimeric retropepsins. The overall fold of the protein follows the retropepsin canon, but the C{sup α} deviations are large and the active-site ‘DTG’ loop (here NTG) deviates up to 2.7 Å from the standard conformation. This structure of a monomeric retropepsin determined at high resolution (1.6 Å) provides important extra information for the design of dimerization inhibitors that might be developed as drugs for the treatment of retroviral infections, including AIDS.« less

Compatibility of Biosimilar Filgrastim with Cytotoxic Chemotherapy during the Treatment of Malignant Diseases (VENICE): A Prospective, Multicenter, Non-Interventional, Longitudinal Study.

PubMed

Fruehauf, Stefan; Otremba, Burkhard; Stötzer, Oliver; Rudolph, Christine

2016-11-01

Febrile neutropenia (FN) is a serious and frequent complication of cytotoxic chemotherapy. Biosimilar filgrastim (Nivestim™, Hospira Inc, A Pfizer Company, Lake Forest, IL, USA) is a granulocyte-colony stimulating factor licensed for the treatment of neutropenia and FN induced by myelosuppressive chemotherapy. The primary goal of this VENICE study (ClinicalTrials.gov identifier, NCT01627990) was to observe the tolerability, safety and efficacy of biosimilar filgrastim in patients receiving cancer chemotherapy. This was a prospective, multicenter, non-interventional, longitudinal study. Consenting adult patients with solid tumors or hematologic malignancies for whom cytotoxic chemotherapy and treatment with biosimilar filgrastim was planned were enrolled. Among the enrolled patients (N = 386), 81% were female, with a median age (range) of 61 (22-92) years, with 39% >65 years old. Most patients (n = 338; 88%) had solid tumors and the remainder (n = 49; 13%) had hematological malignancies. The majority of the patients (64%) received biosimilar filgrastim as primary prophylaxis and 36% as secondary prophylaxis. At the follow-up visits, for the majority of patients (95.6%) there had been no change in chemotherapy dose due to FN. For two patients (0.5%) the chemotherapy was discontinued due to FN and for four patients (1.0%) the chemotherapy dose was reduced due to FN. For the majority of patients (96.9%) the chemotherapy cycle following the first biosimilar filgrastim treatment was not delayed due to FN. For 3 patients (0.8%), the chemotherapy was delayed following the first biosimilar filgrastim treatment. Less than one-third (29.8%) of the patients experienced ≥1 adverse event that was at least potentially related to biosimilar filgrastim treatment. Biosimilar filgrastim was effective and well-tolerated in both the primary and secondary prophylactic setting in patients undergoing chemotherapy for solid tumors and hematological malignancies. ClinicalTrials.gov identifier, NCT01627990. Hospira Inc, A Pfizer Company, Lake Forest, IL, USA.

Embolization with Tornado coils to control bleeding from an arterioureteral fistula.

PubMed

Jacobs, Bruce L; Maranchie, Jodi K

2007-12-01

Arterioureteral fistulae are rare, but potentially life-threatening causes of bleeding. We present a case of an 82 year-old woman with refractory, transfusion-dependent bleeding from an arterial fistula to her right ureteral stump, following right radical nephrectomy for advanced renal cell carcinoma. Cystoscopy with retrograde ureteral stump embolization using Tornado (Cook Medical, Bloomington, Indiana, USA) coils plus a slurry of thrombin-soaked Gelfoam (Pfizer Inc., New York, New York, USA) was performed, which led to prompt resolution of the patient's hematuria requiring no further hospitalizations or transfusions. Retrograde insertion of coils and injection of thrombin-soaked Gelfoam can be a minimally invasive, safe, and durable alternative for controlling hemorrhage from an arterioureteral fistula to a ureteral stump.

Effect of Apixaban Versus Warfarin Use on Health Care Resource Utilization and Costs Among Elderly Patients with Nonvalvular Atrial Fibrillation.

PubMed

Deitelzweig, Steven; Luo, Xuemei; Gupta, Kiran; Trocio, Jeffrey; Mardekian, Jack; Curtice, Tammy; Lingohr-Smith, Melissa; Menges, Brandy; Lin, Jay

2017-11-01

The clinical trial ARISTOTLE showed that apixaban was superior to warfarin in reducing the risks of stroke and bleeding among patients with nonvalvular atrial fibrillation (NVAF). Further study of the effect of apixaban versus warfarin use on health care resource utilization (HCRU) and associated costs in the real-world setting is warranted, especially among elderly patients who are at higher risk of stroke and bleeding. To compare HCRU and costs among elderly NVAF patients treated with apixaban versus warfarin in the United States. Elderly patients (aged ≥ 65 years) with Medicare coverage who initiated apixaban or warfarin were identified from the Humana research database during January 1, 2013-September 30, 2015. Patients were required to have 12 months of continuous insurance coverage before drug initiation (baseline period) and an atrial fibrillation diagnosis during the baseline period or on the date of drug initiation. NVAF patients were grouped into cohorts depending on the drug initiated. Propensity score matching (PSM) was conducted to control for differences in demographics and clinical characteristics of study cohorts. Patients were followed after the index date for a variable length of follow-up. All-cause and disease-specific HCRU and costs during the follow-up were evaluated before and after PSM and reported as per patient per year. Of the overall (unmatched) population, 8,250 patients (mean age: 78.0 years) initiated apixaban and 14,051 patients (mean age: 78.2 years) initiated warfarin. Among NVAF patients who initiated apixaban versus those who initiated warfarin, mean Charlson Comorbidity Index (CCI) scores (3.0 vs. 3.4, P < 0.001); stroke risk scores, including CHADS 2 (2.7 vs. 2.9, P < 0.001) and CHA 2 DS 2 -VASc (4.6 vs. 4.7, P < 0.001); and bleeding risk scores, including HAS-BLED (3.1 vs. 3.2, P < 0.001), were lower. Additionally, total annual all-cause health care costs were lower during the baseline period for patients treated with apixaban versus warfarin ($17,077 vs. $20,236, P < 0.001). After PSM, 14,214 patients were matched, with 7,107 in each cohort. Mean age, CCI score, and stroke and bleeding risks were similar between matched cohorts, as were total all-cause health care costs during the baseline period. During the follow-up among matched cohorts, apixaban versus warfarin treatment was associated with higher annual pharmacy costs ($5,159 vs. $2,867, P < 0.001) but lower annual inpatient ($8,327 vs. $14,296, P < 0.001), outpatient ($9,655 vs. $11,469, P < 0.001), and total all-cause health care costs ($23,141 vs. $28,633, P < 0.001), which were reflective of lower inpatient, outpatient, and all-cause HCRU among apixaban-treated patients. Furthermore, bleeding-related ($2,101 vs. $3,963, P < 0.001) and stroke-related ($652 vs. $1,178, P = 0.001) annual medical costs were lower for patients treated with apixaban versus warfarin. After controlling for differences in patient characteristics, in the real-world setting apixaban versus warfarin use was associated with less HCRU and lower total all-cause health care costs and costs for bleeding- and stroke-related medical services, but greater pharmacy costs, among elderly NVAF patients. This study was sponsored by Pfizer and Bristol-Myers Squibb. Deitelzweig is a consultant for Pfizer and Bristol-Myers Squibb and has served on their advisory boards and received speaker fees. Deitelzweig also serves as consultant and advisory board member to Portola and Janssen. Luo, Trocio, and Mardekian are employees of Pfizer and own stock in the company. Gupta and Curtice are employees of Bristol-Myers Squibb and own stock in the company. Lingohr-Smith, Menges, and Lin are employees of Novosys Health, which received research funds from Pfizer and Bristol-Myers Squibb to conduct this study and develop the manuscript. Study concept and design were primarily contributed by Deitelzweig, Luo, and Gupta, along with Trocio, Mardekian, Curtice, and Lin. Lin, Menges, and Lingohr-Smith took the lead in data collection, with assistance from the other authors. Data interpretation was performed by Deitelzweig, Menges, and Lin, with assistance from the other authors. The manuscript was written by Lingohr-Smith and Menges, along with the other authors, and revised by all the authors. Some aspects of this study were presented at the American Heart Association Scientific Sessions in New Orleans, Louisiana, November 12-16, 2016.

Real-World Economic Outcomes During Time on Treatment Among Patients Who Initiated Sunitinib or Pazopanib as First Targeted Therapy for Advanced Renal Cell Carcinoma: A Retrospective Analysis of Medicare Claims Data.

PubMed

Vogelzang, Nicholas J; Pal, Sumanta K; Ghate, Sameer R; Li, Nanxin; Swallow, Elyse; Peeples, Miranda; Zichlin, Miriam L; Meiselbach, Mark K; Perez, Jose Ricardo; Agarwal, Neeraj

2018-06-01

The median age at renal cell carcinoma (RCC) diagnosis is 64 years. However, few studies have assessed the real-world time on treatment (TOT), health resource utilization (HRU), costs, or treatment compliance associated with targeted therapy use among patients in this age group with RCC. To assess the HRU, costs, and compliance during TOT among Medicare patients aged ≥ 65 years with advanced RCC (aRCC) who initiated first targeted therapy with pazopanib or sunitinib. Patients with aRCC were identified in the 100% Medicare + Part D databases administered by the Centers for Medicare & Medicaid Services. Eligible patients initiated first targeted therapy with sunitinib or pazopanib (index drug) on or after their first diagnosis of secondary neoplasm between October 19, 2009, and January 1, 2014, and were aged ≥ 65 years as of 1 year before first targeted therapy initiation (index date). Included patients were stratified into pazopanib and sunitinib cohorts based on first targeted therapy and matched 1:1 on baseline characteristics using propensity scores. TOT was defined as the time from the index date to treatment discontinuation (prescription gap > 90 days) or death. Compliance was defined as the ratio of drug supply days to TOT. Monthly all-cause costs and costs associated with RCC diagnosis (medical and pharmacy in 2015 U.S. dollars) and HRU (inpatient [admissions, readmissions, and days], outpatient, and emergency room visits) were assessed in the 1-year post-index period during TOT. Matched cohorts' TOT was compared using Kaplan-Meier analyses and univariable Cox models, and compliance, HRU, and costs were compared using Wilcoxon signed-rank tests. Of 1,711 included patients, 526 initiated pazopanib and 1,185 initiated sunitinib. Before matching, more patients in the pazopanib cohort were white, diagnosed in 2010-2014 versus 2006-2009, and had lung metastases compared with the sunitinib cohort (all P < 0.05). The pazopanib cohort also had higher mean outpatient visits and costs but lower mean total all-cause pharmacy costs, than the sunitinib cohort (all P < 0.05). After matching, the pazopanib and sunitinib cohorts had similar characteristics (mean age 75 years, 58% male, and Charlson Comorbidity Index score of 9.2 in both cohorts) and median TOT (4.8 and 4.1 months, respectively). Among the 522 matched pairs, pazopanib was associated with significantly lower total all-cause health care costs ($8,527 vs. $10,924, respectively [mean difference = $2,397]); total medical costs ($3,991 vs. $5,881, respectively, [$1,890]); and inpatient costs ($2,040 vs. $3,731, respectively, [$1,692]; all P < 0.01) compared with sunitinib. Patients receiving pazopanib had significantly fewer inpatient admissions (0.179 vs. 0.289, respectively) and days (1.063 vs. 1.904, respectively; both P < 0.01) than patients receiving sunitinib. Mean treatment compliance was lower for the pazopanib versus sunitinib cohort (0.91 vs. 0.94, respectively; P < 0.01). In this retrospective analysis of Medicare patients with aRCC from a TOT perspective, first targeted therapy with pazopanib was associated with significantly lower all-cause health care costs and HRU, but lower compliance, compared with sunitinib. Funding for this research was provided by Novartis Pharmaceuticals. The sponsor was involved in all stages of the study's conduct and reporting. Vogelzang has been a consultant for Novartis, Amgen, Celgene, Medivation, Eisai, Exelixis, and Roche; has spoken at Novartis, Astellas, Johnson and Johnson, Pfizer, Dendreon, Bayer/Algeta, GSK, and Veridex/Janssen; and has received research support from Novartis, Bayer, Exelixis, Progenics, Bavarian Nordic, and Viamet. Pal has been a consultant for Novartis, Pfizer, Aveo, Dendreon, and Myriad and has spoken at Novartis, Pfizer and Medivation. Agarwal has been a consultant or advisor for Novartis, Pfizer, Exelixis, Cerulean Pharma, Medivation, Eisai, and Argos Therapeutics. Swallow, Peeples, Zichlin, and Meiselbach are employees of Analysis Group, which received consultancy fees from Novartis for this project. Li was an employee of Analysis Group during the conduct of this study. Ghate is an employee of Novartis and owns stock/stock options. Perez was an employee of Novartis during the conduct of this study. A synopsis of the economic outcomes was presented at the Academy of Managed Care Pharmacy Nexus 2017 in Denver, Colorado, during March 27-30, 2017. A synopsis of the clinical outcomes was presented at the 22nd ISPOR Annual International Meeting in Boston, Massachusetts, during May 20-24, 2017.

American Chemical Society--238th National Meeting & Exposition. Developments in medicinal chemistry: part 1. 16-20 August 2009, Washington DC, USA.

PubMed

Gater, Deborah; Macauley, Donald

2009-10-01

The 238th National Meeting and Exposition of the American Chemical Society, held in Washington DC, included topics covering new compounds and developments in the field of medicinal chemistry. This conference report highlights selected presentations on a novel KV1.5 blocker, a state-dependent CaV2.2 antagonist, therapeutic uses of macrocycles, a novel P2X7 antagonist, developments using the StaR technology platform, the optimization of a neuropeptide S receptor antagonist, and type 1 glycine transport modulators. Investigational drugs discussed include WYE-160020 (Wyeth), Trox-1 (Neuromed Pharmaceuticals Inc), ulimorelin (Tranzyme Pharma Inc), E-32224 (Ensemble Discovery Corp) and PF-03463275 (Pfizer Inc); the discontinued compound AZD-9056 is also highlighted.

Continuous bioprocessing: The real thing this time?

PubMed Central

Farid, Suzanne S; Thompson, Bill; Davidson, Andrew

2014-01-01

The Annual bioProcessUK Conference has acted as the key networking event for bioprocess scientists and engineers in the UK for the past 10 years. The following article is a report from the sessions that focused on continuous bioprocessing during the 10th Annual bioProcessUK Conference (London, December 2013). These sessions were organized by the ‘EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies’ hosted at University College London. A plenary lecture and workshop provided a forum for participants to debate topical issues in roundtable discussions with industry and academic experts from institutions such as Genzyme, Janssen, Novo Nordisk, Pfizer, Merck, GE Healthcare and University College London. The aim of these particular sessions was to understand better the challenges and opportunities for continuous bioprocessing in the bioprocessing sector. PMID:25484060

Development of Quality Indicators to Assess Oral Anticoagulant Management in Community Pharmacies for Patients with Atrial Fibrillation.

PubMed

Chartrand, Mylène; Guénette, Line; Brouillette, Denis; Côté, Stéphane; Huot, Roger; Landry, Jérôme; Martineau, Josée; Perreault, Sylvie; White-Guay, Brian; Williamson, David; Martin, Élisabeth; Gagnon, Marie-Mireille; Lalonde, Lyne

2018-04-01

Few studies have evaluated the quality of oral anticoagulant management by community pharmacists. There is no complete set of quality indicators available for this purpose. To develop a set of specific quality indicators to assess oral anticoagulant management by community pharmacists for patients with atrial fibrillation (AF). Quality indicators were developed in 3 phases. In phase 1, potential quality indicators were generated based on clinical guidelines and a literature review. In phase 2, a modified RAND appropriateness method involving 2 rounds was implemented with 9 experts, who judged the appropriateness of quality indicators generated in phase 1 based on the extent to which they were accurate, based on evidence, relevant, representative of best practices, and measurable in community pharmacies. Phase 3 consisted of a feasibility assessment in 5 community pharmacies on 2 patients each. The final set included 38 quality indicators grouped into 6 categories: documentation (n = 29), risk assessment (n = 3), clinical control (n = 1), clinical follow-up (n = 15), choice of therapy (n = 11), and interaction management (n = 8). The quality indicators referred to process of care (n = 34), clinical outcomes (n = 2), or structure of care (n = 2). There were 24 quality indicators related to vitamin K antagonists (VKAs), and 17 were related to direct oral anticoagulants (DOACs). To assess quality indicators, a questionnaire was developed for completion by community pharmacists for each patient, which included 17 questions about VKA patients and 12 questions about DOAC patients. A first set of quality indicators is now available to assess the quality of oral anticoagulant management by community pharmacists for patients with AF. This research was supported by the Réseau Québécois de recherche sur le médicament (RQRM); the Blueprint for Pharmacy in collaboration with Pfizer Canada; and the Cercle du Doyen of the Faculty of Pharmacy, University of Montreal. The study sponsors were not involved in the study design, data collection, data interpretation, the writing of the article, or the decision to submit the report for publication. Chartrand received a scholarship from the Fonds de Recherche du Québec en Santé (FRQ-S), the Réseau Québécois de recherche sur l'usage des médicaments with Pfizer, and the Faculty of Pharmacy, University of Montreal. Guénette holds a Junior-1 Clinician Researcher Award from the FRQ-S in partnership with the Société québécoise d'hypertension artérielle. Williamson holds a Junior-1 Career Award from the FRQ-S. Côté reported being a medical speaker for Bayer, Boehringer Ingelheim Canada, and Pfizer Canada. The other authors reported no conflicts of interest. Study concept and design were contributed by Lalonde, Chartrand, and Martin. Chartrand, Martin, and Lalonde collected the data, along with Brouillette, Côté, Huot, Landry, Martineau, Perreault, Williamson, and White-Guay. Data interpretation was performed by Chartrand, Gagnon, and Lalonde, along with Guénette and Martin. The manuscript was primarily written by Chartrand, along with Guénette and Lalonde, and revised by Chartrand, Guénette, and Lalonde, along with the other authors. A portion of this study's results was presented at the 4th RQRM Annual Meeting on September 22-23, 2014, in Orford, Quebec, Canada, in the form of an abstract, which was published in the Journal of Population Therapeutics and Clinical Pharmacology, 2014;21(2):e312.

A Pragmatic Randomized Trial Comparing Telephone-Based Enhanced Pharmacy Care and Usual Care to Support Smoking Cessation.

PubMed

Gong, Jason; Baker, Christine L; Zou, Kelly H; Bruno, Marianna; Jumadilova, Zhanna; Lawrence, David; Wilson, Beth; Ewel, Cynthia

2016-12-01

Smoking is the leading preventable cause of death, and tobacco control professionals continue to make progress in cessation efforts. Pharmacists can assist smokers seeking to quit by offering counseling on smoking cessation pharmacotherapies. Pragmatic randomized trials are useful for investigating practical questions about an intervention's risks, benefits, and costs in routine clinical practice. To evaluate an enhanced pharmacy care (EPC) program involving personalized pharmacist-provided telephone counseling for supporting prescription smoking cessation medications compared with usual care (UC). Cigarette smokers filling a newly prescribed smoking cessation pharmacotherapy and with pharmacy benefits managed by Express Scripts were recruited. Qualified subjects were randomized 1:1 to EPC and UC. Subjects in EPC received 3 telephone-counseling sessions from specialist pharmacists during the early course of the study, while subjects in UC did not receive any counseling sessions. Study outcomes were collected through telephone contact and using the Express Scripts prescription database. The primary outcome assessed the 1-week point prevalence (PP) of smoking abstinence at the end of the trial (week 12). Secondary outcomes included 4-week PP at week 12 and adherence, evaluated by proportion of days covered (PDC), to prescribed smoking cessation pharmacotherapies. There were 1,017 randomized subjects. Among them, 1,002 subjects were included in the analysis, and 513 were randomized into EPC and 489 into UC. Baseline demographics, smoking history, and prescribed smoking cessation pharmacotherapies were comparable. Varenicline and nicotine replacement therapy (NRT) were most frequently prescribed for smoking cessation. In EPC, 46.0% received all 3 counseling sessions; 29.4% received 2 sessions; and 14.6% received 1 session. Overall, 353 subjects in EPC and 383 subjects in UC completed the week 12 assessment. In the analysis for 1-week PP of smoking abstinence at week 12, the percentage of abstainers in EPC was numerically higher than in UC (42.3% vs. 38.2%) with OR = 1.24, 95% CI = 0.96-1.61. It was not statistically significant. Adherence to prescription smoking cessation medication was significantly higher in EPC versus UC (49.7% vs. 45.6%; P = 0.033). This study evaluated whether a telephone-based pharmacy care program, provided by pharmacists and designed to support attempted quitters, improved quitting and increased adherence over usual care. The findings suggest that an enhanced program may benefit smokers by increasing prescription smoking cessation medication adherence. Future research should explore this program's effect on smokers who are compliant, based on insights on quitting provided by the post hoc analyses and limitations of the current study design. This study was sponsored by Pfizer. Gong, Baker, Zou, Bruno, Jumadilova, and Lawrence are employees and stockholders of Pfizer. Wilson and Ewel are employees of United BioSource Corporation, which received funding from Pfizer for conducting this study and for the development of this manuscript. Study concept and design were contributed by Gong, Bruno, and Ewel, with assistance from Jumadilova, Lawrence, and Zou. Gong, Jumadilova, Lawrence, and Ewel collected the data. Data interpretation was performed by Baker, Zou, and Wilson, assisted by Gong, Lawrence, and Ewel. The manuscript was written by Baker, Ewel, and Gong, with assistance from the other authors, and revised by Baker, Wilson, Zou, and Gong, with assistance from Bruno and Jumadilova.

Mathematical modelling for distribution of heavy metals in estuary area of Red River (Vietnam)

NASA Astrophysics Data System (ADS)

Nguyen, N. T. T.; Volkova, I. V.

2018-05-01

In this paper, the authors studied the features of spatial distribution of some heavy metals (Pb, Hg, As) in the system “suspended substance - bottom sediments” in the mouth area of the Red River (Vietnam). A mathematical modelling for diffusion processes of heavy metals in a suspended form, in bottom sediments and the spatial analysis for the results of these models were proposed and implemented. The studies were carried out during main hydrological seasons of 2014 - 2016 (during the flood and inter-natal periods). The propagation of heavy metals was modeled by solving the equation of turbulent diffusion. A spatial analysis of the content of heavy metals in the suspended form and in the bottom sediments was implemented by using the interpolation model in ArcGIS 10.2.2. The distribution of Pb, Hg, As concentration of the suspended form and bottom sediment phases in the estuary area of the Red River was characterized by maximum in the mouths of the branches and general decreasing gradient towards the sea. Maximum concentrations of Pb, Hg in suspended forms were observed in the surface layer of water at the river-sea barrier. The content of Hg and As in the estuary region of the Red River was observed in the following order: SSsurf< SSbott< BS; and content of Pb – SS >BS.

Stable Isotope Profiling of Internet-Sourced Viagra® and 'generic- Viagra' Tablets

NASA Astrophysics Data System (ADS)

Kemp, Helen; Meier-Augenstein, Wolfram

2013-04-01

Viagra® manufactured by Pfizer was the first prescription drug for the treatment of erectile dysfunction (ED), a condition that is estimated to affect 1 in 10 men at some stage in their lives (1). Viagra® contains the active pharmaceutical ingredient (API) sildenafil, as the citrate salt. Sildenafil, along with Tadalafil and Vardenafil belong to a class of drugs known as phosphodiesterase type 5 (PDE5) inhibitors. Since its first production in 1998, Viagra® has generated well in excess of 10 billion US dollars in sales (2) and with Pfizers' patent extended to April 2020 (3) it still remains the only sildenafil-based treatment option for sufferers of ED in the US. There are no legal 'generic-Viagra' formulations available in the US. However, formulations containing sildenafil citrate as API are widely available over the internet and often sold as 'generic Viagra'. These cheaper alternatives are often manufactured under less than ideal conditions with little or no QA/QC procedures in place. The World Health Organisation recognised the scale of the problem in its 2010 bulletin "Growing threat from counterfeit medicines" (4) and quotes a Dutch study cited in the International Journal of Clinical Practice in which from a cohort of 370 seized Viagra® samples, only 10 were genuine. We sourced a variety of tablets sold for the treatment of ED which claimed to have sildenafil citrate as API. Viagra®, 'generic-Viagra', Kamagra, Silagra and Filagra tablets were ordered via the internet and supplied from both UK-based pharmacies as well as overseas suppliers (Hong Kong, India, Vanuata). In this small-scale pilot study, we present results from bulk 2H/18O and 13C/15N stable isotope analysis performed on crushed tablets from 23 samples of internet-sourced tablets sold for the treatment of ED and purported to contain sildenafil citrate as API. References 1. www.healthcare.org.uk 2. www.moneynews.com 3. US Patent & trademark office (www.uspto.gov) 4. WHO bulletin 2010; 88:247-248

ROCK1 and LIM kinase modulate retrovirus particle release and cell-cell transmission events.

PubMed

Wen, Xiaoyun; Ding, Lingmei; Wang, Jaang-Jiun; Qi, Mingli; Hammonds, Jason; Chu, Hin; Chen, Xuemin; Hunter, Eric; Spearman, Paul

2014-06-01

The assembly and release of retroviruses from the host cells require dynamic interactions between viral structural proteins and a variety of cellular factors. It has been long speculated that the actin cytoskeleton is involved in retrovirus production, and actin and actin-related proteins are enriched in HIV-1 virions. However, the specific role of actin in retrovirus assembly and release remains unknown. Here we identified LIM kinase 1 (LIMK1) as a cellular factor regulating HIV-1 and Mason-Pfizer monkey virus (M-PMV) particle release. Depletion of LIMK1 reduced not only particle output but also virus cell-cell transmission and was rescued by LIMK1 replenishment. Depletion of the upstream LIMK1 regulator ROCK1 inhibited particle release, as did a competitive peptide inhibitor of LIMK1 activity that prevented cofilin phosphorylation. Disruption of either ROCK1 or LIMK1 led to enhanced particle accumulation on the plasma membrane as revealed by total internal reflection fluorescence microscopy (TIRFM). Electron microscopy demonstrated a block to particle release, with clusters of fully mature particles on the surface of the cells. Our studies support a model in which ROCK1- and LIMK1-regulated phosphorylation of cofilin and subsequent local disruption of dynamic actin turnover play a role in retrovirus release from host cells and in cell-cell transmission events. Viruses often interact with the cellular cytoskeletal machinery in order to deliver their components to the site of assembly and budding. This study indicates that a key regulator of actin dynamics at the plasma membrane, LIM kinase, is important for the release of viral particles for HIV as well as for particle release by a distantly related retrovirus, Mason-Pfizer monkey virus. Moreover, disruption of LIM kinase greatly diminished the spread of HIV from cell to cell. These findings suggest that LIM kinase and its dynamic modulation of the actin cytoskeleton in the cell may be an important host factor for the production, release, and transmission of retroviruses. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

A comparison of Listerine® and sodium bicarbonate oral cleansing solutions on dental plaque colonisation and incidence of ventilator associated pneumonia in mechanically ventilated patients: a randomised control trial.

PubMed

Berry, A M

2013-10-01

Effective oral hygiene has been proposed as a key factor in the reduction of dental plaque colonisation and subsequent development of ventilator associated pneumonia (VAP). Listerine(®) oral rinse, while used extensively in dental practice has rarely been tested in mechanically ventilated patients. Sodium bicarbonate as an oral rinse has been more commonly utilised in oral hygiene regimens in intensive care patients. To test the efficacies of the essential oil mouth rinse, Listerine(®) (Pfizer) and sodium bicarbonate in the reduction of dental plaque colonisation with respiratory pathogens and the subsequent development of VAP. The study design was a prospective, single blind randomised comparative study of adult patients mechanically ventilated for at least 4 days. Patients were randomised to Listerine(®) (Pfizer) oral rinse twice daily, sodium bicarbonate oral rinse 2/24 or sterile water 2/24 (control group). All groups received tooth brushing 3 times a day. Dental plaque colonisation (primary outcome) and incidence of ventilator associated pneumonia (secondary outcome) were studied. Three hundred and ninety-eight patients were randomised to either the Listerine group (127), sodium bicarbonate group (133) or the control group (138). Baseline characteristics were similar for all groups. There were no significant differences between the control and study groups in colonisation of dental plaque at Day 4 (p=0.243). Ventilator associated pneumonia was diagnosed in 18 patients. The incidence was, Listerine(®) group 4.7%, sodium bicarbonate group 4.5% and control 4.3% [OR, 0.99; 95% CI, 0.31 to 3.16; p=0.92]. Compared to the control group, Listerine(®) or sodium bicarbonate oral rinses were not more effective in the reduction of colonisation of dental plaque or the incidence of VAP. Given the low incidence of VAP, the common factor of a small, soft toothbrush as part of an oral hygiene regimen suggests possible benefit in mechanically ventilated patients. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Avelumab: First Global Approval.

PubMed

Kim, Esther S

2017-05-01

Avelumab (Bavencio ® ) is an intravenously administered programmed cell death ligand-1-blocking human antibody initially developed by EMD Serono Inc. (the biopharmaceutical division of Merck KGaA, Darmstadt, Germany) [now jointly developed and commercialized by EMD Serono Inc. and Pfizer] for the treatment of various tumours. It has received accelerated approval in the USA for the treatment of metastatic Merkel cell carcinoma (mMCC) in adults and paediatric patients aged ≥12 years. The marketing authorization application for avelumab in the treatment of mMCC is undergoing regulatory review in the EU, the biologics license application for avelumab in the treatment of urothelial carcinoma is undergoing priority review by the FDA, and avelumab is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of avelumab leading to this first approval for mMCC.

Continuous bioprocessing: the real thing this time? 10(th) Annual bioProcessUK Conference, December 3-4, 2013, London, UK.

PubMed

Farid, Suzanne S; Thompson, Bill; Davidson, Andrew

2014-01-01

The Annual bioProcessUK Conference has acted as the key networking event for bioprocess scientists and engineers in the UK for the past 10 years. The following article is a report from the sessions that focused on continuous bioprocessing during the 10(th) Annual bioProcessUK Conference (London, December 2013). These sessions were organized by the 'EPSRC Centre for Innovative Manufacturing in Emergent Macromolecular Therapies' hosted at University College London. A plenary lecture and workshop provided a forum for participants to debate topical issues in roundtable discussions with industry and academic experts from institutions such as Genzyme, Janssen, Novo Nordisk, Pfizer, Merck, GE Healthcare and University College London. The aim of these particular sessions was to understand better the challenges and opportunities for continuous bioprocessing in the bioprocessing sector.

Is exercise important in chronic obstructive pulmonary disease?

PubMed

Make, Barry; Casaburi, Richard

2007-09-01

Chronic obstructive pulmonary disease impairs the ability of patients to perform maximal physical exercise, particularly in patients with severe lung disease. However, differing perceptions of the meaning and importance of exercise to patients and caregivers is likely to impair patient-physician communication about current medical status and outcomes of therapeutic interventions. Other outcomes of importance to patients including actual performance of functional activity during daily life and health-related quality of life may also be affected by impaired exercise capacity. However, the relationships between exercise, activity, and quality of life are inconsistent. Thus, measurement of physiologic and patient-centered outcomes may provide the best approach to assessing responses to therapeutic interventions. These concepts were explored in a conference sponsored by Boehringer Ingelheim Pharmaceuticals, Inc. and Pfizer Inc and reviewed in the articles generated from the symposium in this issue of COPD.

Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Katherine L.; Ambler, Catherine M.; Anderson, David R.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Neratinib: First Global Approval.

PubMed

Deeks, Emma D

2017-10-01

Neratinib (Nerlynx™) is an oral, irreversible inhibitor of the human epidermal growth factor receptors HER1 (EGFR), HER2 and HER4. The drug originally arose from research by Wyeth (now Pfizer) and is now being developed by Puma Biotechnology primarily for the treatment of HER2-positive (HER+) breast cancer. Neratinib is approved in the USA for the extended adjuvant treatment of patients with HER2+ early-stage breast cancer who have been previously treated with a trastuzumab-based adjuvant regimen, and is in the preregistration phase for this indication in the EU. Neratinib, as monotherapy and/or combination therapy, is also in phase 3 development for metastatic breast cancer and in phase 1/2 development for advanced breast cancer and other solid tumours, including non-small cell lung cancer, colorectal cancer and glioblastoma. This article summarizes the milestones in the development of neratinib leading to this first approval for breast cancer.

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

PubMed Central

2010-01-01

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic. PMID:22778836

Donated chemical probes for open science

PubMed Central

Ackloo, Suzanne; Arrowsmith, Cheryl H; Bauser, Marcus; Baryza, Jeremy L; Blagg, Julian; Böttcher, Jark; Bountra, Chas; Brown, Peter J; Bunnage, Mark E; Carter, Adrian J; Damerell, David; Dötsch, Volker; Drewry, David H; Edwards, Aled M; Edwards, James; Elkins, Jon M; Fischer, Christian; Frye, Stephen V; Gollner, Andreas; Grimshaw, Charles E; IJzerman, Adriaan; Hanke, Thomas; Hartung, Ingo V; Hitchcock, Steve; Howe, Trevor; Hughes, Terry V; Laufer, Stefan; Li, Volkhart MJ; Liras, Spiros; Marsden, Brian D; Matsui, Hisanori; Mathias, John; O'Hagan, Ronan C; Owen, Dafydd R; Pande, Vineet; Rauh, Daniel; Rosenberg, Saul H; Roth, Bryan L; Schneider, Natalie S; Scholten, Cora; Singh Saikatendu, Kumar; Simeonov, Anton; Takizawa, Masayuki; Tse, Chris; Thompson, Paul R; Treiber, Daniel K; Viana, Amélia YI; Wells, Carrow I; Willson, Timothy M; Zuercher, William J; Knapp, Stefan

2018-01-01

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project. PMID:29676732

Acquired Resistance to Crizotinib from a Mutation in CD74–ROS1

PubMed Central

Awad, Mark M.; Katayama, Ryohei; McTigue, Michele; Liu, Wei; Deng, Ya-Li; Brooun, Alexei; Friboulet, Luc; Huang, Donghui; Falk, Matthew D.; Timofeevski, Sergei; Wilner, Keith D.; Lockerman, Elizabeth L.; Khan, Tahsin M.; Mahmood, Sidra; Gainor, Justin F.; Digumarthy, Subba R.; Stone, James R.; Mino-Kenudson, Mari; Christensen, James G.; Iafrate, A. John; Engelman, Jeffrey A.; Shaw, Alice T.

2013-01-01

Summary Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74–ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the meta-static sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.) PMID:23724914

National Working Group Meeting on ALK diagnostics in lung cancer.

PubMed

Cooper, Wendy; Fox, Stephen; O'Toole, Sandra; Morey, Adrienne; Frances, Glenn; Pavlakis, Nick; O'Byrne, Kenneth; Dettrick, Andrew; Leong, Trishe; Rathi, Vivek; Spagnolo, Dominic; Hemmings, Chris; Singh, Mahendra; Moffat, David; Tsao, Ming-Sound; Wilner, Keith; Buller, Richard; Pitman Lowenthal, Susan; Arifeen, Shams; Binko, Justin; Alam, Mahmood

2014-04-01

The global landscape of molecular testing is rapidly changing, with the recent publication of the International Association for the Study of Lung Cancer (IASLC)/College of American Pathologists (CAP) guidelines and the ALK Atlas. The IASLC/CAP guidelines recommend that tumors from patients with non-small cell lung cancer (NSCLC) be tested for ALK rearrangements in addition to epidermal growth factor receptor (EGFR) mutations. The spur for this recommendation is the availability of novel therapies that target these rearrangements. This article is based on coverage of a Pfizer-sponsored National Working Group Meeting on ALK Diagnostics in Lung Cancer, held around the 15th World Lung Cancer Conference, in Sydney on October 31, 2013. It is based on the presentations given by the authors at the meeting and the discussion that ensued. The content for this article was discussed and agreed on by the authors. © 2014 Wiley Publishing Asia Pty Ltd.

LEAP into the Pfizer Global Virtual Library (PGVL) space: creation of readily synthesizable design ideas automatically.

PubMed

Hu, Qiyue; Peng, Zhengwei; Kostrowicki, Jaroslav; Kuki, Atsuo

2011-01-01

Pfizer Global Virtual Library (PGVL) of 10(13) readily synthesizable molecules offers a tremendous opportunity for lead optimization and scaffold hopping in drug discovery projects. However, mining into a chemical space of this size presents a challenge for the concomitant design informatics due to the fact that standard molecular similarity searches against a collection of explicit molecules cannot be utilized, since no chemical information system could create and manage more than 10(8) explicit molecules. Nevertheless, by accepting a tolerable level of false negatives in search results, we were able to bypass the need for full 10(13) enumeration and enabled the efficient similarity search and retrieval into this huge chemical space for practical usage by medicinal chemists. In this report, two search methods (LEAP1 and LEAP2) are presented. The first method uses PGVL reaction knowledge to disassemble the incoming search query molecule into a set of reactants and then uses reactant-level similarities into actual available starting materials to focus on a much smaller sub-region of the full virtual library compound space. This sub-region is then explicitly enumerated and searched via a standard similarity method using the original query molecule. The second method uses a fuzzy mapping onto candidate reactions and does not require exact disassembly of the incoming query molecule. Instead Basis Products (or capped reactants) are mapped into the query molecule and the resultant asymmetric similarity scores are used to prioritize the corresponding reactions and reactant sets. All sets of Basis Products are inherently indexed to specific reactions and specific starting materials. This again allows focusing on a much smaller sub-region for explicit enumeration and subsequent standard product-level similarity search. A set of validation studies were conducted. The results have shown that the level of false negatives for the disassembly-based method is acceptable when the query molecule can be recognized for exact disassembly, and the fuzzy reaction mapping method based on Basis Products has an even better performance in terms of lower false-negative rate because it is not limited by the requirement that the query molecule needs to be recognized by any disassembly algorithm. Both search methods have been implemented and accessed through a powerful desktop molecular design tool (see ref. (33) for details). The chapter will end with a comparison of published search methods against large virtual chemical space.

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-life Versus Extended Half-life Products and Those Switching from Standard Half-life to Extended Half-life Products.

PubMed

Tortella, Bartholomew J; Alvir, José; McDonald, Margaret; Spurden, Dean; Fogarty, Patrick F; Chhabra, Amit; Pleil, Andreas M

2018-01-24

Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while median IUs dispensed increased by 4,775 IU. Factor replacement expenditures were higher after switching from the SHL to the EHL product in each of the 3-month periods examined before versus after the switch. This analysis of real-world data showed that switching from the SHL to the EHL product was associated with higher expenditures. Increased expenditures noted in the first 3 months after switching may be related to initial stocking up of the EHL product, but expenditures were sustained throughout the 1-year period of data analysis. Further analysis of these findings with larger numbers of patients should be explored. This study was sponsored by Pfizer. Pfizer employees were involved in the study design; the collection, analysis, and interpretation of data; the review of the manuscript; and the decision to submit for publication. All authors are employees of Pfizer. No author received an honorarium or other form of payment related to the development of this manuscript. All authors participated in the study design, data interpretation, and manuscript review and revisions and granted approval for the submission of the manuscript. Alvir, McDonald, and Tortella also participated in data analysis. Data from this paper were presented in part at the European Association for Haemophilia and Allied Disorders Annual Meeting, February 1-3, 2017, Paris, France; at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 20-24, 2017, Boston, Massachusetts; and at the International Society on Thrombosis and Haemostasis Congress, July 8-13, 2017, Berlin, Germany.

Quand la réadaptation blesse? Éducateurs victimes de violence

PubMed Central

Geoffrion, Steve; Ouellet, Frédéric

2014-01-01

Cette étude vise à comprendre le phénomène de la violence physique vécue par les éducateurs œuvrant dans dix Centres Jeunesse (CJ) du Québec. Pour ce faire, un sondage de victimisation a été administré à 586 éducateurs en internat. En premier lieu, la prévalence de cette problématique sera établie. Par la suite, les facteurs individuels et environnementaux prédisposant aux agressions physiques seront identifiés. Des édu-cateurs sondés, 53,9 % rapportent avoir été victimes de violence physique au cours de la dernière année. Sur le plan individuel, être affecté par les manifestations agressives des clients et la fréquence des violences psychologiques subies augmentent les risques de victimisation physique. Quant au contexte, l’âge de la clientèle et le motif de l’interven-tion (basé sur la loi justifiant le placement) auprès de l’enfant ou de l’adolescent influencent l’occurrence des actes violents dirigés contre les éducateurs. Nos analyses montrent également que les violences physiques dont sont victimes les éducateurs affectent autant l’individu que l’institution. L’identification de facteurs permettant de prédire les risques de victimisation pourrait notamment servir à orienter les programmes de prévention de la violence dans les CJ, mais aussi à cibler les éducateurs les plus à risque afin de leur fournir un soutien adapté. PMID:24976673

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffith, David A.; Kung, Daniel W.; Esler, William P.

We found that Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. Here, we disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 asmore » a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffith, David A.; Kung, Daniel W.; Esler, William P.

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate formore » the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. In conclusion, this demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.« less

Application of PBPK modelling in drug discovery and development at Pfizer.

PubMed

Jones, Hannah M; Dickins, Maurice; Youdim, Kuresh; Gosset, James R; Attkins, Neil J; Hay, Tanya L; Gurrell, Ian K; Logan, Y Raj; Bungay, Peter J; Jones, Barry C; Gardner, Iain B

2012-01-01

Early prediction of human pharmacokinetics (PK) and drug-drug interactions (DDI) in drug discovery and development allows for more informed decision making. Physiologically based pharmacokinetic (PBPK) modelling can be used to answer a number of questions throughout the process of drug discovery and development and is thus becoming a very popular tool. PBPK models provide the opportunity to integrate key input parameters from different sources to not only estimate PK parameters and plasma concentration-time profiles, but also to gain mechanistic insight into compound properties. Using examples from the literature and our own company, we have shown how PBPK techniques can be utilized through the stages of drug discovery and development to increase efficiency, reduce the need for animal studies, replace clinical trials and to increase PK understanding. Given the mechanistic nature of these models, the future use of PBPK modelling in drug discovery and development is promising, however, some limitations need to be addressed to realize its application and utility more broadly.

World Antibody-Drug Conjugate Summit, October 15-16, 2013, San Francisco, CA.

PubMed

Klinguer-Hamour, Christine; Strop, Pavel; Shah, Dhaval K; Ducry, Laurent; Xu, April; Beck, Alain

2014-01-01

The World Antibody-Drug Conjugate (WADC) Summits organized by Hanson Wade are currently the largest meetings fully dedicated to ADCs. The first global ADC Summit was organized in Boston in October 2010. Since 2011, two WADC are held every year in Frankfurt and San Francisco, respectively. The 2013 WADC San Francisco event was structured around plenary sessions with keynote speakers from AbbVie, Agensys, ImmunoGen, Immunomedics, Genentech, Pfizer and Seattle Genetics. Parallel tracks were also organized addressing ADC discovery, development and optimization of chemistry, manufacturing and control (CMC) issues. Discovery and process scientists, regulatory experts (US Food and Drug Administration), academics and clinicians were present, including representatives from biotechnology firms (Concortis, CytomX Therapeutics, Glykos, Evonik, Igenica, Innate Pharma, Mersana Therapeutics, Polytherics, Quanta Biodesign, Redwood Bioscience, Sutro Biopharma, SynAffix), pharmaceutical companies (Amgen, Genmab, Johnson and Johnson, MedImmune, Novartis, Progenics, Takeda) and contract research or manufacturing organizations (Baxter, Bayer, BSP Pharmaceuticals, Fujifilm/Diosynth, Lonza, Pierre Fabre Contract Manufacturing, Piramal, SAFC, SafeBridge).

SUBCLINICAL INFECTION OF DOGS BY CANINE-ADAPTED MEASLES VIRUS EVIDENCED BY THEIR SUBSEQUENT IMMUNITY TO CANINE DISTEMPER VIRUS

PubMed Central

Moura, Roberto A.; Warren, Joel

1961-01-01

Moura, Roberto A. (Chas. Pfizer and Company, Inc., Terre Haute, Ind.) and Joel Warren. Subclinical infection of dogs by canine-adapted measles virus evidenced by their subsequent immunity to canine distemper virus. J. Bacteriol. 82:702–705. 1961.—Young dogs were inoculated with virulent measles virus which had been adapted to canine kidney or human amnion cell culture. None of the animals showed any clinical symptoms nor could virus be isolated from the blood, although measles-neutralizing and complement-fixing antibodies developed during convalescence. All dogs failed to develop antibody to canine distemper. However, when these and normal control animals were subsequently inoculated intracerebrally with virulent distemper virus, each of the controls succumbed to typical symptoms, whereas all of the measles-immune dogs survived. These results suggest that the cross-protection conferred by measles against canine distemper virus infection involves factors other than humoral antibody. The immunity persists for a considerable length of time. PMID:14476677

JAK inhibitors: A broadening approach in rheumatoid arthritis.

PubMed

Lam, S

2016-08-01

Pfizer's Xeljanz (tofacitinib citrate) was the first Janus kinase (JAK) inhibitor to reach the market for rheumatoid arthritis (RA) following its U.S. approval in November 2012, and it has since gained approval in more than 45 countries as a second-line therapy for RA after failure of disease-modifying antirheumatic drugs (DMARDs). This emerging category has heralded an attractive new class of oral treatment options in RA, with a notable opportunity in patients who stop responding to DMARDs, but they are facing a challenging market. Despite RA affecting approximately 23.7 million people worldwide, Xeljanz faces a market dominated by the anti-tumor necrosis factor (anti-TNF) biologicals, which have robust long-term safety and efficacy. The availability of biosimilars of these market leaders is also intensifying competition, and a high price and uncertainty over long-term safety is currently tempering the market for the JAK inhibitors. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

Antiplatelet Therapy and Clinical Outcomes Following Myocardial Infarction Among Patients in a U.S. Employer-Based Insurance Database.

PubMed

Patel, Mehul D; Wu, David; Chase, Monica Reed; Mavros, Panagiotis; Heithoff, Kim; Hanson, Mary E; Simpson, Ross J

2017-06-01

Estimates of residual cardiovascular risks among patients who have experienced a recent acute myocardial infarction (MI) are predominantly derived from secondary prevention trial populations, patient registries, and population-based cohorts. To generate real-world evidence of antiplatelet treatment and recurrent events following MI in patients on antiplatelet treatment among commercial, employer-based insured patients in a large administrative database. This was a retrospective cohort claims database study using the Truven Health MarketScan Commercial Claims and Encounters and Medicare Supplemental databases between 2007-2011. Patients with an acute MI hospitalization with a discharge date between 2008 and 2010 were included. Excluded were those patients with documentation of stroke, transient ischemic attack (TIA), or severe bleeding at or before index hospitalization and with concomitant use of anticoagulant therapy following index hospitalization. Patients treated with clopidogrel following the index MI hospitalization were followed up to 1 year for repeat MI, stroke, and coronary revascularization. Among 33,943 post-MI continuous clopidogrel users without history of stroke, TIA, or bleeding, 22% had diabetes, whereas angina and renal impairment were less prevalent (5% and 7%, respectively). Over the 1-year follow-up, 2.4% experienced a repeat MI or stroke, and 8.2% underwent coronary revascularization. Angina, diabetes, and renal impairment were associated with elevated 1-year risk of repeat MI or stroke. This study suggests that there is residual cardiovascular risk, although relatively low, in an insured, secondary prevention population on antiplatelet treatment following an MI. In patients with MI, identifying angina, diabetes, and renal impairment may aid risk stratification and guide the effective management of these higher-risk patients. Funding for this research was provided by Merck & Co. Although Merck & Co. formally reviewed a penultimate draft, the opinions expressed are those of the authorship and may not necessarily reflect those of the company. Reed Chase, Wu, Mavros, Heithoff, and Hanson are employees of Merck Sharp & Dohme, a subsidiary of Merck & Co., and may own stock and/or hold stock options in the company. Patel was an employee of Merck & Co. during the conduct of this study and preparation of the manuscript. Simpson is a paid consultant for Merck, Pfizer, and Amgen and has received speaker's fees from Merck and Pfizer. Study concept and design were contributed by all authors except Hanson. Heifhoff and Patel collected the data, and data interpretation was performed by Simpson, Mavros, Patel, Wu, and Hanson. The manuscript was written by Hanson, Mavros, and Patel and revised by Heithoff, Wu, Simpson, and Reed Chase.

Summary of the EMA Joint Regulators/Industry QbD workshop (London, UK; 28-29 January 2014).

PubMed

Cook, Graham; France, Georges; Holte, Øyvind; Lorenti, Giampiero; Tainsh, David

2016-01-01

This paper summarizes the discussions and insights gained from the key themes that emerged during the Quality by Design (QbD) Workshop held at the European Medicines Agency (EMA) offices in London, UK, on 28-29 January 2014. Industry and regulators shared practical experiences from six case studies (five approved small molecule products and one phase 3 biotechnological product) based on QbD submissions by five companies (AstraZeneca, GlaxoSmithKline, Novartis, NovoNordisk, and Pfizer).The case studies covered a range of different development, regulatory submission, and post-approval aspects of QbD and were developed through confidential discussions between the company representatives and regulators. Key themes that emerged from the workshop discussions were: 1. presentation of information in submissions (development story and the presentation of information in marketing authorization applications; risk assessment and criticality); 2. development aspects (design space; use of models; control strategy); and 3. post-approval aspects (lifecycle management; dossier-quality system interactions; handling of deviations). Many aspects of QbD for biotechnological products are similar to small molecules, but there are some important differences highlighted in this paper.The final section of the paper discusses some proposals for future developments to address the issues that were identified. This paper summarizes the discussions and insights gained from the key themes that emerged during the Quality by Design (QbD) Workshop held at the European Medicines Agency offices in London, UK, on 28-29 January 2014. Industry and regulators shared practical experiences from six case studies (five approved small-molecule products and one phase 3 biotechnological product) based on QbD submissions by five companies (AstraZeneca, GlaxoSmithKline, Novartis, NovoNordisk, and Pfizer).The case studies covered a range of different development, regulatory submission, and post-approval aspects of QbD and were developed through confidential discussions between the company representatives and regulators. Key themes that emerged from the workshop discussions were: 1. presentation of information in submissions (development story and the presentation of information in marketing authorization applications; risk assessment and criticality); 2. development aspects (design space; use of models; control strategy); and 3. post-approval aspects (lifecycle management; dossier-quality system interactions; handling of deviations). Many aspects of QbD for biotechnological products are similar to small molecules, but there are some important differences highlighted in this paper.The final section of the paper discusses some proposals for future developments to address the issues that were identified. © PDA, Inc. 2016.

Predicting cytotoxicity from heterogeneous data sources with Bayesian learning.

PubMed

Langdon, Sarah R; Mulgrew, Joanna; Paolini, Gaia V; van Hoorn, Willem P

2010-12-09

We collected data from over 80 different cytotoxicity assays from Pfizer in-house work as well as from public sources and investigated the feasibility of using these datasets, which come from a variety of assay formats (having for instance different measured endpoints, incubation times and cell types) to derive a general cytotoxicity model. Our main aim was to derive a computational model based on this data that can highlight potentially cytotoxic series early in the drug discovery process. We developed Bayesian models for each assay using Scitegic FCFP_6 fingerprints together with the default physical property descriptors. Pairs of assays that are mutually predictive were identified by calculating the ROC score of the model derived from one predicting the experimental outcome of the other, and vice versa. The prediction pairs were visualised in a network where nodes are assays and edges are drawn for ROC scores >0.60 in both directions. We observed that, if assay pairs (A, B) and (B, C) were mutually predictive, this was often not the case for the pair (A, C). The results from 48 assays connected to each other were merged in one training set of 145590 compounds and a general cytotoxicity model was derived. The model has been cross-validated as well as being validated with a set of 89 FDA approved drug compounds. We have generated a predictive model for general cytotoxicity which could speed up the drug discovery process in multiple ways. Firstly, this analysis has shown that the outcomes of different assay formats can be mutually predictive, thus removing the need to submit a potentially toxic compound to multiple assays. Furthermore, this analysis enables selection of (a) the easiest-to-run assay as corporate standard, or (b) the most descriptive panel of assays by including assays whose outcomes are not mutually predictive. The model is no replacement for a cytotoxicity assay but opens the opportunity to be more selective about which compounds are to be submitted to it. On a more mundane level, having data from more than 80 assays in one dataset answers, for the first time, the question - "what are the known cytotoxic compounds from the Pfizer compound collection?" Finally, having a predictive cytotoxicity model will assist the design of new compounds with a desired cytotoxicity profile, since comparison of the model output with data from an in vitro safety/toxicology assay suggests one is predictive of the other.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

NASA Astrophysics Data System (ADS)

Lau, Wan F.; Withka, Jane M.; Hepworth, David; Magee, Thomas V.; Du, Yuhua J.; Bakken, Gregory A.; Miller, Michael D.; Hendsch, Zachary S.; Thanabal, Venkataraman; Kolodziej, Steve A.; Xing, Li; Hu, Qiyue; Narasimhan, Lakshmi S.; Love, Robert; Charlton, Maura E.; Hughes, Samantha; van Hoorn, Willem P.; Mills, James E.

2011-07-01

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics.

PubMed

Lau, Wan F; Withka, Jane M; Hepworth, David; Magee, Thomas V; Du, Yuhua J; Bakken, Gregory A; Miller, Michael D; Hendsch, Zachary S; Thanabal, Venkataraman; Kolodziej, Steve A; Xing, Li; Hu, Qiyue; Narasimhan, Lakshmi S; Love, Robert; Charlton, Maura E; Hughes, Samantha; van Hoorn, Willem P; Mills, James E

2011-07-01

Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.

Biologics, Pharmacovigilance, and Patient Safety: It's All in the Name.

PubMed

Stevenson, James G; Green, Larry

2016-08-01

The most appropriate naming convention for biologics and biosimilars has been an area of significant debate. The ultimate decision will have an impact on patient safety, pharmacovigilance program effectiveness, and, potentially, the overall adoption of biosimilars in the United States. This article reviews some of the advantages and disadvantages of various naming approaches. For clarity in communication, optimal pharmacovigilance, and patient safety, it is recommended that biosimilars be named with a common USAN (United States Adopted Name) with the reference product, along with a suffix that is memorable, such as one associated with the original manufacturer of the product. This approach supports the FDA's mission of protecting patient safety and public health, while minimizing the possibility of inadvertent switching of products and facilitating effective pharmacovigilance. No funding supported the writing of this article. Stevenson reports consulting fees from Amgen, Inc., AbbVie, and Pfizer and is employed by Visante. Green is employed by and owns stock in Amgen, Inc. Article concept was contributed primarily by Stevenson, along with Green. The manuscript was written and revised primarily by Stevenson, along with Green. Both authors contributed equally to data interpretation.

Decreasing the Rate of Metabolic Ketone Reduction in the Discovery of a Clinical Acetyl-CoA Carboxylase Inhibitor for the Treatment of Diabetes

DOE PAGES

Griffith, David A.; Kung, Daniel W.; Esler, William P.; ...

2014-11-25

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate formore » the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. In conclusion, this demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.« less

Donated chemical probes for open science.

PubMed

Müller, Susanne; Ackloo, Suzanne; Arrowsmith, Cheryl H; Bauser, Marcus; Baryza, Jeremy L; Blagg, Julian; Böttcher, Jark; Bountra, Chas; Brown, Peter J; Bunnage, Mark E; Carter, Adrian J; Damerell, David; Dötsch, Volker; Drewry, David H; Edwards, Aled M; Edwards, James; Elkins, Jon M; Fischer, Christian; Frye, Stephen V; Gollner, Andreas; Grimshaw, Charles E; IJzerman, Adriaan; Hanke, Thomas; Hartung, Ingo V; Hitchcock, Steve; Howe, Trevor; Hughes, Terry V; Laufer, Stefan; Li, Volkhart Mj; Liras, Spiros; Marsden, Brian D; Matsui, Hisanori; Mathias, John; O'Hagan, Ronan C; Owen, Dafydd R; Pande, Vineet; Rauh, Daniel; Rosenberg, Saul H; Roth, Bryan L; Schneider, Natalie S; Scholten, Cora; Singh Saikatendu, Kumar; Simeonov, Anton; Takizawa, Masayuki; Tse, Chris; Thompson, Paul R; Treiber, Daniel K; Viana, Amélia Yi; Wells, Carrow I; Willson, Timothy M; Zuercher, William J; Knapp, Stefan; Mueller-Fahrnow, Anke

2018-04-20

Potent, selective and broadly characterized small molecule modulators of protein function (chemical probes) are powerful research reagents. The pharmaceutical industry has generated many high-quality chemical probes and several of these have been made available to academia. However, probe-associated data and control compounds, such as inactive structurally related molecules and their associated data, are generally not accessible. The lack of data and guidance makes it difficult for researchers to decide which chemical tools to choose. Several pharmaceutical companies (AbbVie, Bayer, Boehringer Ingelheim, Janssen, MSD, Pfizer, and Takeda) have therefore entered into a pre-competitive collaboration to make available a large number of innovative high-quality probes, including all probe-associated data, control compounds and recommendations on use (https://openscienceprobes.sgc-frankfurt.de/). Here we describe the chemical tools and target-related knowledge that have been made available, and encourage others to join the project. © 2018, Müller et al.

Magnetic resonance imaging and relaxometry to study water transport mechanisms in a commercially available gastrointestinal therapeutic system (GITS) tablet.

PubMed

Broadbent, Amber L; Fell, Rob J; Codd, Sarah L; Lightley, Kim A; Konagurthu, Sanjay; Koehler-King, Dory G; Seymour, Joseph D

2010-09-15

The hydration of 4 mg Cardura XL (Pfizer), a commercially available gastrointestinal therapeutic system (GITS) tablet, was investigated using magnetic resonance imaging (MRI). A short echo time (T(e)=2.81 ms) technique for MRI of the hydration of a GITS tablet was implemented. From the MR images, signal intensity profiles were generated and interpreted in the context of diffusive and osmotic transport mechanisms. A distinct transition from diffusive to osmotic transport was measured at a timescale relevant to the measured drug release time. Diffusion and osmotic rate coefficients for water in the drug and polymer sweller layers of the tablet were quantified. Spin-lattice T(1) and spin-spin T(2) relaxation times of the water signal from within the tablet were measured as a function of hydration time in order to incorporate the effects of relaxation into interpretation of signal intensity and provide unique information on the distribution of water in different physical and chemical environments within the tablet. Copyright 2010 Elsevier B.V. All rights reserved.

The role of user representation and Arthritis and Rheumatism International.

PubMed

Johnstone, Robert

2003-08-01

Arthritis and Rheumatism International (ARi), founded in 1988, is an association of national lay organizations comprising mainly people whose lives are affected by arthritis and rheumatism. ARi's charter defines the organization's aims, including to raise awareness of the needs of people with arthritis/rheumatism, to improve the quality of their lives through education and self-management programs, and to support research into causes, management, prevention, and cure of arthritis. With the aid of a grant from the Pfizer Foundation in 2002, ARi has been able to further develop into a strong organization throughout the world, with a membership of 22 countries. Successful intitiatives include the People with Arthritis and Rheumatism in Europe Manifesto, which has served as a very effective focus for developing action plans, opening dialogues, building partnerships with other organizations, lobbying governments, and gaining media attention throughout Europe. The manifesto (website: www.PAREmanifesto.org) was developed by ARi working in conjunction with The International Organisation of Youth with Rheumatism and the EULAR Social League. These are examples of initiatives that ARi aims to promote on a global scale in the next few years.

Interscience Conference on Antimicrobial Agents and Chemotherapy--49th annual meeting. Part 1. 11-15 September 2009, San Francisco, CA, USA.

PubMed

Turner, Ben; Murch, Lisa

2009-11-01

The Interscience Conference on Antimicrobial Agents and Chemotherapy held in San Francisco included topics covering new therapeutic developments for the treatment of infectious diseases. This conference report highlights selected presentations on a beta-cyclodextrin derivative for the treatment of Staphylococcus aureus infections, a type 3 secretion system inhibitor for the treatment of Pseudomonas aeruginosa infections, a small-molecule inhibitor of the fungal Hos2 HDAC, a TLR9 agonist used as an adjuvant, a CMV vaccine, a glycopeptide-cephalosporin heterodimer antibiotic, a topical quinolone for the treatment of complicated skin and skin structure infections, a broad-spectrum glycylcycline antibiotic and an HCV RNA replication inhibitor. Investigational drugs discussed include IB-201 (Innovative Biologics Inc), MBX-1641 (Microbiotix Inc), MGCD-290 (MethylGene Inc), agatolimod (Coley Pharmaceutical Group Inc/Pfizer Inc/GlaxoSmithKline plc/Merck & Co Inc/Dynavax Technologies Corp/Novartis AG/Emergent BioSolutions Inc), TD-1792 (Theravance Inc), ozenoxacin (Ferrer Internacional SA/Maruho Co Ltd/Toyama Chemical Co Ltd) and ATI-0810 (Arisyn Therapeutics Inc).

Treatment of premenstrual dysphoric disorder with luteal phase dosing of sertraline.

PubMed

Halbreich, Uriel; Kahn, Linda S

2003-11-01

Sertraline (Zoloft, Pfizer Inc.) is a selective serotonin re-uptake inhibitor (SSRI) which has been approved by the US FDA for the treatment of premenstrual dysphoric disorder (PMDD). PMDD is a severe form of premenstrual syndrome (PMS) which affects at least 5 - 8% of women of reproductive age. It is characterised by cyclic appearance at the late luteal phase of the menstrual cycle, and disappearance following the beginning of menses, with no symptoms during at least 1 week of the cycle - usually during the mid-follicular phase. Due to the cyclic luteal occurrence of PMDD, luteal phase dosing of SSRIs has been suggested and proven effective for sertraline as well as several other SSRIs. The clinical response of sertraline is reported to be within several days following initiation of treatment. Despite repeated cyclic discontinuation, no significant discontinuation adverse effects have been reported. In addition to its proven clinical efficacy, luteal-phase dosing may offer the advantages of minimising adverse effects of SSRIs while reducing the personal and economic burden of taking a prescription medication continuously for long periods and thus increasing compliance.

A data-driven approach to quality risk management.

PubMed

Alemayehu, Demissie; Alvir, Jose; Levenstein, Marcia; Nickerson, David

2013-10-01

An effective clinical trial strategy to ensure patient safety as well as trial quality and efficiency involves an integrated approach, including prospective identification of risk factors, mitigation of the risks through proper study design and execution, and assessment of quality metrics in real-time. Such an integrated quality management plan may also be enhanced by using data-driven techniques to identify risk factors that are most relevant in predicting quality issues associated with a trial. In this paper, we illustrate such an approach using data collected from actual clinical trials. Several statistical methods were employed, including the Wilcoxon rank-sum test and logistic regression, to identify the presence of association between risk factors and the occurrence of quality issues, applied to data on quality of clinical trials sponsored by Pfizer. ONLY A SUBSET OF THE RISK FACTORS HAD A SIGNIFICANT ASSOCIATION WITH QUALITY ISSUES, AND INCLUDED: Whether study used Placebo, whether an agent was a biologic, unusual packaging label, complex dosing, and over 25 planned procedures. Proper implementation of the strategy can help to optimize resource utilization without compromising trial integrity and patient safety.

Launching biosimilar rituximab: an industry opinion on biosimilar uptake in Europe.

PubMed

Trollope, Richard; Johnson, Sue; Ireland, Henry

2017-06-01

Richard Trollope and Sue Johnson talk with Henry Ireland, Senior Editor about the recent approval of biosimilar rituximab (Truxima ® ) & the current state of biosimilar uptake across Europe Richard Trollope, Head of Biosimilars, Mundipharma International Limited, qualified as a biochemist before joining Wyeth's commercial operations, prior to its acquisition by Pfizer. Richard later joined Yamanouchi Pharmaceuticals (now Astellas Pharma). His fascination with oncology led him to join Mundipharma in Europe and after joining the company's UK arm (Napp Pharmaceuticals Limited), Richard began his journey in biosimilars. He now heads up the biosimilar franchise at Mundipharma International as it launches biosimilar rituximab (Truxima ® ) - the first biosimilar monoclonal antibody for the treatment of cancer, which will be distributed by Napp Pharmaceuticals in the UK. Sue Johnson, PhD, Medical Insights at Mundipharma International Limited, is a scientist by background and completed her postdoc fellowship at Harvard Medical School. On returning to the UK, she began her career in the pharmaceutical industry, working in UK Medical Affairs before transitioning to a European role with Mundipharma 2 years ago, where she leads on Medical Insights for the biosimilars franchise.

Voriconazole-induced musical hallucinations.

PubMed

Agrawal, A K; Sherman, L K

2004-10-01

1 Voriconazole (Vfend) is a second-generation azole antifungal that is increasing in popularity especially for the treatment of invasive aspergillosis as well as empirically for the febrile neutropenic patient. In addition, voriconazole tends to have a mild side effect profile with reversible visual disturbances being the most widely described effect. We describe a patient who had musical hallucinations secondary to voriconazole. The patient was a 78-year-old man admitted for induction of chemotherapy for acute myelogenous leukemia (AML) who began to have auditory hallucinations, specifically of Christmas music, the 2nd day of voriconazole therapy. His psychiatric evaluation was otherwise unremarkable. After discontinuing voriconazole the hallucinations decreased in intensity by the 2nd day and ceased altogether by the 3rd day. An extensive literature search, including Pfizer drug trial safety data, yielded no other reports of auditory hallucinations with voriconazole. Several other interesting cases of musical hallucinations secondary to a variety of causes have been reported in the literature, and are reviewed. Notably, musical hallucinations tend to occur secondary to temporal lobe insults and often are of a religious or patriotic theme.

The effects of sildenafil citrate (Viagra) on uterine blood flow and well being in the intrauterine growth-restricted fetus.

PubMed

Miller, Suzanne L; Loose, Jan M; Jenkin, Graham; Wallace, Euan M

2009-01-01

This study examined whether the type-5 phosphodiesterase inhibitor sildenafil citrate (Viagra; Pfizer, New York, NY) could increase uterine blood flow in intrauterine growth restriction (IUGR), thereby improving fetal oxygenation and well being. In fetal sheep, we induced IUGR at 105-110 days (0.7 gestation) using single umbilical artery ligation (SUAL). In SUAL and control animals, we measured uterine blood flow (UBF) and blood gases before and after sildenafil administration. SUAL fetuses were hypoxemic compared with controls. Following sildenafil, UBF was significantly decreased in both SUAL and control ewes for approximately 40 minutes. In response to sildenafil, pO(2) was decreased in SUAL and control fetuses and both groups displayed significant hypotension and tachycardia. At postmortem SUAL fetal body weight was significantly reduced by 23% compared with controls. Sildenafil does not improve UBF or fetal well being in SUAL-induced IUGR pregnancies and should be used with caution in IUGR and healthy pregnancies because of its detrimental effects on uteroplacental perfusion and on the fetus.

Randomized noninferiority clinical trial evaluating 3 commercial dry cow mastitis preparations: I. Quarter-level outcomes.

PubMed

Arruda, A G; Godden, S; Rapnicki, P; Gorden, P; Timms, L; Aly, S S; Lehenbauer, T W; Champagne, J

2013-07-01

The study objective was to compare the efficacy of 3 commercial dry cow mastitis formulations regarding quarter-level prevalence of intramammary infections (IMI) postcalving, cure of preexisting infections over the dry period, prevention of new infections during the dry period, and risk for a clinical mastitis case between calving and 100d in milk (DIM). A total of 1,091 cows (4,364 quarters) from 6 commercial dairy herds in 4 different states (California, Iowa, Minnesota, and Wisconsin) were enrolled and randomized to 1 of the 3 treatments at dry-off: Quartermaster (QT; 1,000,000 IU of procaine penicillin G and 1 g of dihydrostreptomycin; Pfizer Animal Health, New York, NY), Spectramast DC (SP; 500 mg of ceftiofur hydrochloride; Pfizer Animal Health), or ToMorrow Dry Cow (TM; 300mg of cephapirin benzathine; Boehringer Ingelheim Vetmedica Inc., St. Joseph, MO). Quarter milk samples were collected for routine bacteriological culture before dry cow therapy treatment at dry-off, 0 to 6 DIM, and 7 to 13 DIM and an on-farm record-keeping system was used to retrieve data on clinical mastitis cases. Noninferiority analysis was used to evaluate the effect of treatment on the primary outcome, risk for a bacteriological cure during the dry period. Multivariable logistic regression techniques were used to describe the effect of treatment on risk for presence of IMI postcalving and risk of a new IMI during the dry period. Cox proportional hazards regression was used to describe the effect of treatment on the risk and time for quarters to experience an episode of clinical mastitis between calving and 100 DIM. The overall crude quarter-level prevalence of infection at dry-off was 19.2%. The most common pathogen isolated from milk samples at dry-off was coagulase-negative Staphylococcus, followed by Aerococcus spp. and other Streptococcus spp. Noninferiority analysis showed no effect of treatment on risk for a cure between dry-off and calving [least squares means (LSM): QT=93.3%, SP=92.6%, and TM=94.0%] and secondary analysis showed no effect of treatment on risk for presence of an IMI at 0 to 6 DIM (LSM: QT=16.5%, SP=14.1%, and TM=16.0%), risk for development of a new IMI between dry-off and 0 to 6 DIM (LSM: QT=14.8%, SP=12.3%, and TM=14.2%), or risk of experiencing a clinical mastitis event between calving and 100 DIM (LSM: QT=5.3%, SP=3.8%, and TM=4.1%). In conclusion, no difference was observed in efficacy among the 3 products evaluated when assessing the aforementioned quarter-level outcomes. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Immunogenicity, Safety, and Tolerability of Bivalent rLP2086 Meningococcal Group B Vaccine Administered Concomitantly With Diphtheria, Tetanus, and Acellular Pertussis and Inactivated Poliomyelitis Vaccines to Healthy Adolescents.

PubMed

Vesikari, Timo; Wysocki, Jacek; Beeslaar, Johannes; Eiden, Joseph; Jiang, Qin; Jansen, Kathrin U; Jones, Thomas R; Harris, Shannon L; O'Neill, Robert E; York, Laura J; Perez, John L

2016-06-01

Concomitant administration of bivalent rLP2086 (Trumenba [Pfizer, Inc] and diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine (DTaP/IPV) was immunologically noninferior to DTaP/IPV and saline and was safe and well tolerated. Bivalent rLP2086 elicited robust and broad bactericidal antibody responses to diverse Neisseria meningitidis serogroup B strains expressing antigens heterologous to vaccine antigens after 2 and 3 vaccinations. Bivalent rLP2086, a Neisseria meningitidis serogroup B (MnB) vaccine (Trumenba [Pfizer, Inc]) recently approved in the United States to prevent invasive MnB disease in individuals aged 10-25 years, contains recombinant subfamily A and B factor H binding proteins (fHBPs). This study evaluated the coadministration of Repevax (diphtheria, tetanus, and acellular pertussis and inactivated poliovirus vaccine [DTaP/IPV]) (Sanofi Pasteur MSD, Ltd) and bivalent rLP2086. Healthy adolescents aged ≥11 to <19 years received bivalent rLP2086 + DTaP/IPV or saline + DTaP/IPV at month 0 and bivalent rLP2086 or saline at months 2 and 6. The primary end point was the proportion of participants in whom prespecified levels of antibodies to DTaP/IPV were achieved 1 month after DTaP/IPV administration. Immune responses to bivalent rLP2086 were measured with serum bactericidal assays using human complement (hSBAs) against 4 MnB test strains expressing fHBP subfamily A or B proteins different from the vaccine antigens. Participants were randomly assigned to receive bivalent rLP2086 + DTaP/IPV (n = 373) or saline + DTaP/IPV (n = 376). Immune responses to DTaP/IPV in participants who received bivalent rLP2086 + DTaP/IPV were noninferior to those in participants who received saline + DTaP/IPV.The proportions of bivalent rLP2086 + DTaP/IPV recipients with prespecified seroprotective hSBA titers to the 4 MnB test strains were 55.5%-97.3% after vaccination 2 and 81.5%-100% after vaccination 3. The administration of bivalent rLP2086 was well tolerated and resulted in few serious adverse events. Immune responses to DTaP/IPV administered with bivalent rLP2086 to adolescents were noninferior to DTaP/IPV administered alone. Bivalent rLP2086 was well tolerated and elicited substantial and broad bactericidal responses to diverse MnB strains in a high proportion of recipients after 2 vaccinations, and these responses were further enhanced after 3 vaccinations.ClinicalTrials.gov identifier NCT01323270. © The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society.

The evolution of histamine H₃ antagonists/inverse agonists.

PubMed

Lebois, Evan P; Jones, Carrie K; Lindsley, Craig W

2011-01-01

This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H₃ antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H₃R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H₃ ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H₃ ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H₃R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H₃R antagonists/inverse agonists.

Feasibility studies of oncornavirus production in microcarrier cultures.

PubMed

Manousos, M; Ahmed, M; Torchio, C; Wolff, J; Shibley, G; Stephens, R; Mayyasi, S

1980-06-01

Studies conducted with virus-infected monolayer cell cultures have demonstrated the feasibility of producing several tumor-associated viruses in microcarrier (mc) cultures (Sephadex G50 beads treated with DEAE-chloride). The efficiency of cell adherence to mc varied with the cell type, the pH of the growth medium, and the stirring force applied to keep the mc in suspension. Most cells attached firmly to the mc and could not be removed easily with routine trypsinization procedures. Techniques using Enzar-T and Pronase were effective in detaching cells from mc in 10 to 15 min while retaining 95% cell viability. After detachment, Ficoll gradients were used for rapid and complete separation of viable cell suspensions from the mc. Retrovirus production in large volumes of mc cultures was investigated with periodic harvesting of growth fluids. Physical, biochemical, and biological properties of the Mason-Pfizer monkey virus and the RD114 virus recovered from the mc cultures were identical to those produced in conventional cultures. The utilization of mc has several applications in research and short-term cultures, but the as-yet-unsolved technical problems met were found to be serious limitations when attempting mass cell culturing on a long-term basis.

A squeeze-type osmotic tablet for controlled delivery of nifedipine.

PubMed

Park, Jung Soo; Shin, Jun Hyun; Lee, Dong Hun; Kim, Moon Suk; Rhee, John M; Lee, Hai Bang; Khang, Gilson

2008-01-01

Osmotic delivery systems are based on osmotic driving force. Nifedipine tablets, available under the trade names Procardia XL (Pfizer) and Adalat (Bayer), are commercialized drug-delivery systems of an elemental osmotic pump that the push-pull osmotic tablet operates successfully in delivering water-insoluble drugs. For the improvement of the release pattern and the solubility of the drug, we developed a squeeze-type osmotic tablet (SQT) for nifedipine as a model drug. The SQT was composed of one or more ring type of squeeze-push layer (squeeze-disc) and a centered drug core. Squeeze-discs were stacked up with different physicochemical properties with gradient such as viscosity, swelling ratio and water absorption ratio using the osmotic agents from a disc of bottom to top. The present work investigated the effect of different preparation factors, such as hydrophilic polymers, the molecular weight of polymers, coating process, orifice size and types of excipient on release performance of nifedipine. With the purpose of delivering water-insoluble nifedipine at an approximate zero-order rate and step-function rate for 24 h, SQT has been successfully prepared, and significantly improved in the release rate and patterns in comparison with the Adalat push-pull system in vitro release features.

A data-driven approach to quality risk management

PubMed Central

Alemayehu, Demissie; Alvir, Jose; Levenstein, Marcia; Nickerson, David

2013-01-01

Aim: An effective clinical trial strategy to ensure patient safety as well as trial quality and efficiency involves an integrated approach, including prospective identification of risk factors, mitigation of the risks through proper study design and execution, and assessment of quality metrics in real-time. Such an integrated quality management plan may also be enhanced by using data-driven techniques to identify risk factors that are most relevant in predicting quality issues associated with a trial. In this paper, we illustrate such an approach using data collected from actual clinical trials. Materials and Methods: Several statistical methods were employed, including the Wilcoxon rank-sum test and logistic regression, to identify the presence of association between risk factors and the occurrence of quality issues, applied to data on quality of clinical trials sponsored by Pfizer. Results: Only a subset of the risk factors had a significant association with quality issues, and included: Whether study used Placebo, whether an agent was a biologic, unusual packaging label, complex dosing, and over 25 planned procedures. Conclusion: Proper implementation of the strategy can help to optimize resource utilization without compromising trial integrity and patient safety. PMID:24312890

Preliminary evidence for biologic activity of toceranib phosphate (Palladia(®)) in solid tumours.

PubMed

London, C; Mathie, T; Stingle, N; Clifford, C; Haney, S; Klein, M K; Beaver, L; Vickery, K; Vail, D M; Hershey, B; Ettinger, S; Vaughan, A; Alvarez, F; Hillman, L; Kiselow, M; Thamm, D; Higginbotham, M L; Gauthier, M; Krick, E; Phillips, B; Ladue, T; Jones, P; Bryan, J; Gill, V; Novasad, A; Fulton, L; Carreras, J; McNeill, C; Henry, C; Gillings, S

2012-09-01

The purpose of this study was to provide an initial assessment of the potential biologic activity of toceranib phosphate (Palladia®, Pfizer Animal Health, Madison, NJ, USA) in select solid tumours in dogs. Cases in which toceranib was used to treat dogs with apocrine gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma (OSA), thyroid carcinoma, head and neck carcinoma and nasal carcinoma were included. Clinical benefit (CB) was observed in 63/85 (74%) dogs including 28/32 AGASACA [8 partial response (PR), 20 stable disease (SD)], 11/23 OSAs (1 PR and 10 SD), 12/15 thyroid carcinomas (4 PR and 8 SD), 7/8 head and neck carcinomas [1 complete response (CR), 5 PR and 1 SD] and 5/7 (1 CR and 4 SD) nasal carcinomas. For dogs experiencing CB, the median dose of toceranib was 2.8 mg kg(-1) , 36/63 (58.7%) were dosed on a Monday/Wednesday/Friday basis and 47/63 (74.6%) were treated 4 months or longer. Although these data provide preliminary evidence that toceranib exhibits CB in dogs with certain solid tumours, future prospective studies are necessary to define its true activity. © 2011 Blackwell Publishing Ltd.

Interlaboratory assessment of mitotic index by flow cytometry confirms superior reproducibility relative to microscopic scoring.

PubMed

Roberts, D J; Spellman, R A; Sanok, K; Chen, H; Chan, M; Yurt, P; Thakur, A K; DeVito, G L; Murli, H; Stankowski, L F

2012-05-01

A flow cytometric procedure for determining mitotic index (MI) as part of the metaphase chromosome aberrations assay, developed and utilized routinely at Pfizer as part of their standard assay design, has been adopted successfully by Covance laboratories. This method, using antibodies against phosphorylated histone tails (H3PS10) and nucleic acid stain, has been evaluated by the two independent test sites and compared to manual scoring. Primary human lymphocytes were treated with cyclophosphamide, mitomycin C, benzo(a)pyrene, and etoposide at concentrations inducing dose-dependent cytotoxicity. Deming regression analysis indicates that the results generated via flow cytometry (FCM) were more consistent between sites than those generated via microscopy. Further analysis using the Bland-Altman modification of the Tukey mean difference method supports this finding, as the standard deviations (SDs) of differences in MI generated by FCM were less than half of those generated manually. Decreases in scoring variability owing to the objective nature of FCM, and the greater number of cells analyzed, make FCM a superior method for MI determination. In addition, the FCM method has proven to be transferable and easily integrated into standard genetic toxicology laboratory operations. Copyright © 2012 Wiley Periodicals, Inc.

The European and American use of exploratory approaches for first-in-human studies.

PubMed

Silva-Lima, Beatriz; Carlson, David; Jones, David R; Laurie, David; Stahl, Elke; Maria, Vasco; Janssens, Walter; Robinson, William T

2010-02-01

Exploratory approaches for first-in-human clinical studies have evolved over the last few years and have stimulated the issuance of national regulatory guidances in some European countries as well as the United States. With the increasing implementation of these approaches and the recent preparation of a multiregional regulatory guidance (ICH M3 rev2), an exchange of experiences on the opportunities and challenges of exploratory clinical trials was desirable; thus, a workshop focusing on the use of this clinical approach was planned and conducted in Lisbon, Portugal, March 18-19, 2009 sponsored by the Portuguese Health Authority (INFARMED) and DIA. The structure of the workshop focused in three main areas. Regulatory representatives from Portugal, Belgium, Germany, the United Kingdom and the United States formally reviewed their experiences. This was followed by a discussion on issues from an ethics review perspective as well as an insight to the opportunities in the area of biologics. The industry perspective was presented by representatives from Merck, Pfizer, J&J, Novartis, Speedel, AstraZeneca, GSK, and Roche. Finally, through break out sessions, issues were identified to be addressed moving forward. It is the purpose of this paper to report on the outcome of this workshop.

Factors Associated with Bovine Neonatal Pancytopenia (BNP) in Calves: A Case-Control Study

PubMed Central

Lambton, Sarah L.; Colloff, Adrian D.; Smith, Richard P.; Caldow, George L.; Scholes, Sandra F. E.; Willoughby, Kim; Howie, Fiona; Ellis-Iversen, Johanne; David, Graham; Cook, Alasdair J. C.; Holliman, Andrew

2012-01-01

Bovine neonatal pancytopenia (BNP; previously known as idiopathic haemorrhagic diathesis and commonly known as bleeding calf syndrome) is a novel haemorrhagic disease of young calves which has emerged in a number of European countries during recent years. Data were retrospectively collected during June to November 2010 for 56 case calves diagnosed with BNP between 17 March and 7 June of the same year. These were compared with 58 control calves randomly recruited from herds with no history of BNP. Multivariable logistic regression analysis showed that increased odds of a calf being a BNP case were associated with its dam having received PregSure® BVD (Pfizer Animal Health) vaccination prior to the birth of the calf (odds ratio (OR) 40.78, p<0.001) and its herd of origin being located in Scotland (OR 9.71, p = 0.006). Decreased odds of a calf being a BNP case were associated with the calf having been kept outside (OR 0.11, p = 0.006). The longer that a cattle herd had been established on the farm was also associated with decreased odds of a calf in that herd being a BNP case (OR 0.97, p = 0.011). PMID:22606224

Targeted chemotherapy, the medical ecosystem, and the future of American health care.

PubMed

Gillick, Muriel R

2014-01-01

In light of the difficulties experienced by the pharmaceutical industry in developing important new drugs, the rapid design and introduction of the targeted chemotherapeutic agent, crizotinib, is a significant achievement. Understanding the roles of the patient, the physician, the regulator (FDA), health insurance companies, and the manufacturer (Pfizer) in the development of this drug can shed light on the prospects for future drugs and on the workings of the complicated health-care ecosystem. Patients were eager for an effective drug against lung cancer with minimal toxicity but were reluctant to enroll in clinical trials. Oncologists were enthusiastic about the new drug but have a financial incentive favoring intravenous medicines over oral agents. The FDA was under pressure to approve new drugs quickly. The drug manufacturer modified its corporate structure and developed collaborations with academics and international partners, but was pressured by stockholders to maximize short-term profitability. Insurance companies balked at the price of the drug and used tiered pricing to limit their costs. The successful design, development, and diffusion of crizotinib may signal a new departure for the pharmaceutical industry, but whether such successes are replicated in the future will depend on the delicately balanced ecosystem that constitutes American health care.

The International Standard for Oxytetracycline

PubMed Central

Humphrey, J. H.; Lightbown, J. W.; Mussett, M. V.; Perry, W. L. M.

1955-01-01

The first attempt to set up an international standard for oxytetracycline, using oxytetracycline hydrochloride, failed because of difficulties in obtaining a preparation whose moisture content was uniform after distribution into ampoules. A preparation of dihydrate of oxytetracycline base was obtained instead, and was compared in an international collaborative assay with a sample of oxytetracycline hydrochloride, which was the current working standard of Chas. Pfizer & Co., Inc., USA. The results of the collaborative assay showed that the potency of the dihydrate was uniform, and that it was a suitable preparation for use as the International Standard. Evidence was obtained, however, that the reference preparation at the time of examination was less potent than had been originally supposed, and that it was hydrated. The potency of the proposed international standard was recalculated after allowance for water in the reference preparation, and the resulting biological potency agreed well with that to be expected on the basis of the physicochemical properties of the preparation. It was agreed, therefore, that the recalculated values should be used, and the preparation of oxytetracycline base dihydrate used in the collaborative assay is established as the International Standard for Oxytetracycline with a potency of 900 International Units per mg. PMID:13284563

Feasibility of Neurapheresis™ as a Therapy for Multidrug Resistant Gram-negative Bacterial Meningitis

PubMed Central

Ballard, Christi; Ashraf, Bilal; Ejikeme, Tiffany; Hansen, Brenda; Charalambous, Lefko; Pagadala, Promila; Sharma-Kuinkel, Batu K; Giamberardino, Charles; Hedstrom, Blake; Verbick, Laura Zitella; Mccabe, Aaron; Lad, Shivanand P; Fowler, Vance; Perfect, John R

2017-01-01

Abstract Background The World Health Organization has identified Pseudomonas, Acinetobacter and Klebsiella (PAK) as three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. The greatest threat lies in hospitals, nursing homes, and patients with devices such as intravenous catheters and ventilators. Gram-negative bacterial meningitis (GBM) manifests when these bacteria invade the central nervous system. Due to the threat of increasing antibiotic resistance and the high mortality associated with MDR GBM, we have tested a closed-loop, extracorporeal cerebrospinal fluid (CSF) filtration system (NeurapheresisTM) for its applicability in this context. Here we demonstrate feasibility of Neurapheresis for MDR GBM and characterize system parameters for bacterial clearance. Methods PAK cultures were grown and diluted to 1 × 107 cells/mL in artificial CSF or Luria-Miller broth. Both single pass and closed loop filtration were performed with various tangential flow filtration (TFF) and dead-end filter paradigms. Samples were taken either immediately post-filter or after every full CSF volume cycle (150 mL) during a long-term closed loop experiment. Bacterial load, endotoxin and cytokines were quantified. Results In single pass tests, 5kDa and 100kDa TFF filters and 0.2µm and 0.45µm dead-end filters excluded all PAK organisms completely. The 100kDa and 5kDa TFF filters significantly reduced endotoxin concentration by >95% and >99% of baseline, respectively. The 5 kDa TFF filters produced a 2-log (>99%) reduction in cytokines (IL-1ra, IL-6, TNF, CRP, and CXCL10). In closed-loop experiments, both TFF filters demonstrated a 1–2 Log CFU (90–99%) reduction of all PAK organisms over 4 filtration cycles. Conclusion Neurapheresis shows potential to be an efficient multi-modal tool for controlling and treating MDR GBM in this in vitro model. Extending closed loop filtration over time demonstrates capability for rapid sterilization of the CSF. Future iterations may include adjunctive intrathecal drug delivery to further accelerate elimination of bacteria. Reduction of both endotoxin and cytokines by Neurapheresis may have significant implications for controlling the damaging neuro-inflammatory response during MDR GBM. Disclosures B. Hedstrom, Minnetronix, Inc.: Employee, Salary; L. Zitella Verbick, Minnetronix, Inc.: Employee, Salary; A. Mccabe, Minnetronix, Inc.: Employee, Salary; S. P. Lad, Minnetronix, Inc.: Collaborator and Scientific Advisor, Licensing agreement or royalty, Research grant and Research support; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Grant recipient; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: Royalties, Royalties

Crystal Structures of Beta- and Gammaretrovirus Fusion Proteins Reveal a Role for Electrostatic Stapling in Viral Entry

PubMed Central

Aydin, Halil; Cook, Jonathan D.

2014-01-01

Membrane fusion is a key step in the life cycle of all envelope viruses, but this process is energetically unfavorable; the transmembrane fusion subunit (TM) of the virion-attached glycoprotein actively catalyzes the membrane merger process. Retroviral glycoproteins are the prototypical system to study pH-independent viral entry. In this study, we determined crystal structures of extramembrane regions of the TMs from Mason-Pfizer monkey virus (MPMV) and xenotropic murine leukemia virus-related virus (XMRV) at 1.7-Å and 2.2-Å resolution, respectively. The structures are comprised of a trimer of hairpins that is characteristic of class I viral fusion proteins and now completes a structural library of retroviral fusion proteins. Our results allowed us to identify a series of intra- and interchain electrostatic interactions in the heptad repeat and chain reversal regions. Mutagenesis reveals that charge-neutralizing salt bridge mutations significantly destabilize the postfusion six-helix bundle and abrogate retroviral infection, demonstrating that electrostatic stapling of the fusion subunit is essential for viral entry. Our data indicate that salt bridges are a major stabilizing force on the MPMV and XMRV retroviral TMs and likely provide the key energetics for viral and host membrane fusion. PMID:24131724

Factors contributing to intervention fidelity in a multi-site chronic disease self-management program.

PubMed

Perrin, Karen M; Burke, Somer Goad; O'Connor, Danielle; Walby, Gary; Shippey, Claire; Pitt, Seraphine; McDermott, Robert J; Forthofer, Melinda S

2006-10-26

Disease self-management programs have been a popular approach to reducing morbidity and mortality from chronic disease. Replicating an evidence-based disease management program successfully requires practitioners to ensure fidelity to the original program design. The Florida Health Literacy Study (FHLS) was conducted to investigate the implementation impact of the Pfizer, Inc. Diabetes Mellitus and Hypertension Disease Self-Management Program based on health literacy principles in 14 community health centers in Florida. The intervention components discussed include health educator recruitment and training, patient recruitment, class sessions, utilization of program materials, translation of program manuals, patient retention and follow-up, and technical assistance. This report describes challenges associated with achieving a balance between adaptation for cultural relevance and fidelity when implementing the health education program across clinic sites. This balance was necessary to achieve effectiveness of the disease self-management program. The FHLS program was implemented with a high degree of fidelity to the original design and used original program materials. Adaptations identified as advantageous to program participation are discussed, such as implementing alternate methods for recruiting patients and developing staff incentives for participation. Effective program implementation depends on the talent, skill and willing participation of clinic staff. Program adaptations that conserve staff time and resources and recognize their contribution can increase program effectiveness without jeopardizing its fidelity.

Therapeutic Efficacy and Safety of GH in Japanese Children with Down Syndrome Short Stature Accompanied by GH Deficiency.

PubMed

Meguri, Kyoko; Inoue, Masaru; Narahara, Koji; Sato, Takahiro; Takata, Ami; Ohki, Nobuhiko; Ozono, Keiichi

2013-10-01

In this study, we investigated the effects of GH treatment in children with Down syndrome who had been diagnosed with GH deficiency (GHD). A total of 20 subjects were investigated in this study. Fourteen Down syndrome children (5 boys and 9 girls) with short stature due to GHD were treated with GH at Okayama Red Cross General Hospital, and 6 Down syndrome children (4 boys and 2 girls) with short stature due to GHD were registered in the Pfizer International Growth Database (KIGS). Height SD score (SDS) increased throughout the three-year GH treatment period. The overall mean height SDS increased from -3.5 at baseline to -2.5 after 3 yr of treatment. The mean change in height SDS during these 3 yr was 1.1. In addition, height assessment of SD score based on Down syndrome-specific growth data in the Japanese population revealed that the height SDS (Down syndrome) also increased across the 3-yr GH treatment period. The mean change in height SDS (Down syndrome) during these three years was 1.3. GH therapy was effective for Down syndrome short stature accompanied by GHD, and no new safety concerns were found in this study.

Innovators, deep fermentation and antibiotics: promoting applied science before and after the Second World War.

PubMed

Bud, Robert

2011-01-01

The historiography of penicillin has tended to overlook the importance of developing and disseminating know-how in fermentation technology. A focus on this directs attention to work before the war of a network in the US and Europe concerned with the production of organic acids, particularly gluconic and citric acids. At the heart of this network was the German-Czech Konrad Bernhauer. Other members of the network were a group of chemists at the US Department of Agriculture who first recognized the production possibilities of penicillin. The Pfizer Corporation, which had recruited a leading Department of Agriculture scientist at the end of the First World War, was also an important centre of development as well as of production. However, in wartime Bernhauer was an active member of the SS and his work was not commemorated after his death in 1975. After the war new processes of fermentation were disseminated by penicillin pioneers such as Jackson Foster and Ernst Chain. Because of its commercial context his work was not well known. The conclusion of this paper is that the commercial context, on the one hand, and the Nazi associations of Bernhauer, on the other, have submerged the significance of know-how development in the history of penicillin.

A drug's life: the pathway to drug approval.

PubMed

Keng, Michael K; Wenzell, Candice M; Sekeres, Mikkael A

2013-10-01

In the United States, drugs and medical devices are regulated by the US Food and Drug Administration (FDA). A drug must undergo rigorous testing prior to marketing to and medical use by the general public. The FDA grants marketing approval for drug products based on a comprehensive review of safety and efficacy data. This review article explains the history behind the establishment of the FDA and examines the historical legislation and approval processes for drugs, specifically in the fields of medical oncology and hematology. The agents imatinib (Gleevec, Novartis) and decitabine (Dacogen, Eisai) are used to illustrate both the current FDA regulatory process-specifically the orphan drug designation and accelerated approval process-and why decitabine failed to gain an indication for acute myeloid leukemia. The purpose and construct of the Oncologic Drugs Advisory Committee are also discussed, along with examples of 2 renal cell cancer drugs-axitinib (Inlyta, Pfizer) and tivozanib-that used progression-free survival as an endpoint. Regulatory approval of oncology drugs is the cornerstone of the development of new treatment agents and modalities, which lead to improvements in the standard of cancer care. The future landscape of drug development and regulatory approval will be influenced by the new breakthrough therapy designation, and choice of drug will be guided by genomic insights.

Tap and Dbp5, but not Gag, are involved in DR-mediated nuclear export of unspliced Rous sarcoma virus RNA

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeBlanc, Jason J.; Uddowla, Sabena; Abraham, Benjamin

2007-07-05

All retroviruses must circumvent cellular restrictions on the export of unspliced RNAs from the nucleus. While the unspliced RNA export pathways for HIV and Mason-Pfizer monkey virus are well characterized, that of Rous sarcoma virus (RSV) is not. We have previously reported that the RSV direct repeat (DR) elements are involved in the cytoplasmic accumulation of unspliced viral RNA. Here, using fluorescent in situ hybridization (FISH), we demonstrate that unspliced viral RNAs bearing a single point mutation (G8863C) in the DR exhibit a restricted cellular localization in and around the nucleus. In contrast, wild type unspliced viral RNA had amore » diffuse localization throughout the nucleus and cytoplasm. Since the RSV Gag protein has a transient localization in the nucleus, we examined the effect of Gag over-expression on a DR-mediated reporter construct. While Gag did not enhance DR-mediated nuclear export, the dominant-negative expression of two cellular export factors, Tap and Dbp5, inhibited expression of the same reporter construct. Furthermore, FISH studies using the dominant-negative Dbp5 demonstrated that unspliced wild type RSV RNA was retained within the nucleus. Taken together, these results further implicate the DR in nuclear RNA export through interactions with Tap and Dbp5.« less

Use of manometric temperature measurement (MTM) and SMART freeze dryer technology for development of an optimized freeze-drying cycle.

PubMed

Gieseler, Henning; Kramer, Tony; Pikal, Michael J

2007-12-01

This report provides, for the first time, a summary of experiments using SMART Freeze Dryer technology during a 9 month testing period. A minimum ice sublimation area of about 300 cm(2) for the laboratory freeze dryer, with a chamber volume 107.5 L, was found consistent with data obtained during previous experiments with a smaller freeze dryer (52 L). Good reproducibility was found for cycle design with different type of excipients, formulations, and vials used. SMART primary drying end point estimates were accurate in the majority of the experiments, but showed an over prediction of primary cycle time when the product did not fully achieve steady state conditions before the first MTM measurement was performed. Product resistance data for 5% sucrose mixtures at varying fill depths were very reproducible. Product temperature determined by SMART was typically in good agreement with thermocouple data through about 50% of primary drying time, with significant deviations occurring near the end of primary drying, as expected, but showing a bias much earlier in primary drying for high solid content formulations (16.6% Pfizer product) and polyvinylpyrrolidone (40 kDa) likely due to water "re-adsorption" by the amorphous product during the MTM test. (c) 2007 Wiley-Liss, Inc.

Antidepressants in paediatric depression: do not look back in anger but around in awareness.

PubMed

Brent, David A; Gibbons, Robert D; Wilkinson, Paul; Dubicka, Bernadka

2018-02-01

In this paper, we summarise and critique a network meta-analysis (NMA) of antidepressant efficacy and tolerability for paediatric depression and an accompanying editorial. Although we agree that many of the extant studies are flawed, this meta-analysis showed clear efficacy of fluoxetine in the NMA, and for sertraline and escitalopram in pairwise analyses. Consequently, these papers underestimate the benefits of antidepressants for paediatric depression, and provide support for current practice guideline, which recommends the use of an antidepressant if the patient does not respond to psychotherapy. In these circumstances, fluoxetine should be the first choice, with escitalopram and sertraline as alternatives. Declaration of interest D.A.B. receives royalties from Guilford Press, has or will receive royalties from the electronic self-rated version of the C-SSRS from eResearch Technology, Inc., is on the editorial board of UpToDate, and is a reviewer for Healthwise. R.D.G. serves as an expert witness for the US Department of Justice, Pfizer, Wyeth and GSK; and is the founder of Adaptive Testing Technologies. P.W. receives personal fees from Lundbeck and Takeda. B.D. reports a licensing agreement with Lundbeck for a psychosocial treatment manual for depression. No other disclosures were reported.

2016 ASMS Workshop Review: Next Generation LC/MS: Critical Insights and Future Perspectives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gao, Hongying; Makarov, Alexander; Smith, Richard D.

The pilot workshop on BNext Generation LC/MS: Critical Insights and Future Perspectives was held on the evening of June 6, 2016 at the 64th ASMS Conference on Mass Spectrometry and Allied Topics held in San Antonio, TX. The workshop, chaired by Hongying Gao (Pfizer), consisted of stimulating talks from distinguished speakers and open discussion among the audience and invited presenters.The objectives of this workshop were to better understand the advances and limitations of current technologies; to exchange perspectives on the next generation LC/MS; and to discuss/debate the features of next generation LC/MS focusing on the following three questions: (1) Whatmore » would the next generation LC/MS look like? (2) How would it change the way we do analysis? and (3) What fundamental issues need to be resolved? A real-world case in the biopharmaceutical industry was presented by Hongying Gao on the needs by industry for LC/MS innovation and technology advancements. The primary invited speakers were Alexander Makarov (Thermo Fisher Scientific) and Richard (Dick) Smith (Pacific Northwest National Laboratory). The open discussions started with Q&A and comments for Alexander Makarov and Dick Smith, followed by insights and perspectives from members of the audience and other invited presenters who shared their thoughts addressing the above questions.« less

Rivastigmine in the treatment of Alzheimer’s disease: an update

PubMed Central

Onor, Maria Luisa; Trevisiol, Marianna; Aguglia, Eugenio

2007-01-01

Alzheimer’s disease is the most common form of dementia in industrialized countries. In the European Union, about 54% of dementia cases are believed to be due to Alzheimer’s disease. The condition is an age-related neurodegenerative disorder characterized by multiple cognitive deficiencies, including loss of memory, judgment, and comprehension. These manifestations are accompanied by behavioral and mood disturbances. Although no cure has yet been discovered for Alzheimer’s disease, symptomatic therapies are now widely available and offer significant relief to patients and benefits to caregivers in terms of reduced care burden. At the start of the 21st century, health technology assessments recommended three agents for the symptomatic treatment of mild to moderate Alzheimer disease: rivastigmine, donepezil, and galantamine. Rivastigmine (Exelon®, Novartis Basel—Switzerland) is a slowly reversible inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), while donepezil (Aricept®, Pfizer, New York, USA) and galantamine (Reminyl®, Janssen, New Jersey,USA) show no functional inhibition of BuChE, and are considered AChE-selective, rapidly-reversible inhibitors. The efficacy of all three agents has been evaluated in large, double-blind, placebo-controlled clinical trials of up to 6 months’ duration. Rivastigmine treatment in mild to moderate Alzheimer’s disease improves cognition, activities of daily living, and global function. PMID:18044073

Plate-based diversity subset screening generation 2: an improved paradigm for high-throughput screening of large compound files.

PubMed

Bell, Andrew S; Bradley, Joseph; Everett, Jeremy R; Loesel, Jens; McLoughlin, David; Mills, James; Peakman, Marie-Claire; Sharp, Robert E; Williams, Christine; Zhu, Hongyao

2016-11-01

High-throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time consuming and costly and the use of subsets as an efficient alternative to screening entire compound collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity or biological target focus. Previously, we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second-generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer.

Next Generation Vaccine Biomarkers workshop October 30–31, 2014 – Ottawa, Canada

PubMed Central

Twine, Susan M; Fulton, Kelly M; Spika, John; Ouellette, Marc; Raven, Jennifer F; Conlan, J Wayne; Krishnan, Lakshmi; Barreto, Luis; Richards, James C

2015-01-01

Vaccine biomarkers are critical to many aspects of vaccine development and licensure, including bridging findings in pre-clinical studies to clinical studies, predicting potential adverse events, and predicting vaccine efficacy. Despite advances in our understanding of various biological pathways, and advances in systems analyses of the immune response, there remains much to learn about qualitative and quantitative aspects of the human host response to vaccination. To stimulate discussion and identify opportunities for collaborative ways to advance the field of vaccine biomarkers, A Next Generation Vaccine Biomarker workshop was held in Ottawa. The two day workshop, sponsored by the National Research Council Canada, Canadian Institutes of Health Research, Public Health Agency of Canada, Pfizer, and Medicago, brought together stakeholders from Canadian and international industry, government and academia. The workshop was grouped in themes, covering vaccine biomarker challenges in the pre-clinical and clinical spaces, veterinary vaccines, regulatory challenges, and development of biomarkers for adjuvants and cancer vaccines. The use of case studies allowed participants to identify the needs and gaps requiring innovation. The workshop concluded with a discussion on opportunities for vaccine biomarker discovery, the Canadian context, and approaches for moving forward. This article provides a synopsis of these discussions and identifies steps forward for advancing vaccine biomarker research in Canada. PMID:26383909

Macro-economic factors influencing the architectural business model shift in the pharmaceutical industry.

PubMed

Dierks, Raphaela Marie Louisa; Bruyère, Olivier; Reginster, Jean-Yves; Richy, Florent-Frederic

2016-10-01

Technological innovations, new regulations, increasing costs of drug productions and new demands are only few key drivers of a projected alternation in the pharmaceutical industry. The purpose of this review is to understand the macro economic factors responsible for the business model revolution to possess a competitive advantage over market players. Areas covered: Existing literature on macro-economic factors changing the pharmaceutical landscape has been reviewed to present a clear image of the current market environment. Expert commentary: Literature shows that pharmaceutical companies are facing an architectural alteration, however the evidence on the rationale driving the transformation is outstanding. Merger & Acquisitions (M&A) deals and collaborations are headlining the papers. Q1 2016 did show a major slowdown in M&A deals by volume since 2013 (with deal cancellations of Pfizer and Allergan, or the downfall of Valeant), but pharmaceutical analysts remain confident that this shortfall was a consequence of the equity market volatility. It seems likely that the shift to an M&A model will become apparent during the remainder of 2016, with deal announcements of Abbott Laboratories, AbbVie and Sanofi worth USD 45billion showing the appetite of big pharma companies to shift from the fully vertical integrated business model to more horizontal business models.

Nonsteroidal antagonists of the mineralocorticoid receptor.

PubMed

Kolkhof, Peter; Nowack, Christina; Eitner, Frank

2015-09-01

The broad clinical use of steroidal mineralocorticoid receptor antagonists (MRAs) is limited by the potential risk of inducing hyperkalemia when given on top of renin-angiotensin system blockade. Drug discovery campaigns have been launched aiming for the identification of nonsteroidal MRAs with an improved safety profile. This review analyses the evidence for the potential of improved safety profiles of nonsteroidal MRAs and the current landscape of clinical trials with nonsteroidal MRAs. At least three novel nonsteroidal MRAs have reportedly demonstrated an improved therapeutic index (i.e. less risk for hyperkalemia) in comparison to steroidal antagonists in preclinical models. Five pharmaceutical companies have nonsteroidal MRAs in clinical development with a clear focus on the treatment of chronic kidney diseases. No clinical data have been published so far for MT-3995 (Mitsubishi), SC-3150 (Daiichi-Sankyo), LY2623091 (Eli Lilly) and PF-03882845 (Pfizer). In contrast, data from two clinical phase II trials are available for finerenone (Bayer) which demonstrated safety and efficacy in patients with heart failure and additional chronic kidney diseases, and significantly reduced albuminuria in patients with diabetic nephropathy. Neither hyperkalemia nor reductions in kidney function were limiting factors to its use. Novel, nonsteroidal MRAs are currently tested in clinical trials. Based on preclinical and first clinical data, these nonsteroidal MRAs might overcome the limitations of today's steroidal antagonists.

The European and American Use of Exploratory Approaches for First‐in‐Human Studies*

PubMed Central

Silva‐Lima, Beatriz; Carlson, David; Jones, David R.; Laurie, David; Stahl, Elke; Maria, Vasco; Janssens, Walter; Robinson, William T.

2010-01-01

Abstract Exploratory approaches for first‐in‐human clinical studies have evolved over the last few years and have stimulated the issuance of national regulatory guidances in some European countries as well as the United States. With the increasing implementation of these approaches and the recent preparation of a multiregional regulatory guidance (ICH M3 rev2), an exchange of experiences on the opportunities and challenges of exploratory clinical trials was desirable; thus, a workshop focusing on the use of this clinical approach was planned and conducted in Lisbon, Portugal, March 18–19, 2009 sponsored by the Portuguese Health Authority (INFARMED) and DIA. The structure of the workshop focused in three main areas. Regulatory representatives from Portugal, Belgium, Germany, the United Kingdom and the United States formally reviewed their experiences. This was followed by a discussion on issues from an ethics review perspective as well as an insight to the opportunities in the area of biologics. The industry perspective was presented by representatives from Merck, Pfizer, J&J, Novartis, Speedel, AstraZeneca, GSK, and Roche. Finally, through break out sessions, issues were identified to be addressed moving forward. It is the purpose of this paper to report on the outcome of this workshop. Clin Trans Sci 2010; Volume #: 1–4 PMID:20443952

What Malaysian women believe about Viagra: a qualitative inquiry.

PubMed

Low, W Y; Zulkifli, S N; Wong, Y L; Tan, H M

2002-03-01

This paper highlights women's perceptions of sildenafil citrate (Viagra, Pfizer). It is based on a qualitative study on perceptions of erectile dysfunction in the Malaysian multicultural society. Six focus groups were conducted, consisting of 69 women, aged between 40 and 70 years, recruited from the general public and who had given informed consent. The findings revealed that the women were aware of erectile dysfunction and Viagra. Due to their concern about the negative aspects of Viagra, the Chinese and Malay traditional methods of treatment were commonly mentioned. The women from three ethnic groups viewed the possibility of their husband starting to take Viagra with lots of suspicion, mistrust and fear. They would prefer their husband discussing with them the issue of resorting to taking Viagra. The Chinese and Indian women perceived that if a man takes Viagra, it will boost his ego and he will feel more manly. Indian women felt that a man taking Viagra is proof of his love for his wife. The Malay women felt that a man would be ashamed and have a low self-esteem if he were to resort to taking Viagra. Although Viagra is meant for the male, understanding of women's perception of it is beneficial for a couple's sexual relationship.

African American patients' attitudes toward proactive health behaviors after exposure to direct-to-consumer advertising.

PubMed

Yang, Yi; Gourley, Dick R; Gourley, Greta A; Faris, Richard J; Womeodu, Robin J; Yang, Jun; Likens, Carol C

2010-05-01

Previous research on direct-to-consumer advertising (DTCA) has not focused exclusively on the African American population. The purpose of this study was to explore African Americans' attitudes toward proactive health behaviors following exposure to DTCA of atorvastatin calcium (Lipitor, Pfizer Inc). One-hundred fifty African American patients participated in the study. Participants' functional health literacy and health locus of control were assessed. The participants were asked to view a DTCA of Lipitor, followed by face-to-face interviews. After watching the DTCA of Lipitor, 89.4% of participants agreed that they would talk to their physician about their cholesterol, 88.6% agreed that they would ask their physician to test their cholesterol level, and 47.3% agreed that they would ask their physician to write them a prescription for Lipitor. Those who had a history of high cholesterol were more likely to agree to ask their physician to test their cholesterol levels. Low household income, having public health insurance, and prior experience with taking Lipitor were significant positive predictors of patients agreeing to ask their physician to write a prescription of the advertised drug. African American patients showed favorable attitudes toward proactive health behaviors after exposure to DTCA of Lipitor.

Strategic deployment of CHO expression platforms to deliver Pfizer's Monoclonal Antibody Portfolio.

PubMed

Scarcelli, John J; Shang, Tanya Q; Iskra, Tim; Allen, Martin J; Zhang, Lin

2017-11-01

Development of stable cell lines for expression of large-molecule therapeutics represents a significant portion of the time and effort required to advance a molecule to enabling regulatory toxicology studies and clinical evaluation. Our development strategy employs two different approaches for cell line development based on the needs of a particular project: a random integration approach for projects where high-level expression is critical, and a site-specific integration approach for projects in which speed and reduced employee time spend is a necessity. Here we describe both our random integration and site-specific integration platforms and their applications in support of monoclonal antibody development and production. We also compare product quality attributes of monoclonal antibodies produced with a nonclonal cell pool or clonal cell lines derived from the two platforms. Our data suggests that material source (pools vs. clones) does not significantly alter the examined product quality attributes. Our current practice is to leverage this observation with our site-specific integration platform, where material generated from cell pools is used for an early molecular assessment of a given candidate to make informed decisions around development strategy. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1463-1467, 2017. © 2017 American Institute of Chemical Engineers.

Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer's disease.

PubMed

Fazal, Karim; Perera, Gayan; Khondoker, Mizanur; Howard, Robert; Stewart, Robert

2017-07-01

Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). To compare cognitive decline and survival after diagnosis of Alzheimer's disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer's disease diagnosis. In the 9 months after Alzheimer's disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. In people with Alzheimer's disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging

PubMed Central

Pocock, Ginger M.; Zimdars, Laraine L.; Yuan, Ming; Eliceiri, Kevin W.; Ahlquist, Paul; Sherer, Nathan M.

2017-01-01

Cis-acting RNA structural elements govern crucial aspects of viral gene expression. How these structures and other posttranscriptional signals affect RNA trafficking and translation in the context of single cells is poorly understood. Herein we describe a multicolor, long-term (>24 h) imaging strategy for measuring integrated aspects of viral RNA regulatory control in individual cells. We apply this strategy to demonstrate differential mRNA trafficking behaviors governed by RNA elements derived from three retroviruses (HIV-1, murine leukemia virus, and Mason-Pfizer monkey virus), two hepadnaviruses (hepatitis B virus and woodchuck hepatitis virus), and an intron-retaining transcript encoded by the cellular NXF1 gene. Striking behaviors include “burst” RNA nuclear export dynamics regulated by HIV-1’s Rev response element and the viral Rev protein; transient aggregations of RNAs into discrete foci at or near the nuclear membrane triggered by multiple elements; and a novel, pulsiform RNA export activity regulated by the hepadnaviral posttranscriptional regulatory element. We incorporate single-cell tracking and a data-mining algorithm into our approach to obtain RNA element–specific, high-resolution gene expression signatures. Together these imaging assays constitute a tractable, systems-based platform for studying otherwise difficult to access spatiotemporal features of viral and cellular gene regulation. PMID:27903772

Bioequivalence of fixed-dose combination RIN®-150 to each reference drug in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Damle, B

2015-03-01

RIN(®)-150 is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg) and isoniazid (INH, 75 mg) developed for the treatment of tuberculosis. This study was conducted at a single center: the Pfizer Clinical Research Unit in Singapore. To demonstrate bioequivalence of each drug component between RIN-150 and individual products in a loose combination. This was a randomized, open-label, single-dose, two-way crossover study. Subjects received single doses of RIN-150 or two individual reference products under fasting conditions in a crossover fashion, with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (Cmax) and the area under plasma concentration-time curve (AUC). Of 28 subjects enrolled, 26 completed the study. The adjusted geometric mean ratios of Cmax and AUClast between the FDC and single-drug references and 90% confidence intervals were respectively 91.63% (90%CI 83.13-101.01) and 95.45% (90%CI 92.07-98.94) for RMP, and 107.58% (90%CI 96.07-120.47) and 103.45% (90%CI 99.33-107.75) for INH. Both formulations were generally well tolerated in this study. The RIN-150 FDC tablet formulation is bioequivalent to the two single-drug references for RMP and INH at equivalent doses.

Bioequivalence of fixed-dose combination Myrin®-P Forte and reference drugs in loose combination.

PubMed

Wang, H F; Wang, R; O'Gorman, M; Crownover, P; Naqvi, A; Jafri, I

2013-12-01

Myrin®-P Forte is a fixed-dose combination (FDC) tablet containing rifampicin (RMP, 150 mg), isoniazid (INH, 75 mg), ethambutol (EMB) hydrochloride (275 mg) and pyrazinamide (PZA, 400 mg) developed for the treatment of tuberculosis (TB). This study was conducted at a single centre--the Pfizer Clinical Research Unit in Singapore. To demonstrate the bioequivalence of each drug component of the Myrin-P Forte FDC and the individual product in loose combination. In a randomized, open-label, single-dose, two-way, crossover study, subjects received single doses of Myrin-P Forte or four individual products under fasting conditions in a crossover fashion with at least 7 days washout between doses. The primary measures for comparison were peak plasma concentration (C(max)) and the area under plasma concentration-time curve (AUC). Of 36 subjects enrolled, 35 completed the study. The adjusted geometric mean ratios and 90% confidence intervals for C(max) and AUC values were completely contained within bioequivalence limits (80%, 125%) for all four drugs in both formulations. Both treatments were generally well tolerated in the study. The Myrin-P Forte FDC tablet formulation is bioequivalent to the four single-drug references for RMP, INH, EMB hydrochloride and PZA at equivalent doses.

In vivo modification of retroviral gag gene-encoded polyproteins by myristic acid.

PubMed Central

Schultz, A M; Oroszlan, S

1983-01-01

It has recently been shown by mass spectral analysis (Henderson et al., Proc. Natl. Acad. Sci. U.S.A. 80:339-343, 1983) that the p15gag protein of murine leukemia viruses contains a novel post-translational modification, an amino-terminal myristyl (tetradecanoyl) amide. In this report we show that p15gag is the only structural protein to contain this fatty acid. In addition, the gag precursor polyproteins of type B, C, and D retroviruses have been examined for the presence of myristic acid by metabolic labeling and immunoprecipitation studies. In a panel of mammalian type C retroviruses we found that the precursor polyprotein Pr65gag homologs, but not the glycosylated forms (gPr80gag homologs), were specifically labeled after a 5-min incubation of infected cells with [3H]myristic acid. The gag precursor polyprotein was also labeled in mouse mammary tumor virus and in Mason-Pfizer monkey virus, but Pr76gag of Rous sarcoma virus failed to incorporate [3H]myristate. Under similar conditions, [3H]palmitate was not found to be incorporated into any viral gag proteins. Thus, myristylation appears to be a common feature of mammalian type B, C, and D retroviruses but not of avian retroviruses. Images PMID:6302307

Antipsychotic metabolic effects: weight gain, diabetes mellitus, and lipid abnormalities.

PubMed

McIntyre, R S; McCann, S M; Kennedy, S H

2001-04-01

To review published and nonpublished literature describing changes in weight, glucose homeostasis, and lipid milieu with antipsychotics. A Medline search was completed using the words weight gain, diabetes mellitus, cholesterol, triglycerides, risperidone, clozapine, olanzapine, quetiapine, ziprasidone, predictors, prolactin, obesity, and conventional antipsychotics. Publications, including original articles, review articles, letters to the editor, abstracts or posters presented at professional meetings in the last 4 years, and references from published articles, were collected. Manufacturers, including Eli Lilly Canada Inc, JanssenOrtho Inc, Pfizer Canada Inc, AstraZeneca Inc, and Novartis Pharmaceuticals, were contacted to retrieve additional medical information. The topic of antipsychotic-induced weight gain is understudied, and there are relatively few well-controlled studies. Weight gain as a side effect has been described with both conventional and atypical antipsychotics. Moreover, some atypical antipsychotics are associated with de novo diabetes mellitus and increased serum triglyceride levels. Predictors of weight gain may be age, baseline body mass index, appetite stimulation, previous antipsychotic exposure, and antipsychotic treatment duration. Significant weight gain is reported with the existing atypical antipsychotics. The weight gain described is highly distressing to patients, may reduce treatment adherence, and may increase the relative risk for diabetes mellitus and hypertriglyceridemia. Physicians employing these agents should routinely monitor weight, fasting blood glucose, and lipid profiles.

Bivalent rLP2086 (Trumenba®): Development of a well-characterized vaccine through commercialization.

PubMed

Sunasara, Khurram; Cundy, John; Srinivasan, Sriram; Evans, Brad; Sun, Weiqiang; Cook, Scott; Bortell, Eric; Farley, John; Griffin, Daniel; Bailey Piatchek, Michele; Arch-Douglas, Katherine

2018-05-24

The phrase "Process is the Product" is often applied to biologics, including multicomponent vaccines composed of complex components that evade complete characterization. Vaccine production processes must be defined and locked early in the development cycle to ensure consistent quality of the vaccine throughout scale-up, clinical studies, and commercialization. This approach of front-loading the development work helped facilitate the accelerated approval of the Biologic License Application for the well-characterized vaccine bivalent rLP2086 (Trumenba®, Pfizer Inc) in 2014 under Breakthrough Therapy Designation. Bivalent rLP2086 contains two rLP2086 antigens and is licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B in individuals 10-25years of age in the United States. This paper discusses the development of the manufacturing process of the two antigens for the purpose of making it amenable to any manufacturing facility. For the journey to commercialization, the operating model used to manage this highly accelerated program led to a framework that ensured "right the first time" execution, robust process characterization, and proactive process monitoring. This framework enabled quick problem identification and proactive resolutions, resulting in a robust control strategy for the commercial process. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tipranavir: PNU 140690, tipranivir.

PubMed

2006-01-01

Tipranavir [PNU 140690, tipranivir, Aptivus] is a second-generation HIV dihydropyrone (a sulphonamide derivative), nonpeptidic protease inhibitor (NPPI) discovered by Pharmacia & Upjohn (now Pfizer) in the US. The compound is in development with Boehringer Ingelheim. Tipranavir has potent in vitro activity against a variety of HIV-1 laboratory strains and clinical isolates, including those resistant to ritonavir, as well as HIV-2. Tipranavir has been shown to act synergistically with other antiretroviral agents. The limited bioavailability of the hard gel (and first available) formulation of tipranavir led to the development of a soft capsule formulation that has better oral bioavailability. Pharmacia Corporation (now Pfizer) considers that the resistance profile of tipranavir may be sufficiently unique for it to be effective against protease inhibitor resistant virus. On 16 April 2003, Pharmacia Corporation was acquired by, and merged into, Pfizer. In February 2000, Boehringer Ingelheim acquired exclusive worldwide rights to tipranavir. Tipranavir was launched in the US in mid-2005. In June 2005, the US FDA granted accelerated approval to tipranavir capsules for use in combination treatment, based on 24-week data from ongoing clinical trials. The approved dose is Aptivus 500 mg taken with ritonavir 200 mg, twice daily. Aptivus 250 mg soft gel capsules are expected to be available in the second half of 2005. A submission was made to the FDA in October 2004 seeking accelerated approval. In May 2005, the Antiviral Drugs Advisory Committee of the FDA recommended the approval of tipranavir. The positive recommendation is based on data from the RESIST-1 and RESIST-2 studies. Also in October 2004, Boehringer Ingelheim submitted a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMEA) for tipranavir for the treatment of HIV-1 infection in combination with other antiretroviral agents in patients who are protease inhibitor experienced. In July 2005, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion for tipranavir in the European Union. If approved, the drug will be marketed in Europe too under the name Aptivus. Marketing authorisation under exceptional circumstances (accelerated approval) is expected before the end of 2005.A phase III clinical programme (RESIST- Randomised Evaluation of Strategic Intervention in Multi-drug ReSistant Patients with Tipranavir) was launched by Boehringer Ingelheim in February 2003. The RESIST programme consists of two phase III pivotal trials (RESIST 1 and RESIST 2) and two companion trials (study 1182.51 and RESIST 3) available at some sites for even more advanced patients. The trials are designed to further study the efficacy and safety of tipranavir (500 mg) boosted with low-dose (200 mg) ritonavir, taken twice daily, versus a low-dose ritonavir boosted comparator protease inhibitor that is chosen by the patient's physician on the basis of the treatment history and baseline resistance testing. Each patient will also receive an individualised background regimen. Study participants will all be highly treatment-experienced HIV-positive adults. RESIST 1 study enrolled 620 patients in the US, Canada and Australia and RESIST 2 enrolled more than 863 patients in Europe and South America. These trials are now fully recruited. The clinical endpoint for RESIST 1 is at 24 weeks and for RESIST 2, the endpoints are at 16 and 24 weeks. Interim data from RESIST 1 (1182.12) were presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy in Washington, DC, USA, in October 2004. Results from this study show that tipranavir is a viable treatment option for patients who have failed other protease inhibitors. In June 2004, Boehringer Ingelheim announced the expansion of enrolment criteria in the international Compassionate Use Programme to allow broader access to tipranavir for HIV patients in need of new treatment options. All countries participating in the tipranavir phase III programme are eligible to take part in the Compassionate Use programme, which is enrolling patients over the age of 18 years, who are triple-antiretroviral class-experienced with at least two PI-based regimens. In November 2004, Boehringer Ingelheim opened the tipranavir Expanded Access Program (EAP) in the US, following a review of the protocol by the FDA. The programme will provide access to tipranavir for HIV-infected patients (> or =18 years old) who are not enrolled in the ongoing tipranavir clinical studies and who are triple-antiretroviral class-experienced with at least two previous PI-based regimens, and have documented PI-resistance and need tipranavir to construct a viable treatment regimen. Eligibility is not dependent upon viral load or CD4+ cell count. Tiparanvir is also being evaluated in phase II studies for use in paediatric and treatment-naive patient populations. Phase II trials completed in the US have established the clinical activity of tiprananvir in both antiretroviral-naive and -experienced patients with HIV infection. The studies have also shown that tipranavir can be combined with ritonavir for maximal clinical benefit. In its 2003 Annual Report, Boehringer Ingelheim stated that the process- and paediatric- formulation development of tipranavir had been completed.

Parallel δ 13C and Conifer Physiognomic Trends Across the Triassic-Jurassic Boundary

NASA Astrophysics Data System (ADS)

Whiteside, J. H.; Olsen, P. E.; Sambrotto, R. N.; Cornet, B.

2003-12-01

The Triassic-Jurassic mass extinction event ( ˜200 Ma) had a profound effect on biotic evolution, and herein we describe trends in cheirolepidaceous conifer leaf physiognomy from the Pangean tropics (present northeastern USA) that at least broadly parallel a negative δ 13C excursion recorded in the same strata. The physiognomic changes appear at an abrupt (<10 ky) negative carbon isotope excursion (1) synchronous with a previously described palynological extinction level, fern spike, and Ir anomaly (2), and continue through a prolonged negative excursion, lasting 900 ky (through all three CAMP basaltic extrusive events), encompassing most of the Hettangian age. The physiognomic changes seen in the cheirolepidaceous conifer leafy shoot forms Brachyphyllum and Pagiophyllum through the δ 13C excursions include primarily the development of microphyllous leaves with thickened cuticle and sunken papillate stomata (3). These floral modifications are consistent with intense thermal stress plausibly due to very high atmospheric CO2 concentrations and corroborate McElwain's (4) thermal damage hypothesis for the Triassic-Jurassic transition that was originally based on different plant taxa from the higher Pangean latitudes in present Greenland and Sweden. Subsequently, a 2- to 5-fold increase in the area of leafy shoots in strata of latest Hettangian age suggest a return to lower thermal stress levels perhaps due to lower CO2, despite the fact that eastern North America continued to drift into more arid latitudes. The floral physiognomic changes associated with the negative δ 13C excursion and likely very elevated CO2 levels is in many ways a microcosm of the Mesozoic in which the dominance of cheiroleps apparently overlaps with the highest CO2 levels of the Mesozoic (5). References. (1) Whiteside JH, Olsen PE, Sambrotto RN. 2003. Geol. Soc. Amer. Abst. Prog. (in press). (2) Olsen PE et al., Science 296:1305-1307 (3) Cornet B. 1989. in Olsen PE, Schlische RW, Gore PJW, Internat. Geol. Cong., Guidebooks T351, p. 115. (4) McElwain JC, Beerling, DJ, Woodward FI. 1999. Science 285:1386. (5) Ekart D, Cerling TR, Montanez IP, Tabor NJ. 1999. Am. J. Sci. 299:805.

Factors contributing to intervention fidelity in a multi-site chronic disease self-management program

PubMed Central

Perrin, Karen M; Burke, Somer Goad; O'Connor, Danielle; Walby, Gary; Shippey, Claire; Pitt, Seraphine; McDermott, Robert J; Forthofer, Melinda S

2006-01-01

Background and objectives Disease self-management programs have been a popular approach to reducing morbidity and mortality from chronic disease. Replicating an evidence-based disease management program successfully requires practitioners to ensure fidelity to the original program design. Methods The Florida Health Literacy Study (FHLS) was conducted to investigate the implementation impact of the Pfizer, Inc. Diabetes Mellitus and Hypertension Disease Self-Management Program based on health literacy principles in 14 community health centers in Florida. The intervention components discussed include health educator recruitment and training, patient recruitment, class sessions, utilization of program materials, translation of program manuals, patient retention and follow-up, and technical assistance. Results This report describes challenges associated with achieving a balance between adaptation for cultural relevance and fidelity when implementing the health education program across clinic sites. This balance was necessary to achieve effectiveness of the disease self-management program. The FHLS program was implemented with a high degree of fidelity to the original design and used original program materials. Adaptations identified as advantageous to program participation are discussed, such as implementing alternate methods for recruiting patients and developing staff incentives for participation. Conclusion Effective program implementation depends on the talent, skill and willing participation of clinic staff. Program adaptations that conserve staff time and resources and recognize their contribution can increase program effectiveness without jeopardizing its fidelity. PMID:17067388

Tolerogenic Dendritic Cells Generated with Tofacitinib Ameliorate Experimental Autoimmune Encephalomyelitis through Modulation of Th17/Treg Balance

PubMed Central

Luo, Shasha; Zou, Qiang

2016-01-01

It is well known that dendritic cells (DCs) play a pivotal role in triggering self-specific responses. Conversely, tolerogenic DCs (tolDCs), a specialized subset, induce tolerance and negatively regulate autoreactive responses. Tofacitinib, a Janus kinase inhibitor developed by Pfizer for treatment of rheumatoid arthritis, is probable to be a promising candidate for inducing tolDCs. The aims of this study were to evaluate the effectiveness of tolDCs induced by tofacitinib in a myelin oligodendrocyte glycoprotein- (MOG-) specific experimental autoimmune encephalomyelitis (EAE) model and to investigate their effects on Th17/Treg balance in the animal model of multiple sclerosis (MS). Our results revealed that tofacitinib-treated DCs maintained a steady semimature phenotype with a low level of proinflammatory cytokines and costimulatory molecules. DCs treated by tofacitinib also induced antigen-specific T cells hyporesponsiveness in a concentration-dependent manner. Upon intravenous injection into EAE mice, MOG pulsed tolDCs significantly dampened disease activity, and adoptive cell therapy (ACT) disturbed Th17/Treg balance with a remarkable decrease of Th1/Th17 cells and an increase in regulatory T cells (Tregs). Overall, DCs modified by tofacitinib exhibited a typical tolerogenic phenotype, and the antigen-specific tolDCs may represent a new avenue of research for the development of future clinical treatments for MS. PMID:28070525

Pretreatment with diphenoxylate hydrochloride/atropine sulfate (Lomotil) does not decrease physiologic bowel FDG activity on PET/CT scans of the abdomen and pelvis.

PubMed

Murphy, Robert; Doerger, Kirk M; Nathan, Mark A; Lowe, Val J

2009-01-01

Physiologic uptake of 2-[(18)F]-fluoro-2-deoxy-D: -glucose (FDG) by bowel can confound positron emission tomography/computed tomography (PET/CT) assessment for abdominal pathology, particularly within the bowel itself. We wished to determine if oral administration of the antimotility agent, Lomotil (5 mg diphenoxylate hydrochloride/0.05 mg atropine sulfate; G.D. Searle and Company, a division of Pfizer), prior to PET/CT scanning would reduce physiologic uptake of FDG by the small bowel and colon (lower gastrointestinal [GI] tract). Patients undergoing PET/CT scans for lymphoma were enrolled in a prospective, randomized, double-blinded study and received either 10 mL water (control group) or 10 mL Lomotil (experimental group) orally 30-60 min prior to scanning. Scans were reviewed independently by two blinded experienced readers and scored for the degree of FDG activity in the lower GI tract relative to liver activity. The administration of Lomotil prior to PET/CT scanning did not reduce physiologic FDG activity in the small bowel and colon. In contrast, increased radiotracer uptake by the lower GI tract was observed in the Lomotil group compared to the control group. Pretreatment with Lomotil prior to PET/CT scanning confers no benefit toward the reduction of physiologic FDG uptake by the small bowel and colon.

Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories

PubMed Central

Kim, Kyuri; Chini, Naseem; Fairchild, David G.; Engle, Steven K.; Reagan, William J.; Summers, Sandra D.; Mirsalis, Jon C.

2016-01-01

There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by three institutions (SRI, Eli Lilly and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the inter-laboratory and inter-platform variation in results. Serum concentrations of natriuretic peptides (NT-proANP, NT-proBNP), cardiac and skeletal troponins (cTnI, cTnT, sTnI), myosin light chain 3 (Myl3) and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil and isoproterenol. Minoxidil caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24 hr postdose without elevation in troponins, Myl3 or FABP3 and with no abnormal histopathological findings. Isoproterenol caused ventricular leukocyte infiltration, myocyte fibrosis and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins and Myl3. These results reinforce the advantages of a multi-marker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24 hr post-treatment. The inter-laboratory and inter-platform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies. PMID:27638646

Using search engine query data to track pharmaceutical utilization: a study of statins.

PubMed

Schuster, Nathaniel M; Rogers, Mary A M; McMahon, Laurence F

2010-08-01

To examine temporal and geographic associations between Google queries for health information and healthcare utilization benchmarks. Retrospective longitudinal study. Using Google Trends and Google Insights for Search data, the search terms Lipitor (atorvastatin calcium; Pfizer, Ann Arbor, MI) and simvastatin were evaluated for change over time and for association with Lipitor revenues. The relationship between query data and community-based resource use per Medicare beneficiary was assessed for 35 US metropolitan areas. Google queries for Lipitor significantly decreased from January 2004 through June 2009 and queries for simvastatin significantly increased (P <.001 for both), particularly after Lipitor came off patent (P <.001 for change in slope). The mean number of Google queries for Lipitor correlated (r = 0.98) with the percentage change in Lipitor global revenues from 2004 to 2008 (P <.001). Query preference for Lipitor over simvastatin was positively associated (r = 0.40) with a community's use of Medicare services. For every 1% increase in utilization of Medicare services in a community, there was a 0.2-unit increase in the ratio of Lipitor queries to simvastatin queries in that community (P = .02). Specific search engine queries for medical information correlate with pharmaceutical revenue and with overall healthcare utilization in a community. This suggests that search query data can track community-wide characteristics in healthcare utilization and have the potential for informing payers and policy makers regarding trends in utilization.

Stimulant use and its impact on growth in children receiving growth hormone therapy: an analysis of the KIGS International Growth Database.

PubMed

Miller, Bradley S; Aydin, Ferah; Lundgren, Frida; Lindberg, Anders; Geffner, Mitchell E

2014-01-01

Children receiving stimulants for attention deficit hyperactivity disorder (ADHD) frequently present to pediatric endocrinology clinics for evaluation and treatment of growth disorders. The worldwide prevalence of stimulant use in children with ADHD also receiving recombinant human growth hormone (rhGH) and the impact on response to rhGH are unknown. Data on children enrolled in the KIGS® (Pfizer International Growth Study) registry were evaluated for the associated diagnosis of ADHD prior to initiation of Genotropin® rhGH. Concomitant stimulant medications and auxological information were captured. Response to rhGH was evaluated using established growth prediction models. The prevalence of ADHD in KIGS was 2.3% (1,748/75,251), with stimulants used in 1.8% (1,326/75,251). Children with idiopathic growth hormone deficiency (IGHD) who received stimulants grew significantly less (1.1 cm) in the first year of rhGH therapy than expected for rhGH-treated non-ADHD IGHD children. After one year of rhGH, idiopathic short stature (ISS) children with ADHD were significantly shorter [0.74 cm (with stimulants) and 0.69 cm (without stimulants)] than non-ADHD ISS children. We demonstrated an impaired response to rhGH in IGHD and ISS children with ADHD. Our findings suggest that the ADHD phenotype, alone or in conjunction with stimulant therapy, may impair the short-term growth response to rhGH.

The American Journal of Cardiology and Journal of Periodontology editors' consensus: periodontitis and atherosclerotic cardiovascular disease.

PubMed

Friedewald, Vincent E; Kornman, Kenneth S; Beck, James D; Genco, Robert; Goldfine, Allison; Libby, Peter; Offenbacher, Steven; Ridker, Paul M; Van Dyke, Thomas E; Roberts, William C

2009-07-01

This Editors' Consensus is supported by an educational grant from Colgate-Palmolive, Inc., New York, New York, and is based on a meeting of the authors held in Boston, Massachusetts, on January 9, 2009. Dr. Friedewald has received honoraria for speaking from Novartis, East Hanover, New Jersey. Dr. Kornman is a full-time employee and shareholder of Interleukin Genetics, Waltham, Massachusetts, which owns patents on genetic biomarkers for chronic inflammatory diseases. Dr. Genco is a consultant to Merck, Whitehouse Station, New Jersey. Dr. Ridker has received research support from AstraZeneca, Wilmington, Delaware; Novartis; Pfizer, New York, New York; Roche, Nutley, New Jersey; Sanofi-Aventis, Bridgewater, New Jersey; and Abbott Laboratories, Abbott Park, Illinois. Dr. Ridker has received non-financial research support from Amgen, Thousand Oaks, California. Dr. Ridker is a co-inventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease. Dr. Ridker is a research consultant for Schering-Plough, Kenilworth, New Jersey; Sanofi-Aventis; AstraZeneca; Isis, Carlsbad, California; Novartis; and Vascular Biogenics, Tel Aviv, Israel. Dr. Van Dyke is a co-inventor on patents held by Boston University, Boston, Massachusetts, that relate to inflammation control, including consulting fees. Dr. Roberts has received honoraria for speaking from Merck, Schering-Plough, AstraZeneca, and Novartis. All other individuals in a position to control content disclosed no relevant financial relationships.

Drug-like properties and the causes of poor solubility and poor permeability.

PubMed

Lipinski, C A

2000-01-01

There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.

Internet versus in-person counseling for patients taking varenicline for smoking cessation.

PubMed

Dezee, Kent J; Wink, Jennifer S; Cowan, Christopher M

2013-04-01

Quit rates for smoking cessation attempts are maximized by using counseling with medication. Internet-based counseling might be a suitable replacement for in-person counseling. Patients in a military medical system in the active phase of quitting presented for study intake. They were randomized to in-person counseling (n = 44) or Internet counseling (n = 173). In-person counseling consisted of four 1.5 hour classes based on the American Cancer Society's Freshstart program. Internet counseling consisted of daily e-mails with recommended activities through Pfizer's GetQuit program. Both groups were concomitantly treated with standard dose varenicline. The primary outcome was the quit rate at 12 weeks, defined as abstinence and an exhaled carbon monoxide level <10 ppm at the 12-week visit. All those lost to follow-up were considered persistent smokers. 217 smokers were randomized, of which 43% returned for the 12-week follow-up visit. Quit rates between the two groups were similar (Internet group: 21%, n = 36/173; in-person group: 18%, n = 8/44, p = 0.7). Internet-based counseling might be equivalent to in-person counseling for smoking cessation in patients taking varenicline. Additional studies with more complete and longer-term (≥1 year) follow-up are needed to confirm these findings. Reprint & Copyright © 2013 Association of Military Surgeons of the U.S.

Sunitinib‐Induced Cardiotoxicity Is Mediated by Off‐Target Inhibition of AMP‐Activated Protein Kinase

PubMed Central

Kerkela, Risto; Woulfe, Kathleen C.; Durand, Jean‐Bernard; Vagnozzi, Ronald; Kramer, David; Chu, Tammy F.; Beahm, Cara; Chen, Ming Hui; Force, Thomas

2009-01-01

Abstract Tyrosine kinase inhibitors (TKIs) are transforming the treatment of patients with malignancies. One such agent, sunitinib (Sutent, Pfizer, New York, NY, USA), has demonstrated activity against a variety of solid tumors. Sunitinib is “multitargeted,” inhibiting growth factor receptors that regulate both tumor angiogenesis and tumor cell survival. However, cardiac dysfunction has been associated with its use. Identification of the target of sunitinib‐associated cardiac dysfunction could guide future drug design to reduce toxicity while preserving anticancer activity. Herein we identify severe mitochondrial structural abnormalities in the heart of a patient with sunitinib‐induced heart failure. In cultured cardiomyocytes, sunitinib induces loss of mitochondrial membrane potential and energy rundown. Despite the latter, 5′ adenosine monophosphate‐activated protein kinase (AMPK) activity, which should be increased in the setting of energy compromise, is reduced in hearts of sunitinib‐treated mice and cardiomyocytes in culture, and this is due to direct inhibition of AMPK by sunitinib. Critically, we find that adenovirus‐mediated gene transfer of an activated mutant of AMPK reduces sunitinib‐induced cell death. Our findings suggest AMPK inhibition plays a central role in sunitinib cardiomyocyte toxicity, highlighting the potential of off‐target effects of TKIs contributing to cardiotoxicity. While multitargeting can enhance tumor cell killing, this must be balanced against the potential increased risk of cardiac dysfunction. PMID:20376335

Due diligence in the characterization of matrix effects in a total IL-13 Singulex™ method.

PubMed

Fraser, Stephanie; Soderstrom, Catherine

2014-04-01

After obtaining her PhD in Cellular and Molecular biology from the University of Nevada, Reno, Stephanie has spent the last 15 years in the field of bioanalysis. She has held positions in academia, biotech, contract research and large pharma where she has managed ligand binding assay (discovery to Phase IIb clinical) and flow cytometry (preclinical) laboratories as well as taken the lead on implementing new/emergent technologies. Currently Stephanie leads Pfizer's Regulated Bioanalysis Ligand Binding Assay group, focusing on early clinical biomarker support. Interleukin (IL)-13, a Th2 cytokine, drives a range of physiological responses associated with the induction of allergic airway diseases and inflammatory bowel diseases. Analysis of IL-13 as a biomarker has provided insight into its role in disease mechanisms and progression. Serum IL-13 concentrations are often too low to be measured by standard enzyme-linked immunosorbent assay techniques, necessitating the implementation of a highly sensitive assay. Previously, the validation of a Singulex™ Erenna(®) assay for the quantitation of IL-13 was reported. Herein we describe refinement of this validation; defining the impact of matrix interference on the lower limit of quantification, adding spiked matrix QC samples, and extending endogenous IL-13 stability. A fit-for-purpose validation was conducted and the assay was used to support a Phase II clinical trial.

Hardness, function, emotional well-being, satisfaction and the overall sexual experience in men using 100-mg fixed-dose or flexible-dose sildenafil citrate

PubMed Central

Ströberg, P; Kaminetsky, J C; Park, N C; Goldfischer, E R; Creanga, D L; Stecher, V J

2010-01-01

The prescribing information for sildenafil citrate (VIAGRA, Pfizer, New York, NY, USA) recommends flexible dosing (50 mg initially, adjusted to 100 or 25 mg based on effectiveness and tolerability) in most men with erectile dysfunction (ED). In many men, however, 100 mg may be the most appropriate initial dose because it would reduce the need for titration and could prevent discouragement and treatment abandonment should 50 mg be insufficient. Results of two previously published double-blind, placebo-controlled sildenafil trials of similar design except for a fixed-dose vs flexible-dose regimen were analyzed. Relative to the flexible-dose, approximately one-third more men were satisfied with an initial and fixed dose of 100 mg. In addition, tolerability was similar, and improvements from baseline in outcomes on validated, ED-specific, patient-reported questionnaires were either similar (erectile function and the percentage of completely hard and fully rigid erections) or greater (emotional well-being and the overall sexual experience). The similarity in outcomes is not surprising given that almost 90% of the men in the flexible-dose trial titrated to 100 mg after 2 weeks. These data suggest prescription of an initial dose of 100 mg for men with ED, except in those for whom it is inappropriate. PMID:20596083

Synthesis and assembly of retrovirus Gag precursors into immature capsids in vitro.

PubMed Central

Sakalian, M; Parker, S D; Weldon, R A; Hunter, E

1996-01-01

The assembly of retroviral particles is mediated by the product of the gag gene; no other retroviral gene products are necessary for this process. While most retroviruses assemble their capsids at the plasma membrane, viruses of the type D class preassemble immature capsids within the cytoplasm of infected cells. This has allowed us to determine whether immature capsids of the prototypical type D retrovirus, Mason-Pfizer monkey virus (M-PMV), can assemble in a cell-free protein synthesis system. We report here that assembly of M-PMV Gag precursor proteins can occur in this in vitro system. Synthesized particles sediment in isopycnic gradients to the appropriate density and in thin-section electron micrographs have a size and appearance consistent with those of immature retrovirus capsids. The in vitro system described in this report appears to faithfully mimic the process of assembly which occurs in the host cell cytoplasm, since M-PMV gag mutants defective in in vivo assembly also fail to assemble in vitro. Likewise, the Gag precursor proteins of retroviruses that undergo type C morphogenesis, Rous sarcoma virus and human immunodeficiency virus, which do not preassemble capsids in vivo, fail to assemble particles in this system. Additionally, we demonstrate, with the use of anti-Gag antibodies, that this cell-free system can be utilized for analysis in vitro of potential inhibitors of retrovirus assembly. PMID:8648705

Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease

PubMed Central

Fazal, Karim; Khondoker, Mizanur; Howard, Robert; Stewart, Robert

2017-01-01

Background Cognitive improvement has been reported in patients receiving centrally acting angiotensin-converting enzyme inhibitors (C-ACEIs). Aims To compare cognitive decline and survival after diagnosis of Alzheimer’s disease between people receiving C-ACEIs, non-centrally acting angiotensin-converting enzyme inhibitors (NC-ACEIs), and neither. Method Routine Mini-Mental State Examination (MMSE) scores were extracted in 5260 patients receiving acetylcholinesterase inhibitors and analysed against C-/NC-ACEI exposure at the time of Alzheimer’s disease diagnosis. Results In the 9 months after Alzheimer’s disease diagnosis, MMSE scores significantly increased by 0.72 and 0.19 points per year in patients on C-ACEIs and neither respectively, but deteriorated by 0.61 points per year in those on NC-ACEIs. There were no significant group differences in score trajectories from 9 to 36 months and no differences in survival. Conclusions In people with Alzheimer’s disease receiving acetylcholinesterase inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression. Declaration of interest R.S. has received research funding from Pfizer, Lundbeck, Roche, Janssen and GlaxoSmithKline. Copyright and usage © The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license. PMID:28713585

Maraviroc: perspectives for use in antiretroviral-naive HIV-1-infected patients.

PubMed

Vandekerckhove, Linos; Verhofstede, Chris; Vogelaers, Dirk

2009-06-01

Maraviroc (Pfizer's UK-427857, Selzentry or Celsentri outside the USA) is the first agent in the new class of oral HIV-1 entry inhibitors to acquire approval by the US Food and Drug Administration and the European Medicine Agency. Considering the mechanism of action, it is expected that this drug will be effective only in a subpopulation of HIV-1-infected people, namely those harbouring the R5 virus. The favourable toxicity profile of the drug has been demonstrated in Phase III clinical trials in treatment-naive (MERIT) and treatment-experienced (MOTIVATE) patients. In the latter population, maraviroc showed a superior antiviral efficacy and immunological activity compared with optimized backbone therapy + placebo. However, in MERIT, a prospective double-blind, randomized trial in treatment-naive patients, maraviroc + zidovudine/lamivudine failed to prove non-inferiority to efavirenz + zidovudine/lamivudine as standard of care regimen in the 48 week intention-to-treat analysis. Using an assay with higher sensitivity for minority CXCR4-using (X4) HIV variants (the enhanced Trofile assay-Monogram), non-inferiority was reached for the maraviroc- versus efavirenz-based combination. These data indicate the important impact of the sensitivity of tropism testing on treatment outcome of maraviroc-containing regimens. This paper discusses both the prospective and retrospective analyses of the MERIT data and highlights the impact of these results on daily practice in HIV care.

Evaluation of Real-World Experience with Tofacitinib Compared with Adalimumab, Etanercept, and Abatacept in RA Patients with 1 Previous Biologic DMARD: Data from a U.S. Administrative Claims Database.

PubMed

Harnett, James; Gerber, Robert; Gruben, David; Koenig, Andrew S; Chen, Connie

2016-12-01

Real-world data comparing tofacitinib with biologic disease-modifying antirheumatic drugs (bDMARDs) are limited. To compare characteristics, treatment patterns, and costs of patients with rheumatoid arthritis (RA) receiving tofacitinib versus the most common bDMARDs (adalimumab [ADA], etanercept [ETN], and abatacept [ABA]) following a single bDMARD in a U.S. administrative claims database. This study was a retrospective cohort analysis of patients aged ≥ 18 years with an RA diagnosis (ICD-9-CM codes 714.0x-714.4x; 714.81) and 1 previous bDMARD filling ≥ 1 tofacitinib or bDMARD claim in the Truven MarketScan Commercial and Medicare Supplemental claims databases (November 1, 2012-October 31, 2014). Monotherapy was defined as absence of conventional synthetic DMARDs within 90 days post-index. Persistence was evaluated using a 60-day gap. Adherence was assessed using proportion of days covered (PDC). RA-related total, pharmacy, and medical costs were evaluated in the 12-month pre- and post-index periods. Treatment patterns and costs were adjusted using linear models including a common set of clinically relevant variables of interest (e.g., previous RA treatments), which were assessed separately using t-tests and chi-squared tests. Overall, 392 patients initiated tofacitinib; 178 patients initiated ADA; 118 patients initiated ETN; and 191 patients initiated ABA. Tofacitinib patients were older versus ADA patients (P = 0.0153) and had a lower proportion of Medicare supplemental patients versus ABA patients (P = 0.0095). Twelve-month pre-index bDMARD use was greater in tofacitinib patients (77.6%) versus bDMARD cohorts (47.6%-59.6%). Tofacitinib patients had greater 12-month pre-index RA-related total costs versus bDMARD cohorts (all P < 0.0001) and greatest index use of monotherapy (P = 0.0080 vs. ABA). A similar (all P > 0.10) proportion of patients were persistent with tofacitinib (42.6%) versus ADA (37.6%), ETN (42.4%), and ABA (43.5%). Mean PDC was 0.55 for tofacitinib versus 0.57 (ADA), 0.59 (ETN), and 0.44 (ABA; P = 0.0003). Adjusted analyses generated similar findings to the unadjusted treatment patterns. Tofacitinib had lower adjusted 12-month post-index mean RA-related total costs ($23,568) versus ADA ($29,278; P < 0.0001), ETN ($26,885; P = 0.0248), and ABA ($30,477; P < 0.0001). In this study, tofacitinib was more commonly used as monotherapy and yielded at least comparable persistence and adherence with lower adjusted mean RA-related total costs versus ADA, ETN, and ABA. Further analysis is warranted given the greater 12-month pre-index bDMARD use and RA-related costs for tofacitinib versus bDMARDs. This study was sponsored by Pfizer. Harnett, Gerber, Gruben, Koenig, and Chen are employees and shareholders of Pfizer. Some data reported in this manuscript have been previously presented at the Academy of Managed Care Nexus 2015; Orlando, Florida; October 26-29, 2015, and was submitted in abstract form to the European League Against Rheumatism Congress; London, United Kingdom; June 8-11, 2016. All authors were involved in the conception and design of this study. Harnett and Gruben were involved in data collection and analysis. All authors interpreted the data, critically reviewed and revised the manuscript, and read and approved the final manuscript.

Sequential Therapies and the Cost-Effectiveness of Treating Metastatic Colon Cancer Patients.

PubMed

Woldemichael, Andinet; Onukwugha, Eberechukwu; Seal, Brian; Hanna, Nader; Mullins, C Daniel

2016-06-01

Technological advances in colon cancer treatment have significantly increased survival outcomes among metastatic patients. With different chemotherapy and biologic regimens administered in first, second, and subsequent lines of treatments, costs and survival outcomes vary considerably. However, there is little evidence on how the type of regime administered in the first line of treatment affects the costs and survival outcomes of the second line of treatment. To examine how the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients varies by the type of regimen administered in the first line of treatment. The Surveillance, Epidemiology and End Results (SEER) cancer registry was used, which is linked with the Medicare claims database, to study elderly metastatic patients diagnosed between 2003 and 2009. Average survivals are estimated using the robust nonparametric Kaplan-Meier method. Selection bias was adjusted for using inverse probability weighting and censoring using robust nonparametric methods of estimating the average of total health care costs. Mean incremental survival was 6.7 months for patients who received second-line treatment (95% CI = 5.7-7.7) compared with those receiving only first-line treatment. However, the mean incremental survival varied between 4 months (95% CI = 0.0-7.3) and 9 months (95% CI = 6.5-11.0) depending on whether fluorouracil with or without leucovorin, irinotecan, oxaliplatin, or other agents were administered in first-line treatment. The mean incremental cost associated with receipt of second-line treatment was $60,231 (95% CI = 52,461-64,198) but ranged between $55,368 (95% CI = 48,294-61,290) and $71,211 (95% CI = 43,168-99,667), depending on the type of regimen administered in the first-line treatment. Combining survival benefits and costs, the incremental cost-effectiveness ratios per life-year gained associated with the receipt of second-line treatment were $97,368 (95% CI = 80,415-117,965); $110,621 (95% CI = 89,560-133,961); $130,689 (95% CI = 101,459-171,918); and $247,951 (95% CI = 112,629808,976) when irinotican, fluorouracil/leucovorin, oxaliplatin, and "other" combinations were, respectively, administered in first-line treatment. In addition, the results varied depending on which statistical method was used. When therapies are administered in a sequential manner, the cost-effectiveness of the second line of therapy depends on what was administered in the first line of therapy. Bayer Healthcare Pharmaceuticals provided funding for this project. Onukwugha has received research funding from Bayer and Amgen and has a consultant/advisory relationship with Jansen Analytics at Johnson & Johnson. Seal was formerly an employee of Bayer and holds stock in Bayer. Mullins has research funding sponsored by Bayer and Pfizer and has a consultant/advisory relationship with Bayer, Amgen, BMS, Genentech, GSK, Novartis, NovoNordisk, and Pfizer. Woldemichael and Nader report no conflicts of interest. All authors contributed to the concept and design of this study. Onukwugha, Seal, and Mullins collected the data, with assistance from Woldemichael and Hanna, while Woldemichael interpreted the data, assisted by the other authors. The manuscript was written primarily by Woldemichael, with assistance from the other authors, and revised by Seal, Hanna, and Mullins, with assistance from Woldemichael and Onukwugha.

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

PubMed

2003-01-01

Erlotinib [Tarceva, R 1415, CP 358774, OSI 774, NSC 718781] is a small molecular, once-a-day, orally active inhibitor of the epidermal growth factor receptor tyrosine kinase. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. It is one of a class of anticancer drugs that target the underlying molecular mechanism involving oncogenes and tumour suppressor genes, which play critical roles in the conversion of normal cells into a cancerous state. Erlotinib is undergoing clinical development as an oral tablet by an alliance between OSI Pharmaceuticals, Genentech and Roche. OSI Pharmaceuticals, Genentech and Roche have entered an agreement for the global development and commercialisation of erlotinib. Under the terms of the agreement, Genentech and OSI will share costs and profit-taking for commercialising the product in the US. The overall costs of the development programme will be shared equally between the three companies. OSI will keep certain co-promotion rights in the US and Genentech will be responsible for commercialising the drug in the US should the FDA approve it. Roche will take the responsibility for obtaining regulatory approval and commercialisation in territories outside the US and pay royalties to OSI on net sales of the product in these markets. Initially, the alliance partners intend to pursue development of erlotinib in all the major tumour markets, particularly for non-small cell lung cancer (NSCLC) in which the group will focus on front-line combination approaches. Pfizer and OSI Pharmaceuticals in the US were developing erlotinib as a treatment for solid tumours. However, in June 2000, Pfizer merged with Warner-Lambert. The resulting company retained the Pfizer name, but in order to meet Federal Trade Commission requirements for the merger Pfizer granted all developmental and marketing rights for erlotinib to OSI Pharmaceuticals. This divestiture of the erlotinib portfolio, in effect, gave OSI a royalty-free, cashless license to the drug. In November 2001, OSI announced a partnership deal with HopeLink Corporation, a healthcare information technology company with an Internet-based Clinical Trial Service. The partnership will enable OSI to heighten awareness of its clinical trials and shorten patient accrual times. It will initially involve the presentation of the OSI phase III pancreatic and refractory NSCLC trials via Hopelink's Syndicated Network. In addition to this the two companies have also agreed to develop additional products and service together that will increase the efficiency of the clinical trial process, increase awareness of clinical trials, and enhance patient accrual techniques. OSI has also entered into an agreement with Therradex, a contract research organisation (CRO) to monitor phase II trials for erlotinib in NSCLC, ovarian and head and neck cancer. In addition, OSI entered into an agreement in 2001 with the US NCI. The NCI is conducting trials in a variety of different cancers. A phase III front-line NSCLC trial (TRIBUTE) of erlotinib in combination with carboplatin and paclitaxel was initiated in July 2001. The multicentre study is being conducted by Genentech in 1000 patients in the US, and will determine whether the addition of erlotinib to carboplatin chemotherapy is able to improve the duration of patient survival. Enrolment for this trial was completed in July 2002. An independent Data Monitoring Committee (DMC) has since reviewed the data from the trial and concluded that there are no safety or efficacy concerns that would warrant stopping the trial. However, the DMC did recommend stopping erlotinib at the time of disease progression or at the start of second-line therapy. A front-line phase III study of erlotinib in NSCLC (TALENT) in combination with gemcitabine and cisplatin chemotherapy was initiated by Roche in Europe in November 2001. Enrolment into this study was completed in September 2002, with approximately 1200 patients. Roche has confirmed that the study woulde has confirmed that the study would be included in the alliance's potential regulatory submission for front-line therapy in chemotherapy-naive patients in the US. Data from the trial is expected in the second half of 2003. OSI has opened two additional phase Ib studies to examine the potential of erlotinib in combination with carboplatin and paclitaxel in one study and gemcitabine and cisplatin in the other. A phase I study of erlotinib is also being conducted in patients with lung cancer in Japan. OSI received fast-track status from the US FDA in September 2002 for erlotinib as a second- or third-line treatment for patients with incurable stage IIIB/IV NSCLC who have failed to respond to standard therapy for advanced metastatic disease. Fast-track status was also granted to erlotinib in May 2002 for the treatment of chemotherapy-naive stage III/IV NSCLC. There are important differences between phase III studies of erlotinib and AstraZeneca's direct competitor drug gefitinib, which recently returned disappointing results in a frontline NSCLC trial with combination chemotherapy. In assessing the survival benefit of erlotinib with chemotherapy, the dose employed of 150 mg/day is the maximum tolerated dose (MTD), whereas the gefitinib trials were conducted at relatively lower doses than the MTD determined in earlier phase I studies. OSI is also investigating the survival benefit of erlotinib in a phase III study in refractory NSCLC patients, a key registration study. Patient size of the NSCLC trial was increased from 330 to 700 as OSI shifted emphasis from its pancreatic cancer trials. Phase II development for this indication was initiated based on data from a phase I trial, which had completed patient enrolment by April 2003. OSI and the US NCI signed a collaborative research agreement in 2001. The NCI is developing erlotinib through its CTEP programme for multiple tumour types including epithelial malignancies, gastrointestinal and genitourinary tracts, gynaecological malignancies and brain tumours. OSI supplies erlotinib for the trial, but the NCI provides the funding and manages the trials. A series of approximately ten phase Ib trials are already underway or were set to start in the US in 2001 to determine safety, tolerance and pharmacokinetic parameters of erlotinib in combination with a number of commonly used chemotherapeutic agents. The Wall Street Journal reported on 25 February 2002, that analysts at Robert Stephens, New York, USA, have forecast Tarceva to reach annual sales of >$US1 billion. Other analysts, at Merrill Lynch & Co., have predicted that products belonging to the same class as Tarceva could reach combined worldwide sales of $US6 billion to $US10 billion annually. In an earlier report by the Financial Times on 10 May 2001, it was stated that approximately 12 new anticancer agents are expected to be approved by the FDA through to the end of 2002. These agents, of which Tarceva is one, were said to have the potential to generate total sales of $US2.6 billion. Goldman Sachs have forecast Tarceva to reach peak sales of $US250 million for the indication of head and neck cancer alone. Previously in January 2001, the Financial Times claimed that OSI Pharmaceuticals, one of the development partners for Tarceva, stood to gain $US187 million pending regulatory approval. Genentech and Roche were each said to be buying $US35 million worth of OSI's stock and paying upfront fees. Tarceva is facing competition by two similar compounds, developed by AstraZeneca and ImClone, respectively.

Factors affecting fetal bradycardia following combined spinal epidural for labor analgesia: a matched case-control study.

PubMed

Cheng, Su Lin Maureen; Bautista, Dianne; Leo, Serene; Sia, Tiong Heng Alex

2013-04-01

The combined spinal epidural (CSE) technique for labor analgesia has become increasingly popular owing to its rapid onset of analgesia. However, incidences of fetal bradycardia following CSE have been reported. This study aimed to identify predictors of fetal bradycardia post CSE, such as a decrease in pain scores, the block height, Prostin (dinoprostone; Pfizer) use, and dosage of oxytocin. From May 2008 to October 2008, 29 patients were identified to have had an episode of fetal bradycardia. Each case was then matched to three controls, according to age and American Society of Anesthesiology status, selected from 2345 parturients who received a CSE during this period. A unit improvement in the pain score was associated with an increase in the odds of fetal bradycardia by 1.28 (95 % confidence interval [CI]: 1.02-1.60). In a second logistic regression model including sensory level higher than T9, the effect size remained consistent with an odds ratio of 1.22 (95 % CI: 0.97-1.53), supporting the theory that a higher level of sympathetic block (with a higher sensory block taken as a surrogate marker) results in an increased risk of fetal bradycardia. The dosage of oxytocin and the quantity of Prostin used were not found to be risk factors. The difference between pre- and post-CSE pain scores, and a higher sensory block height, which are surrogates for a greater degree of sympatholysis, were found to be risk factors for fetal bradycardia post CSE.

Imaging of VEGF Receptor Kinase Inhibitor-Induced Antiangiogenic Effects in Drug-Resistant Human Adenocarcinoma Model1

PubMed Central

Reichardt, Wilfried; Hu-Lowe, Dana; Torres, Denise; Weissleder, Ralph; Bogdanov, Alexei

2005-01-01

Abstract Small molecule vascular endothelial growth factor (VEGF) receptor tyrosinase kinase inhibitors (VEGFR-TKIs) show great promise in inducing antiangiogenic responses in tumors. We investigated whether antiangiogenic tumor responses induced by an experimental VEGFR-TKI (AG013925; Pfizer Global Research and Development) could be reported by magnetic resonance imaging (MRI) during the initial phase of treatment. We used MRI and superparamagnetic nanoparticles for measuring relative vascular volume fraction (rVVF) in a drug-resistant colon carcinoma model. Athymic mice harboring MV522 xenografts were treated with VEGFR-TKI (25 mg/kg, p.o., with a 12-hour interval in between treatments) and were imaged after three consecutive treatments. Relative tumor blood volume fractions were calculated using ΔR2* maps that were scaled by the known VVF value of an in-plane skeletal muscle (1.9%). There was a pronounced and statistically significant (P < .001) decrease of tumor rVVF in treated animals (0.95 ± 0.24%; mean ± SEM, n = 66 slices, eight mice) compared to mice that received a placebo (2.91 ± 0.24%; mean ± SEM, n = 66 slices, nine mice). Tumor histology confirmed a three-fold decrease of vascular density and a concomitant increase of apoptotic cell index. Hence, we demonstrated that: 1) the VEGFR-TKI resulted in antiangiogenic effects that were manifested by a decrease or rVVF; and 2) iron oxide nanoparticles and steady-state MRI enable an early detection of tumor response to antiangiogenic therapies. PMID:16229807

STEPS: A NARRATIVE ACCOUNT OF A GABAPENTIN SEEDING TRIAL

PubMed Central

Krumholz, Samuel D.; Egilman, David S.; Ross, Joseph S.

2012-01-01

Background Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. Methods We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing v. Pfizer and Franklin v. Warner-Lambert, the majority of which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial, in order to identify key themes related to the trial’s conduct and determine the extent of marketing involvement in its planning and implementation. Results Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company’s marketing plans. Documents demonstrated that several external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in two published papers. Conclusions The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation. PMID:21709111

Functional and Structural Characterization of Novel Type of Linker Connecting Capsid and Nucleocapsid Protein Domains in Murine Leukemia Virus.

PubMed

Doležal, Michal; Hadravová, Romana; Kožíšek, Milan; Bednárová, Lucie; Langerová, Hana; Ruml, Tomáš; Rumlová, Michaela

2016-09-23

The assembly of immature retroviral particles is initiated in the cytoplasm by the binding of the structural polyprotein precursor Gag with viral genomic RNA. The protein interactions necessary for assembly are mediated predominantly by the capsid (CA) and nucleocapsid (NC) domains, which have conserved structures. In contrast, the structural arrangement of the CA-NC connecting region differs between retroviral species. In HIV-1 and Rous sarcoma virus, this region forms a rod-like structure that separates the CA and NC domains, whereas in Mason-Pfizer monkey virus, this region is densely packed, thus holding the CA and NC domains in close proximity. Interestingly, the sequence connecting the CA and NC domains in gammaretroviruses, such as murine leukemia virus (MLV), is unique. The sequence is called a charged assembly helix (CAH) due to a high number of positively and negatively charged residues. Although both computational and deletion analyses suggested that the MLV CAH forms a helical conformation, no structural or biochemical data supporting this hypothesis have been published. Using an in vitro assembly assay, alanine scanning mutagenesis, and biophysical techniques (circular dichroism, NMR, microcalorimetry, and electrophoretic mobility shift assay), we have characterized the structure and function of the MLV CAH. We provide experimental evidence that the MLV CAH belongs to a group of charged, E(R/K)-rich, single α-helices. This is the first single α-helix motif identified in viral proteins. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Multinomial modeling and an evaluation of common data-mining algorithms for identifying signals of disproportionate reporting in pharmacovigilance databases.

PubMed

Johnson, Kjell; Guo, Cen; Gosink, Mark; Wang, Vicky; Hauben, Manfred

2012-12-01

A principal objective of pharmacovigilance is to detect adverse drug reactions that are unknown or novel in terms of their clinical severity or frequency. One method is through inspection of spontaneous reporting system databases, which consist of millions of reports of patients experiencing adverse effects while taking one or more drugs. For such large databases, there is an increasing need for quantitative and automated screening tools to assist drug safety professionals in identifying drug-event combinations (DECs) worthy of further investigation. Existing algorithms can effectively identify problematic DECs when the frequencies are high. However these algorithms perform differently for low-frequency DECs. In this work, we provide a method based on the multinomial distribution that identifies signals of disproportionate reporting, especially for low-frequency combinations. In addition, we comprehensively compare the performance of commonly used algorithms with the new approach. Simulation results demonstrate the advantages of the proposed method, and analysis of the Adverse Event Reporting System data shows that the proposed method can help detect interesting signals. Furthermore, we suggest that these methods be used to identify DECs that occur significantly less frequently than expected, thus identifying potential alternative indications for these drugs. We provide an empirical example that demonstrates the importance of exploring underexpected DECs. Code to implement the proposed method is available in R on request from the corresponding authors. kjell@arboranalytics.com or Mark.M.Gosink@Pfizer.com Supplementary data are available at Bioinformatics online.

Evolving landscape of human epidermal growth factor receptor 2-positive breast cancer treatment and the future of biosimilars.

PubMed

Jackisch, Christian; Lammers, Philip; Jacobs, Ira

2017-04-01

Human epidermal growth factor receptor 2-positive (HER2+) breast cancer comprises approximately 15%-20% of all breast cancers and is associated with a poor prognosis. The introduction of anti-HER2 therapy has significantly improved clinical outcomes for patients with HER2+ breast cancer, and multiple HER2-directed agents (ie, trastuzumab, pertuzumab, lapatinib, and ado-trastuzumab emtansine [T-DM1]) are approved for clinical use in various settings. The treatment landscape for patients with HER2+ breast cancer is continuing to evolve. While novel agents and therapeutic strategies are emerging, biologic therapies, particularly trastuzumab, are likely to remain a mainstay of treatment. However, access issues create barriers to the use of biologics, and there is evidence for underuse of trastuzumab worldwide. A biosimilar is a biologic product that is highly similar to a licensed biologic in terms of product safety and effectiveness. Biosimilars of trastuzumab are in development and may soon become available. The introduction of biosimilars may improve access to anti-HER2 therapies by providing additional treatment options and lower-cost alternatives. Because HER2-targeted drugs may be administered for extended periods of time and in combination with other systemic therapies, biosimilars have the potential to result in significant savings for healthcare systems. Herein we review current and emerging treatment options for, and discuss the possible role of biosimilars in, treating patients with HER2+ breast cancer. Copyright © 2017 Authors, Pfizer Inc. Published by Elsevier Ltd.. All rights reserved.

Study of neurontin: titrate to effect, profile of safety (STEPS) trial: a narrative account of a gabapentin seeding trial.

PubMed

Krumholz, Samuel D; Egilman, David S; Ross, Joseph S

2011-06-27

Seeding trials, clinical studies conducted by pharmaceutical companies for marketing purposes, have rarely been described in detail. We examined all documents relating to the clinical trial Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) produced during the Neurontin marketing, sales practices, and product liability litigation, including company internal and external correspondence, reports, and presentations, as well as depositions elicited in legal proceedings of Harden Manufacturing vs Pfizer and Franklin vs Warner-Lambert, most which were created between 1990 and 2009. Using a systematic search strategy, we identified and reviewed all documents related to the STEPS trial in order to identify key themes related to the trial's conduct and determine the extent of marketing involvement in its planning and implementation. Documents demonstrated that STEPS was a seeding trial posing as a legitimate scientific study. Documents consistently described the trial itself, not trial results, to be a marketing tactic in the company's marketing plans. Documents demonstrated that at least 2 external sources questioned the validity of the study before execution, and that data quality during the study was often compromised. Furthermore, documents described company analyses examining the impact of participating as a STEPS investigator on rates and dosages of gabapentin prescribing, finding a positive association. None of these findings were reported in 2 published articles. The STEPS trial was a seeding trial, used to promote gabapentin and increase prescribing among investigators, and marketing was extensively involved in its planning and implementation.

[Periinterventional prophylactic antibiotics in radiological port catheter implantation].

PubMed

Gebauer, B; Teichgräber, U; Werk, M; Wagner, H-J

2007-08-01

To evaluate whether catheter-related infections after radiologically placed port catheters can be reduced by single-shot periinterventional antibiosis. Between January and September 2002, 164 consecutive patients with indication for central venous port catheter implantation were included in the present study. During implantation the interventional radiologist was responsible for deciding whether to administer a prophylactic single-shot antibiosis. The prophylactic antibiosis entailed intravenous administration of ampicillin and sulbactam (3 g Unacid, Pfizer) or 100 mg ciprofloxacine (Ciprobay, Bayer) in the case of an allergy history to penicillins. Catheter-related infection was defined as a local or systemic infection necessitating port catheter extraction. Indication for port catheter implantation was a malignant disease requiring chemotherapy in 158 cases. The port catheter (Chemosite [Tyco Healthcare] [n = 123], low-profile [Arrow International] [n = 35], other port system [n = 6]) was implanted via sonographically guided puncture of the right jugular vein in 139 patients, via the left jugular vein in 24 cases and via the right subclavian vein in one patient. 75 patients received periinterventional prophylactic antibiosis (Unacid [n = 63] Ciprobay [n = 12]) and 89 patients did not receive antibiosis. The prophylactic antibiosis caused a minor allergic reaction in one patient that improved with antihistamic and corticoid medication. A total of 7 ports, 6 without prophylactic antibiosis versus one with periinterventional prophylaxis, were extracted due to infectious complications. Single-shot periinterventional prophylactic antibiosis can reduce early and late infectious complications after radiological-interventional placement of central venous port catheters.

Solid-state characterization and impurities determination of fluconazol generic products marketed in Morocco

PubMed Central

Bourichi, Houda; Brik, Youness; Hubert, Philipe; Cherrah, Yahia; Bouklouze, Abdelaziz

2012-01-01

In this paper, we report the results of quality control based in physicochemical characterization and impurities determination of three samples of fluconazole drug substances marketed in Morocco. These samples were supplied by different pharmaceuticals companies. The sample A, as the discovered product, was supplied by Pfizer, while samples B and C (generics), were manufactured by two different Indian industries. Solid-state characterization of the three samples was realized with different physicochemical methods as: X-ray powder diffraction, Fourier-transformation infrared spectroscopy, differential scanning calorimetry. High performance liquid chromatography was used to quantify the impurities in the different samples. The results from the physicochemical methods cited above, showed difference in polymorph structure of the three drug substances. Sample A consisted in pure polymorph III, sample B consisted in pure polymorph II, sample C consisted in a mixture of fluconazole Form III, form II and the monohydrate. This result was confirmed by differential scanning calorimetry. Also it was demonstrated that solvents used during the re-crystallization step were among the origins of these differences in the structure form. On the other hand, the result of the stability study under humidity and temperature showed that fluconazole polymorphic transformation could be owed to the no compliance with the conditions of storage. The HPLC analysis of these compounds showed the presence of specific impurities for each polymorphic form, and a possible relationship could be exist between impurities and crystalline form of fluconazole. PMID:29403776

Evaluation of an extended-release formulation of ceftiofur crystalline-free acid in koi (Cyprinus carpio).

PubMed

Grosset, C; Weber, E S; Gehring, R; Sanchez-Migallon Guzman, D; Campbell, L A; Enz, C; Groff, J M; Tell, L A

2015-12-01

The use of an extended release ceftiofur crystalline-free acid formulation (CCFA, Excede For Swine(®) , Pfizer Animal Health) in koi was evaluated after administration of single intramuscular (i.m.) or intracoelomic (i.c.) doses. Twenty koi were divided randomly into a control group and four treatment groups (20 mg/kg i.m., 60 mg/kg i.m., 30 mg/kg i.c., and 60 mg/kg i.c.). Serum ceftiofur-free acid equivalents (CFAE) concentrations were quantified. The pharmacokinetic data were analyzed using a nonlinear mixed-effects approach. Following a CCFA injection of 60 mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4 μg/mL ranged from 0.4 to 2.5 weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4 μg/mL for lower doses evaluated. Substantial inter-individual variations and intra-individual fluctuations of CFAE concentrations were observed for all treatment groups. Histological findings following euthanasia included aseptic granulomatous reactions, but no systemic adverse effects were detected. Given the unpredictable time vs. CFAE concentration profiles for treated koi, the authors would not recommend this product for therapeutic use in koi at this time. Further research would be necessary to correlate serum and tissue concentrations and to better establish MIC data for Aeromonas spp. isolated from naturally infected koi. © 2015 John Wiley & Sons Ltd.

FDA Approval: Palbociclib for the Treatment of Postmenopausal Patients with Estrogen Receptor-Positive, HER2-Negative Metastatic Breast Cancer.

PubMed

Beaver, Julia A; Amiri-Kordestani, Laleh; Charlab, Rosane; Chen, Wei; Palmby, Todd; Tilley, Amy; Zirkelbach, Jeanne Fourie; Yu, Jingyu; Liu, Qi; Zhao, Liang; Crich, Joyce; Chen, Xiao Hong; Hughes, Minerva; Bloomquist, Erik; Tang, Shenghui; Sridhara, Rajeshwari; Kluetz, Paul G; Kim, Geoffrey; Ibrahim, Amna; Pazdur, Richard; Cortazar, Patricia

2015-11-01

On February 3, 2015, the FDA granted accelerated approval to palbociclib (IBRANCE, Pfizer Inc.), an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. The approval is based on a randomized, multicenter, open-label phase I/II trial (PALOMA-1) in 165 patients randomized to palbociclib (125 mg orally daily for 21 consecutive days, followed by 7 days off treatment) plus letrozole (2.5 mg orally daily) or letrozole alone. The phase II portion of the trial was divided into two cohorts: cohort 1 enrolled 66 biomarker-unselected patients and cohort 2 enrolled 99 biomarker-positive patients. The major efficacy outcome measure was investigator-assessed progression-free survival (PFS). A large magnitude of improvement in PFS was observed in patients receiving palbociclib plus letrozole compared with patients receiving letrozole alone (HR, 0.488; 95% confidence interval, 0.319-0.748). Multiple sensitivity analyses were supportive of clinical benefit. The most common adverse reaction in patients receiving palbociclib plus letrozole was neutropenia. This article summarizes the FDA thought process and data supporting accelerated approval based on PALOMA-1 that may be contingent upon verification and description of clinical benefit in the ongoing and fully accrued confirmatory trial PALOMA-2. ©2015 American Association for Cancer Research.

[Effects of an additional nonsteroidal anti-inflammatory therapy with carprofen (Rimadyl Rind) in cases of severe mastitis of high yielding cows].

PubMed

Krömker, Volker; Paduch, Jan-Hendrik; Abograra, Ismail; Zinke, Claudia; Friedrich, Julia

2011-01-01

This field study focuses on the possible effects of a combination of nonsteroidal anti-inflammatory treatment (carprofen) and a local and parenteral antibiotic on cure rates, survival rate and return to milk production of severe clinical mastitis cases. 69 cows in 3 herds (blocked by parity) with severe clinical mastitis during the first 120 d of lactation (median = 28 d) were treated with antibiotics and one-half of these cows were treated with 1.4 mg/kg bodyweight carprofen (Rimadyl Rind, Pfizer GmbH Tiergesundheit, Germany). Double milk samples for bacteriology were collected from clinically affected udder quarters before treatment and at 14 (+/- 3) and 21 (+/- 3) days after commencement of treatment for cytomicro-temperature, clinical, bacteriological, cytobacteriological cure rate and in the number of cows that were defined as treatment failures (i.e., died, re-treated, relapse). Six (22.2%) vs. seven (19.4%) cows in the carprofen and control groups failed, respectively. The milk yield was significantly higher in the carprofen-treated group compared with the control group after treatment. The present work gives first indications that treatment of cows with severe clinical mastitis with a combination of carprofen and antibiotics could result in a faster return to milk production compared to treatment with antibiotics alone. If this effect can be affiliated to the administration of carprofen alone has to be examined in further studies.

Evaluation of Cardiac Toxicity Biomarkers in Rats from Different Laboratories.

PubMed

Kim, Kyuri; Chini, Naseem; Fairchild, David G; Engle, Steven K; Reagan, William J; Summers, Sandra D; Mirsalis, Jon C

2016-12-01

There is a great need for improved diagnostic and prognostic accuracy of potential cardiac toxicity in drug development. This study reports the evaluation of several commercially available biomarker kits by 3 institutions (SRI, Eli Lilly, and Pfizer) for the discrimination between myocardial degeneration/necrosis and cardiac hypertrophy as well as the assessment of the interlaboratory and interplatform variation in results. Serum concentrations of natriuretic peptides (N-terminal pro-atrial natriuretic peptide [NT-proANP] and N-terminal pro-brain natriuretic peptide [NT-proBNP]), cardiac and skeletal troponins (cTnI, cTnT, and sTnI), myosin light chain 3 (Myl3), and fatty acid binding protein 3 (FABP3) were assessed in rats treated with minoxidil (MNX) and isoproterenol (ISO). MNX caused increased heart-to-body weight ratios and prominent elevations in NT-proANP and NT-proBNP concentrations detected at 24-hr postdose without elevation in troponins, Myl3, or FABP3 and with no abnormal histopathological findings. ISO caused ventricular leukocyte infiltration, myocyte fibrosis, and necrosis with increased concentrations of the natriuretic peptides, cardiac troponins, and Myl3. These results reinforce the advantages of a multimarker strategy in elucidating the underlying cause of cardiac insult and detecting myocardial tissue damage at 24-hr posttreatment. The interlaboratory and interplatform comparison analyses also showed that the data obtained from different laboratories and platforms are highly correlated and reproducible, making these biomarkers widely applicable in preclinical studies.

Baseline Characteristics and Gender Differences in Prepubertal Children Treated with Growth Hormone in Europe, USA, and Japan: 25 Years' KIGS® Experience (1987-2012) and Review.

PubMed

Ranke, Michael B; Lindberg, Anders; Tanaka, Toshiaki; Camacho-Hübner, Cecilia; Dunger, David B; Geffner, Mitchell E

2017-01-01

Information about disease-specific and gender-associated differences over longer time of short children treated with recombinant human growth hormone is missing. We analyzed data at growth hormone (GH) start in prepubertal children diagnosed with idiopathic GH deficiency (IGHD), congenital GHD, acquired GHD, idiopathic short stature (ISS), and born small for gestational age (SGA) enrolled (1987-2012) in the Pfizer International Growth Study (KIGS®) from Europe, USA, and Japan. The demographic characteristics of patients in the three regions were similar. There was a diagnosis-specific pattern for age and height, and a universal pattern showing that girls were younger and smaller at GH start. There was a predominance of males with IGHD (n = 25,703; 70.1%), congenital GHD (n = 2,860; 63.9%), acquired GHD (n = 3,280; 63.9%), ISS (n = 4,327; 71.4%), and SGA (n = 5,848; 58.0%). Male prevalence in the USA population was more pronounced in IGHD, ISS, and SGA, but less so in congenital and acquired GHD. In IGHD (Europe and Japan) and ISS (Europe), there was a trend toward decreasing male prevalence. The male prevalence in prepubertal children treated with GH varies according to geographical region and is not explained by the underlying diagnoses. A global appreciation of gender biases is required for the proper care of short girls. © 2016 S. Karger AG, Basel.

In situ rutile petrochronology: texture-related T, Paleoproterozoic inheritance and a Pan-African overprint in the oldest subduction-related eclogites, Usagaran Orogen, Tanzania

NASA Astrophysics Data System (ADS)

Moeller, A.; Kraus, K.; Herms, P.; Appel, P.; Raase, P.

2014-12-01

Rutile U-Pb thermochronology is applied successfully by both TIMS and beam methods to date cooling events in mafic and metapelitic rocks, as well as in detrital studies. The Zr-in-rutile thermometer is very robust to thermal diffusion, and generally requires complete recrystallization to change recorded crystallization temperatures. Evidence for diffusion of HFSE elements in rutile is sparse; whereas U-Pb chronology generally records diffusion controlled cooling from the last event. This study follows conventional thermobarometry and U-Pb TIMS results on monazite, sphene and rutile of Möller et al. (1995) establishing a 2 Ga eclogite facies event from MORB-like metabasic, and metapelitic rocks in the Usagaran Orogen of Tanzania, interpreted to be the oldest outcrops of subduction-related eclogites. Rutile from both rock types were discordant near a ca. 500 Ma lower intercept, confirming a thermal overprint postulated on the basis of K-Ar and Rb-Sr mica ages by e.g. Wendt et al. (1972). The age of the eclogite-facies event was confirmed by U-Pb zircon dating of a 1991±2 Ma crosscutting pegmatite (Collins et al., 1999). We present in situ LA-ICP-MS rutile petrochronology on five metabasic and metapelitic eclogite facies samples with variable retrograde amphibolite-facies recrystallization. Thermometry confirms conventional Fe-Mg results, including higher peak temperatures in metabasites. Traverses on rutile inclusions in large garnet prophyroblasts in metapelites show increasing temperatures from cores outwards and a slight decrease towards outermost rims, with peak T coinciding with highest Mg# and highest grossular content, hence consistent with preservation of prograde zoning in the garnets and a brief eclogite facies event. Large rutiles (800μm) in recrystallized samples record temperature zoning profiles. U-Pb results show inheritance of near concordant 2 Ga domains, but dominantly confirm the ca. 490 Ma amphibolite facies overprint. The study is an excellent example of the potential of in-situ rutile petrochronology in complex, polymetamorphic rocks when meticulous attention is given to textural context. Möller et al., 1995, Geology, v. 23, p. 1067-1070. Collins et al., 2004, Earth Planet. Sci. Lett., v. 224, p. 175-192. Wendt et al., 1972, 24th Internat. Geol. Congr., Proc., p. 295-314.

Stability of amlodipine besylate in two liquid dosage forms.

PubMed

Nahata, M C; Morosco, R S; Hipple, T F

1999-01-01

To determine the stability of amlodipine besylate in two liquid dosage forms under refrigeration and at room temperature. Commercially available amlodipine tablets (Norvasc-Pfizer) were used to prepare two suspensions: one in extemporaneously prepared 1% methylcellulose in syrup (1:1), and another in equal volumes of commercially available OraPlus/OraSweet. Each suspension containing amlodipine 1 mg/mL was stored in 10 plastic prescription bottles; 5 were stored at 4 degrees C and 5 at 25 degrees C. Samples were collected immediately after preparation (day 0) and on days 7, 14, 28, 42, 56, 70, and 91. Amlodipine concentration was measured by stability-indicating HPLC method (n = 15). Research laboratory at Children's Hospital. Physical and chemical stability (> 90% of the initial concentration) of amlodipine in the two extemporaneously prepared suspensions during storage in plastic prescription bottles at 4 degrees C and 25 degrees C. Observed mean concentrations exceeded 90% of the initial concentrations in both suspensions for 91 days at 4 degrees C and 56 days at 25 degrees C. No noticeable change in physical appearance or odor was observed; pH changed slightly in the methylcellulose-containing formulation stored at 25 degrees C. Amlodipine was stable in two suspensions when stored in plastic prescription bottles for 91 days at 4 degrees C or 56 days at 25 degrees C. These formulations may be considered for pediatric or elderly patients who are unable to swallow tablets. The liquid dosage form would also permit accurate administration of amlodipine doses to infants and young children based on their body weight.

p21-Activated kinase inhibitors: a patent review.

PubMed

Crawford, James J; Hoeflich, Klaus P; Rudolph, Joachim

2012-03-01

The p21-activated kinase (PAK) family of serine/threonine protein kinases is activated by binding to the small (p21) GTP-binding proteins Cdc42 and Rac. The PAK family plays important roles in cytoskeletal organisation, cellular morphogenesis and survival, and members of this family have been implicated in a wide range of diseases including cancer, infectious diseases, neurological disorders and arthritis. The present review seeks to summarise recent (up to 2011) reports of small-molecule inhibitors of p21-activated kinases. Where patent applications describe activity against a broad range of kinases and no information was provided specifically on PAK inhibition, these are excluded from this review. In patents considered to be relevant, exemplary compounds were selected and highlighted based on their representation of the chemical matter claimed, potencies, structural features and subsequent disclosure of their properties. Selected information from non-patent literature was also included. A considerable amount of research has been devoted over the past 15 years to exploring the role of PAKs in a wide range of diseases, with a focus on oncology. Published PAK inhibitors are still comparatively rare and few exhibit satisfactory kinase selectivity and 'drug-like' properties. A key question is which profile, pan-PAK, group selective or isoform selective, holds the most promise from both therapeutic and safety standpoints. To investigate this question, isoform-selective, as well as kinome-selective, PAK inhibitor tool compounds will be needed. Pfizer was the first company to progress a PAK inhibitor (pan-PAK) to clinical development; it is expected that, despite the difficulties, other PAK inhibitors will soon follow.

Diverse activities of viral cis-acting RNA regulatory elements revealed using multicolor, long-term, single-cell imaging.

PubMed

Pocock, Ginger M; Zimdars, Laraine L; Yuan, Ming; Eliceiri, Kevin W; Ahlquist, Paul; Sherer, Nathan M

2017-02-01

Cis-acting RNA structural elements govern crucial aspects of viral gene expression. How these structures and other posttranscriptional signals affect RNA trafficking and translation in the context of single cells is poorly understood. Herein we describe a multicolor, long-term (>24 h) imaging strategy for measuring integrated aspects of viral RNA regulatory control in individual cells. We apply this strategy to demonstrate differential mRNA trafficking behaviors governed by RNA elements derived from three retroviruses (HIV-1, murine leukemia virus, and Mason-Pfizer monkey virus), two hepadnaviruses (hepatitis B virus and woodchuck hepatitis virus), and an intron-retaining transcript encoded by the cellular NXF1 gene. Striking behaviors include "burst" RNA nuclear export dynamics regulated by HIV-1's Rev response element and the viral Rev protein; transient aggregations of RNAs into discrete foci at or near the nuclear membrane triggered by multiple elements; and a novel, pulsiform RNA export activity regulated by the hepadnaviral posttranscriptional regulatory element. We incorporate single-cell tracking and a data-mining algorithm into our approach to obtain RNA element-specific, high-resolution gene expression signatures. Together these imaging assays constitute a tractable, systems-based platform for studying otherwise difficult to access spatiotemporal features of viral and cellular gene regulation. © 2017 Pocock et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

Assessing the extent and impact of the masking effect of disproportionality analyses on two spontaneous reporting systems databases.

PubMed

Maignen, Francois; Hauben, Manfred; Hung, Eric; Van Holle, Lionel; Dogne, Jean-Michel

2014-02-01

Masking is a statistical issue by which signals are hidden by the presence of other medicines in the database. In the absence algorithm, the impact of the masking effect has not been fully investigated. Our study is aimed at assessing the extent and the impact of the masking effect on two large spontaneous reporting databases. Cross sectional study using a set of terms of importance for public health in two spontaneous reporting databases. The analyses were performed on EudraVigilance (EV) and the Pfizer spontaneous reporting database (PfDB). Using the masking ratio, we have identified and removed the products inducing the highest masking effect. Studying a total of almost 50 000 drug-event combinations masking had an impact on approximately 60% of drug-event combinations were masked by another product with a masking ratio >1 in EV and 84% in PfDB. The prevalence of important masking was quite rare (0.003% of the DECs) and mainly affected events rarely reported in EV. The products involved in the highest masking effects are products known to induce the reaction. The removal of the masking effect of the highest masking product has revealed 974 signals of disproportionate reporting in EV including true signals. The study shows that the original ranking provided by the quantitative methods included in our study is marginally affected by the removal of the masking product. Our study suggests that significant masking is rare in large spontaneous databases and mostly affects events rarely reported in EV. Copyright © 2013 John Wiley & Sons, Ltd.

Safinamide: FCE 26743, NW 1015, PNU 151774, PNU 151774E.

PubMed

2004-01-01

Safinamide [NW 1015, PNU 151774E; FCE 26743] is a potent anticonvulsant and antiparkinsonian compound that is being developed by Newron Pharmaceuticals in Europe. It has been shown to antagonise the calcium and sodium channels, as well as inhibit monoamine oxidase type-B (MAO-B). Phase III trials for the treatment of Parkinson's disease are underway in Germany and Europe, while phase II trials in patients with epilepsy are ongoing in Italy. Newron Pharmaceuticals was founded at the end of 1998 after Pharmacia & Upjohn announced its worldwide restructuring programme. Newron obtained the rights to safinamide, which Pharmacia Corporation (now Pfizer) had been developing as PNU 151774E. Safinamide was originated by Farmitalia-CarloErba in Italy. Newron now owns all intellectual property associated with the drug.A multinational phase II trial for Parkinson's disease in Europe has shown positive results in slowing the progression of the disease; however, due to the placebo-effect seen in this study, a longer (6-month) phase IIb study is planned for the second quarter of 2003. In July 2003, Newron received an IND from the US FDA authorising a phase I trial to confirm that no dietary restrictions are needed in patients while being treated with safinamide. This study is be conducted in 12 healthy volunteers at the University of Vienna, Austria, and will be followed by efficacy studies in Parkinson's disease in the US. Five phase I trials were completed in April 2001 in Switzerland. Safinamide combines sodium and calcium channel modulatory activity with monoamine oxidase B inhibition.

Automatic atlas-based three-label cartilage segmentation from MR knee images

PubMed Central

Shan, Liang; Zach, Christopher; Charles, Cecil; Niethammer, Marc

2016-01-01

Osteoarthritis (OA) is the most common form of joint disease and often characterized by cartilage changes. Accurate quantitative methods are needed to rapidly screen large image databases to assess changes in cartilage morphology. We therefore propose a new automatic atlas-based cartilage segmentation method for future automatic OA studies. Atlas-based segmentation methods have been demonstrated to be robust and accurate in brain imaging and therefore also hold high promise to allow for reliable and high-quality segmentations of cartilage. Nevertheless, atlas-based methods have not been well explored for cartilage segmentation. A particular challenge is the thinness of cartilage, its relatively small volume in comparison to surrounding tissue and the difficulty to locate cartilage interfaces – for example the interface between femoral and tibial cartilage. This paper focuses on the segmentation of femoral and tibial cartilage, proposing a multi-atlas segmentation strategy with non-local patch-based label fusion which can robustly identify candidate regions of cartilage. This method is combined with a novel three-label segmentation method which guarantees the spatial separation of femoral and tibial cartilage, and ensures spatial regularity while preserving the thin cartilage shape through anisotropic regularization. Our segmentation energy is convex and therefore guarantees globally optimal solutions. We perform an extensive validation of the proposed method on 706 images of the Pfizer Longitudinal Study. Our validation includes comparisons of different atlas segmentation strategies, different local classifiers, and different types of regularizers. To compare to other cartilage segmentation approaches we validate based on the 50 images of the SKI10 dataset. PMID:25128683

Suppression of ovulation in Nile Hippopotamus (Hippopotamus amphibious) using melengestrol acetate-treated feed or high dose Depo-Provera injection.

PubMed

Wheaton, Catharine J; Joseph, Sharon; Reid, Kelly; Webster, Tricia; Richards, Mary; Forde, Holly M; Savage, Anne

2007-07-01

Analysis of fecal progestogen profiles during Depo-Provera injection (1,200 mg; DEPO, Pfizer Inc., New York, NY), melengestrol acetate (MGA) in feed (2 or 3 mg/head/day), and a combination treatment (DEPO+MGA) are presented for nine captive female Nile hippos housed at Disney's Animal Kingdom in Florida. All tested treatments reduced fecal progestogen elevations successfully to durations consistent with prevention of ovulation for a portion of the treatment period. Percentage of treatment months with suppression of luteal phases indicative of ovulation was maximal for high-dose MGA (91.7+/-13.9%) and DEPO+MGA (91.7+/-20.4%), followed by DEPO injection alone (69.2+/-13.9%) and low-dose MGA (57.6+/-33.2%). Both 1,200 mg DEPO and low-dose MGA (2.0 mg/day) treatments were insufficient to prevent an apparent seasonal breakthrough of ovarian activity from June-August 2002. Although luteal phases were observed, no females conceived during those months. Overall, in 133.5 treatment months with females housed with an adult male, one female conceived during the transition period between treatments. After cessation of contraceptive treatment, average latency to first normal ovarian cycle was 80.6+/-19.5 days (range = 22-179 days). Up to 12 months post-treatment, however, successive cycles were often irregular with evidence of short periods of anovulation and shortened luteal phases in all females monitored. In conclusion, high dose and combination treatments were most successful in preventing progestogen increases indicative of ovulation in hippos. Zoo Biol 26:259-274, 2007. (c) 2007 Wiley-Liss, Inc.

Positive Effectiveness of Tafamidis in Delaying Disease Progression in Transthyretin Familial Amyloid Polyneuropathy up to 2 Years: An Analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

PubMed

Mundayat, Rajiv; Stewart, Michelle; Alvir, Jose; Short, Sarah; Ong, Moh-Lim; Keohane, Denis; Rill, Denise; Sultan, Marla B

2018-04-09

The effectiveness of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) was evaluated using data from the Transthyretin Amyloidosis Outcomes Survey (THAOS) registry. Subjects receiving tafamidis (n = 252) were compared with untreated subjects in a non-randomized, matched cohort analysis. Subjects were matched with up to four untreated controls by genetic mutation, region of birth, and mean treatment propensity score. The matched, treated sample consisted predominantly of subjects with the Val30Met genotype (92.5%), from Portugal, and with a mean age of 40.4 years. Over the course of the 2-year follow-up period, subjects treated with tafamidis showed significantly less deterioration on the Neuropathy Impairment Score for Lower Limbs (p < 0.001) and its subscales (p < 0.023) compared with untreated subjects. There was significantly less deterioration among tafamidis-treated subjects compared with untreated subjects on the Norfolk Quality of Life scale (p < 0.001). There were no significant differences observed in functional (assessed by Karnofsky Performance Status Scale score) or nutritional (assessed by modified body mass index) status between the treated and untreated groups. The primary model which examined survival from baseline using the matched cohort was not able to yield estimates of the hazard ratio, as there were no deaths in the tafamidis-treated subjects. These findings support the results from clinical trials and strengthen evidence of the effectiveness of tafamidis beyond conventional clinical trials. ClinicalTrials.gov: NCT00628745 FUNDING: Pfizer.

Cross-site strain comparison of pharmacological deficits in the touchscreen visual discrimination test.

PubMed

Mohler, Eric G; Ding, Zhiyong; Rueter, Lynne E; Chapin, Douglas; Young, Damon; Kozak, Rouba

2015-11-01

The low rate of success for identifying effective treatments for cognitive dysfunction has prompted recent efforts to improve pharmaceutical discovery and development. In particular, investigators have emphasized improving translation from pre-clinical to clinical research. A specific area of focus has been touchscreen technology; this computer-automated behavioral testing method provides an objective assessment of performance that can be used across species. As part of a larger multi-site study with partners from the Innovative Medicines Initiative (IMI), two US sites, AbbVie and Pfizer, conducted a cross-site experiment with a common protocol for the visual discrimination (VD) task using identical testing equipment, stimuli, and rats of the same strains, sex, and age from the same supplier. As most touchscreen-based rodent experiments have used Lister-Hooded rats that are not readily available outside of Europe, a strain comparison with male Long-Evans rats was conducted as part of the study. Rats were trained for asymptotic performance, and test sessions were performed once per week in a full crossover design with cognition-impairing drugs. Drugs tested were phencyclidine and S-ketamine (N-methyl-D-aspartate (NMDA) antagonists), D-amphetamine (indirect dopamine agonist), and scopolamine (muscarinic antagonist). Satellite brain and plasma samples were taken to confirm appropriate exposures. Results indicate that both rat strains show similar patterns of impairment, although Lister-Hooded rats were more sensitive than Long-Evans rats to three out of four drugs tested. This suggests that researchers should fully explore dose-response relationships in their strain of choice and use care in the interpretation of reversal of cognitive impairment.

The Effect of Disinfection Techniques on the Flexural Strength of Thermopolymerisable Acrylic Resins With or Without Pigment Addition.

PubMed

Goiato, Marcelo Coelho; Zuccolotti, Bruna Carolina Rossatti; Haddad, Marcela Filié; Moreno, Amália; Pesqueira, Aldiéris Alves; Gennari, Humberto Filho; Dos Santos, Daniela Micheline

2015-12-01

The aim of this study was to assess the flexural strength of two brands of thermopolymerisable acrylic resins (Onda Cryl, Artigos Odontológicos Clássico Ltda, São Paulo, SP, Brazil; and Lucitone 550, Dentsply, York, PA, USA) with varying concentrations of pigment (Poli-Côr, Artigos Odontológicos Clássico Ltda, São Paulo, SP, Brazil) under the influence of thermocycling, storage and disinfection. A total of 210 samples were manufactured (105 for each acrylic resin brand), with dimensions of 64 x 10 x 3.3 mm. The samples were divided into 30 subgroups (n = 7) according to the proportion of pigment used (without pigment, 3% and 7%), the assessment period (initial or thermocycling for 2000 cycles) and disinfection method (immersion in 1% sodium hypochlorite, (Apothicário, Araçatuba, SP, Brazil), microwave energy or immersion in alkaline peroxide (Efferdent, Pfizer, Morris Plains, NJ, USA). The samples were submitted to the flexural strength test before and after thermocycling, and after storage with disinfection. The disinfection process was performed every 3 days, for 60 days. Data were submitted to analysis of variance (ANOVA) and Tukey test (p < 0.05). The factors that provided statistical alteration in flexural strength values were resin type and assessment period. The Onda Cryl resin and the period after disinfection (126 ± 25 MPa) exhibited the higher values of flexural strength. Following disinfection, Onda-Cryl resin exhibited the highest values of flexural strength. All the samples obtained are considered clinically acceptable.

Packaging of Mason-Pfizer monkey virus (MPMV) genomic RNA depends upon conserved long-range interactions (LRIs) between U5 and gag sequences

PubMed Central

Kalloush, Rawan M.; Vivet-Boudou, Valérie; Ali, Lizna M.; Mustafa, Farah; Marquet, Roland; Rizvi, Tahir A.

2016-01-01

MPMV has great potential for development as a vector for gene therapy. In this respect, precisely defining the sequences and structural motifs that are important for dimerization and packaging of its genomic RNA (gRNA) are of utmost importance. A distinguishing feature of the MPMV gRNA packaging signal is two phylogenetically conserved long-range interactions (LRIs) between U5 and gag complementary sequences, LRI-I and LRI-II. To test their biological significance in the MPMV life cycle, we introduced mutations into these structural motifs and tested their effects on MPMV gRNA packaging and propagation. Furthermore, we probed the structure of key mutants using SHAPE (selective 2′hydroxyl acylation analyzed by primer extension). Disrupting base-pairing of the LRIs affected gRNA packaging and propagation, demonstrating their significance to the MPMV life cycle. A double mutant restoring a heterologous LRI-I was fully functional, whereas a similar LRI-II mutant failed to restore gRNA packaging and propagation. These results demonstrate that while LRI-I acts at the structural level, maintaining base-pairing is not sufficient for LRI-II function. In addition, in vitro RNA dimerization assays indicated that the loss of RNA packaging in LRI mutants could not be attributed to the defects in dimerization. Our findings suggest that U5-gag LRIs play an important architectural role in maintaining the structure of the 5′ region of the MPMV gRNA, expanding the crucial role of LRIs to the nonlentiviral group of retroviruses. PMID:27095024

Does bargaining affect Medicare prescription drug plan reimbursements to independent pharmacies?

PubMed

Tang, Yuexin; Xie, Yang; Urmie, Julie M; Doucette, William R

2011-01-01

To examine how pharmacy bargaining activities affect reimbursement rates in Medicare Part D prescription drug plan (PDP) contracts, controlling for pharmacy quality attributes, market structures, and area socioeconomic status. Cross-sectional study. Six Medicare regions throughout the United States between October and December 2009. Random sample of 1,650 independent pharmacies; 321 returned surveys containing sufficient responses for analysis. Pharmacies were surveyed regarding PDP reimbursement rates, costs, and cash prices of two popular prescription drugs (atorvastatin calcium [Lipitor-Pfizer] and lisinopril, 1-month supply of a common strength), as well as pharmacy bargaining activities and quality attributes. Data also were used from the National Council for Prescription Drug Programs pharmacy database, the 2000 U. S. Census, and the 2006 Economic Census on local market structures and area socio-economic status. PDP reimbursement rates. For the brand-name drug atorvastatin calcium, the PDP reimbursement was positively related to a pharmacy's request for a contract change (β = 0.887, P < 0.05), whereas other bargaining activities were not significantly related to PDP reimbursement. However, for the generic drug lisinopril, no bargaining activities were found to be significantly related to the PDP reimbursement. Pharmacy request for a contract change was associated with higher reimbursement rates for the brand-name drug atorvastatin calcium in PDP contracts, after controlling for pharmacy quality attributes, local market structures, and area socioeconomic status; this finding likely applies to other brand-name drugs because of the structure of the contracts. Our results suggest that independent pharmacies are more likely to acquire higher reimbursement rates by engaging in active bargaining with third-party payers.

Prominent expression of phosphodiesterase 5 in striated muscle of the rat urethra and levator ani.

PubMed

Lin, Guiting; Huang, Yun-Ching; Wang, Guifang; Lue, Tom F; Lin, Ching-Shwun

2010-08-01

We investigated phosphodiesterase 5 distribution and activity in the urethra. Rat tissues were examined for phosphodiesterase 5 and alpha-smooth muscle actin expression. Urethral phosphodiesterase 5 activity was examined by tissue bath in the presence of sildenafil (Pfizer, New York, New York). Anti-alpha-smooth muscle actin antibody (Abcam) stained all known smooth muscles in all tested tissues and revealed a few smooth muscle fibers in the levator ani muscle. Anti-phosphodiesterase 5 antibody (Abcam) stained smooth muscle in the penis and bladder but not striated leg muscle. However, it stained predominantly striated muscle in the urethra and the levator ani muscle. In the urethra the amount of phosphodiesterase 5 in striated muscle was 6 times that in smooth muscle. In urethral striated muscle phosphodiesterase 5 expression was localized to Z-band striations. Smooth and striated muscle intermingling was clearly visible on the inner and outer rims of the circularly arranged striated muscle layer. Relaxation of precontracted urethral tissues by sodium nitroprusside (Sigma-Aldrich) was enhanced by sildenafil, indicating phosphodiesterase 5 activity, which was primarily located in the striated muscle according to phosphodiesterase 5 staining. Despite its presumed smooth muscle specificity phosphodiesterase 5 was predominantly expressed in the striated muscle of the urethra and in the levator ani muscle. Results are consistent with earlier studies in which these striated muscles were developmentally related to smooth muscle. They also suggest that these striated muscles are possibly regulated by phosphodiesterase 5. Copyright (c) 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency.

PubMed

Hoybye, Charlotte; Jönsson, Peter; Monson, John P; Koltowska-Häggström, Maria; Hána, Václav; Geffner, Mitchell; Abs, Roger

2007-11-01

The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy. Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement. GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement. The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

Characteristics and Medication Use of Psoriasis Patients Who May or May Not Qualify for Randomized Controlled Trials.

PubMed

Malatestinic, William; Nordstrom, Beth; Wu, Jashin J; Goldblum, Orin; Solotkin, Kathleen; Lin, Chen-Yen; Kistler, Kristin; Fraeman, Kathy; Johnston, Joseph; Hawley, Lcdr Lesley; Sicignano, Nicholas; Araujo, Andre

2017-03-01

Clinical trials impose exclusion criteria that may limit the generalizability of results. To (a) determine the percentage of real-world patients who would qualify for psoriasis randomized controlled trials; (b) ascertain differences between moderate-to-severe psoriasis patients who would be eligible, ineligible, or potentially eligible for clinical trials; and (c) compare their biologic treatment patterns. Moderate-to-severe psoriasis patients were identified from the U.S. Department of Defense health care database from January 1, 2008, to October 31, 2013. Eligibility classification for psoriasis trials was based on common trial exclusion criteria involving medical conditions and recent treatment history. Patient characteristics and treatment patterns of 4 biologics (adalimumab, etanercept, infliximab, and ustekinumab) were compared between groups. Adherence was measured by medication possession ratio and persistence as continuous time on drug with ≤ 90-day gap between supply times. Among 16,284 qualifying psoriasis patients, 4,677 (28.7%) were medically ineligible, and 8,466 (52.0%) had ineligibility-related treatments that could be stopped prior to trial entry; the latter patients were considered potentially eligible for psoriasis trials. Common reasons for medical ineligibility included malignancies and hematologic disorders; treatment ineligibilities included use of topical corticosteroids and phototherapy. Medically ineligible patients were older and had more comorbidities, while potentially eligible patients were younger and healthier than trial-eligible patients. Most treatment patterns were similar across groups, except that, compared with the trial-eligible group, medically ineligible patients had greater adherence to infliximab and potentially trial-eligible patients had greater adherence and persistence to adalimumab. This large real-world study found that patients who may be ineligible for psoriasis trials differ in important respects (e.g., comorbidities, prior treatments) from their trial-eligible counterparts. Regardless of their differences at baseline, adherence, persistence, and switching of biologic medications are largely similar, with few differences noted among groups. Financial support for this study was provided by Lilly USA. Wu has received research funding from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Coherus Biosciences, Dermira, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, Sandoz, and Sun Pharmaceutical Industries, and he is a consultant for AbbVie, Amgen, Celgene, Dermira, Eli Lilly, Pfizer, Regeneron, and Sun Pharmaceutical Industries. Malatestinic, Goldblum, Solotkin, Lin, Johnston, and Araujo are employees and/or stock owners of Lilly. Nordstrom, Kistler, and Fraeman are employees of Evidera, which received funding from Lilly to conduct this study. LCDR Hawley is a military service member. This work was prepared as part of her official duties. Title 17 U.S.C. 105 provides that "copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a U.S. government work as a work prepared by a military service member or employee of the U.S. government as part of that person's official duties. Research data were derived from an approved Naval Medical Center, Portsmouth, Virginia, institutional review board protocol. The views expressed in this work are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. government. Study concept and design were contributed by Malatestinic and Araujo, along with the other authors. Nordstrom, Kistler, Fraeman, and Sicignano collected the data, and data interpretation was performed by Wu, Lin, and Hawley, along with Malatestinic, Nordstrom, Solotkin, and Araujo. The manuscript was written by Johnston, Malatestinic, Kistler, Wu, and Araujo, along with Nordstrom, Goldblum, Solotkin, Hawley, and Sicignano, and revised by Goldblum, Solotkin, Malatestinic, and Araujo, along with Nordstrom, Wu, Fraeman, Johnston, Hawley, and Sicignano.

Detecting Infections Rapidly and Easily for Candidemia Trial (DIRECT1): A Prospective, Multicenter Study of the T2Candida Panel

PubMed Central

Clancy, Cornelius J; Pappas, Peter; Vazquez, Jose; Judson, Marc A; Tobin, Ellis; Kontoyiannis, Dimitrios P; Thompson, George R; Reboli, Annette; Garey, Kevin W; Greenberg, Richard N; Ostrosky-Zeichner, Luis; Wu, Alan; Lyon, G Marshall; Apewokin, Senu; Nguyen, M Hong; Caliendo, Angela

2017-01-01

Abstract Background Blood cultures (BC) are the diagnostic gold standard for candidemia, but sensitivity is <50%. T2 Candida (T2) is a novel, FDA-approved nanodiagnostic panel, which utilizes T2 magnetic resonance and a dedicated instrument to detect Candida within whole blood samples. Methods Candidemic adults were identified at 14 centers by diagnostic BC (dBC). Follow-up blood samples were collected from all patients (pts) for testing by T2 and companion BC (cBC). T2 was run-in batch at a central lab; results are reported qualitatively for three groups of spp. (Candida albicans/C. tropicalis (CA/CT), C. glabrata/C. krusei (CG/CK), or C. parapsilosis (CP)). T2 and cBC were defined as positive (+) if they detected a sp. identified in dBC. Results 152 patients were enrolled (median age: 54 yrs (18–93); 54% (82) men). Candidemia risk factors included indwelling catheters (82%, 125), abdominal surgery (24%, 36), transplant (22%, 33), cancer (22%, 33), hemodialysis (17%, 26), neutropenia (10%, 15). Mean times to Candida detection/spp. identification by dBC were 47/133 hours (2/5.5 d). dBC revealed CA (30%, 46), CG (29%, 45), CP (28%, 43), CT (11%, 17) and CK (3%, 4). Mean time to collection of T2/cBC was 62 hours (2.6 d). 74% (112) of patients received antifungal (AF) therapy prior to T2/cBC (mean: 55 hours (2.3 d)). Overall, T2 results were more likely than cBC to be + (P < 0.0001; Table), a result driven by performance in AF-treated patients (P < 0.0001). T2 was more likely to be + among patients originally infected with CA (61% (28) vs. 20% (9); P = 0.001); there were trends toward higher positivity in patients infected with CT (59% (17) vs. 23% (4; P = 0.08) and CP (42% (18) vs. 28% (12); P = 0.26). T2 was + in 89% (32/36) of patients with + cBC. Conclusion T2 was sensitive for diagnosing candidemia at the time of + cBC, and it was significantly more like to be + than cBC among AF-treated patients. T2 is an important advance in the diagnosis of candidemia, which is likely to be particularly useful in patients receiving prophylactic, pre-emptive or empiric AF therapy. Test results, n (%) Pt group (n) T2+ T2- cBC+ cBC- T2+/cBC+ T2+/cBC- T2-/cBC+ T2-/cBC- All (152) 69 
(45%) 83 
(55%) 36 
(24%) 116 
(76%) 32 
(21%) 37 
(24%) 4 
(3%) 79 
(52%) Prior AF (112) 55 
(49%) 57 
(51%) 23 
(20%) 89 
(80%) 20 
(18%) 35 
(31%) 3 
(3%) 54 
(48%) No AF (40) 14 
(35%) 26 
(65%) 13 
(32%) 27 
(68%) 12 
(30%) 2 
(5%) 1 
(2%) 25 
(62%) Disclosure D. P. Kontoyiannis, Pfizer: Research Contractor, Research support and Speaker honorarium; Astellas: Research Contractor, Research support and Speaker honorarium; Merck: Honorarium, Speaker honorarium; Cidara: Honorarium, Speaker honorarium; Amplyx: Honorarium, Speaker honorarium; F2G: Honorarium, Speaker honorarium; L. Ostrosky-Zeichner, Astellas: Consultant and Grant Investigator, Consulting fee and Research grant; Merck: Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium; Pfizer: Grant Investigator and Speaker’s Bureau, Grant recipient and Speaker honorarium; Scynexis: Grant Investigator and Scientific Advisor, Consulting fee and Grant recipient; Cidara: Grant Investigator and Scientific Advisor, Consulting fee and Research grant; S. Apewokin, T2 biosystems: Investigator, Research support; Astellas: Scientific Advisor, Consulting fee

The Economic Burden of ACPA-Positive Status Among Patients with Rheumatoid Arthritis.

PubMed

Shafrin, Jason; Tebeka, Mahlet Gizaw; Price, Kwanza; Patel, Chad; Michaud, Kaleb

2018-01-01

Anticitrullinated protein antibodies (ACPAs) are serological biomarkers associated with early, rapidly progressing rheumatoid arthritis (RA), including more severe disease and joint damage. ACPA testing has become a routine tool for RA diagnosis and prognosis. Furthermore, treatment efficacy has been shown to vary by ACPA-positive status. However, it is not clear if the economic burden of patients with RA varies by ACPA status. To determine if the economic burden of RA varies by patient ACPA status. IMS PharMetrics Plus health insurance claims and electronic medical record (EMR) data from 2010-2015 were used to identify patients with incident RA. Patients were aged ≥ 18 years, had ≥ 1 inpatient or ≥ 2 outpatient claims reporting an RA diagnosis code (ICD-9-CM code 714.0), and had an anticyclic citrullinated peptide (anti-CCP; a surrogate of ACPA) antibody test within 6 months of diagnosis. Incident patients were defined as those who had no claims with an RA diagnosis code in the 6 months before the first observed RA diagnosis. The primary outcome of interest was RA-related medical expenditures, defined as the sum of payer- and patient-paid amounts for all claims with an RA diagnosis code. Secondary outcomes included health care utilization metrics such as treatment with a disease-modifying antirheumatic drug (DMARD) and physician visits. Generalized linear regression models were used for each outcome, controlling for ACPA-positive status (defined as anti-CCP ≥ 20 AU/mL), age, sex, and Charlson Comorbidity Index score as explanatory variables. Of 647,171 patients diagnosed with RA, 89,296 were incident cases, and 47% (n = 42,285) had an anti-CCP test. After restricting this sample to patients with a linked EMR and reported anti-CCP test result, 859 remained, with 24.7% (n = 212) being ACPA-positive. Compared with ACPA-negative patients, adjusted results showed that ACPA-positive patients were more likely to use either conventional (71.2% vs. 49.6%; P < 0.001) or biologic (20.3% vs. 11.8%; P < 0.001) DMARDs during the first year after diagnosis and had more physician visits (5.58 vs. 3.91 times per year; P < 0.001). Annual RA-associated total expenditures were $7,941 for ACPA-positive and $5,243 for ACPA-negative patients (Δ = $2,698; P = 0.002). RA-associated medical expenditures were $4,380 for ACPA-positive and $3,427 for ACPA-negative patients (Δ = $954; P = 0.168), whereas DMARD expenditures were $3,560 and $1,817, respectively (Δ = $1,743; P = 0.001). RA-related economic burden is higher for patients who are ACPA-positive compared with those who are ACPA-negative. Providers may wish to inform patients diagnosed with ACPA-positive RA about the likely future disease and economic burden in hopes that both stakeholders can be more proactive in addressing them. Funding for this research was contributed by Bristol-Myers Squibb. Patel and Price are employees and stockholders of Bristol-Myers Squibb. Shafrin and Tebeka are employees of Precision Health Economics, a health care consulting firm that received funding from Bristol-Myers Squibb to conduct this study. Michaud has received a grant from Pfizer and is employed by the National Data Bank for Rheumatic Diseases, which has received funds from Amgen, Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer, and Regeneron. Study concept and design were contributed by Shafrin, Price, Patel, and Michaud. Shafrin, Price, and Patel collected the data, and all authors contributed equally to data analysis. The manuscript was written by Shafrin and Tebeka and revised by Shafrin, Price, Patel, and Michaud.

Reconstruction of Late Quaternary Climate in Central Europe - A Comparison of Stable Isotope and Trace Element Variations in Speleothems From Different Cave Systems in Germany.

NASA Astrophysics Data System (ADS)

Nordhoff, P.; Wiegand, B.; Simon, K.; Rosendahl, W.; Hansen, B. T.; Kempe, S.

2003-12-01

Speleothems (stalagmites, stalactites, flowstones) are important archives for Late Quaternary continental climatic and paleo-environmental reconstruction. Speleothems form when calcium carbonate precipitates from solutions seeping into caves hosted e.g. in limestone or dolomite complexes. Information of past climate variability and changes in local environmental conditions can be obtained from signatures of the stable isotopes of oxygen and carbon as well as trace element pattern recorded in speleothems. Reconstruction of paleo-temperature and past environmental conditions from stable isotopes, however, require isotopic equilibrium between the drip water and the precipitating calcium carbonate. Results from Dietzel et al. (1992) and Johnson and Ingram (2001) indicate that the formation of modern travertine and speleothem calcite occurs under isotopic equilibrium. Factors that influence the stable oxygen and carbon isotope composition during speleothem precipitation include e.g. the moisture source and precipitation, photosynthetic pathways, the bedrock proportion, and the drip rate. This often leads to a situation with several variables. However, a specific interpretation is possible when dealing with environments where only one of the factors is dominant, or specific settings are assumed to be invariant, or further proxies like trace element variations help to define the frame conditions during speleothem formation. Concentrations of trace elements (e.g. Sr, Mg) which are co-precipitated with calcite are related to changes in the composition of the solution and strongly depend on the dissolution/precipitation dynamics along drip water flow paths. In a multiproxy approach they are a valuable tool for the interpretation of the recorded stable isotope variations. We present first results from different cave systems located in the Swabian Alps and the Harz Mountains (Germany). Our study includes a high-resolution multiproxy approach, using U/Th-TIMS data, stable oxygen/carbon isotope data, and geochemical compositions of speleothems, covering ages from the Late Pleistocene to the Early Holocene. The results are compared to geochemical data from host rocks, soil zones, cave sediments, drip water compositions, and recent calcium carbonate precipitates. Understanding the response of a cave system to the actual climatic, hydrologic and environmental regimen is a main requirement for the interpretation of "paleo-information" conserved in speleothems in order to lead to a coherent picture of past continental climate dynamics. References: Dietzel M., Usdowski E., and Hoefs J., (1992): Applied Geochemistry 7: 177-184. Johnson, K.R. and Ingram, B.L. (2001): Abstract volume, 4th Internat. Symp. On Applied Isotope Geochemistry, Pacific Groove, USA: 70-72.

Micro-FTIR Spectroscopy of Experimentally Shocked Basaltic Andesite (SP Flow, AZ)

NASA Astrophysics Data System (ADS)

Johnson, J. R.; Jaret, S.; Glotch, T. D.; Sims, M.

2017-12-01

As part of an ongoing systematic study of experimental shock transformations in plagioclase using micro-Raman and micro-FTIR thermal infrared hyperspectral imaging and point spectroscopy [1-7], we report new micro-FTIR results on experimentally shocked, fine-grained basaltic andesite from SP Flow (AZ). This sample has relatively high primary glass content and an average plagioclase composition of labradorite/bytownite. The powder propellant gun at the Johnson Space Center was used to conduct the original shock experiments at peak pressures from 15 to 60 GPa [6-8], from which <10 mm fragments were recovered. Polished thin sections were made from portions of these fragments, and micro-FTIR point spectra were collected from 400-4000 cm-1 (2.5-25 µm) using a spot size of 40 x 40 mm at 8 cm-1 spectral sampling. Micro-FTIR hyperspectral maps of thin sections were acquired using the same instrument equipped with a 16 pixel HgCdTe linear array detector to provide spectra between 7000 and 715 cm-1 (1.4-14.0 µm) at 25 µm/pixel and 8 cm-1 spectral sampling (see figure for color composite and band depth images from unshocked sample). Micro-FTIR results show that the unshocked sample is dominated by the glassy matrix (light green in the color composite), with contributions from plagioclase and pyroxene. Initial analyses suggest that the SP Flow samples become dominantly amorphous at relatively low shock pressures, reflective of the high primary glass content and consistent with macro-scale spectra from [7]. Results from additional shock pressures and Raman spectra will be presented at the conference. Future work will include (1) Raman and FTIR analyses of basalt from Grand Falls (AZ), which has minimal primary glass content and relatively higher calcic plagioclase than SP Flow; and (2) comparison of these basalts to results from shocked plagioclase and to similar analyses of naturally shocked samples from Ries and Lonar Craters. [1] Jaret, S. et al., 11th Internat. GeoRaman Conf., #5095, 2014; [2] Jaret, S., et al., LPSC # 2056, 2015; [3] Jaret, S., et al., LPSC #1530, 2016; [4] Jaret, S., et al., LPSC, abs. #2484, 2017; [5] Jaret, S., et al. GSA, abstract #267947, 2015; [6] Johnson, J., et al., Amer. Mineral., 88, 1575-1582, 2003; [7] Johnson, J., Icarus 221 359-364, 2012; [8] Johnson, J., et al., Amer. Mineral., 92, 1148-1157, 2007.

Ultrabasic-basic change over primary inclusions in lower-mantle diamonds: Mineralogical and experimental evidence for crucial role of stishovite paradox

NASA Astrophysics Data System (ADS)

Litvin, Yuriy; Spivak, Anna

2017-04-01

Melting relations of the lower-mantle magmatic system MgO - FeO - CaO - SiO2 are characterized by peritectic reaction of bridgmanite (Mg,Fe)SiO3 and melt with formation of Fe-rich phases of periclase-wustite solid solutions (MgO•FeO)ss and stishovite SiO2. The reaction proceeds also in melts-solutions of lower-mantle diamond-parental system MgO - FeO - CaO - SiO2 - (Mg-Fe-Ca-Na-carbonate) - C. Xenoliths of lower mantle rocks were never found among the deep mantle derived materials. Estimation of lower-mantle mineralogy as ferropericlase+ bridgmanite+ Ca-perovskite association is inferred from high-pressure subsolidus experiments with ultrabasic pyrolite composition (Akaogi, 2007). The paradoxical in situ paragenesis of stishovite and ferropericlase as primary inclusions in lower-mantle diamonds (Kaminsky, 2012) takes its explanation from the bridgmanite peritectic reaction (effect of "stishovite paradox") (Litvin et al., 2014). Based on the data for inclusions, physico-chemical study on syngenesis of diamonds and primary inclusions has experimentally revealed the ferropericlase-bridgmanite-Ca-perovskite-stishovite-magnesiowustite-(Mg-Fe-Ca-Na-carbonate)-carbon compositions of the lower-mantle diamond-forming system .(Litvin et al., 2016). The generalized diagram of diamong-forming media characterizes the variable compositions of growths melts for diamonds and paragenetic phases and their genetic relationships with lower mantle matter, and it is the reason for genetic classifying primary inclusions. Fractional ultrabasic-basic evolution and continuous paragenetic transition from ultrabasic bridgmanite-ferropericlase to basic stishovite-magnesiowustite assemblages in the of lower-mantle diamond-parental melts-solutions are providing by the physico-chemical mechanism of stishovite paradox. References Akaogi M. (2007). Phase transformations of minerals in the transition zone and upper part of the lower mantle. In Advances in High-Pressure Mineralogy (Ohtani E., ed.). Geol. Soc. Am. Spec. Paper 421, 1-13. Kaminsky F.V. (2012). Mineralogy of the lower mantle: a review of "supper-deep" mineral inclusions in diamonds. Earth Sci. Rev. 110, 127-147. Litvin Yu.A., Spivak A.V., Solopova N.A., Dubrovinsky L.S. (2014). On origin of lower-mantle diamonds and their primary inclusions. Phys. Earth Planet. Inter. 228, 176-185. Litvin Yu.A., Spivak A.V., Dubrovinsky L.S. (2016). Magmatic evolution of the material of the Earth's lower mantle: stishovite paradox and origin of superdeep diamonds (experiments at 24-26 GPa). Geochemistry Internat. 54(11, 936-947.)

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study.

PubMed

Sauter-Louis, Carola; Jones, Bryony A; Henning, Jörg; Stoll, Alexander; Nielen, Mirjam; Van Schaik, Gerdien; Smolenaars, Anja; Schouten, Matthijs; den Uijl, Ingrid; Fourichon, Christine; Guatteo, Raphael; Madouasse, Aurélien; Nusinovici, Simon; Deprez, Piet; De Vliegher, Sarne; Laureyns, Jozef; Booth, Richard; Cardwell, Jacqueline M; Pfeiffer, Dirk U

2017-01-01

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named 'bovine neonatal pancytopenia' (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0-280.1). This was also the case for the practices of feeding calves colostrum from the calf's own dam (OR 2.0; 95% CI: 1.1-3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9-8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves.

Effects of two eye drop products on computer users with subjective ocular discomfort.

PubMed

Skilling, Francis C; Weaver, Tony A; Kato, Kenneth P; Ford, Jerry G; Dussia, Elyse M

2005-01-01

An increasing number of people seek medical attention for symptoms of visual discomfort due to computer vision syndrome (CVS). We compared the efficacy and adverse event rates of a new eye lubricant, OptiZen (InnoZen, Inc., polysorbate 80 0.5%) and Visine Original (Pfizer Consumer Healthcare, tetrahydrozoline HCl 0.05%). In this double-blind parallel arm trial, 50 healthy men and women, ages 18 to 65 years, with symptoms of CVS who use a video display terminal for a minimum of 4 hours per day were randomized to OptiZen (n = 25) or Visine Original (n= 25), 1 to 2 drops b.i.d. for 5 days. The primary end-points were ocular discomfort and adverse events. OptiZen and Visine Original had similar efficacy in alleviating symptoms of ocular discomfort (odds ratio of 1.23 [95% confidence interval, 0.63 to 2.42], P= 0.55). OptiZen and Visine Original were very similar with respect to odds ratios and 95% confidence interval (CI) for each of the measurement times (P= 0.72). Visine Original users reported a significantly higher incidence of temporary ocular stinging/burning immediately after drug instillation (28%, 7/25) than did OptiZen users (4%, 1/24) (P= 0.05). Patients using OptiZen were 89% less likely to have stinging/burning effects than those patients using Visine Original (95% CI: 0.01 to 0.95). OptiZen and Visine Original are effective at alleviating ocular discomfort associated with prolonged computer use. Adverse event findings suggest that OptiZen causes less ocular discomfort on instillation, potentially attributable to its milder ingredient profile.

[Bacterial etiology of acute otitis media in Spain in the post-pneumococcal conjugate vaccine era].

PubMed

Pumarola, Felix; Salamanca de la Cueva, Ignacio; Sistiaga-Hernando, Alessandra; García-Corbeira, Pilar; Moraga-Llop, Fernando A; Cardelús, Sara; McCoig, Cynthia; Gómez Martínez, Justo Ramón; Rosell Ferrer, Rosa; Iniesta Turpin, Jesús; Devadiga, Raghavendra

2016-11-01

Acute otitis media (AOM) is common in children aged <3 years. A pneumococcal conjugate vaccine (PCV) (PCV7; Prevenar, Pfizer/Wyeth, USA) has been available in Spain since 2001, which has a coverage rate of 50-60% in children aged <5 years. Children aged ≥3 to 36 months with AOM confirmed by an ear-nose-throat specialist were enrolled at seven centers in Spain (February 2009-May 2012) (GSK study identifier: 111425). Middle-ear-fluid samples were collected by tympanocentesis or spontaneous otorrhea and cultured for bacterial identification. Culture-negative samples were further analyzed using polymerase chain reaction (PCR). Of 125 confirmed AOM episodes in 124 children, 117 were analyzed (median age: 17 months (range: 3-35); eight AOM episodes were excluded from analyses. Overall, 69% (81/117) episodes were combined culture- and PCR-positive for ≥1 bacterial pathogen; 44% (52/117) and 39% (46/117) were positive for Haemophilus influenzae (Hi) and Streptococcus pneumoniae (Spn), respectively. 77 of 117 episodes were cultured for ≥1 bacteria, of which 63 were culture-positive; most commonly Spn (24/77; 31%) and Hi (32/77; 42%). PCR on culture-negative episodes identified 48% Hi- and 55% Spn-positive episodes. The most common Spn serotype was 19F (4/24; 17%) followed by 19A (3/24; 13%); all Hi-positive episodes were non-typeable (NTHi). 81/117 AOM episodes (69%) occurred in children who had received ≥1 pneumococcal vaccine dose. NTHi and Spn were the main etiological agents for AOM in Spain. Impact of pneumococcal vaccination on AOM requires further evaluation in Spain, after higher vaccination coverage rate is reached. Copyright © 2015 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Effect of Discontinuation or Initiation of Methotrexate or Glucocorticoids on Tofacitinib Efficacy in Patients with Rheumatoid Arthritis: A Post Hoc Analysis.

PubMed

Fleischmann, Roy; Wollenhaupt, Jürgen; Cohen, Stanley; Wang, Lisy; Fan, Haiyun; Bandi, Vara; Andrews, John; Takiya, Liza; Bananis, Eustratios; Weinblatt, Michael E

2018-06-01

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). We evaluated the effect of concomitant methotrexate (MTX) or glucocorticoid (GC) use on tofacitinib clinical efficacy. Data were pooled from two open-label, long-term extension studies of tofacitinib 5 or 10 mg twice daily in patients with RA. Response according to Clinical Disease Activity Index (CDAI) was assessed separately in patients who discontinued (no MTX/GC use within 30 days prior to year-3 visit; assessment at month 3/year 3) or initiated (on/before year 3; assessment at initiation and year 3) MTX/GC. By year 3, among patients receiving background MTX at baseline, 186/1608 (11.6%) discontinued MTX, and 319/1434 (22.2%) patients receiving GC at baseline discontinued GC. Overall, 70.4/69.1% of patients who discontinued/continued MTX and 72.7/65.9% who discontinued/continued GC achieved CDAI remission or low disease activity (LDA) at year 3. Month 3 remission/LDA rates were maintained at year 3 in the majority of patients, irrespective of MTX/GC discontinuation/continuation. By year 3, 6.2% of patients receiving tofacitinib without MTX at baseline had initiated concomitant MTX, and 25.1% receiving tofacitinib without GC initiated GC; 69.0% and 45.4% initiating MTX or GC, respectively, had a CDAI-defined incomplete response prior to initiation. RA signs/symptoms improved following MTX initiation; only modest improvement was observed with GC initiation. Patients achieving remission/LDA with tofacitinib may discontinue MTX or GC and maintain treatment response. Patients with an incomplete response may benefit from adding concomitant MTX. Pfizer Inc. Study A3921024 [NCT00413699] and Study A3921041 [NCT00661661].

The efficacy and safety of tofacitinib in Asian patients with moderate to severe chronic plaque psoriasis: A Phase 3, randomized, double-blind, placebo-controlled study.

PubMed

Zhang, JianZhong; Tsai, Tsen-Fang; Lee, Min-Geol; Zheng, Min; Wang, Gang; Jin, HongZhong; Gu, Jun; Li, RuoYu; Liu, QuanZhong; Chen, Jin; Tu, CaiXia; Qi, ChunMei; Zhu, Hua; Ports, William C; Crook, Tim

2017-10-01

Tofacitinib is an oral Janus kinase inhibitor. This study assessed tofacitinib efficacy and safety vs placebo in Asian patients with moderate to severe chronic plaque psoriasis. Patients from China mainland, Taiwan, and Korea were randomized 2:2:1:1 to tofacitinib 5mg (N=88), tofacitinib 10mg (N=90), placebo→5mg (N=44), or placebo→10mg (N=44), twice daily (BID) for 52 weeks. Placebo-treated patients advanced to tofacitinib at Week 16. Co-primary efficacy endpoints: proportions of patients achieving Physician's Global Assessment (PGA) response ('clear' or 'almost clear') and proportion achieving ≥75% reduction from baseline Psoriasis Area and Severity Index (PASI75) at Week 16. At Week 16, more patients achieved PGA and PASI75 responses with tofacitinib 5mg (52.3%; 54.6%) and 10mg (75.6%; 81.1%) BID vs placebo (19.3%; 12.5%; all p<0.0001). Of patients with a Week 16 response, 73.6% and 75.0% maintained PGA response, and 76.8% and 84.9% maintained PASI75 to Week 52 with tofacitinib 5mg and 10mg BID, respectively. Over 52 weeks, 2.2-4.5% of patients across treatment groups experienced serious adverse events, and 1.1-6.8% discontinued due to adverse events. Tofacitinib demonstrated efficacy vs placebo at Week 16 in Asian patients with moderate to severe plaque psoriasis; efficacy was maintained through Week 52. No unexpected safety findings were observed. [NCT01815424]. Copyright © 2017 The Authors and Pfizer Inc. Published by Elsevier B.V. All rights reserved.

Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality.

PubMed

Burman, P; Mattsson, A F; Johannsson, G; Höybye, C; Holmer, H; Dahlqvist, P; Berinder, K; Engström, B E; Ekman, B; Erfurth, E M; Svensson, J; Wahlberg, J; Karlsson, F A

2013-04-01

Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

The survival of micro-organisms in space. Further rocket and balloon-borne exposure experiments.

PubMed

Hotchin, J; Lorenz, P; Markusen, A; Hemenway, C

1967-01-01

This report describes the results of survival studies of terrestrial micro-organisms exposed directly to the space environment on two balloons and in two rocket flights. The work is part of a program to develop techniques for the collection of micro-organisms in the size range of micrometeorite particles in space or non-terrestrial atmospheres, and their return to earth in a viable state for further study. Previous survival studies were reported (J. Hotchin, P. Lorenz and C. Hemenway, Nature 206 (1965) 442) in which a few relatively large area samples of micro-organisms were exposed on millipore filter cemented to aluminum plates. In the present series of experiments, newly developed techniques have resulted in a 25-fold miniaturization resulting in a corresponding increase in the number of experiments performed. This has enabled a statistical evaluation of the results to be made. A total of 756 separate exposure units (each approximately 5 x 5 mm in size) were flown in four experiments, and organisms used were coliphage T1, penicillium roqueforti (THOM) mold spores, poliovirus type I (Pfizer attenuated Sabin vaccine strain), and bacillus subtilis spores. The organisms were deposited either by spraying directly upon the vinyl-coated metal units, or by droplet seeding into shallow depressions in the millipore filter membrane-coated units. Groups of units were prepared comprising fully exposed, inverted (screened by 2 mm of Al), and filter-protected organisms. All of these were included in the flight set, the back up set, and a laboratory control set. The altitude of the exposures varied from 35 km in the balloon experiments to 150 km in the rocket experiments. Times of exposures at altitude were approximately 6 hours for the balloon flights and about 3 minutes for the rocket experiments.

Supplementation with rumen-protected L-arginine-HCl increased fertility in sheep with synchronized estrus.

PubMed

de Chávez, Julio Agustín Ruiz; Guzmán, Adrian; Zamora-Gutiérrez, Diana; Mendoza, Germán David; Melgoza, Luz María; Montes, Sergio; Rosales-Torres, Ana María

2015-08-01

The aim of the present study was to evaluate the effects of L-arginine-HCl supplementation on ovulation rate, fertility, prolificacy, and serum VEGF concentrations in ewes with synchronized oestrus. Thirty Suffolk ewes with a mean body weight of 45 ± 3 kg and a mean body condition score (BCS) of 2.4 ± 0.28 were synchronized for estrus presentation with a progestin-containing sponge (20 mg Chronogest® CR) for 9 days plus PGF2-α (Lutalyse; Pfizer, USA) on day 7 after the insertion of the sponge. The ewes were divided into two groups; i.e., a control group (n = 15) that was fed on the native pasture (basal diet) and an L-arginine-HCl group (n = 15) that received 7.8 g of rumen-protected L-arginine-HCl from day 5 of the sponge insertion until day 25 after mating plus the basal diet. The L-arginine-HCl was administered daily via an esophageal probe between days 5 and 9 of the synchronization protocol and every third day subsequently. Blood samples were drawn from the jugular vein every 6 days throughout the entire experimental period. The results revealed that the L-arginine-HCl supplementation increased fertility during the synchronized estrus (P = 0.05). However, no effects were observed on the final BCS (P = 0.78), estrus presentation (P = 0.33), multiple ovulations (P = 0.24), prolificacy (P = 0.63), or serum VEGF concentration. In conclusion, L-arginine-HCl supplementation during the period used in this study increased fertility in sheep with synchronized estrus possibly due to improved embryo-fetal survival during early pregnancy.

Tiotropium and Salmeterol in COPD Patients at Risk of Exacerbations: A Post Hoc Analysis from POET-COPD(®).

PubMed

Vogelmeier, Claus F; Asijee, Guus M; Kupas, Katrin; Beeh, Kai M

2015-06-01

Among patients with chronic obstructive pulmonary disease (COPD), the frequency and severity of past exacerbations potentiates future events. The impact of current therapies on exacerbation frequency and severity in patients with different exacerbation risks is not well known. A post hoc analysis of patients at low (≤1 exacerbation [oral steroids/antibiotics requirement] and no COPD-related hospitalization in the year preceding trial entry) or high (≥2 exacerbations [oral steroids/antibiotics requirement] or ≥1 COPD-related hospitalization[s] in the year preceding trial entry) exacerbation risk, from the Prevention of Exacerbations with Tiotropium in Chronic Obstructive Pulmonary Disease (POET-COPD(®)) database. Compared with salmeterol, tiotropium significantly increased time to first COPD exacerbation (hazard ratio 0.84; 95% confidence interval [CI] 0.76-0.92; p = 0.0002) and reduced the number of COPD exacerbations (rate ratio 0.90; 95% CI 0.81-0.99; p = 0.0383) in patients at high exacerbation risk. With treatment, the risk of remaining in the high-risk exacerbator subgroup was statistically lower with tiotropium versus salmeterol (risk ratio [RR] 0.89; 95% CI 0.80-1.00; p = 0.0478). For low-risk patients, time to first COPD exacerbation and number of COPD exacerbations were numerically lower with tiotropium versus salmeterol. With treatment, the risk of transitioning from a low to a high exacerbation risk was lower with tiotropium versus salmeterol (RR 0.87; 95% CI 0.71-1.07; p = 0.1968). This analysis confirms the higher efficacy of tiotropium versus salmeterol in prolonging time to first COPD exacerbation and reducing number of exacerbations in patients both at low and high exacerbation risk. Boehringer Ingelheim and Pfizer. ClinicalTrials.gov NCT00563381.

Nationwide survey on the use of horse antithymocyte globulins (ATGAM) in patients with acquired aplastic anemia: A report on behalf of the French Reference Center for Aplastic Anemia.

PubMed

Peffault de Latour, Régis; Tabrizi, Reza; Marcais, Ambroise; Leblanc, Thierry; Lamy, Thierry; Mohty, Mohamad; Tavitian, Suzanne; Jubert, Charlotte; Pasquet, Marlène; Galambrun, Claire; Nguyen, Stéphanie; Cahn, Jean Yves; Braun, Thorsten; Deconinck, Eric; Bay, Jacques Olivier; Sicre de Fontbrune, Flore; Barraco, Fiorenza; Socié, Gérard

2018-05-01

Antithymocyte globulins (ATG) plus cyclosporine (CSA) is the gold standard immunosuppressive treatment (IST) for patients with aplastic anemia. A prospective randomized trial showed in 2011 that hATG was superior to rabbit ATG for first-line treatment of severe AA. The French Health Agency (ANSM) permitted a patient-named authorization for temporary use (ATU) program of hATG (ATGAM, Pfizer) in patients with AA in 2011 since commercial access to hATG is not approved. We took advantage of this program to analyze the outcomes of 465 patients who received antithymocyte globulins (ATGAM) plus CSA as first line treatment (n = 379; 81.5%), or for refractory (n = 26) or relapsed disease (n = 33), from September 2011 to March 2017. In the entire cohort one year, 72% of the patients had partial and 13% had complete response, with worse response for patients with severe AA and a longer interval between diagnosis and IST (more than 6 months). Severe adverse events were mainly linked to infections (24%), hemorrhages (6%), and elevated liver function tests (5%). Overall at 12 months, 9.7% of patients required second line IST and 15.6% received transplantation. Fifty-five patients died during the study mainly because of infections (53%). Factors predicting independently worse survival were age over 40 years, neutrophils less than 0.5 × 10 9 /L, male gender and longer delay between diagnosis and hATG (>6 months period). This study does illustrate the results of ATGAM with CSA in a true-life perspective and confirms ATGAM as standard of care IST to treat patients with AA not eligible for HSCT. © 2018 Wiley Periodicals, Inc.

Pain conditions ranked by healthcare costs for members of a national health plan.

PubMed

Pasquale, Margaret K; Dufour, Robert; Schaaf, David; Reiners, Andrew T; Mardekian, Jack; Joshi, Ashish V; Patel, Nick C

2014-02-01

Healthcare resource utilization (HCRU) and associated costs specific to pain are a growing concern, as increasing dollar amounts are spent on pain-related conditions. Understanding which pain conditions drive the highest utilization and cost burden to the healthcare system would enable providers and payers to better target conditions to manage pain adequately and efficiently. The current study focused on 36 noncancer chronic and 14 noncancer acute pain conditions and measured the HCRU and costs per member over 365 days. These conditions were ranked by per-member costs and total adjusted healthcare costs to determine the most expensive conditions to a national health plan. The top 5 conditions for the commercial line of business were back pain, osteoarthritis (OA), childbirth, injuries, and non-hip, non-spine fractures (adjusted annual total costs for the commercial members were $119 million, $98 million, $69 million, $61 million, and $48 million, respectively). The top 5 conditions for Medicare members were OA, back pain, hip fractures, injuries, and non-hip, non-spine fractures (adjusted annual costs for the Medicare members were $327 million, $218 million, $117 million, $82 million, and $67 million, respectively). The conditions ranked highest for both per-member and total healthcare costs were hip fractures, childbirth, and non-hip, non-spine fractures. Among these, hip fractures in the Medicare member population had the highest mean cost per member (adjusted per-member cost was $21,058). Further examination specific to how pain is managed in these high-cost conditions will enable providers and payers to develop strategies to improve patient outcomes through appropriate pain management. © 2013 Humana Inc. and Pfizer Inc. Pain Practice © 2013 World Institute of Pain.

Assessing the usefulness of B-mode and colour Doppler sonography, and measurements of circulating progesterone concentrations for determining ovarian responses in superovulated ewes.

PubMed

Oliveira, Mef; Ribeiro, I F; Rodriguez, Mgk; Maciel, G S; Fonseca, J F; Brandão, F Z; Bartlewski, P M

2018-06-01

The main goal of this study was to assess the usefulness of two imaging modalities, namely the B-mode and colour Doppler sonography, and serum progesterone (P 4 ) concentrations for determining the ovarian response in superovulated ewes. Twenty-four sexually mature Santa Inês ewes underwent the superovulatory treatment consisting of eight injections of porcine FSH (total dose of 200 or 133 or 100 mg; n = 8 ewes/total dose) given at 12-hr intervals and initiated 48 hr before CIDR ® (Pfizer Inc., Auckland, New Zealand) removal. Six days after natural mating, the ovaries of all donor ewes were visualized and examined with transrectal ultrasonography and then with videolaparoscopy to identify and enumerate corpora lutea (CL) and luteinized unovulated follicles (LUFs). Jugular blood samples were collected just prior to ovarian examinations. The total number of CL (r = .78 and 0.83, p < .0001) and LUFs (r = .74 and 0.90, p < .0001) enumerated using the B-mode and colour Doppler ultrasonographic technique, respectively, were correlated with that ascertained by videolaparoscopy. Circulating concentrations of P 4 were related directly to the number of healthy CL (r = .73, p = .0002) and inversely to the number of prematurely regressing CL (r = -.46, p = .03), but the accuracy of predicting the number of short-lived CL with serum P 4 concentrations was very poor. The present results indicate that ultrasonographic imaging and serum P 4 measurements on the day of embryo recovery are useful indicators of total/normal CL numbers and both ultrasonographic techniques can be used to quantify LUFs in superovulated ewes. © 2018 Blackwell Verlag GmbH.

A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency.

PubMed

Chatelain, Pierre; Malievskiy, Oleg; Radziuk, Klaudziya; Senatorova, Ganna; Abdou, Magdy O; Vlachopapadopoulou, Elpis; Skorodok, Yulia; Peterkova, Valentina; Leff, Jonathan A; Beckert, Michael

2017-05-01

TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD). To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer). Thirty-eight centers in 14 European countries and Egypt. Prepubertal male and female treatment-naïve children with GHD (n = 53). Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks. GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity. Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development. Copyright © 2017 Endocrine Society

Packaging of Mason-Pfizer monkey virus (MPMV) genomic RNA depends upon conserved long-range interactions (LRIs) between U5 and gag sequences.

PubMed

Kalloush, Rawan M; Vivet-Boudou, Valérie; Ali, Lizna M; Mustafa, Farah; Marquet, Roland; Rizvi, Tahir A

2016-06-01

MPMV has great potential for development as a vector for gene therapy. In this respect, precisely defining the sequences and structural motifs that are important for dimerization and packaging of its genomic RNA (gRNA) are of utmost importance. A distinguishing feature of the MPMV gRNA packaging signal is two phylogenetically conserved long-range interactions (LRIs) between U5 and gag complementary sequences, LRI-I and LRI-II. To test their biological significance in the MPMV life cycle, we introduced mutations into these structural motifs and tested their effects on MPMV gRNA packaging and propagation. Furthermore, we probed the structure of key mutants using SHAPE (selective 2'hydroxyl acylation analyzed by primer extension). Disrupting base-pairing of the LRIs affected gRNA packaging and propagation, demonstrating their significance to the MPMV life cycle. A double mutant restoring a heterologous LRI-I was fully functional, whereas a similar LRI-II mutant failed to restore gRNA packaging and propagation. These results demonstrate that while LRI-I acts at the structural level, maintaining base-pairing is not sufficient for LRI-II function. In addition, in vitro RNA dimerization assays indicated that the loss of RNA packaging in LRI mutants could not be attributed to the defects in dimerization. Our findings suggest that U5-gag LRIs play an important architectural role in maintaining the structure of the 5' region of the MPMV gRNA, expanding the crucial role of LRIs to the nonlentiviral group of retroviruses. © 2016 Kalloush et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

Relative Risks of Contributing Factors to Morbidity and Mortality in Adults With Craniopharyngioma on Growth Hormone Replacement.

PubMed

Yuen, Kevin C J; Mattsson, Anders F; Burman, Pia; Erfurth, Eva-Marie; Camacho-Hubner, Cecilia; Fox, Janet L; Verhelst, Johan; Geffner, Mitchell E; Abs, Roger

2018-02-01

In adults, craniopharyngioma (CP) of either childhood-onset (CO-CP) or adult-onset (AO-CP) is associated with increased morbidity and mortality, but data on the relative risks (RRs) of contributing factors are lacking. To assess the RRs of factors contributing to morbidity and mortality in adults with CO-CP and AO-CP. Data on 1669 patients with CP from KIMS (Pfizer International Metabolic Database) were analyzed using univariate and multiple Poisson and Cox regression methods. When CO-CP and AO-CP groups were combined, history of stroke and hyperlipidemia increased cardiovascular risk, higher body mass index (BMI) and radiotherapy increased cerebrovascular risk, and increased waist circumference increased the risk of developing diabetes mellitus (DM). Compared with patients with CO-CP, patients with AO-CP had a threefold higher risk of tumor recurrence, whereas being female and previous radiotherapy exposure conferred lower risks. Radiotherapy and older age with every 10 years from disease onset conferred a 2.3- to 3.5-fold risk for developing new intracranial tumors, whereas older age, greater and/or increasing BMI, history of stroke, and lower insulinlike growth factor I (IGF-I) standard deviation score measured at last sampling before death were related to increased all-cause mortality. Compared with the general population, adults with CP had 9.3-, 8.1-, and 2.2-fold risks of developing DM, new intracranial tumors, and early death, respectively. Conventional factors that increase the risks of cardio- and cerebrovascular diseases and DM and risks for developing new intracranial tumors contributed to excess morbidity and mortality. In addition, lower serum IGF-I level measured from the last sample before death was inversely associated with mortality risk in patients with CP. Copyright © 2017 Endocrine Society

Mechanisms employed by retroviruses to exploit host factors for translational control of a complicated proteome

PubMed Central

Bolinger, Cheryl; Boris-Lawrie, Kathleen

2009-01-01

Retroviruses have evolved multiple strategies to direct the synthesis of a complex proteome from a single primary transcript. Their mechanisms are modulated by a breadth of virus-host interactions, which are of significant fundamental interest because they ultimately affect the efficiency of virus replication and disease pathogenesis. Motifs located within the untranslated region (UTR) of the retroviral RNA have established roles in transcriptional trans-activation, RNA packaging, and genome reverse transcription; and a growing literature has revealed a necessary role of the UTR in modulating the efficiency of viral protein synthesis. Examples include a 5' UTR post-transcriptional control element (PCE), present in at least eight retroviruses, that interacts with cellular RNA helicase A to facilitate cap-dependent polyribosome association; and 3' UTR constitutive transport element (CTE) of Mason-Pfizer monkey virus that interacts with Tap/NXF1 and SR protein 9G8 to facilitate RNA export and translational utilization. By contrast, nuclear protein hnRNP E1 negatively modulates HIV-1 Gag, Env, and Rev protein synthesis. Alternative initiation strategies by ribosomal frameshifting and leaky scanning enable polycistronic translation of the cap-dependent viral transcript. Other studies posit cap-independent translation initiation by internal ribosome entry at structural features of the 5' UTR of selected retroviruses. The retroviral armamentarium also commands mechanisms to counter cellular post-transcriptional innate defenses, including protein kinase R, 2',5'-oligoadenylate synthetase and the small RNA pathway. This review will discuss recent and historically-recognized insights into retrovirus translational control. The expanding knowledge of retroviral post-transcriptional control is vital to understanding the biology of the retroviral proteome. In a broad perspective, each new insight offers a prospective target for antiviral therapy and strategic improvement of gene transfer vectors. PMID:19166625

Immunisation against East Coast fever by the infection and treatment method: evaluation of the use of ice baths for field delivery and appraisal of an acid formulation of long-acting tetracycline.

PubMed

Marcotty, T; Billiouw, M; Chaka, G; Berkvens, D; Losson, B; Brandt, J

2001-08-20

Immunisation by the infection and treatment method using the Katete strain is currently the most efficient prophylactic technique to control East Coast fever (ECF) in the endemic areas of the Eastern Province of Zambia. The maintenance of the cold chain in liquid nitrogen up to the time of inoculation and the cost of the reference long-acting oxytetracycline (Terramycin LA, Pfizer) are the main drawbacks of the method. The work presented in this paper aims at reducing the cost of immunisation against ECF by using an ice bath for the field delivery and a cheaper long-acting oxytetracycline formulation as chemotherapeutic agent. In experimental conditions, the results from 40 calves immunised after various periods of storage on ice ranging from 4 to 32 h indicate that deferred immunisation performed with a stabilate kept on ice for up to 6h after thawing has an efficiency of 90%. Moreover, sporozoites kept on ice were still surviving 32 h after thawing. In a field trial, 91 calves were inoculated with a stabilate kept for 3.5-5.5 h after thawing and dilution whereas 86 calves were immunised using the standard method. Clinical and parasitological reactions to immunisation were monitored as well as the seroconversion. In the field trial, the deferred immunisation was more efficient than the standard method. The acid formulation of oxytetracycline that was tested was found as suitable as the reference alkaline formulation for the chemotherapeutic control of the Katete strain in ECF immunisation. One indoor trial was carried out on 10 animals and a field trial involved 93 calves.

Herd-level animal management factors associated with the occurrence of bovine neonatal pancytopenia in calves in a multi-country study

PubMed Central

Jones, Bryony A.; Henning, Jörg; Stoll, Alexander; Nielen, Mirjam; Van Schaik, Gerdien; Smolenaars, Anja; Schouten, Matthijs; den Uijl, Ingrid; Fourichon, Christine; Guatteo, Raphael; Madouasse, Aurélien; Nusinovici, Simon; Deprez, Piet; De Vliegher, Sarne; Laureyns, Jozef; Booth, Richard; Cardwell, Jacqueline M.; Pfeiffer, Dirk U.

2017-01-01

Since 2007, mortality associated with a previously unreported haemorrhagic disease has been observed in young calves in several European countries. The syndrome, which has been named ‘bovine neonatal pancytopenia’ (BNP), is characterised by thrombocytopenia, leukocytopenia and a panmyelophthisis. A herd-level case-control study was conducted in four BNP affected countries (Belgium, France, Germany and the Netherlands) to identify herd management risk factors for BNP occurrence. Data were collected using structured face-to-face and telephone interviews of farm managers and their local veterinarians. In total, 363 case farms and 887 control farms were included in a matched multivariable conditional logistic regression analysis. Case-control status was strongly associated with the odds of herd level use of the vaccine PregSure® BVD (PregSure, Pfizer Animal Health) (matched adjusted odds ratio (OR) 107.2; 95% CI: 41.0–280.1). This was also the case for the practices of feeding calves colostrum from the calf’s own dam (OR 2.0; 95% CI: 1.1–3.4) or feeding pooled colostrum (OR 4.1; 95% CI: 1.9–8.8). Given that the study had relatively high statistical power and represented a variety of cattle production and husbandry systems, it can be concluded with some confidence that no other herd level management factors are competent causes for a sufficient cause of BNP occurrence on herd level. It is suggested that genetic characteristics of the dams and BNP calves should be the focus of further investigations aimed at identifying the currently missing component causes that together with PregSure vaccination and colostrum feeding represent a sufficient cause for occurrence of BNP in calves. PMID:28678850

Moving mountains.

PubMed

2003-01-01

What could be more fundamental to management, or more difficult, than motivating people? After all, a manager, by definition, is someone who gets work done through others. But how? A typical recipe for motivation calls for a mixture of persuasion, encouragement, and compulsion. Yet the best leaders, we suspect, need no recipe: They get people to produce great results by appealing to their deepest drives, needs, and desires. And so we discovered when we asked a dozen of the world's top leaders to describe how they each met a daunting challenge in motivating an individual, a team, or an organization. Their answers are as varied as human nature. Some of the leaders appeal to people's need for the rational and the orderly: Mattel's Robert Eckert emphasizes the reassuring power of delivering a consistent message, and HP's Carly Fiorina focuses on facing hard truths on setting step-by-step goals. Some, like celebrated oceanographer Robert Ballard, Pfizer CEO Hank McKinnell, and BP America president Ross Pillari, see the powerful motivating effects of asking people to rise to difficult challenges. Others focus more on the human spirit, appealing to the desire to do something, as BMW's Chris Bangle puts it, "rare, marvelous, and lasting." And quite a few inspire through example, as Dial chairman Herb Baum did when he donated $1,000 from his bonus to each of the company's 155 lowest-paid people. "If you draw the line on your own greed, and your employees see it," he says, "they will be incredibly loyal and perform much better for you." And he has the numbers to prove it. "Right now," he adds, "we're experiencing our lowest level of attrition in 11 years, and we're tracking toward another banner year because people are happy."

Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline: An important pharmacological fragment of VEGFR2 and other inhibitors

PubMed Central

Murár, Miroslav; Addová, Gabriela

2013-01-01

Summary Background: 5-(Ethylsulfonyl)-2-methoxyaniline (5) is part of the structure in 131 compounds possessing different biological activities. In most cases, they have antitumor properties (112 compounds). Other compounds are described as cardiovascular agents, ion-channel blockers, nervous-system blockers, anti-inflammatory agents, or antidiabetic, antiosteoporotic and hypolipemic species. Compound 5 is a precursor of different protein-kinase inhibitors or enzyme modulators (EGFR, PDGFR, ckit, CDK 2 and 4, MMPs 2, 3, 9 and 13, etc.). The structure of 5 represents a fragment for several powerful inhibitors of VEGFR2, a key angiogenic receptor. Antiangiogenic inhibitors slow down or stop new blood-vessel formation from pre-existing vasculature. Some antiangiogenic drugs inhibiting the VEGFR2 receptor are successfully used in clinics for the treatment of several types of tumours in synergy with chemotherapy (e.g., Nexavar® from Bayer, Sutent® from Pfizer and Votrient® from GlaxoSmithKline, approved by the FDA in 2005, 2006 and 2009, respectively). The structure of 5 is an important pharmacophoric fragment of potent VEGFR2 inhibitors (e.g., AAZ from PDB complex 1Y6A, enzymatic IC50 = 22 nM). Up to now, 25 VEGFR2 inhibitors possessing a fragment of 5 can be found in the literature. Despite the high significance of 5-(ethylsulfonyl)-2-methoxyaniline (5) its preparation has not yet been described. Results: Here we have developed a convenient synthesis of important polyheterosubstituted aniline 5 starting from commercially available 4-methoxybenzene-1-sulfonyl chloride (1) in four steps and 59% overall yield. The target 5-(ethylsulfonyl)-2-methoxyaniline (5) and its synthetic intermediates 2–4 together with a new compound 5-(ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene (4a) have been precisely physicochemically characterised. PMID:23399884

YC-1 BINDING TO THE BETA SUBUNIT OF SOLUBLE GUANYLYL CYCLASE OVERCOMES ALLOSTERIC INHIBITION BY THE ALPHA SUBUNIT

PubMed Central

Purohit, Rahul; Fritz, Bradley G.; The, Juliana; Issaian, Aaron; Weichsel, Andrzej; David, Cynthia L.; Campbell, Eric; Hausrath, Andrew C.; Rassouli-Taylor, Leida; Garcin, Elsa D.; Gage, Matthew J.; Montfort, William R.

2014-01-01

Soluble guanylate cyclase (sGC) is a heterodimeric heme protein and the primary nitric oxide receptor. NO binding stimulates cyclase activity, leading to regulation of cardiovascular physiology and making sGC an attractive target for drug discovery. YC-1 and related compounds stimulate sGC both independently and synergistically with NO and CO binding; however, where the compounds bind and how they work remains unknown. Using linked-equilibria binding measurements, surface plasmon resonance, and domain truncations in Manduca sexta and bovine sGC, we demonstrate that YC-1 binds near or directly to the heme-containing domain of the beta subunit. In the absence of CO, YC-1 binds with Kd = 9–21 μM, depending on construct. In the presence of CO, these values decrease to 0.6–1.1 μM. Pfizer compound 25 bound ~10-fold weaker than YC-1 in the absence of CO whereas compound BAY 41–2272 bound particularly tightly in the presence of CO (Kd = 30–90 nM). Additionally, we found that CO binding is much weaker to heterodimeric sGC proteins (Kd = 50–100 μM) than to the isolated heme domain (Kd = 0.2 μM for Manduca beta H-NOX/PAS). YC-1 greatly enhanced CO binding to heterodimeric sGC, as expected (Kd = ~1 μM). These data indicate the alpha subunit induces a heme pocket conformation with lower affinity for CO and NO. YC-1 family compounds bind near the heme domain, overcoming the alpha subunit effect and inducing a heme pocket conformation with high affinity. We propose this high-affinity conformation is required for the full-length protein to achieve high catalytic activity. PMID:24328155

Primary treatment regimen and diabetes insipidus as predictors of health outcomes in adults with childhood-onset craniopharyngioma.

PubMed

Yuen, Kevin C J; Kołtowska-Häggström, Maria; Cook, David M; Fox, Janet L; Jönsson, Peter J; Geffner, Mitchell E; Abs, Roger

2014-04-01

Craniopharyngiomas are often associated with significant morbidity due to their location and treatment effects. Little is known of the effects of primary treatment regimen and diabetes insipidus (DI), a clinical surrogate of hypothalamic obesity, on health outcomes in adults with childhood-onset craniopharyngioma (COCP). The objective of the study was to examine health outcomes of adults with COCP based on primary treatment regimens and the presence of DI. This study included a retrospective KIMS (Pfizer International Metabolic Database) data analysis of 180 adults with COCP according to the primary treatment regimen [one surgery (1Surg) vs complex treatment regimen (CTrR) of more than 1Surg and/or radiotherapy] and the presence of DI. The majority of COCP patients underwent transcranial surgery (77%) without receiving radiotherapy (84%). Compared with the 1Surg group, more CTrR patients developed visual field defects and ophthalmoplegia (all P < .01). Compared with patients without DI, those with DI had higher rates of anterior pituitary hormone deficits, body mass index, and fat mass (all P < .01). By contrast, fasting glucose, hemoglobin A1c, lipid panel, and quality of life were comparable among 1Surg vs CTrR patients, and patients with vs without DI. Regardless of primary treatment received, the presence of DI in either group was associated with higher rates of anterior pituitary hormone deficits and obesity. CTrR and DI predicted health outcomes differently. CTrR predisposed to the development of visual dysfunction, whereas DI was associated with higher rates of anterior pituitary dysfunction and weight gain. Higher body mass index and fat mass in patients with DI further implicate the role of hypothalamic damage as an important causal factor of obesity in these patients.

Response of feline eosinophilic plaques and lip ulcers to amoxicillin trihydrate-clavulanate potassium therapy: a randomized, double-blind placebo-controlled prospective study.

PubMed

Wildermuth, Brett E; Griffin, Craig E; Rosenkrantz, Wayne S

2012-04-01

In this study, we evaluated the treatment of feline eosinophilic plaques and lip ulcers with amoxicillin trihydrate-potassium clavulanate (Clavamox(®); Pfizer Animal Health). Nineteen cats with clinical and cytological findings consistent with eosinophilic plaques and/or lip ulcers were enrolled. Lesions were photographed and their areas measured in square centimetres before and after 21 days of therapy with either flavoured amoxicillin-clavulanate suspension or flavoured placebo suspension. Sixteen cats completed the study, with nine plaque lesions (four treatment and five placebo) and eight lip ulcer lesions (four treatment and four placebo) included in the analysis. All lesions were shown to have infection, with bacterial phagocytosis present on cytological examination. Coagulase-positive staphylococci were the most commonly isolated bacteria. The amoxicillin-clavulanate-treated eosinophilic plaque group had a statistically significant 96.2% reduction in mean lesion size (-7.60 cm(2), P = 0.0078) and an 80% reduction in mean percentage of microscopic fields demonstrating evidence of bacterial infection (P < 0.0001), whereas the placebo group did not. The amoxicillin-clavulanate-treated lip ulcer group had a 42.6% decrease in mean lesion size (-0.25 cm(2), P = 0.4125) and the placebo group a 36.6% increase (+0.49 cm(2), P = 0.1575), although neither change was statistically significant. The amoxicillin-clavulanate-treated lip ulcer group had a statistically significant 65.0% reduction in mean percentage of microscopic fields demonstrating evidence of bacterial infection (P < 0.0001), while no significant reduction was observed in the placebo group. A suspension of amoxicillin trihydrate-potassium clavulanate is an effective monotherapy for the treatment of feline eosinophilic plaques. © 2011 The Authors. Veterinary Dermatology. © 2011 ESVD and ACVD.

Pharmacokinetics, phenotype and product choice in haemophilia B: how to strike a balance?

PubMed

Berntorp, E; Dolan, G; Hermans, C; Laffan, M; Santagostino, E; Tiede, A

2014-11-01

At the 7th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD) held in Brussels, Belgium, in February 2014, Pfizer sponsored a satellite symposium entitled: "Pharmacokinetics, phenotype and product choice in haemophilia B: How to strike a balance?" Co-chaired by Cedric Hermans (Cliniques Universitaires Saint Luc, Brussels, Belgium) and Mike Laffan (Imperial College, London, UK), the symposium provided an opportunity to debate whether pharmacokinetic (PK) parameters are good surrogates for clinical efficacy for haemophilia B in clinical practice, consider the perceptions and evidence of disease severity, and examine how these considerations can inform approaches to balancing the potential risks and benefits of the currently available treatment options for haemophilia B. PK parameters are routinely measured in clinical practice and are a requirement of regulatory bodies to demonstrate the clinical efficacy of products; however, the relationship between measured PK parameters and clinical efficacy is yet to be determined, an issue that was debated by Gerry Dolan (University Hospital, Queen's Medical Centre, Nottingham, UK) and Erik Berntorp (Lund University, Malmö Centre for Thrombosis and Haemostasis, Malmö, Sweden). Elena Santagostino (Universita degli Studi di Milano, Milano, Italy) reviewed how differing perceptions on the severity of haemophilia B compared with haemophilia A may have an impact on clinical decision-making. Finally, Andreas Tiede (Hannover Medical School, Hannover, Germany), examined the considerations for balancing the potential risks and benefits of the currently available treatment options for haemophilia B. Although the pathophysiology of haemophilia B has been widely studied and is largely understood, continued investigation and discussion around the optimal management course and appropriate therapeutic choice is warranted. © 2014 John Wiley & Sons Ltd.

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

PubMed Central

Manning, M; Misicka, A; Olma, A; Bankowski, K; Stoev, S; Chini, B; Durroux, T; Mouillac, B; Corbani, M; Guillon, G

2012-01-01

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V1a, V1b and V2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V2/V1a antagonist, conivaptan and the V2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V1a, V1b and V2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences. PMID:22375852

A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity.

PubMed

Reed, Karen L; Fruin, A Brent; Gower, Adam C; Stucchi, Arthur F; Leeman, Susan E; Becker, James M

2004-06-15

Fibrous adhesions remain a major sequela of abdominal surgery. The proinflammatory peptide substance P (SP), known to participate in inflammatory events, may play a key role in adhesion formation. This hypothesis was tested by using an antagonist, CJ-12,255 (Pfizer), that blocks the binding of SP to the neurokinin 1 receptor (NK-1R). Adhesion formation was surgically induced in the peritoneum of rats receiving daily doses of the NK-1R antagonist (NK-1RA; 5.0 or 10.0 mg/kg per day) or saline. On postoperative day 7, both the low and high doses of NK-1RA significantly (P < 0.05) reduced adhesion formation by 45% and 53%, respectively, compared with controls. Subsequently, the effect of NK-1RA administration on peritoneal fibrinolytic activity was investigated to determine a potential mechanism for SP action in the peritoneum. Samples were collected from nonoperated controls and from animals 24 h postsurgery that were administered either NK-1RA or saline. Fibrinolytic activity in peritoneal fluid was assayed by zymography, and expression of tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1, both regulators of fibrinolytic activity, was assessed in peritoneal tissue and fluid by RT-PCR and bioassay, respectively. NK-1RA administration led to a marked (P < 0.05) increase in tPA mRNA levels in peritoneal tissue compared with nonoperated and saline-administered animals. Likewise, NK-1RA administration significantly (P < 0.05) increased tPA in the peritoneal fluid. These data suggest that activation of the NK-1R promotes peritoneal adhesion formation by limiting fibrinolytic activity in the postoperative peritoneum, thus enabling fibrinous adhesions to persist.

A randomized controlled trial comparing mupirocin versus Polysporin Triple for the prevention of catheter-related infections in peritoneal dialysis patients (the MP3 study).

PubMed

Jassal, Sarbjit V; Lok, Charmaine E

2008-01-01

Peritonitis remains the most serious complication of peritoneal dialysis (PD). Gram-positive organisms are among the most common causes of PD peritonitis; however, recent trends show increasing rates of gram-negative and fungal infections. Strategies to prevent peritonitis include the use of prophylactic topical mupirocin at the site where the PD catheter exits from the abdominal wall; however, mupirocin does not afford protection against gram-negative or fungal infections. The aim of this study is to determine if the incidence of catheter-related infections (exit-site infection, tunnel infection, or peritonitis) is significantly reduced by the routine application of Polysporin Triple antibiotic ointment (Pfizer Canada, Markham, Ontario, Canada) in comparison to mupirocin ointment. The Mupirocin Versus Polysporin Triple Study (MP3) is a multicenter, randomized, double-blinded controlled study comparing Polysporin Triple (P3) against the current standard of care. The aim of the study is to recruit 200 patients being treated with or starting on PD and randomize them to receive either mupirocin or P3 at the catheter exit site. Patients will be followed for 18 months or until death or transfer from PD to an alternate treatment modality. The primary outcome will be the time to first catheter-related infection. Catheter-related infections will be strictly defined using current guidelines and categorized into exit-site infections, infective peritonitis, or tunnel infections. The primary analysis will be an intention-to-treat analysis. The results of this study will help determine if the use of P3 is superior to mupirocin ointment in the prevention of catheter-related infections and will help guide evidence-based best practices.

Effect of sildenafil citrate on secondary healing in full thickness skin defects in experiment.

PubMed

Cakmak, E; Karasoy Yesilada, A; Sevim, K Z; Sumer, O; Tatlidede, H S; Sakiz, D

2014-01-01

An acceleration of the wound healing process expedites chronic wound patient's return to normal social environments significantly. Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase- 5 inhibitor has been shown to be a potent stimulator of angiogenesis through upregulation of cGMP. In our study, sildenafil was administered orally as a cost-effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity. Randomly selected 72 Wistar-Albino rats were divided into the two groups, 36 rats in each group. Control group (n =36) was divided further into a secondary healing group consisting of 9 rats and a pathology group consisting of 27 rats (pathology group 1: 9 rats, 4th and 7th day of wound healing, pathology group 2: 9 rats, 10th and 14th day of wound healing, pathology group 3: 9 rats, 21st and 28th day of wound healing. Experimental group consisted of 36 rats which received sildenafil citrate (Viagra® Pfizer, Germany) for secondary wound healing to proceed. The average wound healing period in the control group was 17.89 days and in the sildenafil citrate administered group 14.56 days. The difference of the epithelialisation on full thickness defects were more prominent on days 5 and 11 postoperatively. In the sildenafil citrate applied group, on the 7th day, the defect was 25% smaller and on the 13th day, the defect contracted by 38%. In conclusion, we believe that sildenafil citrate administered orally is a cost- effective supplement in the treatment of full thickness defects and chronic wounds in that manner with low incidence of side effects and morbidity (Tab. 4, Fig. 7, Ref. 34).

Effect of sildenafil citrate (Viagra®) on trace element concentration in serum and brain of rats.

PubMed

Fayed, Abdel-Hasseb A; Gad, Shereen B

2011-12-01

As a vasodilator with good hemodynamic effects, sildenafil has been successfully used in the treatment of patients with pulmonary hypertension and cardiovascular diseases. By selectively inhibiting phosphodiestrase type 5 (PDE-5) and thus effectively reducing the breakdown of c GMP, sildenafil administration can markedly improve the erectile dysfunction. Sildenafil also elevates localized cerebral blood flow in rat brain. The objective of the present study was to investigate the effect of sildenafil on the level of trace elements (Zinc (Zn), copper (Cu), iron (Fe), selenium (Se), cobalt (Co), and chromium (Cr)) in blood and brain of rats. Sixteen male albino rats weighing 180-200 g were divided into two groups (8 rats/group). Sildenafil (Viagra, Pfizer Inc.) was dissolved in saline and administered at a dose of 10mg/kg i.p. (0.5 ml volume) to rats in the treated group every 72 h for 12 injections. Rats in the control group were administered the same volume of saline as in treated group. All rats were sacrificed 24h after the last injection. Blood samples were collected and serum was separated and stored at -20°C. Brains were dissected and stored frozen until analysis. Trace elements concentrations were determined by flame emission atomic absorption spectrophotometer. Results showed that sildenafil injection significantly (P<0.05) increased serum and brain Se and Cu concentrations. Moreover, sildenafil increased the Cr concentration in the brain tissue. It was concluded that sildenafil citrate administration increased serum Se and Cu as well as, increased brain Se, Cu, and Cr concentrations in rats. Copyright © 2011 Elsevier GmbH. All rights reserved.

Treatment benefit and the risk of suicidality in multicenter, randomized, controlled trials of sertraline in children and adolescents.

PubMed

March, John S; Klee, Brian J; Kremer, Charlotte M E

2006-01-01

The aim of this study was to examine the balance between the benefits of treatment and the risk of suicidality in children and adolescents in multicenter, randomized, controlled trials of sertraline versus placebo. The published literature was searched for multicenter, randomized, placebo-controlled trials of sertraline for pediatric mental disorders. Four trials were identified: Two (pooled) in pediatric major depressive disorder (MDD; Wagner 2003) and two in obsessive-compulsive disorder (OCD; March et al. 1998; POTS Team 2004). Using intent-to-treat (ITT) analysis populations, the authors calculated the number needed to treat (NNT) for response and remission and the number needed to harm (NNH) for suicidality, and their ratio, for each clinical trial. NNTs ranged from 2 to 10, indicating clinically meaningful benefits. Benefit was greater for OCD than for MDD, and for adolescents as compared with children in MDD. No age effect was apparent for OCD. Suicidality was reported in 8 patients (5 assigned to sertraline and 3 assigned to placebo). All but 1 (a placebo-treated patient in the Pfizer OCD trial) were enrolled in the sertraline MDD trial. The NNH for suicidality in MDD was 64. Treatment emergent suicidality was more common in children (NNH 28.7) than in adolescents (NNH 706.3). Because no patient developed suicidality in sertraline-treated OCD patients, the NNH for sertraline in OCD approaches infinity. With the stipulation that doctor and patient preferences necessarily play a critical role in the choice of treatment, NNT to NNH ratios indicate a positive benefit-to-risk ratio for sertraline in adolescents with MDD and in patients of all ages with OCD.

Proposal of a clinical response score and predictors of clinical response to 2 years of GH replacement therapy in adult GH deficiency.

PubMed

Schneider, Harald J; Buchfelder, Michael; Wallaschofski, Henri; Luger, Anton; Johannsson, Gudmundur; Kann, Peter H; Mattsson, Anders

2015-12-01

There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT. © 2015 European Society of Endocrinology.

Social, educational and vocational outcomes in patients with childhood-onset and young-adult-onset growth hormone deficiency.

PubMed

Mitra, M Tanya; Jönsson, Peter; Åkerblad, Ann-Charlotte; Clayton, Peter; Kołtowska-Häggström, Maria; Korbonits, Márta; Toogood, Andy; Gleeson, Helena

2017-04-01

Hypopituitarism diagnosed in childhood, adolescence and young adulthood has the potential to affect growth and somatic development. Less is known about the impact of such a diagnosis on other aspects of development. An analysis of the KIMS database (Pfizer International Metabolic Database) was performed to explore social, educational and vocational outcomes of adult patients diagnosed in childhood, adolescence and young adulthood compared with adult-onset controls. A total of 2952 adult patients diagnosed with hypothalamic pituitary conditions before the age of 25 were divided into two groups: childhood-onset [<16 years (CO)] (n = 1782) and young-adult-onset [16 to <25 years (YAO)] (n = 1170). A total of 1617 adult patients diagnosed with a nonfunctioning pituitary adenoma at the age of 25 or older formed the adult-onset control group (AO). KIMS Patient Life Situation Form which provided information on social, educational and vocational outcomes. Compared with the AO control group, CO and YAO patients were between 4·5 and 8·0 times more likely to live with their parents in adulthood; CO and YAO patients were also less likely to live in partnership and to have children. The impact on educational and vocational outcomes was less marked than on social outcomes with no significant differences compared with the AO control group. Educational and vocational outcomes showed the lowest level in male and female CO and YAO patients who had been previously diagnosed with a brain tumour. Social outcomes were more affected than educational and vocational outcomes. Although CO patients are more adversely affected, YAO patients were also failing to achieve social milestones. This has consequences for the delivery of endocrine care in both paediatric and adult services. © 2016 John Wiley & Sons Ltd.

High-Throughput Screening of Na(V)1.7 Modulators Using a Giga-Seal Automated Patch Clamp Instrument.

PubMed

Chambers, Chris; Witton, Ian; Adams, Cathryn; Marrington, Luke; Kammonen, Juha

2016-03-01

Voltage-gated sodium (Na(V)) channels have an essential role in the initiation and propagation of action potentials in excitable cells, such as neurons. Of these channels, Na(V)1.7 has been indicated as a key channel for pain sensation. While extensive efforts have gone into discovering novel Na(V)1.7 modulating compounds for the treatment of pain, none has reached the market yet. In the last two years, new compound screening technologies have been introduced, which may speed up the discovery of such compounds. The Sophion Qube(®) is a next-generation 384-well giga-seal automated patch clamp (APC) screening instrument, capable of testing thousands of compounds per day. By combining high-throughput screening and follow-up compound testing on the same APC platform, it should be possible to accelerate the hit-to-lead stage of ion channel drug discovery and help identify the most interesting compounds faster. Following a period of instrument beta-testing, a Na(V)1.7 high-throughput screen was run with two Pfizer plate-based compound subsets. In total, data were generated for 158,000 compounds at a median success rate of 83%, which can be considered high in APC screening. In parallel, IC50 assay validation and protocol optimization was completed with a set of reference compounds to understand how the IC50 potencies generated on the Qube correlate with data generated on the more established Sophion QPatch(®) APC platform. In summary, the results presented here demonstrate that the Qube provides a comparable but much faster approach to study Na(V)1.7 in a robust and reliable APC assay for compound screening.

Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis.

PubMed

Foster, Shonda A; Zhu, Baojin; Guo, Jiaying; Nikai, Enkeleida; Ojeh, Clement; Malatestinic, William; Goldblum, Orin; Kornberg, Lori J; Wu, Jashin J

2016-04-01

Psoriasis is a chronic, incurable, and immune-mediated skin disorder that is characterized by erythematous scaly papules and plaques. Understanding of psoriasis at the molecular level has led to the development of biologic agents that target disease-specific inflammatory mediators in psoriatic lesions. Biologic agents have become important components of the psoriasis armamentarium, but some patients become refractory to these agents over time or fail to respond to subsequent biologics. To (a) evaluate demographic and clinical characteristics of psoriasis patients who have treatment patterns suggestive of failure to a newly initiated biologic agent (treatment-regimen failures) compared with those who do not (non-treatment-regimen failures) and (b) to assess health care-related resource utilization and costs in non-treatment-regimen failures and treatment-regimen failures. In this retrospective observational cohort study, patients were selected from the MarketScan claims database of commercially insured individuals and individuals with Medicare supplemental insurance. The index event was a newly initiated biologic agent for the treatment of psoriasis (etanercept, adalimumab, ustekinumab, or infliximab) between January 2010 and December 2011. The analysis included psoriasis patients aged ≥ 18 years with ≥ 1 prescription claim for a biologic and continuous enrollment 12 months pre- and post-index date. Patients with claims for a biologic in the pre-index period were excluded. Patients were divided into treatment-regimen-failure and non-treatment-regimen-failure groups based on their treatment patterns post-index date. The treatment-regimen-failure group included patients who switched to another biologic, discontinued the biologic without restarting, increased the dose of the biologic, or augmented treatment with a nontopical psoriasis medication during the post-index period. Between-group patient characteristics and medication use were compared using analysis of variance for continuous variables and chi-square tests for categorical variables without adjustment. Cost differences were compared using the propensity score-adjusted bin bootstrapping method. Overall, 2,146 patients met the enrollment criteria. The mean age was 45.1 years. Of these patients, 41.5% were considered treatment-regimen failures. Among treatment-regimen failures, 53% were females, and among non-treatment-regimen failures, 61% were male. Patients who experienced treatment-regimen failure had higher incidences of comorbid cerebrovascular disease, hypertension, chronic pulmonary disease, depression, and anxiety in the pre-index period and were more likely to use concomitant topicals (67.0% vs. 58.4%; P < 0.001), methotrexate (20.2% vs. 7.3%; P < 0.001), and cyclosporine (3.1% vs. 1.0%; P < 0.001) in the post-index period. Mean total all-cause health care costs were higher in patients with treatment-regimen failure versus non-treatment-regimen failure during the pre-index period ($8,024 vs. $6,637; P = 0.002), but patients with non-treatment-regimen failure had higher all-cause costs ($30,759 vs. $28,012; P = 0.002) and psoriasis-related costs ($25,286 vs. $19,625; P < 0.001) during the post-index period. The results of the current study demonstrated that psoriasis patients with treatment patterns suggestive of treatment-regimen failure on an index biologic had different characteristics and incurred higher all-cause health care costs than did patients without treatment-regimen failure during the pre-index period. This study was supported by Eli Lilly and Company. Foster, Zhu, Guo, Nikai, Malatestinic, Ojeh, and Goldblum are full-time employees and stockholders of Eli Lilly and Company. Kornberg is a full-time employee of INC Research, which was contracted by Eli Lilly to assist with medical writing. Wu has received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Janssen, Merck, Novartis, Pfizer, Regeneron, and Sandoz; he is a consultant for AbbVie, Amgen, Celgene, Dermira, DUSA Pharmaceuticals, Eli Lilly, and Pfizer. Study concept was developed by Foster, Ojeh, Malatestinic, and Goldblum. Zhu and Guo, along with Foster, took the lead in data collection, and data interpretation was performed by Nikai, Wu, and Foster, with assistance from the other authors. The manuscript was primarily written by Kornberg, along with Foster, with assistance from the other authors. All of the authors were involved with manuscript revision.

Maintenance of Remission with Etanercept-DMARD Combination Therapy Compared with DMARDs Alone in African and Middle Eastern Patients with Active Rheumatoid Arthritis.

PubMed

Bassiouni, Hassan; Spargo, Catherine Elizabeth; Vlahos, Bonnie; Jones, Heather E; Pedersen, Ron; Shirazy, Khalid

2018-06-01

To compare etanercept (ETN) and placebo (PBO) for maintaining low disease activity (LDA) achieved with ETN in patients with rheumatoid arthritis (RA) from Africa and the Middle East. In this subset analysis of the Treat-to-Target trial (ClinicalTrials.gov identifier NCT01981473), 53 adult patients with moderate-to-severe RA nonresponsive to methotrexate were treated with 50 mg ETN/week for 24 weeks (Period 1). Patients achieving LDA were randomized to continue ETN treatment or switched to PBO for an additional 28 weeks (Period 2). The proportion of patients maintaining LDA or remission in each arm at the end of Period 2 was determined. Additional efficacy and patient-reported outcomes (PROs) were also evaluated. During Period 1, 51 patients achieved LDA according to the disease activity score-28 joints-erythrocyte sedimentation rate (DAS28-ESR LDA) and 30 achieved remission. At week 52, nine of 22 and eight of 29 in the ETN and PBO groups, respectively, remained in DAS28-ESR LDA without experiencing a flare. Additionally, six of 14 and five of 16 in the ETN and PBO groups, respectively, remained in remission. Among patients experiencing a flare during Period 2, 13 of 22 and 21 of 29 received ETN or PBO, respectively. The median time to flare was 193 and 87 days in the ETN and PBO groups, respectively. At week 52, consistently more patients in the ETN group than in the PBO group achieved predetermined efficacy and PRO endpoints. These data suggest continuing ETN maintenance therapy is beneficial to patients after they have achieved their treatment target. However, this subset analysis is limited by the small patient population and must be interpreted with caution. Pfizer. ClinicalTrials.gov identifier, NCT0198147.

Cost-effectiveness of everolimus vs sunitinib in treating patients with advanced, progressive pancreatic neuroendocrine tumors in the United States.

PubMed

Casciano, Roman; Chulikavit, Maruit; Perrin, Allison; Liu, Zhimei; Wang, Xufang; Garrison, Louis P

2012-01-01

Everolimus (Afinitor) and sunitinib (Sutent) were recently approved to treat patients with advanced, progressive pancreatic neuroendocrine tumors (pNETs). (Afinitor is a registered trademark of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; Sutent is a registered trademark of Pfizer Inc., New York, NY, USA.) This analysis examined the projected cost-effectiveness of everolimus vs sunitinib in this setting from a US payer perspective. A semi-Markov model was developed to simulate a cohort of patients with advanced, progressive pNET and to estimate the cost per life-year gained (LYG) and per quality-adjusted life-year (QALY) gained when treating with everolimus vs sunitinib. Efficacy data were based on a weight-adjusted indirect comparison of the agents using phase 3 trial data. Model health states included: stable disease with no adverse events, stable disease with adverse events, disease progression, and death. Therapy costs were based on wholesale acquisition cost. Other costs such as physician visits, tests, hospitalizations, and adverse event costs were obtained from literature and/or primary research. Utility inputs were based on primary research. Sensitivity analyses were conducted to test the model's robustness. In the base-case analysis, everolimus was associated with an incremental 0.448 LYG (0.304 QALYs) at an incremental cost of $12,673, resulting in an incremental cost-effectiveness ratio (ICER) of $28,281/LYG ($41,702/QALY gained). The ICER fell within the cost per QALY range for many widely used oncology drugs. Sensitivity analyses demonstrated that, overall, there is a trend that everolimus is cost-effective compared to sunitinib in this setting. Results of the indirect analysis were not statistically significant (p > 0.05). Assumptions that treatment patterns are the same across therapies may not represent real-world practice. While the analysis is limited by its reliance on an indirect comparison of two phase 3 studies, everolimus is expected to be cost-effective relative to sunitinib in advanced, progressive pNET.

Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets.

PubMed

Tung, Nguyen-Thach; Tran, Cao-Son; Nguyen, Tran-Linh; Hoang, Tung; Trinh, Thanh-Dat; Nguyen, Thi-Ngan

2018-05-01

The objective of this study was to prepare and evaluate some physiochemical and biopharmaceutical properties of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets. In the first stage of the study, the bitter taste masking microparticles were prepared by solvent evaporation and spray drying method. When compared to the bitter threshold (32.43µg/ml) of azithromycin (AZI), the microparticles using AZI:Eudragit L100=1:4 and having a size distribution of 45-212µm did significantly mask the bitter taste of AZI. Fourier transform infrared spectroscopy (FTIR), and proton nuclear magnetic resonance spectroscopy ( 1 H NMR) proved that the taste masking of microparticles resulted from the intermolecular interaction of the amine group in AZI and the carbonyl group in Eudragit L100. Differential scanning calorimeter (DSC) analysis was used to display the amorphous state of AZI in microparticles. Images obtaining from optical microscopy and scanning electron microscopy (SEM) indicated the existence of microparticles in regular cube shape with many layers. In the second stage, dispersible tablets containing microparticles (DTs-MP) were prepared by direct compression technique. Stability study was conducted to screen pH modulators for DTs-MP, and a combination of alkali agents (CaCO 3 :NaH 2 PO 4 , 2:1) was added into DTs-MP to create microenvironment pH of 5.0-6.0 for the tablets. The disintegration time of optimum DTs-MP was 53±5.29s and strongly depended on the kinds of lubricant and diluent. The pharmacokinetic study in the rabbit model using liquid chromatography tandem mass spectrometry showed that the mean relative bioavailability (AUC) and mean maximum concentration (C max ) of DTs-MP were improved by 2.19 and 2.02 times, respectively, compared to the reference product (Zithromax®, Pfizer). Copyright © 2017 Elsevier B.V. All rights reserved.

Experience with an extended-release opioid formulation designed to reduce abuse liability in a community-based pain management clinic

PubMed Central

Rubino, Daniel

2011-01-01

Context With the growing public health concern over rising rates of opioid abuse, physicians have a responsibility to incorporate safeguards into their practice to minimize the potential for opioid misuse, abuse, and diversion. Patient-specific treatment regimens should include steps to monitor treatment success with regard to optimal pain management as well as inappropriate use of opioids and other substances. Opioid formulations designed to be less attractive for abuse are also being developed. While future studies are needed to determine the impact of such formulations in addressing the issue of opioid misuse in the community as a whole, the experience of practitioners who have utilized these formulations can highlight the practical steps to incorporate such formulations into the everyday patient-care setting. Purpose The purpose of this report is to describe experience in managing patients with chronic, moderate-to-severe pain using morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT) (EMBEDA®, King Pharmaceuticals® Inc, Bristol, TN, which was acquired by Pfizer Inc, New York, NY, in March 2011), a formulation designed with features to deter abuse/misuse, in a community-based pain management clinic. Case presentations Case reports demonstrating a clinical management plan for assessment, initial interview procedures, explanation/discussion of proposed therapies, patients’ treatment goals, conversion to MS-sNT, and titration and treatment outcomes are provided. Results The management approach yielded successful outcomes including pain relief, improved quality of life, treatment satisfaction, and patient acceptance of a formulation designed to deter abuse/misuse. Discussion The cases presented demonstrate that the communication accompanying complete pretreatment assessment, goal-setting and expectations, and attention to individual patient needs can enable optimization of pain-related outcomes, resulting in improved quality of life for patients and fostering patient acceptance of formulations designed to help address opioid abuse/misuse issues in the community at large. PMID:22069367

Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study.

PubMed

Kett, Daniel H; Cano, Ennie; Quartin, Andrew A; Mangino, Julie E; Zervos, Marcus J; Peyrani, Paula; Cely, Cynthia M; Ford, Kimbal D; Scerpella, Ernesto G; Ramirez, Julio A

2011-03-01

The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator-associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0·0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. Pfizer, US Medical. Copyright © 2011 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of a CRM or TT conjugated meningococcal vaccine in healthy toddlers.

PubMed

Bona, Gianni; Castiglia, Paolo; Zoppi, Giorgio; de Martino, Maurizio; Tasciotti, Annaelisa; D'Agostino, Diego; Han, Linda; Smolenov, Igor

2016-06-17

MenACWY-CRM (Menveo(®); GlaxoSmithKline) and MenACWY-TT (Nimenrix(®); Pfizer) are two meningococcal vaccines licensed in the European Union for use in both children and adults. While both vaccines target meningococcal serogroups A, C, W and Y, immunogenicity and reactogenicity of these quadrivalent meningococcal conjugate vaccines may differ due to differences in formulation processes and chemical structure. Yet data on the comparability of these two vaccines are limited. The reactogenicity and immunogenicity of one dose of either MenACWY-CRM or MenACWY-TT were evaluated in healthy toddlers aged 12-15 months. Immunogenicity was assessed using serum bactericidal antibody assays (SBA) with human (hSBA) and rabbit (rSBA) complement. A total of 202 children aged 12-15 months were enrolled to receive one dose of MenACWY-CRM or MenACWY-TT. Similar numbers of subjects reported solicited reactions within 7 days following either vaccination. Tenderness at the injection site was the most common local reaction. Systemic reactions reported were similar for both vaccines and mostly mild to moderate in severity: irritability, sleepiness and change in eating habits were most commonly reported. Immunogenicity at 1 month post-vaccination was generally comparable for both vaccines across serogroups. At 6 months post-vaccination antibody persistence against serogroups C, W, and Y was substantial for both vaccines, as measured by both assay methodologies. For serogroup A, hSBA titers declined in both groups, while rSBA titers remained high. Despite differences in composition, the MenACWY-CRM and MenACWY-TT vaccines have comparable reactogenicity and immunogenicity profiles. Immediate immune responses and short-term antibody persistence were largely similar between groups. Both vaccines were well-tolerated and no safety concerns were identified. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

The Use of Long Acting Reversible Contraceptives and the Relationship between Discontinuation Rates due to Menopause and to Female and Male Sterilizations.

PubMed

Ferreira, Jessica Mayra; Monteiro, Ilza; Castro, Sara; Villarroel, Marina; Silveira, Carolina; Bahamondes, Luis

2016-05-01

Introduction Women require effective contraception until they reach menopause. The long acting reversible contraceptives (LARC) and the depot-medroxyprogesterone acetate (DMPA, Depo-Provera®, Pfizer, Puurs, Belgium) are great options and can replace possible sterilizations. Purpose To assess the relationship between the use of LARCs and DMPA and terminations ascribed to menopause and sterilizations in a Brazilian clinic. Methods We reviewed the records of women between 12 and 50 years of age attending the clinic that chose to use a LARC method or DMPA. Cumulative termination rates due to sterilization or because the woman had reached menopause were computed using single decrement life-table analysis over 32 years. We also examined all records of surgical sterilization at our hospital between the years 1980-2012. Results Three hundred thirty-two women had continuously used the same contraceptive until menopause, and 555 women had discontinued the method because they or their partners underwent sterilization. From year 20 to year 30 of use, levonorgestrel intrauterine-releasing system (LNG-IUS - Mirena®, Bayer Oy, Turku, Finland; available since 1980), copper intrauterine device (IUD - available since 1980) and DMPA users showed a trend of cumulative higher discontinuation rates due to menopause when compared with the discontinuation rates due to sterilization. Over the study period, a steep decline in the use of sterilization occurred. Conclusion Over the past 15 years of research we have observed a trend: women usually preferred to continue using LARC methods or DMPA until menopause rather than decide for sterilization, be it their own, or their partners'. The annual number of sterilizations dropped in the same period. The use of LARC methods and DMPA until menopause is an important option to avoid sterilization, which requires a surgical procedure with potential complications. Thieme Publicações Ltda Rio de Janeiro, Brazil.

Weight gain in Turner Syndrome: association to puberty induction? - longitudinal analysis of KIGS data.

PubMed

Reinehr, Thomas; Lindberg, Anders; Toschke, Christina; Cara, Jose; Chrysis, Dionisis; Camacho-Hübner, Cecilia

2016-07-01

Girls with Turner Syndrome (TS) treated or not treated with growth hormone (GH) are prone to overweight. Therefore, we hypothesize that puberty induction in TS is associated with weight gain. We analyzed weight changes (BMI-SDS) between onset of GH treatment and near adult height (NAH) in 887 girls with TS enrolled in KIGS (Pfizer International Growth Database). Puberty was induced with estrogens in 646 (72·8%) girls with TS. Weight status did not change significantly between GH treatment start and 1 year later (mean difference -0·02 BMI-SDS), but increased significantly (P < 0·001) until NAH (+0·40 BMI-SDS). The BMI-SDS increased +0·21 until start of puberty (P < 0·001). Girls with spontaneous and induced puberty showed similar BMI-SDS changes. Puberty induction at ≥12 years was associated with a significant (P < 0·001) less increase of BMI-SDS (+0·7 BMI-SDS) between baseline and NAH compared to puberty induction at <12 year (+1·0 BMI-SDS). In multiple linear regression analyses changes of BMI-SDS between baseline and NAH were negatively associated with baseline BMI-SDS (P < 0·001), GH doses (P = 0·015), and age at puberty induction (P < 0·001), positively with years on GH treatment (P = 0·004), while duration and dose of estrogens, its route of administration (transdermal/oral), changes of height-SDS, thyroxin and oxandrolone treatment, and karyotype did not correlate significantly to changes of BMI-SDS in this time period. Puberty does not seem to play a major role in weight gain in girls with TS since the majority of the increases in BMI-SDS occurred before puberty. However, late puberty induction seems to decrease the risk of weight gain. © 2016 John Wiley & Sons Ltd.

Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies.

PubMed

Alexander, Joe; Edwards, Roger A; Manca, Luigi; Grugni, Roberto; Bonfanti, Gianluca; Emir, Birol; Whalen, Edward; Watt, Stephen; Parsons, Bruce

2018-03-01

Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined "what if" scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive-moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0-1 dose change, and 15.2% had ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction with tolerability (range 90.3-96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. Pfizer, Inc.

Adjuvant Exemestane with Ovarian Suppression in Premenopausal Breast Cancer

PubMed Central

Pagani, Olivia; Regan, Meredith M.; Walley, Barbara A.; Fleming, Gini F.; Colleoni, Marco; Láng, István; Gomez, Henry L.; Tondini, Carlo; Burstein, Harold J.; Perez, Edith A.; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R.; Martino, Silvana; Geyer, Charles E.; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P.; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N.; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S.; Gelber, Richard D.; Goldhirsch, Aron; Francis, Prudence A.

2014-01-01

BACKGROUND Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor–positive breast cancer. METHODS In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor–positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. RESULTS After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane–ovarian suppression group and 87.3% in the tamoxifen–ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane–ovarian suppression group, as compared with 88.8% in the tamoxifen–ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane–ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P = 0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane–ovarian suppression group and 29.4% of those in the tamoxifen–ovarian suppression group, with profiles similar to those for postmenopausal women. CONCLUSIONS In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.) PMID:24881463

Localization of Nucleoporin Tpr to the Nuclear Pore Complex Is Essential for Tpr Mediated Regulation of the Export of Unspliced RNA

PubMed Central

Rajanala, Kalpana; Nandicoori, Vinay Kumar

2012-01-01

Nucleoporin Tpr is a component of the nuclear pore complex (NPC) that localizes exclusively to intranuclear filaments. Tpr functions as a scaffolding element in the nuclear phase of the NPC and plays a role in mitotic spindle checkpoint signalling. Export of intron-containing mRNA in Mason Pfizer Monkey Virus is regulated by direct interaction of cellular proteins with the cis-acting Constitutive Transport Element (CTE). In mammalian cells, the transport of Gag/Pol-CTE reporter construct is not very efficient, suggesting a regulatory mechanism to retain this unspliced RNA. Here we report that the knockdown of Tpr in mammalian cells leads to a drastic enhancement in the levels of Gag proteins (p24) in the cytoplasm, which is rescued by siRNA resistant Tpr. Tpr's role in the retention of unspliced RNA is independent of the functions of Sam68 and Tap/Nxf1 proteins, which are reported to promote CTE dependent export. Further, we investigated the possible role for nucleoporins that are known to function in nucleocytoplasmic transport in modulating unspliced RNA export. Results show that depletion of Nup153, a nucleoporin required for NPC anchoring of Tpr, plays a role in regulating the export, while depletion of other FG repeat-containing nucleoporins did not alter the unspliced RNA export. Results suggest that Tpr and Nup153 both regulate the export of unspliced RNA and they are most likely functioning through the same pathway. Importantly, we find that localization of Tpr to the NPC is necessary for Tpr mediated regulation of unspliced RNA export. Collectively, the data indicates that perinuclear localization of Tpr at the nucleopore complex is crucial for regulating intron containing mRNA export by directly or indirectly participating in the processing and degradation of aberrant mRNA transcripts. PMID:22253824

HIV-1 and M-PMV RNA Nuclear Export Elements Program Viral Genomes for Distinct Cytoplasmic Trafficking Behaviors.

PubMed

Pocock, Ginger M; Becker, Jordan T; Swanson, Chad M; Ahlquist, Paul; Sherer, Nathan M

2016-04-01

Retroviruses encode cis-acting RNA nuclear export elements that override nuclear retention of intron-containing viral mRNAs including the full-length, unspliced genomic RNAs (gRNAs) packaged into assembling virions. The HIV-1 Rev-response element (RRE) recruits the cellular nuclear export receptor CRM1 (also known as exportin-1/XPO1) using the viral protein Rev, while simple retroviruses encode constitutive transport elements (CTEs) that directly recruit components of the NXF1(Tap)/NXT1(p15) mRNA nuclear export machinery. How gRNA nuclear export is linked to trafficking machineries in the cytoplasm upstream of virus particle assembly is unknown. Here we used long-term (>24 h), multicolor live cell imaging to directly visualize HIV-1 gRNA nuclear export, translation, cytoplasmic trafficking, and virus particle production in single cells. We show that the HIV-1 RRE regulates unique, en masse, Rev- and CRM1-dependent "burst-like" transitions of mRNAs from the nucleus to flood the cytoplasm in a non-localized fashion. By contrast, the CTE derived from Mason-Pfizer monkey virus (M-PMV) links gRNAs to microtubules in the cytoplasm, driving them to cluster markedly to the centrosome that forms the pericentriolar core of the microtubule-organizing center (MTOC). Adding each export element to selected heterologous mRNAs was sufficient to confer each distinct export behavior, as was directing Rev/CRM1 or NXF1/NXT1 transport modules to mRNAs using a site-specific RNA tethering strategy. Moreover, multiple CTEs per transcript enhanced MTOC targeting, suggesting that a cooperative mechanism links NXF1/NXT1 to microtubules. Combined, these results reveal striking, unexpected features of retroviral gRNA nucleocytoplasmic transport and demonstrate roles for mRNA export elements that extend beyond nuclear pores to impact gRNA distribution in the cytoplasm.

HIV-1 and M-PMV RNA Nuclear Export Elements Program Viral Genomes for Distinct Cytoplasmic Trafficking Behaviors

PubMed Central

Pocock, Ginger M.; Becker, Jordan T.; Swanson, Chad M.; Ahlquist, Paul; Sherer, Nathan M.

2016-01-01

Retroviruses encode cis-acting RNA nuclear export elements that override nuclear retention of intron-containing viral mRNAs including the full-length, unspliced genomic RNAs (gRNAs) packaged into assembling virions. The HIV-1 Rev-response element (RRE) recruits the cellular nuclear export receptor CRM1 (also known as exportin-1/XPO1) using the viral protein Rev, while simple retroviruses encode constitutive transport elements (CTEs) that directly recruit components of the NXF1(Tap)/NXT1(p15) mRNA nuclear export machinery. How gRNA nuclear export is linked to trafficking machineries in the cytoplasm upstream of virus particle assembly is unknown. Here we used long-term (>24 h), multicolor live cell imaging to directly visualize HIV-1 gRNA nuclear export, translation, cytoplasmic trafficking, and virus particle production in single cells. We show that the HIV-1 RRE regulates unique, en masse, Rev- and CRM1-dependent “burst-like” transitions of mRNAs from the nucleus to flood the cytoplasm in a non-localized fashion. By contrast, the CTE derived from Mason-Pfizer monkey virus (M-PMV) links gRNAs to microtubules in the cytoplasm, driving them to cluster markedly to the centrosome that forms the pericentriolar core of the microtubule-organizing center (MTOC). Adding each export element to selected heterologous mRNAs was sufficient to confer each distinct export behavior, as was directing Rev/CRM1 or NXF1/NXT1 transport modules to mRNAs using a site-specific RNA tethering strategy. Moreover, multiple CTEs per transcript enhanced MTOC targeting, suggesting that a cooperative mechanism links NXF1/NXT1 to microtubules. Combined, these results reveal striking, unexpected features of retroviral gRNA nucleocytoplasmic transport and demonstrate roles for mRNA export elements that extend beyond nuclear pores to impact gRNA distribution in the cytoplasm. PMID:27070420

Body-Weight Fluctuations and Outcomes in Coronary Disease.

PubMed

Bangalore, Sripal; Fayyad, Rana; Laskey, Rachel; DeMicco, David A; Messerli, Franz H; Waters, David D

2017-04-06

Body-weight fluctuation is a risk factor for death and coronary events in patients without cardiovascular disease. It is not known whether variability in body weight affects outcomes in patients with coronary artery disease. We determined intraindividual fluctuations in body weight from baseline weight and follow-up visits and performed a post hoc analysis of the Treating to New Targets trial, which involved assessment of the efficacy and safety of lowering low-density lipoprotein cholesterol levels with atorvastatin. The primary outcome was any coronary event (a composite of death from coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, revascularization, or angina). Secondary outcomes were any cardiovascular event (a composite of any coronary event, a cerebrovascular event, peripheral vascular disease, or heart failure), death, myocardial infarction, or stroke. Among 9509 participants, after adjustment for risk factors, baseline lipid levels, mean body weight, and weight change, each increase of 1 SD in body-weight variability (measured according to average successive variability and used as a time-dependent covariate) was associated with an increase in the risk of any coronary event (2091 events; hazard ratio, 1.04; 95% confidence interval [CI], 1.01 to 1.07; P=0.01), any cardiovascular event (2727 events; hazard ratio, 1.04; 95% CI, 1.02 to 1.07; P<0.001), and death (487 events; hazard ratio,1.09; 95% CI, 1.07 to 1.12; P<0.001). Among patients in the quintile with the highest variation in body weight, the risk of a coronary event was 64% higher, the risk of a cardiovascular event 85% higher, death 124% higher, myocardial infarction 117% higher, and stroke 136% higher than it was among those in the quintile with the lowest variation in body weight in adjusted models. Among participants with coronary artery disease, fluctuation in body weight was associated with higher mortality and a higher rate of cardiovascular events independent of traditional cardiovascular risk factors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00327691 .).

Differences in reporting of analyses in internal company documents versus published trial reports: comparisons in industry-sponsored trials in off-label uses of gabapentin.

PubMed

Vedula, S Swaroop; Li, Tianjing; Dickersin, Kay

2013-01-01

Details about the type of analysis (e.g., intent to treat [ITT]) and definitions (i.e., criteria for including participants in the analysis) are necessary for interpreting a clinical trial's findings. Our objective was to compare the description of types of analyses and criteria for including participants in the publication (i.e., what was reported) with descriptions in the corresponding internal company documents (i.e., what was planned and what was done). Trials were for off-label uses of gabapentin sponsored by Pfizer and Parke-Davis, and documents were obtained through litigation. For each trial, we compared internal company documents (protocols, statistical analysis plans, and research reports, all unpublished), with publications. One author extracted data and another verified, with a third person verifying discordant items and a sample of the rest. Extracted data included the number of participants randomized and analyzed for efficacy, and types of analyses for efficacy and safety and their definitions (i.e., criteria for including participants in each type of analysis). We identified 21 trials, 11 of which were published randomized controlled trials, and that provided the documents needed for planned comparisons. For three trials, there was disagreement on the number of randomized participants between the research report and publication. Seven types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including ITT and six others. The protocol or publication described ITT using six different definitions, resulting in frequent disagreements between the two documents (i.e., different numbers of participants were included in the analyses). Descriptions of analyses conducted did not agree between internal company documents and what was publicly reported. Internal company documents provide extensive documentation of methods planned and used, and trial findings, and should be publicly accessible. Reporting standards for randomized controlled trials should recommend transparent descriptions and definitions of analyses performed and which study participants are excluded.

Outlet strut fracture of Björk-Shiley convexo-concave valves: can valve-manufacturing characteristics explain the risk?

PubMed

Omar, R Z; Morton, L S; Beirne, M; Blot, W J; Lawford, P V; Hose, R; Taylor, K M

2001-06-01

Björk-Shiley 60 degrees convexo-concave prosthetic heart valves (Shiley, Inc, Irvine, Calif, a subsidiary of Pfizer, Inc) continue to be a concern for approximately 35,000 nonexplanted patients worldwide, with approximately 600 events reported to the manufacturer to date. Fractures of the outlet struts of the valves began to appear in the early 1980s and have continued to the present, but their causes are only partially understood. A matched case-control study was conducted evaluating manufacturing records for 52 valves with outlet strut fractures and 248 control subjects matched for age at implantation, valve size, and valve position. In addition to the risk factors recognized as determinants of outlet strut fracture, the United Kingdom case-control study has observed 7- to 9-fold increased risk with performance of multiple hook deflection tests. This test was performed more than once, usually after rework on the valve. Six valves in this study underwent multiple hook deflection tests, of which 4 experienced an outlet strut fracture. Cracks and further rework were noted for these valves. Significant associations were also observed between outlet strut fracture and disc-to-strut gap measurements taken before the attachment of the sewing ring. It is our view that a combination of factors related to valve design, manufacturing process, and patient characteristics are responsible for outlet strut fractures of Björk-Shiley convexo-concave valves. Multiple hook deflection tests have emerged as a potential new risk factor for outlet strut fracture in both The Netherlands and the United Kingdom. This factor appears to be correlated with the presence of other abnormalities. A further study is needed to investigate the factors correlated with multiple hook deflection tests. On confirmation of risk, the presence of multiple hook deflection tests may be added to equations, quantifying the risk of outlet strut fracture for comparison against risk of mortality and serious morbidity from explant operations.

Estimated Budget Impact of Adopting the Affordable Care Act's Required Smoking Cessation Coverage on United States Healthcare Payers.

PubMed

Baker, Christine L; Ferrufino, Cheryl P; Bruno, Marianna; Kowal, Stacey

2017-01-01

Despite abundant information on the negative impacts of smoking, more than 40 million adult Americans continue to smoke. The Affordable Care Act (ACA) requires tobacco cessation as a preventive service with no patient cost share for all FDA-approved cessation medications. Health plans have a vital role in supporting smoking cessation by managing medication access, but uncertainty remains on the gaps between smoking cessation requirements and what is actually occurring in practice. This study presents current cessation patterns, real-world drug costs and plan benefit design data, and estimates the 1- to 5-year pharmacy budget impact of providing ACA-required coverage for smoking cessation products to understand the fiscal impact to a US healthcare plan. A closed cohort budget impact model was developed in Microsoft Excel ® to estimate current and projected costs for US payers (commercial, Medicare, Medicaid) covering smoking cessation medicines, with assumptions for coverage and smoking cessation product utilization based on current, real-world national and state-level trends for hypothetical commercial, Medicare, and Medicaid plans with 1 million covered lives. A Markov methodology with five health states captures quit attempt and relapse patterns. Results include the number of smokers attempting to quit, number of successful quitters, annual costs, and cost per-member per-month (PMPM). The projected PMPM cost of providing coverage for smoking cessation medications is $0.10 for commercial, $0.06 for Medicare, and $0.07 for Medicaid plans, reflecting a low incremental PMPM impact of covering two attempts ranging from $0.01 for Medicaid to $0.02 for commercial and Medicare payers. The projected PMPM impact of covering two quit attempts with access to all seven cessation medications at no patient cost share remains low. Results of this study reinforce that the impact of adopting the ACA requirements for smoking cessation coverage will have a limited near-term impact on health plan's budgets. Pfizer Inc.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Chemokine Receptor 5 (CCR5) Antagonist to Decrease the Occurrence of Immune Reconstitution Inflammatory Syndrome in HIV-Infection: The CADIRIS Study.

PubMed

Sierra-Madero, Juan G; Ellenberg, Susan; Rassool, Mohammed S; Tierney, Ann; Belaunzarán-Zamudio, Pablo F; López-Martínez, Alondra; Piñeirúa-Menéndez, Alicia; Montaner, Luis J; Azzoni, Livio; Benítez, César Rivera; Sereti, Irini; Andrade-Villanueva, Jaime; Mosqueda-Gómez, Juan L; Rodriguez, Benigno; Sanne, Ian; Lederman, Michael M

2014-11-01

Immune Reconstitution Inflammatory Syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in HIV-infected patients. IRIS is associated with an increased risk of hospitalization and death. We ascertained whether CCR5 blockade using maraviroc reduces the risk of IRIS. The CADIRIS study was a randomized, double-blind, placebo-controlled, clinical trial that accrued subjects from five clinical sites in Mexico and one in South Africa between November 2009 and January 2012, and followed them for one year. The primary outcome was occurrence of IRIS by 24 weeks. HIV-infected adults, naïve to ART, with CD4 cells <100/μL, and HIVRNA >1,000 copies/mL were eligible. We screened 362 subjects; 279 met inclusion criteria, 3 refused participation, and 276 were randomized. Participants received maraviroc 600 mg twice daily or placebo added to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. There were 276 patients randomized (140 received maraviroc and 136 placebo). There was no difference in the time to IRIS events between treatment arms (HR 1·08, 95% CI (0·66, 1·77), log-rank test p =0·743). In total, 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc arm and 31 (23%) in the placebo arm ( p =0·88). Maraviroc had no significant effect on frequency, time or severity of IRIS events after ART initiation. Including a CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in persons with advanced HIV infection. The trial was funded as investigator initiated research by Pfizer Inc, New York, NY, USA. ClinicalTrials.gov . ID: NCT00988780 (http://clinicaltrials.gov/ct2/show/NCT00988780).

Efficacy and safety of imidacloprid 10% plus moxidectin 2.5% spot-on in the treatment of sarcoptic mange and otoacariosis in dogs: results af a European field study.

PubMed

Krieger, K; Heine, J; Dumont, P; Hellmann, K

2005-10-01

Efficacy and safety of treatment with imidacloprid 10%+moxidectin 2.5% spot-on (Advocate, Advantage multi; Bayer AG, Leverkusen, Germany) were tested in dogs naturally infested with Sarcoptes scabiei or Otodectes cynotis in a multi-centre, controlled, randomized, blinded field study conducted in France, Germany, Albania and the UK. The study was performed according to a non-inferiority design to demonstrate that the efficacy of imidacloprid/moxidectin spot-on was not inferior to that of a control product containing selamectin (Stronghold spot-on; Pfizer). All Sarcoptes-infested dogs were topically treated twice (days 0 and 28) with the dosage recommended by the respective manufacturer (27 dogs with imidacloprid/moxidectin, 26 with selamectin). All Otodectes-infested dogs were treated on day 0 (35 dogs with imidacloprid/moxidectin, 34 with selamectin), and only those still positive on day 28 received a second treatment. Parasitological cure rate in Sarcoptes-infested dogs was 100% for both treatments, while parasitological cures rates in the Otodectes-infested dogs at day 28 and day 56 were 68.6 and 85.7% with imidacloprid/moxidectin, and 64.7 and 88.2% with Stronghold. Non-inferiority of Advocate was confirmed statistically. Clinical assessment of skin lesion scores at day 56 showed that with either product >96% of the dogs treated against sarcoptic mange were improved or cured, the difference between the groups being non-significant. On the basis of a final clinical assessment of lesion scores, 80% of the dogs treated with imidacloprid/moxidectin against otoacariosis and 85.3% of those treated with selamectin were rated cured or improved. Only three mild, possibly drug-related adverse reactions were observed among alI treated animals (two in the imidacloprid/moxidectin group, one in the selamectin group). It is concluded that imidacloprid/moxidectin spot-on is an effective and safe treatment for sarcoptic mange and otoacariosis in the dog.

Impact of a pregabalin step therapy policy among medicare advantage beneficiaries.

PubMed

Suehs, Brandon T; Louder, Anthony; Udall, Margarita; Cappelleri, Joseph C; Joshi, Ashish V; Patel, Nick C

2014-06-01

Managed healthcare organizations often utilize formulary management strategies such as prior authorization and step therapy to guide appropriate medication use and to control medication expenditures. The objective of this study was to examine clinical and economic outcomes associated with implementation of a pregabalin step therapy (ST) policy among Medicare Advantage Prescription Drug (MAPD) members. Pharmacy and medical claims data from Humana (restricted cohort; ST policy implemented 01/01/2009) and Thomson Reuters MarketScan(®) (unrestricted cohort) were analyzed for MAPD members aged 65 to 89 years receiving treatment for painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN) or fibromyalgia (FM). Difference-in-differences (DID) was used to examine year-over-year changes in disease-related and all-cause utilization and costs. Regression analyses examined medication utilization and healthcare expenditures after controlling for between-group compositional differences. We identified 13,911 members in the restricted cohort and matched to members from unrestricted health plans. FM (51.0%) and pDPN (41.8%) were the most common diagnoses. Members in the unrestricted cohort were older and had a greater level of comorbidity than members in the restricted cohort. The restricted cohort demonstrated greater year-over-year decrease in pregabalin utilization and increase in year-over-year gabapentin utilization compared with the unrestricted cohort. ST restriction was associated with an increase in disease-related pharmacy costs and a decrease in total medical costs for the restricted cohort compared with the unrestricted cohort. There was no difference between cohorts in total healthcare cost. After controlling for differences in age and comorbidity burden between the groups, implementation of a pregabalin ST restriction was associated with increased disease-related pharmacy costs and decreased total medical costs; however, there was no net difference in total healthcare cost or total pharmacy cost. © 2013 Pfizer Inc and Humana, Inc. Pain Practice © 2013 World Institute of Pain.

The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels.

PubMed

Zhu, Bing; Strada, Samuel J

2007-01-01

PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

A Phase I study to determine the pharmacokinetic profile, safety and tolerability of sildenafil (Revatio®) in cardiac surgery: the REVAKI‐1 study

PubMed Central

Ring, Arne; Morris, Tom; Wozniak, Marcin; Sullo, Nikol; Dott, William; Verheyden, Veerle; Kumar, Tracy; Brunskill, Nigel; Vaja, Rakesh

2016-01-01

Aims Acute kidney injury (AKI) is a common and severe complication of cardiac surgery. There is no effective prevention or treatment. Sildenafil citrate (Revatio®, Pfizer Inc.), a phosphodiesterase type 5 inhibitor, prevents post cardiac surgery AKI in pre‐clinical studies, however its use is contraindicated in patients with symptomatic cardiovascular disease. The aim of this study is to assess the safety and pharmacokinetics of intravenous sildenafil in cardiac surgery patients. Methods We conducted an open label, dose escalation study with six patients per dose level. The six doses were 2.5 mg, 5 mg or 10 mg as a bolus, either alone or followed by an additional 2 h infusion of 2.5 mg sildenafil. Results Thirty‐six patients entered the trial, of which 33 completed it. The mean age was 69.9 years. One patient died during surgery, two others were removed from the trial before dosing (all at dose level 5 mg + 2.5 mg). The pharmacokinetic profile of sildenafil was similar to previously published studies. For a dose of 10 mg administered as a bolus followed by 2.5 mg administered over 2 h the results were AUC∞ 537 ng h ml−1, C max 189.4 ng ml−1 and t 1/2 10.5 h. The drug was well tolerated with no serious adverse events related to drug administration. Higher sildenafil doses stabilized post‐surgery nitric oxide bioavailability. Conclusions Pharmacokinetics of sildenafil during cardiopulmonary bypass were comparable to those of other patient groups. The drug was well tolerated at therapeutic plasma levels. These results support the further evaluation of sildenafil for the prevention of AKI in cardiac surgery. PMID:27779776

Bioequivalence of 2 Formulations of Sildenafil Oral Soluble Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral Tablets in Healthy Male Volunteers.

PubMed

Dadey, Eric

Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the treatment of erectile dysfunction. However, in some cases, patients may have difficulty in swallowing tablets, and the need to use water to aid in the oral administration of the tablets has the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed using MonoSol Rx's proprietary PharmFilm technology. Both films were formulated to dissolve rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed without the use of water. From a patient perspective, it is anticipated that the film formulations of sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations (MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose, randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals for plasma sildenafil AUC0-t, AUC0-∞, and Cmax for both sildenafil OSF formulations as compared with sildenafil citrate tablets were all within the 80%-125% range, indicating bioequivalence of both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF may provide an attractive alternative to sildenafil citrate oral tablets.

Immunogenicity and safety of 23-valent pneumococcal polysaccharide vaccine as a booster dose in 12- to 18-month-old children primed with 3 doses of 7-valent pneumococcal conjugate vaccine

PubMed Central

Thisyakorn, Usa; Chokephaibulkit, Kulkanya; Kosalaraksa, Pope; Benjaponpitak, Suwat; Pancharoen, Chitsanu; Chuenkitmongkol, Sunate

2014-01-01

The current study examined the safety and immunogenicity of 23-valent pneumococcal capsular polysaccharide vaccine (Pneumo23® [PPV23], Sanofi Pasteur) as a booster dose in 12- to 18-month-old children primed with heptavalent pneumococcal vaccine (PCV7; Prevnar®, Pfizer). This was a randomized, observer-blinded, 2-arm, controlled, multicenter phase III study performed in Thailand to assess and describe the immunogenicity and safety of PPV23 as a booster dose in children who had received the 3 primary doses of PCV7, the pneumococcal vaccine available during the study period. Children primed with 3 doses of PCV7 were randomized 1:1 to receive a booster immunization with PPV23 or PCV7. Pneumococcal antibody concentrations were measured by enzyme-linked immunosorbent assay and functional antibody levels by multiplex opsonophagocytosis assay on day 30. A total of 339 children were enrolled. Geometric mean serum antibody concentrations against serotypes common to PCV7 and PPV23 (4, 6B, 9V, 14, 18C, 19F, and 23F) increased in both groups but they were higher for serotypes 4, 9V, 18C, and 19F in the PPV23 group. Opsonization indices increased in both groups for all measured serotypes (1, 6B, 14, 19A, and 23F) and were higher for serotypes 6B, 14, and 23F in the PCV7 group and for serotypes 1 and 19A in PPV23 group. Solicited reactions and unsolicited adverse events were similar in the 2 groups and generally mild and transient. No treatment-related serious adverse events were reported. These results confirm that boosting with PPV23 is immunogenic and well tolerated in healthy toddlers primed with PCV7. PMID:25424793

Vaccine purchasing groups in the United States: An overview of their policies and practices.

PubMed

Cowan, Anne E; Clark, Sarah J; Gordon, Jennifer L; Bok, Karin; Shen, Angela K

2016-09-30

Vaccine purchasing groups (VPGs) may help reduce the upfront cost of vaccines. The objective of this study was to describe key business practices of VPGs in the United States. Semi-structured, qualitative telephone interviews were conducted with representatives from 11 VPGs, based on a sampling frame of 53 VPGs. Interviews were transcribed and summarized by topic. Characteristics of the 11 VPGs interviewed reflect the broader VPG population: 64% national vs 36% regional; 8% charge a membership fee; membership ranging from 40 to over 300,000 sites. VPGs establish agreements with vaccine manufacturers, typically with either GlaxoSmithKline or Merck and Sanofi Pasteur; 1 VPG reported a single-product (Trumenba) agreement with Pfizer. VPG agreements specify "product loyalty" benchmarks (proportion of that manufacturer's product line) that the VPG and its members must meet to receive discounted vaccine pricing. The amount of discount is considered proprietary. Practices may actively participate with only one VPG; the member discount is automatically applied by the manufacturer at the time of ordering. Vaccine manufacturers monitor sales data to ensure compliance with product loyalty terms; practices that do not meet benchmarks may be removed from the VPG. VPGs are paid administration fees by the manufacturers. VPGs use these fees to cover their operating expenses and often rebate a portion of these fees back to their members. All 11 VPGs offer additional services to members, ranging from immunization-focused education and technical assistance to discounts on a broad range of medical and business supplies. VPGs can facilitate access to reduced purchase prices for most vaccines routinely recommended in the United States. Data on the magnitude of the price reductions were not publicly available. VPG members must balance loyalty-based price reductions against considerations of having a wider choice of vaccine products. Copyright © 2016 Elsevier Ltd. All rights reserved.

Immunogenicity, Safety and Reactogenicity of a Booster Dose of the 10-Valent Pneumococcal Nontypeable H. influenzae Protein D Conjugate Vaccine Coadministered With DTPa-IPV-Hib in Dutch Children: A Randomized Controlled Trial.

PubMed

van den Bergh, Menno R; Spijkerman, Judith; François, Nancy; Swinnen, Kristien; Borys, Dorota; Schuerman, Lode; Veenhoven, Reinier H; Sanders, Elisabeth A M

2016-07-01

Immune responses and safety profiles may be affected when vaccines are coadministered. We evaluated the immunogenicity, safety and reactogenicity of a booster dose of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate (PHiD-CV; Synflorix GSK Vaccines) and DTPa-IPV-Hib (Pediacel Sanofi Pasteur MSD) when coadministered. We performed booster assessment in a randomized controlled trial in the Netherlands. Of 780 enrolled healthy infants, 774 toddlers participated in the booster phase and received (1:1:1) (1) PHiD-CV + DTPa-HBV-IPV/Hib (Infanrix hexa, GSK Vaccines), (2) PHiD-CV + DTPa-IPV-Hib, or (3) 7-valent pneumococcal conjugate vaccine (7vCRM, Prevenar/Prevnar, Pfizer, Inc.) + DTPa-IPV-Hib at 2, 3, 4 and 11-13 months old. Blood samples were taken postprimary, prebooster, 1 and 12 months postbooster. Antipneumococcal antibody responses were comparable between both PHiD-CV groups, except for serotype 18C (conjugated to tetanus toxoid). Anti-18C antibody geometric mean concentrations (GMCs) were higher when coadministered with DTPa-HBV-IPV/Hib. For each vaccine serotype, the percentages of children with antibody concentration ≥ 0.20 μg/mL were within the same ranges between PHiD-CV groups (93.8%-100%). The same was observed for the percentages of participants with opsonophagocytic activity titer ≥ 8 (90.9%-100%). When comparing both DTPa-IPV-Hib groups, postbooster antidiphtheria antibody GMCs were higher when coadministered with 7vCRM, while antitetanus and antipolyribosyl-ribitol phosphate antibody GMCs were higher with PHiD-CV coadministration. Regardless, antibody levels to these antigens were well above thresholds. Safety and reactogenicity profiles were comparable between groups. Coadministration of a booster dose of PHiD-CV and DTPa-IPV-Hib was immunogenic and well tolerated.

First-line crizotinib versus chemotherapy in ALK-positive lung cancer.

PubMed

Solomon, Benjamin J; Mok, Tony; Kim, Dong-Wan; Wu, Yi-Long; Nakagawa, Kazuhiko; Mekhail, Tarek; Felip, Enriqueta; Cappuzzo, Federico; Paolini, Jolanda; Usari, Tiziana; Iyer, Shrividya; Reisman, Arlene; Wilner, Keith D; Tursi, Jennifer; Blackhall, Fiona

2014-12-04

The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Combined Treatment with Amlodipine and Atorvastatin Calcium Reduces Circulating Levels of Intercellular Adhesion Molecule-1 and Tumor Necrosis Factor-α in Hypertensive Patients with Prediabetes.

PubMed

Huang, Zhouqing; Chen, Chen; Li, Sheng; Kong, Fanqi; Shan, Peiren; Huang, Weijian

2016-01-01

To assess the effect of amlodipine and atorvastatin on intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α expression, as endothelial function and inflammation indicators, respectively, in hypertensive patients with and without prediabetes. Forty-five consecutive patients with hypertension, diagnosed according to JNC7, were divided into two groups based on the presence (HD group, n = 23) or absence (H group, n = 22) of prediabetes, diagnosed according to 2010 ADA criteria, including impaired glucose tolerance (IGT) and fasting glucose tests. All patients simultaneously underwent 12-week treatment with daily single-pill amlodipine besylate/atorvastatin calcium combination (5/10 mg; Hisun-Pfizer Pharmaceuticals Co. Ltd). Serum isolated before and after treatment from overnight fasting blood samples was analyzed by ELISA. In the HD and H groups after vs. before 12-week amlodipine/atorvastatin treatment, there were significantly (all P < 0.01) lower levels of ICAM-1 (3.06 ± 0.34 vs. 4.07 ± 0.70 pg/ml; 3.26 ± 0.32 vs. 3.81 ± 0.60 pg/ml, respectively) and TNF-α (78.71 ± 9.19 vs. 110.94 ± 10.71 pg/ml; 80.95 ± 9.33 vs. 101.79 ± 11.72 pg/ml, respectively), with more pronounced reductions in HD vs. H group (ICAM-1Δ: 1.01 ± 0.80 vs. 0.55 ± 0.64 pg/ml, respectively, P = 0.037; TNF-αΔ: 32.23 ± 14.33 vs. 20.84 ± 14.89 pg/ml, respectively, P = 0.011), independent of the blood pressure (BP) and cholesterol level reduction. Amlodipine/atorvastatin improved endothelial function and inflammation, as reflected by lower circulating levels of ICAM-1 and TNF-α, more prominently in hypertensives with than without prediabetes. Starting statin treatment before overt diabetes in hypertensives might thus improve cardiovascular outcomes.

Tofacitinib, an Oral Janus Kinase Inhibitor: Pooled Efficacy and Safety Analyses in an Australian Rheumatoid Arthritis Population.

PubMed

Hall, Stephen; Nash, Peter; Rischmueller, Maureen; Bossingham, David; Bird, Paul; Cook, Nicola; Witcombe, David; Soma, Koshika; Kwok, Kenneth; Thirunavukkarasu, Krishan

2018-06-11

In Australia, there is an unmet need for improved treatments for rheumatoid arthritis (RA). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. To provide an overview of key study outcomes for tofacitinib in Australian patients, we analyzed the efficacy and safety of tofacitinib in the Australian subpopulation of global RA phase III and long-term extension (LTE) studies. Data were pooled from the Australian subpopulation of four phase III studies and one LTE study (database not locked at cut-off date: January 2016). Patients in the phase III studies received tofacitinib 5 or 10 mg twice daily (BID), placebo (advancing to tofacitinib at months 3 or 6), or adalimumab, with background methotrexate or conventional synthetic disease-modifying antirheumatic drugs. Patients in the LTE study received tofacitinib 5 or 10 mg BID. Efficacy endpoints were American College of Rheumatology (ACR) 20/50/70 response rates, and change from baseline in the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Safety endpoints included incidence of adverse events (AEs), serious AEs, and discontinuations due to AEs. AEs of special interest and laboratory parameters were analyzed in the LTE study. Across phase III studies (N = 100), ACR response rates and improvements in DAS28-4(ESR) and HAQ-DI scores were numerically greater with tofacitinib vs. placebo at month 3, and increased until month 12. The results were sustained in the LTE study (N = 99) after 60 months' observation. In general, the efficacy and safety profiles of tofacitinib were similar to those of the global RA population. In Australian patients with RA, tofacitinib therapy demonstrated sustained efficacy and consistent safety over ≥ 60 months' treatment. Pfizer Inc. TRIAL REGISTRATION NUMBERS (ALL CLINICALTRIALS.GOV): NCT00960440; NCT00847613; NCT00856544; NCT00853385; NCT00413699.

Services provided by community pharmacies in Wayne County, Michigan: a comparison by ZIP code characteristics.

PubMed

Erickson, Steven R; Workman, Paul

2014-01-01

To document the availability of selected pharmacy services and out-of-pocket cost of medication throughout a diverse county in Michigan and to assess possible associations between availability of services and price of medication and characteristics of residents of the ZIP codes in which the pharmacies were located. Cross-sectional telephone survey of pharmacies coupled with ZIP code-level census data. 503 pharmacies throughout the 63 ZIP codes of Wayne County, MI. The out-of-pocket cost for a 30 days' supply of levothyroxine 50 mcg and brand-name atorvastatin (Lipitor-Pfizer) 20 mg, availability of discount generic drug programs, home delivery of medications, hours of pharmacy operation, and availability of pharmacy-based immunization services. Census data aggregated at the ZIP code level included race, annual household income, age, and number of residents per pharmacy. The overall results per ZIP code showed that the average cost for levothyroxine was $10.01 ± $2.29 and $140.45 + $14.70 for Lipitor. Per ZIP code, the mean (± SD) percentages of pharmacies offering discount generic drug programs was 66.9% ± 15.0%; home delivery of medications was 44.5% ± 22.7%; and immunization for influenza was 46.7% ± 24.3% of pharmacies. The mean (± SD) hours of operation per pharmacy per ZIP code was 67.0 ± 25.2. ZIP codes with higher household income as well as higher percentage of residents being white had lower levothyroxine price, greater percentage of pharmacies offering discount generic drug programs, more hours of operation per week, and more pharmacy-based immunization services. The cost of Lipitor was not associated with any ZIP code characteristic. Disparities in the cost of generic levothyroxine, the availability of services such as discount generic drug programs, hours of operation, and pharmacy-based immunization services are evident based on race and household income within this diverse metropolitan county.

Lost in Translation: The Unintended Consequences of Advance Directive Law on Clinical Care

PubMed Central

Castillo, Lesley S.; Williams, Brie A.; Hooper, Sarah M.; Sabatino, Charles P.; Weithorn, Lois A.; Sudore, Rebecca L.

2011-01-01

Background Advance directive law may compromise the clinical effectiveness of advance directives. Purpose To identify unintended legal consequences of advance directive law that may prevent patients from communicating end-of-life preferences. Data Sources Advance directive legal statutes for all 50 U.S. states and the District of Columbia and English-language searches of LexisNexis, Westlaw, and MEDLINE from 1966 to August 2010. Study Selection Two independent reviewers selected 51 advance directive statutes and 20 articles. Three independent legal reviewers selected 105 legal proceedings. Data Extraction Two reviewers independently assessed data sources and used critical content analysis to determine legal barriers to the clinical effectiveness of advance directives. Disagreements were resolved by consensus. Data Synthesis Legal and content-related barriers included poor readability (that is, laws in all states were written above a 12th-grade reading level), health care agent or surrogate restrictions (for example, 40 states did not include same-sex or domestic partners as default surrogates), and execution requirements needed to make forms legally valid (for example, 35 states did not allow oral advance directives, and 48 states required witness signatures, a notary public, or both). Vulnerable populations most likely to be affected by these barriers included patients with limited literacy, limited English proficiency, or both who cannot read or execute advance directives; same-sex or domestic partners who may be without legally valid and trusted surrogates; and unbefriended, institutionalized, or homeless patients who may be without witnesses and suitable surrogates. Limitation Only appellate-level legal cases were available, which may have excluded relevant cases. Conclusion Unintended negative consequences of advance directive legal restrictions may prevent all patients, and particularly vulnerable patients, from making and communicating their end-of-life wishes and having them honored. These restrictions have rendered advance directives less clinically useful. Recommendations include improving readability, allowing oral advance directives, and eliminating witness or notary requirements. Primary Funding Source U.S. Department of Veterans Affairs and the Pfizer Foundation. PMID:21242368

Maraviroc (UK-427,857), a Potent, Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity

PubMed Central

Dorr, Patrick; Westby, Mike; Dobbs, Susan; Griffin, Paul; Irvine, Becky; Macartney, Malcolm; Mori, Julie; Rickett, Graham; Smith-Burchnell, Caroline; Napier, Carolyn; Webster, Rob; Armour, Duncan; Price, David; Stammen, Blanda; Wood, Anthony; Perros, Manos

2005-01-01

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 μM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS. PMID:16251317

Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors.

PubMed

Yohn, Nicole L; Turner, Jill R; Blendy, Julie A

2014-05-01

Although nicotine mediates its effects through several nicotinic acetylcholine receptor (nAChR) subtypes, it remains to be determined which nAChR subtypes directly mediate heightened anxiety during withdrawal. Relative success in abstinence has been found with the nAChR partial agonist varenicline (Chantix; Pfizer, Groton, CT); however, treatment with this drug fails to alleviate anxiety in individuals during nicotine withdrawal. Therefore, it is hypothesized that success can be found by the repurposing of other nAChR partial agonists for cessation therapies that target anxiety. It is noteworthy that the selective partial agonists for α4β2, ABT-089 [2-methyl-3-[2(S)-pyrrolidinylmethoxy]pyridine], and α7, ABT-107 [5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole] (AbbVie, North Chicago, IL), have not been evaluated as possible therapeutics for nicotine cessation. Therefore, we examined the effect of ABT-089 and ABT-107 on anxiety during withdrawal from nicotine in the novelty-induced hypophagia (NIH) paradigm. We found that short-term administration of ABT-089 and ABT-107 alleviate anxiety-like behavior during withdrawal from nicotine while long-term administration of ABT-089 but not ABT-107 reduces anxiety-like behavior during withdrawal. After behavioral testing, brains were harvested and β2-containing nAChRs were measured using [(3)H]epibaditine. ABT-089 and ABT-107 do not upregulate nAChRs, which is in contrast to the upregulation of nAChRs observed after nicotine. Furthermore, ABT-089 is anxiogenic in nicotine naive animals, suggesting that the effects on anxiety are specifically related to the nicotine-dependent state. Together, these studies identify additional nAChR partial agonists that may aid in the rational development of smoking cessation aids.

Adjuvant exemestane with ovarian suppression in premenopausal breast cancer.

PubMed

Pagani, Olivia; Regan, Meredith M; Walley, Barbara A; Fleming, Gini F; Colleoni, Marco; Láng, István; Gomez, Henry L; Tondini, Carlo; Burstein, Harold J; Perez, Edith A; Ciruelos, Eva; Stearns, Vered; Bonnefoi, Hervé R; Martino, Silvana; Geyer, Charles E; Pinotti, Graziella; Puglisi, Fabio; Crivellari, Diana; Ruhstaller, Thomas; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Bernhard, Jürg; Luo, Weixiu; Ribi, Karin; Viale, Giuseppe; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Francis, Prudence A

2014-07-10

Adjuvant therapy with an aromatase inhibitor improves outcomes, as compared with tamoxifen, in postmenopausal women with hormone-receptor-positive breast cancer. In two phase 3 trials, we randomly assigned premenopausal women with hormone-receptor-positive early breast cancer to the aromatase inhibitor exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 years. Suppression of ovarian estrogen production was achieved with the use of the gonadotropin-releasing-hormone agonist triptorelin, oophorectomy, or ovarian irradiation. The primary analysis combined data from 4690 patients in the two trials. After a median follow-up of 68 months, disease-free survival at 5 years was 91.1% in the exemestane-ovarian suppression group and 87.3% in the tamoxifen-ovarian suppression group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.72; 95% confidence interval [CI], 0.60 to 0.85; P<0.001). The rate of freedom from breast cancer at 5 years was 92.8% in the exemestane-ovarian suppression group, as compared with 88.8% in the tamoxifen-ovarian suppression group (hazard ratio for recurrence, 0.66; 95% CI, 0.55 to 0.80; P<0.001). With 194 deaths (4.1% of the patients), overall survival did not differ significantly between the two groups (hazard ratio for death in the exemestane-ovarian suppression group, 1.14; 95% CI, 0.86 to 1.51; P=0.37). Selected adverse events of grade 3 or 4 were reported for 30.6% of the patients in the exemestane-ovarian suppression group and 29.4% of those in the tamoxifen-ovarian suppression group, with profiles similar to those for postmenopausal women. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence. (Funded by Pfizer and others; TEXT and SOFT ClinicalTrials.gov numbers, NCT00066703 and NCT00066690, respectively.).

Apixaban with antiplatelet therapy after acute coronary syndrome.

PubMed

Alexander, John H; Lopes, Renato D; James, Stefan; Kilaru, Rakhi; He, Yaohua; Mohan, Puneet; Bhatt, Deepak L; Goodman, Shaun; Verheugt, Freek W; Flather, Marcus; Huber, Kurt; Liaw, Danny; Husted, Steen E; Lopez-Sendon, Jose; De Caterina, Raffaele; Jansky, Petr; Darius, Harald; Vinereanu, Dragos; Cornel, Jan H; Cools, Frank; Atar, Dan; Leiva-Pons, Jose Luis; Keltai, Matyas; Ogawa, Hisao; Pais, Prem; Parkhomenko, Alexander; Ruzyllo, Witold; Diaz, Rafael; White, Harvey; Ruda, Mikhail; Geraldes, Margarida; Lawrence, Jack; Harrington, Robert A; Wallentin, Lars

2011-08-25

Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome. We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events. The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo. The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

In vitro activity of tigecycline and comparators against a European collection of anaerobes collected as part of the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) 2010-2016.

PubMed

Rodloff, Arne C; Dowzicky, Michael J

2018-04-19

The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global program that aims to monitor the in vitro antimicrobial activities of current therapeutic agents against clinical isolates. This study presents surveillance data for Gram-positive and Gram-negative anaerobic isolates (N = 7008) collected from nine European countries between 2010 and 2016. Presented in this study are antimicrobial susceptibility data, according to the European Committee for Antimicrobial Susceptibility Testing (EUCAST) breakpoints, and minimum inhibitory concentration (MIC) distributions. The antimicrobial agents tested were cefoxitin (Gram-negative isolates only), clindamycin, meropenem, metronidazole, penicillin (Gram-positive isolates only), piperacillin-tazobactam and tigecycline. Among all Gram-positive and Gram-negative anaerobes, the lowest rates of resistance were to meropenem and metronidazole (0.0%-1.7% and 0.0%-1.9%, respectively). High rates of resistance were reported to clindamycin, in particular among isolates of the Bacteroides fragilis group (22.1%-48.1%) and Prevotella spp. (10.9%-32.2%). The majority of MIC distributions were unimodal, with the exception of clindamycin, which were mostly bimodal. Fifty percent of Gram-negative isolates gave tigecycline MICs between 0.06 and 1 mg/L, and 50% of Gram-positive isolates exhibited tigecycline MICs between 0.06 and 0.25 mg/L. The findings of this study suggest that the majority of anaerobic isolates were susceptible to meropenem and metronidazole, and that tigecycline remained active, but clindamycin resistance is a cause for concern in Europe. Surveillance studies, such as T.E.S.T., provide information on changes in the susceptibility of clinically important pathogens to commonly prescribed antimicrobial agents, and can highlight problems of antimicrobial resistance that need to be addressed. Copyright © 2018 Pfizer Inc. Published by Elsevier Ltd.. All rights reserved.

A Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Chemokine Receptor 5 (CCR5) Antagonist to Decrease the Occurrence of Immune Reconstitution Inflammatory Syndrome in HIV-Infection: The CADIRIS Study

PubMed Central

Sierra-Madero, Juan G.; Ellenberg, Susan; Rassool, Mohammed S.; Tierney, Ann; Belaunzarán-Zamudio, Pablo F.; López-Martínez, Alondra; Piñeirúa-Menéndez, Alicia; Montaner, Luis J.; Azzoni, Livio; Benítez, César Rivera; Sereti, Irini; Andrade-Villanueva, Jaime; Mosqueda-Gómez, Juan L.; Rodriguez, Benigno; Sanne, Ian; Lederman, Michael M.

2015-01-01

Background Immune Reconstitution Inflammatory Syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in HIV-infected patients. IRIS is associated with an increased risk of hospitalization and death. We ascertained whether CCR5 blockade using maraviroc reduces the risk of IRIS. Methods The CADIRIS study was a randomized, double-blind, placebo-controlled, clinical trial that accrued subjects from five clinical sites in Mexico and one in South Africa between November 2009 and January 2012, and followed them for one year. The primary outcome was occurrence of IRIS by 24 weeks. HIV-infected adults, naïve to ART, with CD4 cells <100/μL, and HIVRNA >1,000 copies/mL were eligible. We screened 362 subjects; 279 met inclusion criteria, 3 refused participation, and 276 were randomized. Participants received maraviroc 600 mg twice daily or placebo added to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. Findings There were 276 patients randomized (140 received maraviroc and 136 placebo). There was no difference in the time to IRIS events between treatment arms (HR 1·08, 95% CI (0·66, 1·77), log-rank test p=0·743). In total, 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc arm and 31 (23%) in the placebo arm (p=0·88). Interpretation Maraviroc had no significant effect on frequency, time or severity of IRIS events after ART initiation. Including a CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in persons with advanced HIV infection. Funding The trial was funded as investigator initiated research by Pfizer Inc, New York, NY, USA. Trial Registration ClinicalTrials.gov. ID: NCT00988780 (http://clinicaltrials.gov/ct2/show/NCT00988780) PMID:26366430

New quantitative, in-situ characterization of weathering in geomaterials.

NASA Astrophysics Data System (ADS)

Scrivano, Simona; Gaggero, Laura; Gisbert Aguilar, Josep; Yus Gonzalez, Adrian

2016-04-01

The mineralogical and microtextural analyses of weathered rocks and mortars are the main diagnostic tools to address the materials exposed under different environmental conditions in order to enucleate and mitigate the decay factors. The characterization of weathering intensity is mostly descriptive and non-quantitative (ICOMOS Glossary, 2008); the Fitzner indexes in arenites (Fitzner et al., 2002) and more recently applied to marbles (Scrivano et al., 2013) provide an operator dependent method. The current diagnostic of decay (Drdàcky & Slìzkovà, 2014) based on a scotch tape tearing off the surface was improved by a specifically adapted pocket penetrometer, and a joint gravimetric + minero-chemical analysis under SEM of ablational decay products. The steps are the following: i) Preparation of stubs for SEM with adherent conductive carbon tape (surface area 1.3 cm2) ii) Weighing of stub + tape + its plastic envelope at 0.001 g precision iii) Connecting the stub to a pocket penetrometer iv) Non invasive sampling of the incoherent dust applying a constant pressure of 2 kgf for 1 minute, and then packing away the stub without loosing grains v) Weighing of stub + tape + weathering products + their plastic envelope at 0.001 g precision vi) Recast the weight of removed material vii) Addressing the weathering products to SEM - EDS. Our quantitative peeling test was applied on a 96m long cladded wall in the Staglieno Monumental Cemetery in Genoa. The wall shows weathering gradients due to a neighbouring interred stream and to different insulation. Slabs of ophicalcite marble were tested from three different areas (5 samples were collected to the E, 5 samples at the centre, 5 samples to the W). The results highlighted capillary rise up to 2 meters height and a more weathered central area. On the whole, our protocol allows a delicate, virtually not impacting and reproducible factual sampling. Moreover, if carried out on a statistically significant population, the decay intensity results are defined and categorized. Drdàcky M. & Slìzkovà Z., 2014. In situ peeling tests for assessing the cohesion and consolidation characteristics of historic plasters and render surfaces. Studies in conservation, vol 0. Fitzner B. & Heinrichs K., 2002. Damage diagnosis on stone monuments weathering forms, damage categories and damage indices. - In: Prikryl R. and Viles H.A. (eds.): Understanding and managing stone decay. - Proceedings Internat. Conf. "Stone weathering and atmospheric pollution network (SWAPNET)": 11-56, Charles Univ. Prague (Karolinum Press). ICOMOS.ISCS, 2008 Illustrated glossary on stone deterioration patterns, 78 pp. Scrivano S., Gaggero L. & Taddei A., 2013. Alteration patterns of marble under different environmental exposures: a systematic approach from the Staglieno Monumental cemetery and museum collections in Genoa (Italy). In: Proceedings of the 12th International Congress on Deterioration and Conservation of Stone, New York, 22-26 October 2012. In press.

Comparative Assessment of Medical Resource Use and Costs Associated with Patients with Symptomatic Peripheral Artery Disease in the United States.

PubMed

Chase, Monica Reed; Friedman, Howard S; Navaratnam, Prakash; Heithoff, Kim; Simpson, Ross J

2016-06-01

There is growing concern about appropriate disease management for peripheral artery disease (PAD) because of the rapidly expanding population at risk for PAD and the high burden of illness associated with symptomatic PAD. A better understanding of the potential economic impact of symptomatic PAD relative to a matched control population may help improve care management for these patients. To compare the medical resource utilization, costs, and medication use for patients with symptomatic PAD relative to a matched control population. In this retrospective longitudinal analysis, the index date was the earliest date of a symptomatic PAD record (symptomatic PAD cohort) or any medical record (control cohort), and a period of 1 year pre-index and 3 years post-index was the study time frame. Symptomatic PAD patients and control patients (aged ≥ 18 years) enrolled in the MarketScan Commercial and Encounters database from January 1, 2006, to June 30, 2010, were identified. Symptomatic PAD was defined as having evidence of intermittent claudication (IC) and/or acute critical limb ischemia requiring medical intervention. Symptomatic PAD patients were selected using an algorithm comprising a combination of PAD-related ICD-9-CM diagnostic and diagnosis-related group codes, peripheral revascularization CPT-4 procedure codes, and IC medication National Drug Code numbers. Patients with stroke/transient ischemic attack, bleeding complications, or contraindications to antiplatelet therapy were excluded from the symptomatic PAD group but not the control group. A final 1:1 symptomatic PAD to control population with an exact match based on age, sex, index year, and Charlson Comorbidity Index (CCI) was identified. Descriptive statistics comparing patient demographics, comorbidities, medical resource utilization, cost, and medication use outcomes were generated. Generalized linear models were developed to compare the outcomes while controlling for residual difference in demographics, comorbidities, pre-index resource use, and pre-index costs. 3,965 symptomatic PAD and 3,965 control patients were matched. In both cohorts, 54.7% were male, with a mean age (SD) of 69.0 (12.9) years and a CCI score of 1.3 (0.9). Symptomatic PAD patients had more cardiovascular comorbidities than control patients (27.7% vs. 12.6% coronary artery disease, 27.1% vs. 15.9% hyperlipidemia, and 49.8% vs. 28.2% hypertension) in the pre-index period. Post-index rates of ischemic stroke, non-ST segment elevation myocardial infarction, unstable angina, and cardiovascular- or PAD-related procedures (limb amputations, endovascular procedures, open surgical procedures, percutaneous coronary intervention, and coronary artery bypass graft) were higher among symptomatic PAD patients versus control patients. All-cause annualized inpatient admissions (0.46 vs. 0.22 admissions), emergency department/urgent care days (0.27 vs. 0.22 days), and office visit days (12.5 vs. 10.2 days) were higher among symptomatic PAD versus control patients post-index. Annualized all-cause inpatient costs ($8,494 vs. $3,778); outpatient costs ($8,459 vs. $5,692); and total costs ($20,880 vs. $12,501) were higher among symptomatic PAD versus control patients post-index. Only 17.8% of symptomatic PAD patients versus 6.6% of control patients were on clopidogrel pre-index. In the post-index period, clopidogrel prescriptions in the symptomatic PAD population increased to 38.0%. Results were consistent in the regression models with the symptomatic PAD population having a higher number of all-cause post-index inpatient admissions, emergency department/urgent care days, office visit days, inpatient costs, outpatient costs, and total costs versus control patients (P ≤ 0.026). Symptomatic PAD patients have significantly higher medical resource use and costs when compared with a matched control population. As the prevalence of symptomatic PAD increases, there will be a significant impact on the population and health care system. The rates of use of evidence-based secondary prevention therapies, such as antiplatelet medication, were low. Therefore, greater effort must be made to increase utilization rates of appropriate treatments to determine if the negative economic and clinical impacts of symptomatic PAD can be minimized. This study was funded by Merck & Co., Kenilworth, New Jersey. Chase and Heithoff are employees of Merck & Co., Kenilworth, New Jersey, and Upper Gwynedd, Pennsylvania. Friedman and Navaratnam are paid consultants for Merck & Co. Simpson is a paid consultant for Merck, Pfizer, and Amgen and has received speaker's fees from Merck and Pfizer. Study concept and design were contributed by Chase, Navaratnam, and Heilhoff, along with Simpson and Friedman. Friedman collected the data, which was interpreted by Simpson and Navaratnam, along with Friedman. The manuscript was written by Navaratnam and Friedman, along with Chase, Heilhoff and Simpson, and revised by all of the authors.

Evaluation of Brazilian biotechnology patent activity from 1975 to 2010.

PubMed

Dias, F; Delfim, F; Drummond, I; Carmo, A O; Barroca, T M; Horta, C C; Kalapothakis, E

2012-08-01

The analysis of patent activity is one methodology used for technological monitoring. In this paper, the activity of biotechnology-related patents in Brazil were analyzed through 30 International Patent Classification (IPC) codes published by the Organization for Economic Cooperation and Development (OECD). We developed a program to analyse the dynamics of the major patent applicants, countries and IPC codes extracted from the Brazilian Patent Office (INPI) database. We also identified Brazilian patent applicants who tried to expand protection abroad via the Patent Cooperation Treaty (PCT). We had access to all patents published online at the INPI from 1975 to July 2010, including 9,791 biotechnology patent applications in Brazil, and 163 PCTs published online at World Intellectual Property Organization (WIPO) from 1997 to December 2010. To our knowledge, there are no other online reports of biotechnology patents previous to the years analyzed here. Most of the biotechnology patents filed in the INPI (10.9%) concerned measuring or testing processes involving nucleic acids. The second and third places belonged to patents involving agro-technologies (recombinant DNA technology for plant cells and new flowering plants, i.e. angiosperms, or processes for obtaining them, and reproduction of flowering plants by tissue culture techniques). The majority of patents (87.2%) were filed by nonresidents, with USA being responsible for 51.7% of all biotechnology patents deposited in Brazil. Analyzing the resident applicants per region, we found a hub in the southeast region of Brazil. Among the resident applicants for biotechnology patents filed in the INPI, 43.5% were from São Paulo, 18.3% were from Rio de Janeiro, and 9.7% were from Minas Gerais. Pfizer, Novartis, and Sanofi were the largest applicants in Brazil, with 339, 288, and 245 biotechnology patents filed, respectively. For residents, the largest applicant was the governmental institution FIOCRUZ (Oswaldo Cruz Foundation), which filed 69 biotechnology patents within the period analyzed. The first biotechnology patent applications via PCT were submitted by Brazilians in 1997, with 3 from UFMG (university), 2 from individuals, and 1 from EMBRAPA (research institute).

Tiotropium versus salmeterol for the prevention of exacerbations of COPD.

PubMed

Vogelmeier, Claus; Hederer, Bettina; Glaab, Thomas; Schmidt, Hendrik; Rutten-van Mölken, Maureen P M H; Beeh, Kai M; Rabe, Klaus F; Fabbri, Leonardo M

2011-03-24

Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent. We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD. In a 1-year, randomized, double-blind, double-dummy, parallel-group trial, we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year. A total of 7376 patients were randomly assigned to and treated with tiotropium (3707 patients) or salmeterol (3669 patients). Tiotropium, as compared with salmeterol, increased the time to the first exacerbation (187 days vs. 145 days), with a 17% reduction in risk (hazard ratio, 0.83; 95% confidence interval [CI], 0.77 to 0.90; P<0.001). Tiotropium also increased the time to the first severe exacerbation (hazard ratio, 0.72; 95% CI, 0.61 to 0.85; P<0.001), reduced the annual number of moderate or severe exacerbations (0.64 vs. 0.72; rate ratio, 0.89; 95% CI, 0.83 to 0.96; P=0.002), and reduced the annual number of severe exacerbations (0.09 vs. 0.13; rate ratio, 0.73; 95% CI, 0.66 to 0.82; P<0.001). Overall, the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups. There were 64 deaths (1.7%) in the tiotropium group and 78 (2.1%) in the salmeterol group. These results show that, in patients with moderate-to-very-severe COPD, tiotropium is more effective than salmeterol in preventing exacerbations. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov number, NCT00563381.).

[Fertility after treatment with Eazi-breedTM CIDR G for 6 or 12 days outside the breeding season in Lacaune dairy sheep].

PubMed

Fleisch, A; Piechotta, M; Bollwein, H; Janett, F

2013-07-01

This study compares the fertility after short- and long-term synchronization using a progesterone intravaginal device in Lacaune dairy sheep outside the breeding season. For the experiment 108 Lacaune sheep were treated with Eazi-breed™ CIDR® G intravaginal devices (Pfizer Animal Health, Zürich) for 12 days (Group L, n = 60) or 6 days (Group K, n = 48) in combination with eCG (Group L) or with eCG and 125 μg Cloprostenol (Group K) at device removal. Thereafter the ewes were kept together with rams for 60 days, ewes in estrus were recorded and the fertility was assessed after lambing. Blood progesterone concentration was measured at device application, withdrawal and 14 days later. Results show that neither treatment nor parity had an influence on estrus rate (Group L 91.7 %, Group K 93.8 %, nulli- and pluriparous animals 96.9 % and 90.8 %, respectively). Group L showed a tendency towards a better first cycle lambing rate and a significantly (P < 0.05) higher overall lambing rate compared to sheep of Group K (71.7 % vs. 60.4 % and 83.3 % vs. 72.9 %). Pluriparous ewes had higher (P < 0.05) lambing rates and greater (P < 0.05) numbers of lambs born per synchronized ewe than nulliparous sheep for the first cycle (75.0 % vs. 46.9 % and 1.4 ± 1.0 vs. 0.9 ± 1.1) as well as for the overall service period (92.1 % vs. 46.9 % and 1.7 ± 0.8 vs. 0.9 ± 1.1). Fourteen days after insert withdrawal progesterone concentrations were higher (P < 0.05) in Group L than in Group K (7.7 ± 4.3 vs. 5.6 ± 2.7 ng/mL) and in nulli- compared to pluriparous (9.1 ± 5.6 vs. 5.7 ± 2.1 ng/mL) ewes. In conclusion, the overall lambing rate was higher after long-term compared to short progesterone treatment and nulliparous ewes were less suitable for estrus induction outside the breeding season.

Efficacy of Growth Hormone Treatment in Children with Type 1 Diabetes Mellitus and Growth Hormone Deficiency-An Analysis of KIGS Data.

PubMed

Bonfig, Walter; Lindberg, Anders; Carlsson, Martin; Cutfield, Wayne; Dunger, David; Camacho-Hübner, Cecilia; Holl, Reinhard W

2018-04-12

To analyze first-year treatment growth response and growth hormone (GH) dosage in prepubertal patients with the combination of type 1 diabetes mellitus (T1DM) and growth hormone deficiency (GHD). A total of 69 patients with T1DM and GHD treated with GH have been enrolled in KIGS (Pfizer International Growth Database). Of these, 24 prepubertal patients had developed T1DM before GHD and were included in this analysis. Of 30 570 patients with GHD without T1DM, 15 024 were prepubertal and served as controls. Values are expressed as mean ± SD. Patients with T1DM and GHD had similar characteristics compared with the GHD-alone group. Neither age (10.2 ± 3.13 vs 8.42 ± 3.46 years, P = .14), height SDS corrected for midparental height SDS at start of treatment (-1.62 ± 1.38 vs -1.61 ± 1.51, P = .80), nor GH dosage (0.24 ± 0.08 mg/kg/wk vs 0.20 ± 0.04 mg/kg/wk, P = .09) were different between those with and without T1DM. First-year catch-up growth was comparable between the 2 patient groups (first treatment year height velocity 7.54 ± 3.11 cm/year compared with 8.35 ± 2.54 cm/year in control patients, P = .38). Height SDS of children with T1DM and GHD improved from -2.62 ± 1.04 to -1.88 ± 1.11 over 1 year of GH treatment. Short-term response to GH therapy appeared similar in subjects with T1DM who then developed GHD and in those with GHD alone. Thus, T1DM does not appear to compromise GH response in children with GHD and should not exclude GH treatment in these children. GH treatment was safe in both subgroups of patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Health Economic Data Requirements and Availability in the European Union: Results of a Survey Among 10 European Countries.

PubMed

Skoupá, Jana; Annemans, Lieven; Hájek, Petr

2014-09-01

To compare data requirements and their availability for health economic (HE) evaluations in five countries in Central/Eastern Europe (CEE) (Poland, the Czech Republic, Slovakia, Hungary, and Romania) and five countries in Western Europe (WE) (the United Kingdom, France, Germany, The Netherlands, and Sweden). A questionnaire was developed and distributed to market access personnel from Pfizer who were asked to complete the questionnaire either from their own knowledge or with support of external experts. The questionnaire focused on the obligation to conduct HE assessment for reimbursement submissions, local HE guidelines, applied discount rates for future costs and effects, willingness-to-pay thresholds, and available data sources. HE is mandatory in all CEE and three WE participating countries for reimbursement applications of innovative drugs. Usually, cost-effectiveness analysis and budget-impact analyses are required. The preferred outcome of cost-effectiveness analysis is quality-adjusted-life years. In Romania, France, and the Czech Republic, guidelines could not be identified at the time of the survey. The applicant usually prepares HE evaluations; in Sweden, the United Kingdom, The Netherlands, and Poland, unlocked models have to be presented for scrutiny. Discount rates vary from 1.5% to 5%, and, usually, is the same for costs and outcomes (except in The Netherlands and Poland). Only the United Kingdom, Poland, and Slovakia have an explicit willingness-to-pay threshold. In Poland, it is based on the gross domestic product per capita, and in Slovakia, it is based on multiples of average monthly salary. Differences were found on data availability. In WE, data can be acquired easier than in CEE. Health insurance funds do not provide their data unless they were published. Patient registries are either not available in CEE or difficult to access, so applicants mostly rely on retrospective medical chart data, hospital information systems, or expert panels. We found similar requirements for HE analyses in CEE and WE but differences in data availability. This results in less accurate inputs across the CEE, influencing analyses' outcomes. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer.

PubMed

Turner, Nicholas C; Ro, Jungsil; André, Fabrice; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Loibl, Sibylle; Huang Bartlett, Cynthia; Zhang, Ke; Giorgetti, Carla; Randolph, Sophia; Koehler, Maria; Cristofanilli, Massimo

2015-07-16

Growth of hormone-receptor-positive breast cancer is dependent on cyclin-dependent kinases 4 and 6 (CDK4 and CDK6), which promote progression from the G1 phase to the S phase of the cell cycle. We assessed the efficacy of palbociclib (an inhibitor of CDK4 and CDK6) and fulvestrant in advanced breast cancer. This phase 3 study involved 521 patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that had relapsed or progressed during prior endocrine therapy. We randomly assigned patients in a 2:1 ratio to receive palbociclib and fulvestrant or placebo and fulvestrant. Premenopausal or perimenopausal women also received goserelin. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, objective response, rate of clinical benefit, patient-reported outcomes, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 195 events of disease progression or death had occurred. The median progression-free survival was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with palbociclib-fulvestrant and 3.8 months (95% CI, 3.5 to 5.5) with placebo-fulvestrant (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32 to 0.56; P<0.001). The most common grade 3 or 4 adverse events in the palbociclib-fulvestrant group were neutropenia (62.0%, vs. 0.6% in the placebo-fulvestrant group), leukopenia (25.2% vs. 0.6%), anemia (2.6% vs. 1.7%), thrombocytopenia (2.3% vs. 0%), and fatigue (2.0% vs. 1.2%). Febrile neutropenia was reported in 0.6% of palbociclib-treated patients and 0.6% of placebo-treated patients. The rate of discontinuation due to adverse events was 2.6% with palbociclib and 1.7% with placebo. Among patients with hormone-receptor-positive metastatic breast cancer who had progression of disease during prior endocrine therapy, palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone. (Funded by Pfizer; PALOMA3 ClinicalTrials.gov number, NCT01942135.).

Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study.

PubMed

Olmos, David; Postel-Vinay, Sophie; Molife, L Rhoda; Okuno, Scott H; Schuetze, Scott M; Paccagnella, M Luisa; Batzel, Gretchen N; Yin, Donghua; Pritchard-Jones, Kathryn; Judson, Ian; Worden, Francis P; Gualberto, Antonio; Scurr, Michelle; de Bono, Johann S; Haluska, Paul

2010-02-01

Figitumumab is a fully human IgG2 monoclonal antibody targeting the insulin-like growth-factor-1 receptor (IGF-1R). Preclinical data suggest a dependence on insulin-like growth-factor signalling for sarcoma subtypes, including Ewing's sarcoma, and early reports show antitumour activity of IGF-1R-targeting drugs in these diseases. Between January, 2006, and August, 2008, patients with refractory, advanced sarcomas received figitumumab (20 mg/kg) in two single-stage expansion cohorts within a solid-tumour phase 1 trial. The first cohort (n=15) included patients with multiple sarcoma subtypes, age 18 years or older, and the second cohort (n=14) consisted of patients with refractory Ewing's sarcoma, age 9 years or older. The primary endpoint was to assess the safety and tolerability of figitumumab. Secondary endpoints included pharmacokinetic profiling and preliminary antitumour activity (best response by Response Evaluation Criteria in Solid Tumours [RECIST]) in evaluable patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, number NCT00474760. 29 patients, 16 of whom had Ewing's sarcoma, were enrolled and received a total of 177 cycles of treatment (median 2, mean 6.1, range 1-24). Grade 3 deep venous thrombosis, grade 3 back pain, and grade 3 vomiting were each noted once in individual patients; one patient had grade 3 increases in aspartate aminotransferase and gammaglutamyltransferase concentrations. This patient also had grade 4 increases in alanine aminotransferase concentrations. The only other grade 4 adverse event was raised concentrations of uric acid, noted in one patient. Pharmacokinetics were comparable between patients with sarcoma and those with other solid tumours. 28 patients were assessed for response; two patients, both with Ewing's sarcoma, had objective responses (one complete response and one partial response) and eight patients had disease stabilisation (six with Ewing's sarcoma, one with synovial sarcoma, and one with fibrosarcoma) lasting 4 months or longer. Figitumumab is well tolerated and has antitumour activity in Ewing's sarcoma, warranting further investigation in this disease. Pfizer Global Research and Development. Copyright 2010 Elsevier Ltd. All rights reserved.

Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

PubMed

Weinhold, Kent J; Bukowski, Jack F; Brennan, Todd V; Noveck, Robert J; Staats, Janet S; Lin, Liwen; Stempora, Linda; Hammond, Constance; Wouters, Ann; Mojcik, Christopher F; Cheng, John; Collinge, Mark; Jesson, Michael I; Hazra, Anasuya; Biswas, Pinaki; Lan, Shuping; Clark, James D; Hodge, Jennifer A

2018-06-01

This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal. Copyright © 2018 Pfizer Inc. Published by Elsevier Inc. All rights reserved.

Palbociclib and Letrozole in Advanced Breast Cancer.

PubMed

Finn, Richard S; Martin, Miguel; Rugo, Hope S; Jones, Stephen; Im, Seock-Ah; Gelmon, Karen; Harbeck, Nadia; Lipatov, Oleg N; Walshe, Janice M; Moulder, Stacy; Gauthier, Eric; Lu, Dongrui R; Randolph, Sophia; Diéras, Véronique; Slamon, Dennis J

2016-11-17

A phase 2 study showed that progression-free survival was longer with palbociclib plus letrozole than with letrozole alone in the initial treatment of postmenopausal women with estrogen-receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We performed a phase 3 study that was designed to confirm and expand the efficacy and safety data for palbociclib plus letrozole for this indication. In this double-blind study, we randomly assigned, in a 2:1 ratio, 666 postmenopausal women with ER-positive, HER2-negative breast cancer, who had not had prior treatment for advanced disease, to receive palbociclib plus letrozole or placebo plus letrozole. The primary end point was progression-free survival, as assessed by the investigators; secondary end points were overall survival, objective response, clinical benefit response, patient-reported outcomes, pharmacokinetic effects, and safety. The median progression-free survival was 24.8 months (95% confidence interval [CI], 22.1 to not estimable) in the palbociclib-letrozole group, as compared with 14.5 months (95% CI, 12.9 to 17.1) in the placebo-letrozole group (hazard ratio for disease progression or death, 0.58; 95% CI, 0.46 to 0.72; P<0.001). The most common grade 3 or 4 adverse events were neutropenia (occurring in 66.4% of the patients in the palbociclib-letrozole group vs. 1.4% in the placebo-letrozole group), leukopenia (24.8% vs. 0%), anemia (5.4% vs. 1.8%), and fatigue (1.8% vs. 0.5%). Febrile neutropenia was reported in 1.8% of patients in the palbociclib-letrozole group and in none of the patients in the placebo-letrozole group. Permanent discontinuation of any study treatment as a result of adverse events occurred in 43 patients (9.7%) in the palbociclib-letrozole group and in 13 patients (5.9%) in the placebo-letrozole group. Among patients with previously untreated ER-positive, HER2-negative advanced breast cancer, palbociclib combined with letrozole resulted in significantly longer progression-free survival than that with letrozole alone, although the rates of myelotoxic effects were higher with palbociclib-letrozole. (Funded by Pfizer; PALOMA-2 ClinicalTrials.gov number, NCT01740427 .).

Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial.

PubMed

Shakur, Haleema; Roberts, Ian; Bautista, Raúl; Caballero, José; Coats, Tim; Dewan, Yashbir; El-Sayed, Hesham; Gogichaishvili, Tamar; Gupta, Sanjay; Herrera, Jorge; Hunt, Beverley; Iribhogbe, Pius; Izurieta, Mario; Khamis, Hussein; Komolafe, Edward; Marrero, María-Acelia; Mejía-Mantilla, Jorge; Miranda, Jaime; Morales, Carlos; Olaomi, Oluwole; Olldashi, Fatos; Perel, Pablo; Peto, Richard; Ramana, P V; Ravi, R R; Yutthakasemsunt, Surakrant

2010-07-03

Tranexamic acid can reduce bleeding in patients undergoing elective surgery. We assessed the effects of early administration of a short course of tranexamic acid on death, vascular occlusive events, and the receipt of blood transfusion in trauma patients. This randomised controlled trial was undertaken in 274 hospitals in 40 countries. 20 211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial coordinating centre staff) were masked to treatment allocation. The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury, and other. All analyses were by intention to treat. This study is registered as ISRCTN86750102, Clinicaltrials.govNCT00375258, and South African Clinical Trial RegisterDOH-27-0607-1919. 10 096 patients were allocated to tranexamic acid and 10 115 to placebo, of whom 10 060 and 10 067, respectively, were analysed. All-cause mortality was significantly reduced with tranexamic acid (1463 [14.5%] tranexamic acid group vs 1613 [16.0%] placebo group; relative risk 0.91, 95% CI 0.85-0.97; p=0.0035). The risk of death due to bleeding was significantly reduced (489 [4.9%] vs 574 [5.7%]; relative risk 0.85, 95% CI 0.76-0.96; p=0.0077). Tranexamic acid safely reduced the risk of death in bleeding trauma patients in this study. On the basis of these results, tranexamic acid should be considered for use in bleeding trauma patients. UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.

A public health evaluation of 13-valent pneumococcal conjugate vaccine impact on adult disease outcomes from a randomized clinical trial in the Netherlands.

PubMed

Gessner, Bradford D; Jiang, Qin; Van Werkhoven, Cornelis H; Sings, Heather L; Webber, Chris; Scott, Daniel; Neuzil, Kathleen M; O'Brien, Katherine L; Wunderink, Richard G; Grobbee, Diederick E; Bonten, Marc J M; Jodar, Luis

2018-05-31

We conducted a post-hoc analysis of a double blind, randomized, placebo-controlled trial of 13-valent pneumococcal conjugate vaccine (PCV13) among adults aged 65 years or older to assess public health impact. For all outcomes, we included all randomized subjects, using a modified intention-to-treat (mITT) approach to determine vaccine efficacy (VE), vaccine preventable disease incidence (VPDI) defined as control minus vaccinated group incidence, and numbers needed to vaccinate (NNV) (based on a five-year duration of protection). Results are reported for, in order, clinical, adjudicated (clinical plus radiologic infiltrate determined by committee), pneumococcal, and vaccine-type pneumococcal (VT-Sp) community-acquired pneumonia; invasive pneumococcal disease (IPD) and VT-IPD. VEs (95% CI) for all hospital episodes were 8.1% (-0.6%, 16.1%), 6.7% (-4.1%, 16.3%), 22.2% (2.0%, 38.3%), 37.5% (14.3%, 54.5%), 49.3% (23.2%, 66.5%), and 75.8% (47.6%, 88.8%). VPDIs per 100,000 person-years of observation (PYOs) were 72, 37, 25, 25, 20, and 15 with NNVs of 277, 535, 816, 798, 1016, and 1342. For clinical CAP, PCV13 was associated with a reduction of 909 (-115, 2013) hospital days per 100,000 PYOs translating to a reduction over 5 years of one hospital day for every 22 people vaccinated. When comparing at-risk persons (defined by self-report of diabetes, chronic lung disease, or other underlying conditions) to not at-risk persons, VEs were similar or lower, but because baseline incidences were higher the VPDIs were approximately 2-10 times higher and NNVs 50-90% lower. A public health analysis of pneumonia and IPD outcomes in a randomized controlled trial found substantial burden reduction following adult PCV13 immunization implemented in a setting with an ongoing infant PCV7-PCV10 program. VPDIs were higher among at-risk adults. The original study and the current analysis were funded by Pfizer. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Apixaban for extended treatment of venous thromboembolism.

PubMed

Agnelli, Giancarlo; Buller, Harry R; Cohen, Alexander; Curto, Madelyn; Gallus, Alexander S; Johnson, Margot; Porcari, Anthony; Raskob, Gary E; Weitz, Jeffrey I

2013-02-21

Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

Center-level variability in broad-spectrum antibiotic prescribing for children undergoing hematopoietic cell transplantion for acute leukemia.

PubMed Central

Elgarten, Caitlin; Arnold, Staci; Li, Yimei; Huang, Y Vera; Gerber, Jeffrey S; Saber, Wael; Aplenc, Richard; Fisher, Brian T

2017-01-01

Abstract Background Antibiotic exposure after allogeneic hematopoietic cell transplant (HCT) is common. Exposure to specific classes of antibiotics after HCT has been associated with mortality, relapse and graft-vs.-host disease. Exploring differences in antibiotic utilization across hospitals could provide opportunities for comparative effectiveness studies and quality improvement interventions. Methods We conducted a retrospective cohort study of patients undergoing HCT for acute leukemia using a dataset merged from two sources: the Pediatric Health Information System and the Center for International Blood and Marrow Transplant Research. Medication use data were obtained from the day of transplant through engraftment. Hospital antibiotic utilization rates were reported as antibiotic days/1000 neutropenic days. Adjusted rates were calculated using a poisson regression controlling for age, sex, race, graft characteristics and days of ICU-level care. Results After adjustment, hospital rates of anti-pseudomonal antibiotic use varied from 410 to 1037 antibiotic days/1000 neutropenic days (Figure 1A) and for Gram-positive antibiotic use from 109 to 771 antibiotic days/1000 neutropenic days (Figure 1B). As shown in Figure 1, within anti-pseudomonal antibiotics, there was variation by hospital in the use of Fourth and 5th generation cephalosporins, anti-pseudomonal penicillins and carbapenems; variation in Gram-positive exposure was driven by vancomycin. Gram-positive antibiotic use was moderately associated with days of ICU-level of care (spearman correlation coefficient = .55) but anti-pseudomonal antibiotic use was not (Figure 2). There was no association between days of antibiotic exposure and 30-day mortality. Conclusion Among a homogenous population of children undergoing transplantation for acute leukemia, both the volume and spectrum of antibiotic exposure in the immediate post-transplant period varied widely. These data present an opportunity for hospitals to benchmark their antibiotic utilization practices and can be further leveraged to assess the clinical impact of differential antibiotic exposure. Disclosures B. T. Fisher, Pfizer, Inc.: Grant Investigator, Research support. Merck, Inc.: Investigator, Research support. T2 Biosystems, Inc.: Investigator, Research support. Ansun Biopharma: Investigator, Research support

Adjuvant ovarian suppression in premenopausal breast cancer.

PubMed

Francis, Prudence A; Regan, Meredith M; Fleming, Gini F; Láng, István; Ciruelos, Eva; Bellet, Meritxell; Bonnefoi, Hervé R; Climent, Miguel A; Da Prada, Gian Antonio; Burstein, Harold J; Martino, Silvana; Davidson, Nancy E; Geyer, Charles E; Walley, Barbara A; Coleman, Robert; Kerbrat, Pierre; Buchholz, Stefan; Ingle, James N; Winer, Eric P; Rabaglio-Poretti, Manuela; Maibach, Rudolf; Ruepp, Barbara; Giobbie-Hurder, Anita; Price, Karen N; Colleoni, Marco; Viale, Giuseppe; Coates, Alan S; Goldhirsch, Aron; Gelber, Richard D

2015-01-29

Suppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain. We randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal. After a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87). Adding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).

A phase II study of axitinib (AG-013736) in patients with incurable adenoid cystic carcinoma.

PubMed

Ho, A L; Dunn, L; Sherman, E J; Fury, M G; Baxi, S S; Chandramohan, R; Dogan, S; Morris, L G T; Cullen, G D; Haque, S; Sima, C S; Ni, A; Antonescu, C R; Katabi, N; Pfister, D G

2016-10-01

Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Differences in Reporting of Analyses in Internal Company Documents Versus Published Trial Reports: Comparisons in Industry-Sponsored Trials in Off-Label Uses of Gabapentin

PubMed Central

Vedula, S. Swaroop; Li, Tianjing; Dickersin, Kay

2013-01-01

Background Details about the type of analysis (e.g., intent to treat [ITT]) and definitions (i.e., criteria for including participants in the analysis) are necessary for interpreting a clinical trial's findings. Our objective was to compare the description of types of analyses and criteria for including participants in the publication (i.e., what was reported) with descriptions in the corresponding internal company documents (i.e., what was planned and what was done). Trials were for off-label uses of gabapentin sponsored by Pfizer and Parke-Davis, and documents were obtained through litigation. Methods and Findings For each trial, we compared internal company documents (protocols, statistical analysis plans, and research reports, all unpublished), with publications. One author extracted data and another verified, with a third person verifying discordant items and a sample of the rest. Extracted data included the number of participants randomized and analyzed for efficacy, and types of analyses for efficacy and safety and their definitions (i.e., criteria for including participants in each type of analysis). We identified 21 trials, 11 of which were published randomized controlled trials, and that provided the documents needed for planned comparisons. For three trials, there was disagreement on the number of randomized participants between the research report and publication. Seven types of efficacy analyses were described in the protocols, statistical analysis plans, and publications, including ITT and six others. The protocol or publication described ITT using six different definitions, resulting in frequent disagreements between the two documents (i.e., different numbers of participants were included in the analyses). Conclusions Descriptions of analyses conducted did not agree between internal company documents and what was publicly reported. Internal company documents provide extensive documentation of methods planned and used, and trial findings, and should be publicly accessible. Reporting standards for randomized controlled trials should recommend transparent descriptions and definitions of analyses performed and which study participants are excluded. Please see later in the article for the Editors' Summary PMID:23382656

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

PubMed

Ravaud, Alain; Motzer, Robert J; Pandha, Hardev S; George, Daniel J; Pantuck, Allan J; Patel, Anup; Chang, Yen-Hwa; Escudier, Bernard; Donskov, Frede; Magheli, Ahmed; Carteni, Giacomo; Laguerre, Brigitte; Tomczak, Piotr; Breza, Jan; Gerletti, Paola; Lechuga, Mariajose; Lin, Xun; Martini, Jean-Francois; Ramaswamy, Krishnan; Casey, Michelle; Staehler, Michael; Patard, Jean-Jacques

2016-12-08

Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial.

PubMed

van de Velde, Cornelis J H; Rea, Daniel; Seynaeve, Caroline; Putter, Hein; Hasenburg, Annette; Vannetzel, Jean-Michel; Paridaens, Robert; Markopoulos, Christos; Hozumi, Yasuo; Hille, Elysee T M; Kieback, Dirk G; Asmar, Lina; Smeets, Jan; Nortier, Johan W R; Hadji, Peyman; Bartlett, John M S; Jones, Stephen E

2011-01-22

Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer-generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0·97, 95% CI 0·88-1·08; p=0·60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone-receptor-positive early breast cancer. Pfizer. Copyright © 2011 Elsevier Ltd. All rights reserved.

Epidemiology and Microbiology of First Ventricular Assist Device Infection and Their Effect on Outcomes

PubMed Central

Guzman, Merilda Blanco; Vader, Justin; Olsen, Margaret; Dubberke, Erik R

2017-01-01

Abstract Background Left ventricular assist devices (VADs) are life-saving for patients with end stage heart failure but their benefits are limited due to infectious complications. Large studies looking at the site of infection and microbiology on outcomes are not available. Methods We conducted a single center retrospective cohort study of patients who underwent VAD implantation from 2009 to 2015. VAD infections were defined according to the criteria by the International Society for Heart and Lung Transplantation (ISHLT). Only the first VAD infection was included. Patients were followed until transplant, death or end of study. Descriptive statistics were performed. Time to event data was analyzed using Kaplan Meier and Cox Proportional Hazards. Results A total of 451 patients had a VAD placed during the study period. Median duration of follow up was 293 days (IQR-503) in patients without infection and 585 days (IQR 577) in those with VAD infection. 175 patients (38.8%) had at least 1 VAD infection, 29.1% involved the endovascular space and 70.9% involved local VAD infection. Median survival time was 1,430 days with local infection, 592 days with endovascular infection and 661 days in patients without infection (P < 0.001, Figure). The most common endovascular infection involved the pump/cannula (52.9%) and the most common local infection involved the superficial driveline (61.3%). Of the infections with a single identifiable organism, 74.5% were Gram-positives, 19.6 % were Gram-negatives and 5.2% were candida species. The predominant microorganisms were Staphylococcus aureus (35.9%), S. epidermidis (8.5%), Pseudomonas aeruginosa (7.8%) and Enterococcus faecalis (6.5%). There was no difference in mortality when Gram-positive, Gram-negative and Candida infections were compared. Conclusion Patients who survive the early post-VAD period frequently develop infectious complications. Patients with endovascular infections had significantly decreased survival compared with those with local infection. Further studies to develop strategies for prevention of VAD infections are needed. Disclosures M. Olsen, Pfizer: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant; sanofi pasteur: Grant Investigator, Research grant

CME/CNE Article: A Framework of Care in Multiple Sclerosis, Part 1: Updated Disease Classification and Disease-Modifying Therapy Use in Specific Circumstances.

PubMed

Newsome, Scott D; Aliotta, Philip J; Bainbridge, Jacquelyn; Bennett, Susan E; Cutter, Gary; Fenton, Kaylan; Lublin, Fred; Northrop, Dorothy; Rintell, David; Walker, Bryan D; Weigel, Megan; Zackowski, Kathleen; Jones, David E

2016-01-01

Activity Available Online: To access the article, post-test, and evaluation online, go to http://www.cmscscholar.org. The target audience for this activity is physicians, physician assistants, nursing professionals, and other health-care providers involved in the management of patients with multiple sclerosis (MS). Apply new information about MS to a comprehensive individualized treatment plan for patients with MSIntegrate the team approach into long-term planning in order to optimize rehabilitation care of patients with MSAccreditation Statement: This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Consortium of Multiple Sclerosis Centers (CMSC), Nurse Practitioner Alternatives (NPA), and Delaware Media Group. The CMSC is accredited by the ACCME to provide continuing medical education for physicians. The CMSC designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s) ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Practitioner Alternatives (NPA) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NPA designates this enduring material for 1.0 Continuing Nursing Education credit. Laurie Scudder, DNP, NP, has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Disclosures: Francois Bethoux, MD , Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has received royalties from Springer Publishing and has received intellectual property rights from Biogen. Laurie Scudder, DNP, NP , has served as Nurse Planner for this activity. She has disclosed no relevant financial relationships. Scott D. Newsome, DO, MSCS (author), has served on scientific advisory boards for Biogen, Genentech, Novartis, and Genzyme, and has performed contracted research (institution received funds) for Biogen, Genentech, and Novartis. Philip J. Aliotta, MD, MSHA, CHCQM, FACS (author), has served on speakers' bureaus for Astellas Pharma, Actavis, Augmenix, and Allergan and has performed contracted research for Allergan. Jacquelyn Bainbridge, PharmD (author), has disclosed no relevant financial relationships. Susan E. Bennett, PT, DPT, EdD, NCS, MSCS (author), has served on speakers' bureaus for Acorda Therapeutics, Biogen, and Medtronic; has received consulting fees from and performed contracted research for Acorda Therapeutics; and is chair of the Clinical Events Committee at Innovative Technologies. Gary Cutter, PhD (author), has participated on Data and Safety Monitoring Committees for AMO Pharma, Apotek, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck, Merck/Pfizer, Opko Biologics, Neuren, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), and NICHD (OPRU Oversight Committee); has received consulting fees from and/or served on speakers' bureaus and scientific advisory boards for Cerespir, Genzyme, Genentech, Innate Therapeutics, Janssen Pharmaceuticals, Klein-Buendel Incorporated, MedImmune, Medday, Nivalis, Novartis, Opexa Therapeutics, Roche, Savara, Somahlution, Teva Pharmaceuticals, Transparency Life Sciences, and TG Therapeutics; and is President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Kaylan Fenton, CRNP, APNP, MSCN (author), has disclosed no relevant financial relationships. Fred Lublin, MD (author), has received consulting fees/fees for non-CME/CE activities from Bayer HealthCare Pharmaceuticals, Biogen, EMD Serono, Novartis, Teva Neuroscience, Actelion, Sanofi/Genzyme, Acorda, Questcor/Mallinckrodt, Roche/Genentech, MedImmune, Osmotica, Xenoport, Receptos/Celgene, Forward Pharma, Akros, TG Therapeutics, AbbVie, Toyama, Amgen, Medday, Atara Biotherapeutics, Polypharma, Pfizer, Johnson & Johnson, Revalesio, Coronado Bioscience, and Bristol-Myers Squibb; has served on speakers' bureaus for Genentech/Roche and Genzyme/Sanofi; has performed contracted research for Acorda, Biogen, Novartis, Teva Neuroscience, Genzyme, Xenoport, and Receptos; is the co-chief editor of Multiple Sclerosis and Related Disorders ; and has an ownership interest in Cognition Pharmaceuticals. Dorothy Northrop, MSW, ACSW (author), has disclosed no relevant financial relationships. David Rintell, EdD (author), has received consulting fees from Novartis and has served as a patient education speaker for Teva Neuroscience. He started as a salaried employee of Sanofi Genzyme in November 2015. Dr. Rintell's work on this project was completed before he became a salaried employee of Sanofi Genzyme. Bryan D. Walker, MHS, PA-C (author), has served on scientific advisory boards for EMD Serono and Sanofi Genzyme and owns stock in Biogen. Megan Weigel, DNP, ARNP-C, MSCN (author), has received consulting fees from Mallinckrodt, Genzyme, and Genentech, and has served on speakers' bureaus for Bayer Corp, Acorda Therapeutics, Teva Neuroscience, Biogen, Mallinckrodt, Genzyme, Novartis, and Pfizer. Kathleen Zackowski, PhD, OTR, MSCS (author), has performed contracted research for Acorda Therapeutics. David E. Jones, MD (author), has received consulting fees from Biogen and Novartis, and has performed contracted research for Biogen. One anonymous peer reviewer for the IJMSC has performed contracted research (institution received funds) for Novartis, Chugai, and Biogen. Another reviewer has received consulting fees and served on speakers' bureaus for Biogen, Sanofi Genzyme, Genentech, EMD Serono, and Novartis. The third reviewer has disclosed no relevant financial relationships. Lori Saslow, MS (medical writer), has disclosed no relevant financial relationships. The staff at the IJMSC, CMSC, NPA, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Note: Disclosures listed for authors are those applicable at the time of their work on this project and within 12 months previously. Financial relationships for some authors may have changed in the interval between the time of their work on this project and publication of the article. Funding/Support: Funding for the Framework of Care consensus conference was provided by the Consortium of Multiple Sclerosis Centers, Mallinckrodt Pharmaceuticals, and Mylan Pharmaceuticals. Method of Participation: Release Date: December 1, 2016 Valid for Credit Through: December 1, 2017 In order to receive CME/CNE credit, participants must: Review the CME/CNE information, including learning objectives and author disclosures.Study the educational content.Complete the post-test and evaluation, which are available at http://www.cmscscholar.org. Statements of Credit are awarded upon successful completion of the post-test with a passing score of >70% and the evaluation. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This CME/CNE activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. CMSC, NPA, and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of CMSC, NPA, or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health-care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.

Fractional ultrabasic-basic evolution of upper-mantle magmatism: Evidence from xenoliths in kimberlites, inclusions in diamonds and experiments

NASA Astrophysics Data System (ADS)

Litvin, Yuriy; Kuzyura, Anastasia

2017-04-01

Ultrabasic peridotites and pyroxenites together with basic eclogites are the upper-mantle in situ rocks among xenoliths in kimberlites. Occasionally their diamond-bearing varieties have revealed within the xenoliths. Therewith the compositions of rock-forming minerals demonstrate features characteristic for primary diamond-included minerals of peridotite and eclogite parageneses (the elevated contents of Cr-component in peridotitic garnets and Na-jadeitic component in eclogitic clinopyroxenes). High-pressure experimental study of melting equilibria on the multicomponent peridotie-pyroxenite system olivine Ol - orthopyroxene Opx - clinopyroxene Cpx - garnet Grt showed that Opx disappeared in the peritectic reaction Opx+L→Cpx (Litvin, 1991). As a result, the invariant peritectic equilibrium Ol+Opx+Cpx+Grt+L of the ultrabasic system was found to transform into the univariant cotectic assemblage Ol+Cpx+Grt+L. Further experimental investigation showed that olivine reacts with jadeitic component (Jd) with formation of garnet at higher 4.5 GPa (Gasparik, Litvin, 1997). Study of melting relations in the multicomponent system Ol - Cpx - Jd permits to discover the peritectic point Ol+Omph+Grt+L (where Omph - omphacitic clinopyroxene) at concentration 3-4 wt.% Jd-component in the system. The reactionary loss of Opx and Ol makes it possible to transform the 4-phase garnet lherzolite ultrabasic association into the bimineral eclogite assemblage. The regime of fractional Ol, Cpx and Grt crystallization must be accompanied by increasing content of jadeitic component in residual melts that causes the complete "garnetization of olivine". In the subsequent evolution, the melts would have to fractionate for basic SiO2-saturated compositions responsible for petrogenesis of eclogite varieties marked with accessory corundum Crn, kyanite Ky and coesite Coe. Both the peritectic mechanisms occur in regime of fractional crystallization. The sequence of the upper-mantle fractional ultrabasic-basic magmatic evolution and petrogenesis may be controlled by the following melting relations: from Ol, Opx, L field to cotectic curve Ol, Opx, Cpx, L, peritectic point Ol, Opx, Cpx, Grt, L (loss of Opx), cotectic curve Ol, (Cpx+Jd), Grt, L, peritectic point Ol, (Cpx→Omph), Grt, L (loss of Ol), divariant field Omph,Grt,L, cotectic curve Ky, Omph, Grt, L, eutectic point Ky,Coe,Omph, Grt,L, subsolidus assemblage Ky,Coe,Omph, Grt. The fractional ultrabasic-basic evolution of the upper-mantle silicate-carbonate-carbon melts-solutions, which are responsible for genesis of diamond-and-inclusions associations and diamond-bearing peridotites and eclogites, follows the similar physico-chemical mechanisms (Litvin et al., 2016). This is illustrated by fractional syngenesis diagram for diamonds and associated minerals which construction is based on evidence from high pressure experiments. References Gasparik T., Litvin Yu.A (1997). Stability of Na2Mg2Si2O7 and melting relations on the forsterite - jadeite join at pressures up to 22 GPa. Eur, J. Mineral. 9(2), 311-326. Litvin Yu.A. (1991). Physico-Chemical Study of Melting of Materials from the Deep Earth. Moscow: Nauka. 312 p. Litvin Yu.A., Spivak A.V., Kuzyura A.V. (2016). Fundamentals of the mantle-carbonatite concept of diamond genesis, Geochemistry Internat. 34(10), 839-857.

Mineral inclusions and geochemical characteristics of microdiamonds from the DO27, A154, A21, A418, DO18, DD17 and Ranch Lake kimberlites at Lac de Gras, Slave Craton, Canada

NASA Astrophysics Data System (ADS)

Davies, Rondi M.; Griffin, William L.; O'Reilly, Suzanne Y.; Doyle, Buddy J.

2004-09-01

A mineral inclusion, carbon isotope, nitrogen content, nitrogen aggregation state and morphological study of 576 microdiamonds from the DO27, A154, A21, A418, DO18, DD17 and Ranch Lake kimberlites at Lac de Gras, Slave Craton, was conducted. Mineral inclusion data show the diamonds are largely eclogitic (64%), followed by peridotitic (25%) and ultradeep (11%). The paragenetic abundances are similar to macrodiamonds from the DO27 kimberlite (Davies, R.M., Griffin, W.L., O'Reilly, S.Y., 1999. Diamonds from the deep: pipe DO27, Slave craton, Canada. In: Gurney, J.J., Gurney, J.L., Pascoe, M.D., Richardson, S.H. (Eds.), The J. B. Dawson Vol., Proc. 7th Internat. Kimberlite Conf., Red Roof Designs, Cape Town, pp. 148-155) but differ to diamonds from nearby kimberlites at Ekati (e.g., Lithos (2004); Tappert, R., Stachel, T., Harris, J.W., Brey, G.P., 2004. Mineral Inclusions in Diamonds from the Panda Kimberlite, S. P., Canada. 8th International Kimberlite Conference, extended abstracts) and Snap Lake to the south (Dokl. Earth Sci. 380 (7) (2001) 806), that are dominated by peridotitic stones. Eclogitic diamonds with variable inclusion compositions and temperatures of formation (1040-1300 °C) crystallised at variable lithospheric depths sometimes in changing chemical environments. A large range to very 13C-depleted C-isotope compositions ( δ13C=-35.8‰ to -2.2‰) and an NMORB bulk composition, calculated from trace elements in garnet and clinopyroxene inclusions, are consistent with an origin from subducted oceanic crust and sediments. Carbon isotopes in the peridotitic diamonds have mantle compositions ( δ13C mode -4.0‰). Mineral inclusion compositions are largely harzburgitic. Variable temperatures of formation (garnet TNi=800-1300 °C) suggest the peridotitic diamonds originate from the shallow ultra-depleted and deeper less depleted layers of the central Slave lithosphere. Carbon isotopes ( δ13C av.=-5.1‰) and mineral inclusions in the ultradeep diamonds suggest they formed in peridotitic mantle (˜670 km). The diamonds may have been entrained in a plume and subcreted to the base of the central Slave lithosphere. Poorly aggregated nitrogen (IaA without platelets) in a large number of eclogitic (67%) and peridotitic (32%) diamonds, with similar nitrogen contents, indicates the diamonds were stored in the mantle at low temperatures (1060-<1100 °C) following crystallisation in the Archean. Type IaA diamonds have largely cubo-octahedral growth forms, and Type II and Type IaAB diamonds, with higher nitrogen aggregation states, mostly have octahedral morphologies. However, no correlation between these groups and their mineral inclusion compositions, C-isotopes, and N-contents rules out the possibility of unique source origins and suggests eclogitic and peridotitic diamonds experienced variable mantle thermal states. Variation in mineral inclusion chemistries in single diamonds, possible overgrowths of 13C-depleted eclogitic diamond on diamonds with peridotitic and ultradeep inclusions, and Type I ultradeep diamond with low N-aggregation is consistent with diamond growth over time in changing chemical environments.

Searching for an Improved Spectral Match to TES and IRIS Sinus Meridiani Spectra: Coatings and Cemented Materials

NASA Astrophysics Data System (ADS)

Kirkland, L. E.; Herr, K. C.; Adams, P. M.

2001-05-01

A region on Mars within Sinus Meridiani has been interpreted as a surface partially covered by coarse-grained (gray) hematite, using spectra measured by the 1996 Global Surveyor Thermal Emission Spectrometer (TES) [Lane et al., 1999; Christensen et al., 2000]. The band strengths recorded by TES of this region are consistent with either coarse-grained hematite, or cemented poorly crystalline or cemented fine-grained hematite. The band strengths are inconsistent with unconsolidated, poorly crystalline or fine-grained hematite, including nanophase hematite dust [Christensen et al., 2000]. Currently the gray hematite interpretation is based on bands centered near 22 and 33 microns. TES also records a band centered near 18 microns that was used in early hematite interpretations [Lane et al., 1999]. However, it was noted [Kirkland et al., 1999a] that the 18 micron band is too narrow in both TES and the 1971 Mariner Mars IRIS spectra to be a good match to typical spectra of well-crystalline hematite [e.g. Salisbury et al., 1991]. The 18 micron band is near the very strong 15 micron atmospheric CO2 band, but if anything the nearby CO2 band should cause the 18 micron band to appear wider, not narrower. In addition, the higher spectral resolution of IRIS allows improved separation of the bands [Kirkland et al., 1999b]. More recent publications no longer show the TES 18 micron band [e.g. Lane et al., 2000; Christensen et al., 2000], which temporarily resolved the issue. However, we feel it is important to understand why TES and IRIS spectra exhibit an 18 micron band that is too narrow to match typical spectra of coarse-grained hematite. Smooth-surfaced cemented (e.g. ferricrete) or coated materials (e.g. desert varnish) have spectral contrast that is consistent with the observed IRIS and TES band contrast. On Mars, one possible source for cemented material or coatings would be the nanophase hematite dust. Cemented materials may occur in bulk (e.g. duricrust or ferricrete), or as a thin coating (e.g. desert varnish). We have investigated the signatures of naturally occurring cemented materials that contain hematite, and found samples that exhibit 22 and 33 micron bands that are consistent with coarse-grained hematite signatures, and yet also exhibit narrower 18 micron bands. We are continuing to study the materials more in-depth to examine the variations in spectral shape, and to determine the cause of varied 18 micron band width. References. Christensen, P. R. et al., JGR 105, 9632, 2000. Kirkland, L., K. Herr, P. Forney, and J. Salisbury, LPSC XXX, abs. 1693 and oral presentation, 1999a. Kirkland, L., K. Herr, and P. Forney, 5th Internat'l Conf. on Mars, abs. 6174, 1999b. Lane, M., R. Morris, and P. Christensen, LPSC XXX, abs. 1469, 1999. Lane, M., R. Morris, and P. Christensen, LPSC XXXI, abs. 1140, 2000. Salisbury, J., L. Walter, N. Vergo, D. D'Aria, Infrared (2.1-25 micron) Spectra of Minerals, Johns Hopkins UP, 1991.

Terrestrial multi-view photogrammetry for landslide monitoring

NASA Astrophysics Data System (ADS)

Stumpf, A.; Malet, J.; Allemand, P.; Skupinski, G.; Pierrot-Deseilligny, M.

2013-12-01

Multi-view stereo (MVS) surface reconstruction from large photo collections is being increasingly used for geoscience applications, and a number of different software solution and processing streamlines have been suggested. Open source libraries to perform feature point extraction, pose estimation, bundle adjustment and dense matching are available providing high quality results at low costs, and transparency of the implemented algorithms. Within the computer vision community benchmark datasets with toy examples and architectural scenes are frequently used to evaluate dense matching algorithms but relatively few studies have addressed the evaluation of complete processing pipelines for complex natural landscapes such as landslides developed in high mountain terrains. In order to obtain surface displacement maps of an active landslide (Super-Sauze, Southern French Alps) from multi-temporal terrestrial photographs over a period of three years, this work targeted the evaluation of three different non-commercial processing pipelines. The tested packages include VisualSfM[1], CMVS-PMVS [2], Apero and MicMac [URL]. The image acquisition focused on either subparts of the landslide (toe, main scarp) or targeted the reconstruction of a global model of the entire landslide. All images were processed with three different pipelines namely VisualSfM + CMVS-PMVS, Apero + CMVS-PMVS and Apero + MicMac and the resulting point clouds were evaluated with terrestrial and airborne LiDAR. Our results show that all multi-view stereo pipelines provide useful results to quantify surface displacement at accuracies between 1-10 cm depending on the acquisition geometry and the object distance. For pose estimation and bundle adjustment, Apero is the more accurate and versatile tool allowing the use of more sophisticated lens models and the direct integration of ground control points in the bundle adjustment. The dense matching algorithms with MicMac enables the reconstruction of denser point clouds, with fewer outliers, better spatial coverage and at lower computational costs, whereas CMVS-PMVS requires less manual tuning and produces fewer artifacts at discontinuities and areas with very low incidence angles. Change detection among the multi-temporal photogrammetric point clouds allowed to measure surface displacement rates greater than 1 m.yr-1 at the landslide toe, and greater than 3 m.yr-1 in the upper most active landslide part, indicating and important mass-accumulation in the central part. Large low frequency rockfall dominate the mass wasting process at the main scarp when compared to erosive retrogression. The study demonstrates that MVS has a great potential to replace LiDAR surveys for operational landslide monitoring providing comparable accuracies at significantly lower logistic and material costs. However, an optimal acquisition geometry and parameterization of the processing algorithms are important factors for its successful application and some recommendations, potential pitfalls and limitations are highlighted. [1] C. Wu, Towards Linear-time Incremental Structure from Motion, Internat. Conf. on 3D Vision, University of Washington, Seattle, USA, 2013. [2] Y. Furukawa and J. Ponce, "Accurate, Dense, and Robust Multiview Stereopsis," Pattern Analysis and Machine Intelligence, IEEE Transactions on, 32, pp. 1362-1376, 2010.

Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer.

PubMed

Francis, Prudence A; Pagani, Olivia; Fleming, Gini F; Walley, Barbara A; Colleoni, Marco; Láng, István; Gómez, Henry L; Tondini, Carlo; Ciruelos, Eva; Burstein, Harold J; Bonnefoi, Hervé R; Bellet, Meritxell; Martino, Silvana; Geyer, Charles E; Goetz, Matthew P; Stearns, Vered; Pinotti, Graziella; Puglisi, Fabio; Spazzapan, Simon; Climent, Miguel A; Pavesi, Lorenzo; Ruhstaller, Thomas; Davidson, Nancy E; Coleman, Robert; Debled, Marc; Buchholz, Stefan; Ingle, James N; Winer, Eric P; Maibach, Rudolf; Rabaglio-Poretti, Manuela; Ruepp, Barbara; Di Leo, Angelo; Coates, Alan S; Gelber, Richard D; Goldhirsch, Aron; Regan, Meredith M

2018-06-04

Background In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. Methods Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. Results In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group. Conclusions Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

Multiple-level stakeholder engagement in malaria clinical trials: addressing the challenges of conducting clinical research in resource-limited settings.

PubMed

Mtove, George; Kimani, Joshua; Kisinza, William; Makenga, Geofrey; Mangesho, Peter; Duparc, Stephan; Nakalembe, Miriam; Phiri, Kamija S; Orrico, Russell; Rojo, Ricardo; Vandenbroucke, Pol

2018-03-22

Multinational clinical trials are logistically complex and require close coordination between various stakeholders. They must comply with global clinical standards and are accountable to multiple regulatory and ethical bodies. In resource-limited settings, it is challenging to understand how to apply global clinical standards to international, national, and local factors in clinical trials, making multiple-level stakeholder engagement an important element in the successful conduct of these clinical trials. During the planning and implementation of a large multinational clinical trial for intermittent preventive treatment of malaria in pregnancy in resource-limited areas of sub-Saharan Africa, we encountered numerous challenges, which required implementation of a range of engagement measures to ensure compliance with global clinical and regulatory standards. These challenges included coordination with ongoing global malaria efforts, heterogeneity in national regulatory structures, sub-optimal healthcare infrastructure, local practices and beliefs, and perspectives that view healthcare providers with undue trust or suspicion. In addition to engagement with international bodies, such as the World Health Organization, the Malaria in Pregnancy Consortium, the Steve Biko Centre for Bioethics, and the London School of Hygiene and Tropical Medicine, in order to address the challenges just described, Pfizer Inc. and Medicines for Malaria Venture (the "Sponsoring Entities" for these studies) and investigators liaised with national- and district-level stakeholders such as health ministers and regional/local community health workers. Community engagement measures undertaken by investigators included local meetings with community leaders to explain the research aims and answer questions and concerns voiced by the community. The investigators also engaged with family members of prospective trial participants in order to be sensitive to local practices and beliefs. Engagement with key stakeholders at international and national levels enabled the Sponsoring Entities to address challenges by aligning the study design with the requirements of health and regulatory agencies and to understand and address healthcare infrastructure needs prior to trial initiation. Local stakeholder engagement, including community members, study participants, and family enabled the investigators to address challenges by ensuring that study design and conduct were adapted to local considerations and ensuring accurate information about the study aims was shared with the public. ClinicalTrials.gov, ID: NCT01103063 . Registered on 7 April 2010.

Antimicrobial resistance patterns of colonizing Streptococcus pneumoniae among young child-mother pairs in the rural highlands of the Peruvian Andes

PubMed Central

Howard, Leigh; Edwards, Kathryn; Griffin, Marie; Gil, Ana; Minaya, Gina; Mercado, Erik; Ochoa, Theresa; Lanata, Claudio; Grijalva, Carlos G

2017-01-01

Abstract Background Despite widespread use of pneumococcal conjugate vaccines (PCVs), Streptococcus pneumoniae (pneumococcus) remains an important cause of pneumonia. Prior to widespread PCV use, we found a high prevalence of nasopharyngeal (NP) colonization with pneumococcus resistant to multiple antibiotic classes among young children in the rural highlands of Peru. We sought to confirm contemporary resistance profiles among young children, their mothers, and animal contacts in the post-PCV era. Methods We enrolled eligible members of Peruvian households whose children had participated in our previous study. Mothers were questioned about antibiotic use for themselves and their children age <3 years. NP samples were collected from children, mothers, and their animal contacts including cows, guinea pigs, and dogs, when available. Samples were cultured for pneumococcus using standard methods and routine disk antibiotic susceptibility testing was performed. Drinking water and milk samples were tested, when available, for the presence of β-lactam and tetracycline residues (IDEXX Β-Tetra testing kit; Westbrook, ME). Results Members of 47 households were enrolled, including 50 children and 47 mothers (3 sibling pairs). The median (IQR) age of children was 1.2 years (0.6-2.2) and number of household members was 5 (4-6). Sixteen of 50 (32%) children and 7/47 (15%) mothers had received antibiotics in the prior 6 months (Fig 1). Pneumococcus was detected in 31/50 (62%) children, 9/47 (19%) mothers, and 1/31 (3%) guinea pigs. Pneumococci were not detected in dogs (n = 29) or cows (n = 7). Resistance to multiple classes of antibiotics, including TMP-SMX, tetracyclines, and β-lactams, was common among children and adults (Fig 2). No antibiotic residues were detected in water (n = 41) or milk (n = 7) samples. Conclusion Pneumococcal colonization was common among young children, less prevalent among adults, and rare among animals. Resistance to macrolides and tetracyclines was common despite very little reported use of these antibiotics in people. Additional studies should evaluate whether this high prevalence of resistance is a result of local prescribing practices or unintentional environmental exposures. ADDIN EN.REFLIST Disclosures K. Edwards, Novartis: Grant Investigator, Research grant. M. Griffin, MedImmune: Grant Investigator, Grant recipient. C. Lanata, Takeda: Scientific Advisor, Consulting fee. C. G. Grijalva, Pfizer: Consultant, Consulting fee.

An alkalinizing oral rehydration solution containing lecithin-coated citrus fiber is superior to a nonalkalinizing solution in treating 360 calves with naturally acquired diarrhea.

PubMed

Goodell, G M; Campbell, J; Hoejvang-Nielsen, L; Stansen, W; Constable, P D

2012-11-01

The aim of this field study was to compare the efficacy and cost of 2 commercially available oral rehydration therapy (ORT) solutions in treating dairy calves with naturally acquired diarrhea. A total of 1,349 newborn Holstein-Friesian calves were prospectively enrolled in the study. Calves were housed in individual hutches and fed a mixture of pasteurized hospital milk and an all-milk protein milk replacer twice per day. Calves were monitored twice each day from d 2 of life until 30 d of age for the presence or absence of diarrhea, and were assigned a fecal score and a hydration score at each examination. Calves that developed mild to severe diarrhea that did not need intravenous fluids and did not have clinical evidence of concurrent disease (n = 360) were assigned randomly to receive 1 of 2 commercial ORT solutions: a hypertonic alkalinizing ORT containing lecithin-coated citrus fibers (Diaque, group D, n = 180; Boehringer Ingelheim, Ingelheim, Germany), and an isotonic nonalkalinizing ORT (RE-SORB, group R, n = 180; Pfizer Animal Health, New York, NY) for 2 to 8d; the duration of treatment depended on whether diarrhea was still present. No significant differences were observed in mortality rates or treatment failure rates between the 2 treatment groups. Fecal consistency returned to normal more quickly in group D calves than in group R calves; consequently, group D calves were treated for 1d less than were group R calves. The increase in body weight after 4d of treatment was larger in group D than in group R. The average daily gain from birth to weaning in calves that did not develop concurrent disease (such as pneumonia) during the study period tended to be higher in group D calves (0.53±0.11 kg/d) than in group R calves (0.51±0.09 kg/d). The smaller number of treatments at a lower cost per treatment produced a cost advantage of $4.82 per treated calf in group D calves compared with group R calves. Our findings support the concept that milk should continue to be fed to diarrheic calves that are being administered an ORT solution in order to maintain growth. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Cerebral Biochemical Effect of Pregabalin in Patients with Painful Diabetic Neuropathy: A Randomized Controlled Trial.

PubMed

De Jaeger, Mats; Goudman, Lisa; Van Schuerbeek, Peter; De Mey, Johan; Keymeulen, Bart; Brouns, Raf; Moens, Maarten

2018-06-27

With the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy ( 1 H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin. A double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1 H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC), left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel. The concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014). No differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses. This study is registered at ClinicalTrials.gov (NCT01180608). Lyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

Study of the Effects of Total Modulation Transfer Function Changes on Observer Performance Using Clinical Mammograms.

NASA Astrophysics Data System (ADS)

Bencomo, Jose Antonio Fagundez

The main goal of this study was to relate physical changes in image quality measured by Modulation Transfer Function (MTF) to diagnostic accuracy. One Hundred and Fifty Kodak Min-R screen/film combination conventional craniocaudal mammograms obtained with the Pfizer Microfocus Mammographic system were selected from the files of the Department of Radiology, at M.D. Anderson Hospital and Tumor Institute. The mammograms included 88 cases with a variety of benign diagnosis and 62 cases with a variety of malignant biopsy diagnosis. The average age of the patient population was 55 years old. 70 cases presented calcifications with 30 cases having calcifications smaller than 0.5mm. 46 cases presented irregular bordered masses larger than 1 cm. 30 cases presented smooth bordered masses with 20 larger than 1 cm. Four separated copies of the original images were made each having a different change in the MTF using a defocusing technique whereby copies of the original were obtained by light exposure through different thicknesses (spacing) of transparent film base. The mammograms were randomized, and evaluated by three experienced mammographers for the degree of visibility of various anatomical breast structures and pathological lesions (masses and calicifications), subjective image quality, and mammographic interpretation. 3,000 separate evaluations were anayzed by several statistical techniques including Receiver Operating Characteristic curve analysis, McNemar test for differences between proportions and the Landis et al. method of agreement weighted kappa for ordinal categorical data. Results from the statistical analysis show: (1) There were no statistical significant differences in the diagnostic accuracy of the observers when diagnosing from mammograms with the same MTF. (2) There were no statistically significant differences in diagnostic accuracy for each observer when diagnosing from mammograms with the different MTF's used in the study. (3) There statistical significant differences in detail visibility between the copies and the originals. Detail visibility was better in the originals. (4) Feature interpretations were not significantly different between the originals and the copies. (5) Perception of image quality did not affect image interpretation. Continuation and improvement of this research ca be accomplished by: using a case population more sensitive to MTF changes, i.e., asymptomatic women with minimum breast cancer, more observers (including less experienced radiologists and experienced technologists) must collaborate in the study, and using a minimum of 200 benign and 200 malignant cases.

Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft.

PubMed

Raub, Thomas J; Wishart, Graham N; Kulanthaivel, Palaniappan; Staton, Brian A; Ajamie, Rose T; Sawada, Geri A; Gelbert, Lawrence M; Shannon, Harlan E; Sanchez-Martinez, Concepcion; De Dios, Alfonso

2015-09-01

Effective treatments for primary brain tumors and brain metastases represent a major unmet medical need. Targeting the CDK4/CDK6-cyclin D1-Rb-p16/ink4a pathway using a potent CDK4 and CDK6 kinase inhibitor has potential for treating primary central nervous system tumors such as glioblastoma and some peripheral tumors with high incidence of brain metastases. We compared central nervous system exposures of two orally bioavailable CDK4 and CDK6 inhibitors: abemaciclib, which is currently in advanced clinical development, and palbociclib (IBRANCE; Pfizer), which was recently approved by the U.S. Food and Drug Administration. Abemaciclib antitumor activity was assessed in subcutaneous and orthotopic glioma models alone and in combination with standard of care temozolomide (TMZ). Both inhibitors were substrates for xenobiotic efflux transporters P-glycoprotein and breast cancer resistant protein expressed at the blood-brain barrier. Brain Kp,uu values were less than 0.2 after an equimolar intravenous dose indicative of active efflux but were approximately 10-fold greater for abemaciclib than palbociclib. Kp,uu increased 2.8- and 21-fold, respectively, when similarly dosed in P-gp-deficient mice. Abemaciclib had brain area under the curve (0-24 hours) Kp,uu values of 0.03 in mice and 0.11 in rats after a 30 mg/kg p.o. dose. Orally dosed abemaciclib significantly increased survival in a rat orthotopic U87MG xenograft model compared with vehicle-treated animals, and efficacy coincided with a dose-dependent increase in unbound plasma and brain exposures in excess of the CDK4 and CDK6 Ki values. Abemaciclib increased survival time of intracranial U87MG tumor-bearing rats similar to TMZ, and the combination of abemaciclib and TMZ was additive or greater than additive. These data show that abemaciclib crosses the blood-brain barrier and confirm that both CDK4 and CDK6 inhibitors reach unbound brain levels in rodents that are expected to produce enzyme inhibition; however, abemaciclib brain levels are reached more efficiently at presumably lower doses than palbociclib and are potentially on target for a longer period of time. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Calf-Level Factors Associated with Bovine Neonatal Pancytopenia – A Multi-Country Case-Control Study

PubMed Central

Jones, Bryony A.; Sauter-Louis, Carola; Henning, Joerg; Stoll, Alexander; Nielen, Mirjam; Van Schaik, Gerdien; Smolenaars, Anja; Schouten, Matthijs; den Uijl, Ingrid; Fourichon, Christine; Guatteo, Raphael; Madouasse, Aurélien; Nusinovici, Simon; Deprez, Piet; De Vliegher, Sarne; Laureyns, Jozef; Booth, Richard; Cardwell, Jackie M.; Pfeiffer, Dirk U.

2013-01-01

Bovine neonatal pancytopenia (BNP), a high fatality condition causing haemorrhages in calves aged less than 4 weeks, was first reported in 2007 in Germany and subsequently observed at low incidence in other European countries and New Zealand. A multi-country matched case-control study was conducted in 2011 to identify calf-level risk factors for BNP. 405 BNP cases were recruited from 330 farms in Belgium, France, Germany and the Netherlands by laboratory confirmation of farmer-reported cases. Up to four calves of similar age from the same farm were selected as controls (1154 calves). Risk factor data were collected by questionnaire. Multivariable modelling using conditional logistic regression indicated that PregSure®BVD (PregSure, Pfizer Animal Health) vaccination of the dam was strongly associated with BNP cases (adjusted matched Odds Ratio - amOR 17.8 first lactation dams; 95% confidence interval – ci 2.4, 134.4; p = 0.005), and second or more lactation PregSure-vaccinated dams were more likely to have a case than first lactation vaccinated dams (amOR 2.2 second lactation; ci 1.1, 4.3; p = 0.024; amOR 5.3 third or more lactation; ci 2.9, 9.8; p = <0.001). Feeding colostrum from other cows was strongly associated with BNP if the dam was not PregSure-vaccinated (amOR 30.5; ci 2.1, 440.5; p = 0.012), but the effect was less if the dam was PregSure-vaccinated (amOR 2.1; ci 1.1, 4.0; p = 0.024). Feeding exclusively dam’s milk was a higher risk than other types of milk (amOR 3.4; ci 1.6, 7.5; p = 0.002). The population attributable fractions were 0.84 (ci 0.68, 0.92) for PregSure vaccination, 0.13 (ci 0.06, 0.19) for feeding other cows’ colostrum, and 0.15 (ci 0.08, 0.22) for feeding dam’s milk. No other calf-level factors were identified, suggesting that there are other important factors that are outside the scope of this study, such as genetics, which explain why BNP develops in some PregSure-colostrum-exposed calves but not in others. PMID:24312485

WAAVP/Pfizer award for excellence in teaching veterinary parasitology: teaching of veterinary parasitology--quo vadis?

PubMed

Eckert, J

2000-02-29

Some thoughts on training and recruitment of academic teachers and future trends in teaching veterinary parasitology are presented with emphasis on the European situation. It is underlined that research is an indispensable basis for academic teaching. Besides a broad scientific background of the teacher, motivation and teaching methods are also important. Many academic teachers do not receive formal training in teaching methods. In order to improve future education, training of staff members in teaching methods should be promoted. Quality control of teaching and research, already established in many schools, should generally be introduced. Teaching is mostly underestimated in relation to research. Therefore, more weight should be placed on the former both in selecting scientists for the career as academic teachers and in evaluating and ranking departments for their academic activities. In the future veterinary medicine will have to cope with profound changes in the society and the veterinary profession, and the progressing European unification will enhance trends for internationalizing teaching curricula. Therefore, veterinary medicine has to reconsider the teaching subjects and methods and to lay more emphasis on flexibility, skills of problem-solving and self-learning and on training for life-long learning. At present there is an ongoing discussion on the question how to teach veterinary medicine, including veterinary parasitology. There are various options, and some of them are discussed, namely, the disciplinary and the problem-based/organ-focussed approaches. It is concluded that for teaching of veterinary parasitology and related disciplines a combined disciplinary and problem-based approach offers the best chances for fulfilling the requirements of teaching for the future. In the curriculum of undergraduate teaching of veterinary medicine at least 70-90 h should be dedicated to veterinary parasitology using a disciplinary and taxonomic approach. Additional hours are required for instructions on clinical cases in approaches focussed on animal species and/or organ diseases. As there is a need for discussing teaching issues, post-graduate specialization, and continuing education in parasitology and related disciplines on national and international levels, it is recommended to WAAVP to include regular workshops on teaching in the programmes of the biannual conferences, and to establish a permanent committee which should collect information and submit proposals for improvement of teaching veterinary parasitology.

A 20-year follow-up of the mesh wallstent in the treatment of detrusor external sphincter dyssynergia in patients with spinal cord injury.

PubMed

Abdul-Rahman, Ahmad; Ismail, Soran; Hamid, Rizwan; Shah, Julian

2010-11-01

To assess the long-term (20 years) effectiveness of the UroLume wallstent(TM) (Pfizer Inc., UK) in the treatment of detrusor external sphincter dyssynergia (DESD) in patients with spinal cord injury (SCI). Twelve patients with quadriplegia secondary to SCI underwent external striated sphincter stenting with the UroLume wallstent in place of sphincterotomy for DESD ≈ 20 years ago. The mean (range) age was 41.8 (26-65) years. Eleven patients had cervical level injury whilst one had a thoracic injury. All the patients were shown to have high-pressure neurogenic detrusor overactivity and DESD with incomplete emptying on preoperative video-cystometrograms (VCMG). Six of the 12 patients have now been followed-up for a mean (range) of 20 (19-21) years. Of the remaining six, two were lost to follow-up at 1 and 3 years, but both remained free of complications during that time. Two patients developed encrustation causing obstruction, requiring stent removal within 1 year of insertion. Another patient with an adequately functioning stent died 7 years after stent insertion from a chest infection. The twelfth patient developed bladder cancer 14 years after stent insertion and underwent cystectomy with urinary diversion. VCMG follow-up of the six patients showed a significantly sustained reduction of maximum detrusor pressure and duration of detrusor contraction at the 20-year follow-up. Five of these six patients developed bladder neck dyssynergia of varying degrees as shown on VCMG within the first 9 years of follow-up. All were successfully treated with bladder neck incision (BNI) where the last BNI needed was at 12 years. We did not encounter any problem with stent migration, urethral erosion, erectile dysfunction or autonomic dysreflexia. Urethral stenting using the UroLume wallstent is effective in the management of DESD in patients with SCI and provides an acceptable long-term (20-year follow-up) alternative to sphincterotomy. The failures manifest within the first few years and can be managed easily with stent removal without any significant problems. Bladder neck dyssynergia was the long-term complication which was treated successfully with BNI. It has no significant interference with erectile function, being reversible, minimally invasive and has a shorter hospital stay. © 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.

Apixaban in patients with atrial fibrillation.

PubMed

Connolly, Stuart J; Eikelboom, John; Joyner, Campbell; Diener, Hans-Christoph; Hart, Robert; Golitsyn, Sergey; Flaker, Greg; Avezum, Alvaro; Hohnloser, Stefan H; Diaz, Rafael; Talajic, Mario; Zhu, Jun; Pais, Prem; Budaj, Andrzej; Parkhomenko, Alexander; Jansky, Petr; Commerford, Patrick; Tan, Ru San; Sim, Kui-Hian; Lewis, Basil S; Van Mieghem, Walter; Lip, Gregory Y H; Kim, Jae Hyung; Lanas-Zanetti, Fernando; Gonzalez-Hermosillo, Antonio; Dans, Antonio L; Munawar, Muhammad; O'Donnell, Martin; Lawrence, John; Lewis, Gayle; Afzal, Rizwan; Yusuf, Salim

2011-03-03

Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients. In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism. Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups. In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

Commentary on: "Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial." Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, Escudier B. Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; Joaquim Bellmunt, University Hospital del Mar-IMIM, Barcelona, Spain; Jill Clancy, Kongming Wang, Andreas G. Niethammer, Subramanian Hariharan, Pfizer, New York, NY; and Bernard Escudier, Institut Gustave Roussy, Villejuif, France.: J Clin Oncol. 2014 Mar 10;32(8):752-9; doi: 10.1200/JCO.2013.50.5305. [Epub 2013 Dec 2].

PubMed

Trump, Donald

2016-05-01

To prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC). In a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25mg intravenously, weekly) or IFN (9MIU subcutaneously thrice weekly) with bevacizumab (10mg/kg intravenously, every 2weeks). The primary end point was independently assessed progression-free survival (PFS). Median PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR] = 1.1; 95% CI: 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR = 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI)-15 and FKSI Disease-Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade≥3 adverse events more common (P<.001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2. Temsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC. Copyright © 2016 Elsevier Inc. All rights reserved.

Adequacy of pharmacological information provided in pharmaceutical drug advertisements in African medical journals

PubMed Central

Oshikoya, Kazeem A.; Senbanjo, Idowu O.; Soipe, Ayo

2008-01-01

Pharmaceutical advertisement of drugs is a means of advocating drug use and their selling but not a substitute for drug formulary to guide physicians in safe prescribing. Objectives: To evaluate drug advertisements in Nigerian and other African medical journals for their adequacy of pharmacological information. Methods: Twenty four issues from each of West African Journal of Medicine (WAJM), East African Medical Journal (EAMJ), South African Medical Journal (SAMJ), Nigerian Medical Practitioner (NMP), Nigerian Quarterly Journal of Hospital Medicine (NQJHM) and Nigerian Postgraduate Medical Journal (NPMJ) were reviewed. While EAMJ, SAMJ and NMP are published monthly, the WAJM, NQJHM and NPMJ are published quarterly. The monthly journals were reviewed between January 2005 and December 2006, and the quarterly journals between January 2001 and December 2006. The drug information with regards to brand/non-proprietary name, pharmacological data, clinical information, pharmaceutical information and legal aspects was evaluated as per World Health Organisation (WHO) criteria. Counts in all categories were collated for each advertiser. Results: Forty one pharmaceutical companies made 192 advertisements. 112 (58.3%) of these advertisements were made in the African medical journals. Pfizer (20.3%) and Swipha (12.5%) topped the list of the advertising companies. Four (2.1%) adverts mentioned generic names only, 157 (81.8%) mentioned clinical indications. Adults and children dosage (39.6%), use in special situations such as pregnancy and renal or liver problems (36.5%), adverse effects (30.2%), average duration of treatment (26.0%), and potential for interaction with other drugs (18.7%) were less discussed. Pharmaceutical information such as available dosage forms and product and package information {summary of the generic and proprietary names, the formulation strength, active ingredient, route of administration, batch number, manufactured and expiry dates, and the manufacturer on both the container and pack of the drug} were mentioned in 65.6% and 50% adverts, respectively. The product and package descriptions were provided in 57 (72.2%) Nigerian medical journals, which was significantly higher than in other African medical journals 39 (37.9%) (P<0.001). Conclusions: None of the drug advertisements in the journals adequately provided the basic information required by the WHO for appropriate prescribing. More guidance and regulation is needed to ensure adequate information is provided. PMID:25152785

The Zodiak workshop: an innovative model for teaching financial management through partnership with industry.

PubMed

Lloyd, James W; Frawley, Suzanne L; Neer, Charles A; Merle, Christine; Goebel, Richard

2004-01-01

The National Commission on Veterinary Economic Issues (NCVEI) is working to enhance the non-technical skills, knowledge, aptitudes, and attitudes (SKAs) of veterinarians. This report describes the development of an innovative model for teaching the principles of financial management as they apply to the veterinary practice. Zodiak: The Game of Business Finance and Strategy is a "business literacy" game in which players work together in small teams (generally four people) to run a fictional multi-million-dollar company called Zodiak Industries for three "years" in order to learn principles of business finance and strategy. After finishing the 4.5-hour game, participants spend the rest of the workshop making the right "Connections"-exercises designed to connect what they have learned to business strategies, financial statements, and operational tactics drawn from veterinary practice. Issues addressed for the veterinary practice, with parallels drawn to Zodiak, included return on owner investment in a veterinary practice (vs. salary drawn by owner veterinarians); pricing (setting prices, price elasticity of demand, and relationships between volume, quality, and price); human resources and operations management as they relate to profitability and efficiency; cash flow and management of accounts receivable; and commonly used financial benchmarks. Workshop venues have included Michigan State University, The Ohio State University, the University of Illinois, and Purdue University. Financial and in-kind support were provided through partnership with Pharmacia Animal Health (now Pfizer Animal Health) and Hill's Pet Nutrition, Inc. Through course evaluations, participants generally rated the workshop high as an educational experience and indicated that the most important things learned were related to financial management (principles, terminology, and methods). The most enjoyable aspects of the workshop tended to be group discussions, teamwork, the dynamic/interactive environment, and the "game" atmosphere. Based on these experiences, the Zodiak workshop provides a useful model for teaching career development and practice management topics to veterinary students. The business simulation in a workshop format was especially useful for teaching these "non-mainstream" topics, as traditional classroom lecture approaches might not have engaged students sufficiently to achieve effective learning. In addition, the partnership developed between academia and industry offered substantial benefits to both parties. Similar educational approaches should be considered for additional aspects of the non-technical SKAs.

Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial.

PubMed

Ellis, Paul; Barrett-Lee, Peter; Johnson, Lindsay; Cameron, David; Wardley, Andrew; O'Reilly, Susan; Verrill, Mark; Smith, Ian; Yarnold, John; Coleman, Robert; Earl, Helena; Canney, Peter; Twelves, Chris; Poole, Christopher; Bloomfield, David; Hopwood, Penelope; Johnston, Stephen; Dowsett, Mitchell; Bartlett, John M S; Ellis, Ian; Peckitt, Clare; Hall, Emma; Bliss, Judith M

2009-05-16

Incorporation of a taxane as adjuvant treatment for early breast cancer offers potential for further improvement of anthracycline-based treatment. The UK TACT study (CRUK01/001) investigated whether sequential docetaxel after anthracycline chemotherapy would improve patient outcome compared with standard chemotherapy of similar duration. In this multicentre, open-label, phase III, randomised controlled trial, 4162 women (aged >18 years) with node-positive or high-risk node-negative operable early breast cancer were randomly assigned by computer-generated permuted block randomisation to receive FEC (fluorouracil 600 mg/m(2), epirubicin 60 mg/m(2), cyclophosphamide 600 mg/m(2) at 3-weekly intervals) for four cycles followed by docetaxel (100 mg/m(2) at 3-weekly intervals) for four cycles (n=2073) or control (n=2089). For the control regimen, centres chose either FEC for eight cycles (n=1265) or epirubicin (100 mg/m(2) at 3-weekly intervals) for four cycles followed by CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2), and fluorouracil 600 mg/m(2) at 4-weekly intervals) for four cycles (n=824). The primary endpoint was disease-free survival. Analysis was by intention to treat (ITT). This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN79718493. All randomised patients were included in the ITT population. With a median follow-up of 62 months, disease-free survival events were seen in 517 of 2073 patients in the experimental group compared with 539 of 2089 controls (hazard ratio [HR] 0.95, 95% CI 0.85-1.08; p=0.44). 75.6% (95% CI 73.7-77.5) of patients in the experimental group and 74.3% (72.3-76.2) of controls were alive and disease-free at 5 years. The proportion of patients who reported any acute grade 3 or 4 adverse event was significantly greater in the experimental group than in the control group (p<0.0001); the most frequent events were neutropenia (937 events vs 797 events), leucopenia (507 vs 362), and lethargy (456 vs 272). This study did not show any overall gain from the addition of docetaxel to standard anthracycline chemotherapy. Exploration of predictive biomarker-defined subgroups might have the potential to better target the use of taxane-based therapy. Cancer Research UK (CRUK 01/001), Sanofi-Aventis, Pfizer, and Roche.

A pragmatic, randomized, controlled study evaluating the impact of access to smoking cessation pharmacotherapy coverage on the proportion of successful quitters in a Canadian population of smokers motivated to quit (ACCESSATION).

PubMed

Selby, Peter; Brosky, Gerald; Oh, Paul; Raymond, Vincent; Arteaga, Carmen; Ranger, Suzanne

2014-05-07

Many smokers find the cost of smoking cessation medications a barrier. Financial coverage for these medications increases utilization of pharmacotherapies. This study assesses whether financial coverage increases the proportion of successful quitters. A pragmatic, open-label, randomized, controlled trial was conducted in 58 Canadian sites between March 2009 and September 2010. Smokers (≥10 cigarettes/day) without insurance coverage who were motivated to quit within 14 days were randomized (1:1) in a blinded manner to receive either full coverage eligibility for 26 weeks or no coverage. Pharmacotherapies covered were varenicline, bupropion, or nicotine patches/gum. Investigators/subjects were unblinded to study group assignment after randomization and prior to choosing a smoking cessation method(s). All subjects received brief smoking cessation counseling. The primary outcome measure was self-reported 7-day point prevalence of abstinence (PPA) at week 26. Of the 1380 randomized subjects (coverage, 696; no coverage, 684), 682 (98.0%) and 435 (63.6%), respectively, were dispensed at least one smoking cessation medication dose. The 7-day PPA at week 26 was higher in the full coverage versus no coverage group: 20.8% (n = 145) and 13.9% (n = 95), respectively; odds ratio (OR) = 1.64, 95% confidence interval (CI) 1.23-2.18; p = 0.001. Urine cotinine-confirmed 7-day PPA at week 26 was 15.7% (n = 109) and 10.1% (n = 69), respectively; OR = 1.68, 95% CI 1.21-2.33; p = 0.002. After pharmacotherapy, coverage eligibility was withdrawn from the full coverage group, continuous abstinence between weeks 26 and 52 was 6.6% (n = 46) and 5.6% (n = 38), in the full coverage and no coverage groups, respectively; OR = 1.19, 95% CI 0.76-1.87; p = 0.439. In this study, the adoption of a smoking cessation medication coverage drug policy was an effective intervention to improve 26-week quit rates in Canada. The advantages were lost once coverage was discontinued. Further study is required on the duration of coverage to prevent relapse to smoking. (clinicaltrials.gov identifier: NCT00818207; the study was sponsored by Pfizer Inc.).

Obesity, overweight and cancer mortality in the Asia-Pacific Cohort Studies Collaboration: pooled analyses of 424 519 participants

PubMed Central

Parr, Christine Louise; Batty, G. David; Lam, Tai Hing; Barzi, Federica; Fang, Xianghua; Ho, Suzanne C; Jee, Sun Ha; Ansary-Moghaddam, Alireza; Ueshima, Hirotsugu; Woodward, Mark; Huxley, Rachel R

2014-01-01

SUMMARY Background Excess weight is an established risk factor for several cancers but there are sparse data from Asian populations in whom overweight and obesity is increasing rapidly and adiposity can be substantially greater for the same body mass index (BMI) compared to Caucasians. Methods We examined associations of adult BMI with cancer mortality (overall and 20 sites) in geographic populations from Asia and Australia/New Zealand (ANZ) within the Asia Pacific Cohort Studies Collaboration using Cox regression. Pooled data from 39 cohorts (recruitment 1961-99, median follow-up 4 years) were analyzed for 424 519 participants (77% Asian; 41% female; mean recruitment age 48 years) with individual data on BMI. Findings After excluding follow-up < 3 years, 4872 cancer deaths occurred in 401 215 participants. Hazard ratios (95% CI) for cancer sites with increased mortality risk in the obese (≥30 kg/m2) relative to the normal weight (18.5-24.9 kg/m2) were: 1.21 (1.09-1.36) for all-cause cancer (excluding lung and upper-aero digestive tract), 1.50 (1.13-1.99) for colon, 1.68 (1.06-2.67) for rectum, 1.63 (1.13-2.35) for breast in women aged ≥ 60 years, 2.62 (1.57-4.37) for ovary, 4.21 (1.89-9.39) for cervix, 1.45 (0.97-2.19) for prostate, and 1.66 (1.03-2.68) for leukaemia with the increased risk associated with a 5-unit increment in BMI ≥ 18.5 kg/m2 ranging from 1.13 (0.91-1.40) for rectum to 1.45 (1.00-2.11) for cervix. There was little evidence of regional differences in relative risk except for oropharynx and larynx where the association was inverse in ANZ but absent in Asia. Interpretation Overweight and obese individuals in populations across the Asia-Pacific region are at significantly increased risk of mortality from cancer. Strategies to prevent overweight and obesity across Asia are required to reduce the burden of cancer expected to occur if the obesity epidemic continues. Funding The APCSC has been funded by the National Health and Medical Research Council of Australia, the Health Research Council of New Zealand and Pfizer Inc., through an unrestricted medical grant. PMID:20594911

FDA Approval Summary: Mylotarg for Treatment of Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia.

PubMed

Norsworthy, Kelly J; Ko, Chia-Wen; Lee, Jee Eun; Liu, Jiang; John, Christy S; Przepiorka, Donna; Farrell, Ann T; Pazdur, Richard

2018-04-12

On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin (GO; Mylotarg; Pfizer, New York City, NY) for treatment of relapsed or refractory (R/R) CD33-positive acute myeloid leukemia (AML) in patients 2 years of age and older. GO is a CD33-directed antibody drug conjugate linked to the cytotoxic antibiotic calicheamicin. It originally received accelerated approval for treatment of older patients with relapsed CD33-positive AML in 2000, but it was withdrawn from the market in 2010 when the confirmatory trial failed to demonstrate clinical benefit among safety concerns, such as a higher rate of induction fatalities on the GO combination arm compared with chemotherapy alone. In addition, GO was associated with hepatic veno-occlusive disease (VOD), which has substantial morbidity and mortality. Pharmacokinetic analyses suggested a lower maximum concentration of GO would result in less VOD without affecting target saturation or efficacy. A meta-analysis across dose schedules of GO in patients with R/R AML showed that a lower-dose "fractionated" schedule of 3 mg/m 2 days 1, 4, and 7 was associated with less early mortality, hemorrhage, and VOD, without an apparent decrease in complete remission (CR) rate. MyloFrance 1 was a single-arm study evaluating response rates in patients with relapsed CD33-positive AML treated with the lower-dose fractionated GO regimen. The CR rate was 26% (95% confidence interval 16%-40%). Common adverse reactions were fever, infections, nausea, vomiting, constipation, bleeding, increased liver enzymes, and mucositis. There were no cases of VOD. These results supported the approval of GO as monotherapy for R/R CD33-positive AML using the lower-dose fractionated regimen. Gemtuzumab ozogamicin (GO) 3 mg/m 2 days 1, 4, and 7 is an active regimen for induction of remission when used to treat patients with relapsed or refractory CD33-positive acute myeloid leukemia without curative intent. The risks of hepatic veno-occlusive disease and early mortality with this regimen appear to be lower than reported previously for GO 9 mg/m 2 days 1 and 15. The data were not sufficient to enable conclusions about the safety of GO in children younger than 2 years of age. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.

Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.

PubMed

Salloway, Stephen; Sperling, Reisa; Fox, Nick C; Blennow, Kaj; Klunk, William; Raskind, Murray; Sabbagh, Marwan; Honig, Lawrence S; Porsteinsson, Anton P; Ferris, Steven; Reichert, Marcel; Ketter, Nzeera; Nejadnik, Bijan; Guenzler, Volkmar; Miloslavsky, Maja; Wang, Daniel; Lu, Yuan; Lull, Julia; Tudor, Iulia Cristina; Liu, Enchi; Grundman, Michael; Yuen, Eric; Black, Ronald; Brashear, H Robert

2014-01-23

Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Apixaban versus warfarin in patients with atrial fibrillation.

PubMed

Granger, Christopher B; Alexander, John H; McMurray, John J V; Lopes, Renato D; Hylek, Elaine M; Hanna, Michael; Al-Khalidi, Hussein R; Ansell, Jack; Atar, Dan; Avezum, Alvaro; Bahit, M Cecilia; Diaz, Rafael; Easton, J Donald; Ezekowitz, Justin A; Flaker, Greg; Garcia, David; Geraldes, Margarida; Gersh, Bernard J; Golitsyn, Sergey; Goto, Shinya; Hermosillo, Antonio G; Hohnloser, Stefan H; Horowitz, John; Mohan, Puneet; Jansky, Petr; Lewis, Basil S; Lopez-Sendon, Jose Luis; Pais, Prem; Parkhomenko, Alexander; Verheugt, Freek W A; Zhu, Jun; Wallentin, Lars

2011-09-15

Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).

Oral microbiota, dental caries and periodontal status in smokeless tobacco chewers in Karnataka, India: a case-control study.

PubMed

Nagarajappa, Sandesh; Prasad, Kakarla V V

2010-01-01

The aim of the present study was to compare dental caries and periodontal disease status associated with oral microflora among smokeless tobacco chewers and non-chewers. Forty-two smokeless tobacco chewers and 42 non-chewers (age 20 to 60 years) were assessed for dental caries and periodontal disease status using the Decayed Missing Filled Surface (DMFS) Index, Community Periodontal Index (CPI) and Loss of Attachment (LA) Index. Stimulated saliva and subgingival plaque samples were collected from each subject for performing a culture-based analysis of 20 types of oral microorganisms. Qualitative and semi-quantitative culture-based analysis using MacConkey agar, and aerobic and anaerobic blood agar was carried out to determine the total cultivable microflora. Mutans-Sanguis agar, Pfizer selective Enterococcus agar and Rogosa SL agar were used for the culture of microorganisms associated with dental caries. Mann–Whitney U test and Student t test were employed to compare colony-forming units (CFUs) and caries experience between smokeless tobacco chewers and nonchewers. Z proportionality test was used to compare the periodontal disease status. Caries experience among chewers (26 of 42), that is those subjects who were affected by caries, was significantly less at 61.9% (mean DMFS = 3.5) compared to non-chewers (38 of 42, 90.5%) (mean DMFS = 5.5) (P < 0.05). Deep pockets measuring > 5.5 mm on a CPI probe were found among 26.2% of chewers and 19.1% of nonchewers, with no statistically significant differences (P > 0.05). Counts of Lactobacillus species were significantly lower among chewers (median CFU = 0.788 x 10⁵) than among non-chewers (median CFU = 1.52 x 10⁵) (P < 0.05). Prevotella and Porphyromonas species had a median CFU of 0.04 x 105 in chewers and 0.15 x 10⁵ in non-chewers, whereas Fusobacterium species had a median CFU of 0.02 x 10⁵ in chewers and 0.1 x 10⁵ in non-chewers (P < 0.05). A higher percentage of caries among non-chewers can be explained by greater numbers of Lactobacillus species in this population. Chewers experienced a slightly higher incidence of periodontal disease than non-chewers, but the difference was not significant. These clinical observations suggest a lower ability of Gram-negative bacteria to mediate more periodontal disease in this population.

A multilocation clinical trial in lactating dairy cows affected with clinical mastitis to compare the efficacy of treatment with intramammary infusions of a lincomycin/neomycin combination with an ampicillin/cloxacillin combination.

PubMed

Deluyker, H A; Chester, S T; Van Oye, S N

1999-08-01

A study was conducted to compare the efficacy in lactating dairy cows of intramammary infusions in quarters affected with clinical mastitis between a formulation containing 330 mg lincomycin and 100 mg neomycin in a 10-mL aqueous solution (LINCOCIN FORTE S, Pharmacia & Upjohn) and a formulation containing 75 mg ampicillin and 200 mg cloxacillin in an oil suspension (AMPICLOX, Pfizer Animal Health). This study was designed as a multicentre clinical trial involving investigators in France, Germany and Belgium and carried out according to the European Commission guidelines on Good Clinical Practices. Cows in the herds were monitored for clinical mastitis. When evidence of clinical mastitis was detected in a single quarter, a pretherapy milk sample was collected from the affected quarter. After milk sampling, the cow was assigned to one of the two treatment groups at random and treated with an intramammary infusion of one syringe of either LINCOCIN FORTE S or AMPICLOX for three successive milkings in the mastitic quarter. At 4-5, 13-15 and 20-22 days after first infusion, the veterinarian returned to the farm to conduct a clinical examination and collect milk samples from the affected quarter. Milk samples were cultured for the presence of mastitis organisms and somatic cell count (SCC) was measured. Following a 10-month study period, 256 cases were enrolled in the study. A total of 232 and 189 cases were analysed for clinical cure and for clinical-plus-bacteriological cure, respectively. The proportions of cases cured clinically and cured clinically-plus-bacteriologically were compared between the two treatment groups. Somatic cell count differences between treatment groups were also tested. The clinical cure rate for LINCOCIN FORTE S (62.5%) was significantly better than for AMPICLOX (51.8%) (P = 0.035). The clinical-plus-bacteriological cure rate was also significantly better for LINCOCIN FORTE S (38.1%) than for AMPICLOX (21.7%) (P = 0.005). Among bacteriologically cured cases, the SCC declined in both treatment groups but the SCC was significantly higher for the AMPICLOX group than for the LINCOCIN FORTE S group (P = 0.036). In conclusion, clinical cure rate, clinical-plus-bacteriological cure rate, and SCC level were significantly better with LINCOCIN FORTE S than for AMPICLOX.

Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real-World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches.

PubMed

Serrano, Daniel; Atzinger, Christopher B; Botteman, Marc F

2018-06-01

Hereditary transthyretin (TTR) amyloidosis with polyneuropathy (hATTR-PN) is a rare, autosomal dominant amyloidosis characterized primarily by progressive ascending sensorimotor neuropathy often associated with  autonomic involvement. hATTR-PN is caused by a mutation in the TTR gene leading to protein misfolding and amyloid accumulation in peripheral nerves and vital organs. The latest global prevalence estimates point to 10,000 cases worldwide, with an upper end of about 40,000. Tafamidis has been approved in over 40 countries for delaying neurologic disease progression in early-stage hATTR-PN. Multiple observational studies have examined clinical outcomes in hATTR-PN patients treated with tafamidis in the routine clinical setting. Integrative data analysis (IDA) is a technique for optimally constructing synthetic treatment and control cohorts from multiple independent studies, which allows meta-analysis of patient-level data. Herein, we provide a proof of concept for the application of IDA to real-world and natural history hATTR-PN data. IDA permits increased understanding of outcomes in tafamidis-treated and untreated persons with hATTR-PN by optimally pooling all available information. Summary statistics corresponding to the Neuropathy Impairment Score-Lower Limb (NIS-LL) from five published studies were pooled, converted to change from baseline means and variances, and analyzed using IDA. IDA-based synthetic cohorts were generated by averaging across studies stratified on treatment versus control cohort. Trends in change from baseline in each study and the corresponding synthetic cohorts were plotted. Patient-level data were simulated from the synthetic cohort trends in a Monte Carlo simulation to highlight the ability to contrast synthetic cohort trends using the mixed model for repeated measures (MMRM). The average sample size among the five studies was 71 (37-128) patients. The average NIS-LL trends indicated that tafamidis-treated patients experienced slower progression in neuropathy compared to untreated patients. Synthetic cohort trends reflected the trends observed in the contributing studies, while simultaneously shrinking the width of corresponding confidence bands. Monte Carlo simulation results demonstrated precise recovery of the synthetic cohort and time-dependent simulated NIS-LL means by the MMRM. This proof of concept demonstrates the utility of IDA-based synthetic cohorts for increased precision in characterizing and testing hypotheses about treatment outcomes and prognosis in hATTR-PN. Pfizer. Plain language summary available for this article.

Medicine As a Corporate Enterprise, Patient Welfare Centered Profession, or Patient Welfare Centered Professional Enterprise?

PubMed Central

Singh, Ajai; Singh, Shakuntala

2005-01-01

There is an alarming trend in the field of medicine, whose portents are ominous but do not seem to shake the complacency and merry making doing the rounds. The wants of the medical man have multiplied beyond imagination. The cost of organizing conferences is no longer possible on delegate fees. The bottom-line is: Crores for a Conference Millions for a Mid-Term. However, the problem is that sponsors keep a discreet but careful tab on docs. All in all, costs of medicines escalate, and quality medical care becomes a luxury. The whole brunt of this movement is borne by the patient. Companies like GlaxoSmithKline, Bayer, Pfizer, Bristol-Myers Squibb, AstraZeneca, Schering-Plough, Abbott Labs, TAP Pharmaceuticals, Wyeth and Merck have paid millions of dollars each as compensation in the last few years. The financial condition of many pharmaceutical majors is not buoyant either. Price deflation, increased Rand D spending, and litigation costs are the main reasons. In the future, the messy lawsuits situation would no longer be restricted to industry. It would involve academia and practising doctors as well. Indian pharma industry captains, who were busy raking in the profits at present, would also come under the scanner. If nothing else, it means industry and docs will have to sit down and do some soul searching. Both short and long-term measures will have to be put into place. Short-term measures involve reduction in i) pharma spending over junkets and trinkets; ii) hype over ‘me too’ drugs; iii) manipulation of drug trials; iv) getting pliant researchers into drug trials; iv) manipulation of Journal Editors to publish positive findings about their drug trials and launches; v) and for Indian Pharma, to conduct their own unbiased clinical trial of the latest drug projected as a blockbuster in the West, before pumping in their millions. The long-term measures are related to the way biomedical advance is to be charted. We have to decide whether medicine is to become a corporate enterprise or remain a patient welfare centered profession. A third approach involves an eclectic resolution of the two. Such amount of patient welfare as also ensures profit, and such amount of profit as also ensures patient welfare is to be forwarded. For, profit, without patient welfare, is blind. And patient welfare, without profit, is lame. According to this approach, medicine becomes a patient welfare centered professional enterprise. The various ramifications of each of these approaches are discussed in this monograph. PMID:22679354

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors.

PubMed

Gladman, Dafna; Rigby, William; Azevedo, Valderilio F; Behrens, Frank; Blanco, Ricardo; Kaszuba, Andrzej; Kudlacz, Elizabeth; Wang, Cunshan; Menon, Sujatha; Hendrikx, Thijs; Kanik, Keith S

2017-10-19

Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. In this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire-Disability Index (HAQ-DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. At 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439 .).

Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis.

PubMed

Sandborn, William J; Su, Chinyu; Sands, Bruce E; D'Haens, Geert R; Vermeire, Séverine; Schreiber, Stefan; Danese, Silvio; Feagan, Brian G; Reinisch, Walter; Niezychowski, Wojciech; Friedman, Gary; Lawendy, Nervin; Yu, Dahong; Woodworth, Deborah; Mukherjee, Arnab; Zhang, Haiying; Healey, Paul; Panés, Julian

2017-05-04

Tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. We further evaluated the efficacy of tofacitinib as induction and maintenance therapy. We conducted three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the OCTAVE Sustain trial, 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks. In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. In patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

Psychiatric adverse events in randomized, double-blind, placebo-controlled clinical trials of varenicline: a pooled analysis.

PubMed

Tonstad, Serena; Davies, Simon; Flammer, Martina; Russ, Cristina; Hughes, John

2010-04-01

Varenicline (Chantix), Champix) has shown efficacy and tolerability as an aid to smoking cessation. In postmarketing surveillance, neuropsychiatric symptoms have appeared; however, their incidence and causal relationship to varenicline is not known. We assessed the incidence and relative risk (RR) of psychiatric disorders in ten randomized, double-blind, placebo-controlled trials of varenicline for smoking cessation. All smoking cessation phase II, III and IV randomized controlled clinical trials of varenicline versus placebo completed as of 31 December 2008, on file with the manufacturer (Pfizer, Inc.), were included. All studies have been published. All 3091 participants who received at least one dose of varenicline and all 2005 participants who received placebo were included in this analysis. These were men and women smoking > or =10 cigarettes/day, aged 18-75 years and without current psychiatric disease who received varenicline or placebo for 6 (one study), 12 (eight studies) or 52 (one study) weeks. Adverse events were recorded at each study visit and classified according to standard Medical Dictionary for Regulatory Activities (MedDRA) terms (version 11.0). The incidence of psychiatric disorders other than solely sleep disorders and disturbances was 10.7% in subjects treated with varenicline and 9.7% in subjects treated with placebo, with an RR of 1.02 (95% CI 0.86, 1.22). The RRs (95% CI) versus placebo of psychiatric adverse events with an incidence > or =1% in the varenicline group were 0.86 (0.67, 1.12) for anxiety disorders and symptoms, 0.76 (0.42, 1.39) for changes in physical activity, 1.42 (0.96, 2.08) for depressed mood disorders and disturbances, 1.21 (0.79, 1.83) for mood disorders and disturbances not elsewhere classified and 1.70 (1.50, 1.92) for sleep disorders and disturbances. There were no cases of suicidal ideation or behaviour in varenicline-treated subjects in the ten placebo-controlled studies analysed. However, among three trials that were excluded from the analysis because of their open-label design, two cases of suicidal ideation and one completed suicide were reported in patients who had been treated with varenicline. With the exception of sleep disorders and disturbances, there was no evidence of dose-responsivity. There was no significant increase in overall psychiatric disorders, other than sleep disorders and disturbances, in varenicline-treated subjects in this sample of smokers without current psychiatric disorders. Ongoing studies are testing the use of varenicline in psychiatric patients.

Ketamine as an adjuvant to opioids for cancer pain.

PubMed

Bell, Rae F; Eccleston, Christopher; Kalso, Eija A

2012-11-14

This is an update of the original review published in Issue 1, 2003. Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of cancer pain, particularly when opioids alone prove to be ineffective. Ketamine is known to have psychotomimetic (including hallucinogenic), urological and hepatic adverse effects. To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids in the treatment of cancer pain. Studies were originally identified from MEDLINE (1966 to 2002), EMBASE (1980 to 2002), CancerLit (1966 to 2002), The Cochrane Library (Issue 1, 2001); by handsearching reference lists from review articles, trials, and chapters from standard textbooks on pain and palliative care. The manufacturer of ketamine (Pfizer Parke-Davis) provided search results from their in-house database, PARDLARS.An improved and updated search of the following was performed in May 2012: CENTRAL, MEDLINE & OVID MEDLINE R, EMBASE. Randomized controlled trials (RCTs) of adult patients with cancer and pain being treated with an opioid, and receiving either ketamine (any dose and any route of administration) or placebo or an active control. Studies having a group size of at least 10 participants who completed the trial. Two independent review authors identified four RCTs for possible inclusion in the review, and 32 case studies/case series reports. Quality and validity assessment was performed by three independent review authors, and two RCTs were excluded because of inappropriate study design. Patient-reported pain intensity and pain relief was assessed using visual analogue scales (VAS), verbal rating scales or other validated scales, and adverse effects data were collated. For the update three RCTs were identified for possible inclusion in the review. Three new studies were identified by the updated search. All three were excluded from the review. Two studies were eligible for inclusion in the original review and both concluded that ketamine improves the effectiveness of morphine in the treatment of cancer pain. However, pooling of the data was not appropriate because of the small total number of participants (30), and the presence of clinical heterogeneity. Some patients experienced hallucinations on both ketamine plus morphine and morphine alone and were treated successfully with diazepam. No other serious adverse effects were reported. Since the last version of this review three new studies were identified but excluded from the review. Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of cancer pain. More RCTs are needed.

Non-invasive assessment of the reproductive cycle in free-ranging female African elephants (Loxodonta africana) treated with a gonadotropin-releasing hormone (GnRH) vaccine for inducing anoestrus.

PubMed

Benavides Valades, Gabriela; Ganswindt, Andre; Annandale, Henry; Schulman, Martin L; Bertschinger, Henk J

2012-08-25

In southern Africa, various options to manage elephant populations are being considered. Immunocontraception is considered to be the most ethically acceptable and logistically feasible method for control of smaller and confined populations. In this regard, the use of gonadotropin-releasing hormone (GnRH) vaccine has not been investigated in female elephants, although it has been reported to be safe and effective in several domestic and wildlife species. The aims of this study were to monitor the oestrous cycles of free-ranging African elephant cows using faecal progestagen metabolites and to evaluate the efficacy of a GnRH vaccine to induce anoestrus in treated cows. Between May 2009-June 2010, luteal activity of 12 elephant cows was monitored non-invasively using an enzyme immunoassay detecting faecal 5alpha-reduced pregnanes (faecal progestagen metabolites, FPM) on a private game reserve in South Africa. No bulls of breeding age were present on the reserve prior to and for the duration of the study. After a 3-month control period, 8 randomly-selected females were treated twice with 600 micrograms of GnRH vaccine (Improvac®, Pfizer Animal Health, Sandton, South Africa) 5-7 weeks apart. Four of these females had been treated previously with the porcine zona pellucida (pZP) vaccine for four years (2004-2007). All 12 monitored females (8 treated and 4 controls) showed signs of luteal activity as evidenced by FPM concentrations exceeding individual baseline values more than once. A total of 16 oestrous cycles could be identified in 8 cows with four of these within the 13 to 17 weeks range previously reported for captive African elephants. According to the FPM concentrations the GnRH vaccine was unable to induce anoestrus in the treated cows. Overall FPM levels in samples collected during the wet season (mean 4.03 micrograms/gram dry faeces) were significantly higher (P<0.002) than the dry season (mean 2.59 micrograms/gram dry faeces). The GnRH vaccination protocol failed to induce anoestrus in the treated female elephants. These results indicate that irregular oestrous cycles occur amongst free-ranging elephants and are not restricted to elephants in captivity. The relationship between ecological conditions and endocrine activity were confirmed. Free-ranging female elephants were observed to not cycle continuously throughout the year in the absence of adult bulls.

Salvage Chemoimmunotherapy With Inotuzumab Ozogamicin Combined With Mini-Hyper-CVD for Patients With Relapsed or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Phase 2 Clinical Trial.

PubMed

Jabbour, Elias; Ravandi, Farhad; Kebriaei, Partow; Huang, Xuelin; Short, Nicholas J; Thomas, Deborah; Sasaki, Koji; Rytting, Michael; Jain, Nitin; Konopleva, Marina; Garcia-Manero, Guillermo; Champlin, Richard; Marin, David; Kadia, Tapan; Cortes, Jorge; Estrov, Zeev; Takahashi, Koichi; Patel, Yogin; Khouri, Maria R; Jacob, Jovitta; Garris, Rebecca; O'Brien, Susan; Kantarjian, Hagop

2018-02-01

The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL. To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL. A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston. The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles. The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate. Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03). The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates. clinicaltrials.gov Identifier: NCT01371630.

Effect of the Medicare Part D coverage gap on medication use among patients with hypertension and hyperlipidemia.

PubMed

Li, Pengxiang; McElligott, Sean; Bergquist, Henry; Schwartz, J Sanford; Doshi, Jalpa A

2012-06-05

Prior studies of the Medicare Part D coverage gap are limited in generalizability and scope. To determine the effect of the coverage gap on drugs used for asymptomatic (antihypertensive and lipid-lowering drugs) and symptomatic (pain relievers, acid suppressants, and antidepressants) conditions in elderly patients with hypertension and hyperlipidemia. Quasi-experimental study using pre-post design and contemporaneous control group. Medicare claims files from 2005 and 2006 for 5% random sample of Medicare beneficiaries. Part D plan enrollees with hypertension or hyperlipidemia aged 65 years or older who had no coverage, generic-only coverage, or both brand-name and generic coverage during the gap in 2006. Patients who were fully eligible for the low-income subsidy served as the control group. Monthly 30-day supply prescriptions available, medication adherence, and continuous medication gaps of 30 days or more for antihypertensive or lipid-lowering drugs; monthly 30-day supply prescriptions available for pain relievers, acid suppressants, or antidepressants before and after coverage gap entry. Patients with no gap coverage had a decrease in monthly antihypertensive and lipid-lowering drug prescriptions during the coverage gap. Nonadherence also increased in this group (antihypertensives: odds ratio [OR], 1.60 [95% CI, 1.50 to 1.71]; lipid-lowering drugs: OR, 1.59 [CI, 1.50 to 1.68]). The proportion of patients with no gap coverage who had continuous medication gaps in lipid-lowering medication use and antihypertensive use increased by an absolute 7.3% (OR, 1.38 [CI, 1.29 to 1.46]) and 3.2% (OR, 1.35 [CI, 1.25 to 1.45]), respectively, because of the coverage gap. Decreases in use were smaller for pain relievers and antidepressants and larger for acid suppressants in patients with no gap coverage. Patients with generic-only coverage had decreased use of cardiovascular medications but no change in use of drugs for symptomatic conditions. No measures changed in the brand-name and generic coverage groups. Results of sensitivity analyses were consistent with the main findings. Because this study was nonrandomized, unobserved differences may still exist between study groups. The Part D coverage gap was associated with decreased use of medications for hypertension and hyperlipidemia in patients with no gap coverage and generic-only gap coverage. The proposed phasing out of the gap by 2020 will benefit such patients; however, use of low-value medications may also increase. Penn-Pfizer Alliance and American Heart Association.

Apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from AVERROES, a randomised trial.

PubMed

Diener, Hans-Christoph; Eikelboom, John; Connolly, Stuart J; Joyner, Campbell D; Hart, Robert G; Lip, Gregory Y H; O'Donnell, Martin; Hohnloser, Stefan H; Hankey, Graeme J; Shestakovska, Olga; Yusuf, Salim

2012-03-01

In the AVERROES study, apixaban, a novel factor Xa inhibitor, reduced the risk of stroke or systemic embolism in patients with atrial fibrillation who were at high risk of stroke but unsuitable for vitamin K antagonist therapy. We aimed to investigate whether the subgroup of patients with previous stroke or transient ischaemic attack (TIA) would show a greater benefit from apixaban compared with aspirin than would patients without previous cerebrovascular events. In AVERROES, 5599 patients (mean age 70 years) with atrial fibrillation who were at increased risk of stroke and unsuitable for vitamin K antagonist therapy were randomly assigned to receive apixaban (5 mg twice daily) or aspirin (81-324 mg per day). The mean follow-up was 1·1 years. The primary efficacy outcome was stroke or systemic embolism; the primary safety outcome was major bleeding. Patients and investigators were masked to study treatment. In this prespecified subgroup analysis, we used Kaplan-Meier estimates of 1-year event risk and Cox proportional hazards regression models to compare the effects of apixaban in patients with and without previous stroke or TIA. AVERROES is registered at ClinicalTrials.gov, number NCT00496769. In patients with previous stroke or TIA, ten events of stroke or systemic embolism occurred in the apixaban group (n=390, cumulative hazard 2·39% per year) compared with 33 in the aspirin group (n=374, 9·16% per year; hazard ratio [HR] 0·29, 95% CI 0·15-0·60). In those without previous stroke or TIA, 41 events occurred in the apixaban group (n=2417, 1·68% per year) compared with 80 in the aspirin group (n=2415, 3·06% per year; HR 0·51, 95% CI 0·35-0·74). The p value for interaction of the effects of aspirin and apixaban with previous cerebrovascular events was 0·17. Major bleeding was more frequent in patients with history of stroke or TIA than in patients without (HR 2·88, 95% CI 1·77-4·55) but risk of this event did not differ between treatment groups. In patients with atrial fibrillation, apixaban is similarly effective whether or not patients have had a previous stroke or TIA. Given that those with previous stroke or TIA have a higher risk of stroke, the absolute benefits might be greater in these patients. Bristol-Myers Squibb and Pfizer. Copyright © 2012 Elsevier Ltd. All rights reserved.

Gammaretroviral pol sequences act in cis to direct polysome loading and NXF1/NXT-dependent protein production by gag-encoded RNA.

PubMed

Bartels, Hanni; Luban, Jeremy

2014-09-12

All retroviruses synthesize essential proteins via alternatively spliced mRNAs. Retrovirus genera, though, exploit different mechanisms to coordinate the synthesis of proteins from alternatively spliced mRNAs. The best studied of these retroviral, post-transcriptional effectors are the trans-acting Rev protein of lentiviruses and the cis-acting constitutive transport element (CTE) of the betaretrovirus Mason-Pfizer monkey virus (MPMV). How members of the gammaretrovirus genus translate protein from unspliced RNA has not been elucidated. The mechanism by which two gammaretroviruses, XMRV and MLV, synthesize the Gag polyprotein (Pr65Gag) from full-length, unspliced mRNA was investigated here. The yield of Pr65Gag from a gag-only expression plasmid was found to be at least 30-fold less than that from an otherwise isogenic gag-pol expression plasmid. A frameshift mutation disrupting the pol open reading frame within the gag-pol expression plasmid did not decrease Pr65Gag production and 398 silent nucleotide changes engineered into gag rendered Pr65Gag synthesis pol-independent. These results are consistent with pol-encoded RNA acting in cis to promote Pr65Gag translation. Two independently-acting pol fragments were identified by screening 17 pol deletion mutations. To determine the mechanism by which pol promoted Pr65Gag synthesis, gag RNA in total and cytoplasmic fractions was quantitated by northern blot and by RT-PCR. The pol sequences caused, maximally, three-fold increase in total or cytoplasmic gag mRNA. Instead, pol sequences increased gag mRNA association with polyribosomes ~100-fold, a magnitude sufficient to explain the increase in Pr65Gag translation efficiency. The MPMV CTE, an NXF1-binding element, substituted for pol in promoting Pr65Gag synthesis. A pol RNA stem-loop resembling the CTE promoted Pr65Gag synthesis. Over-expression of NXF1 and NXT, host factors that bind to the MPMV CTE, synergized with pol to promote gammaretroviral gag RNA loading onto polysomes and to increase Pr65Gag synthesis. Conversely, Gag polyprotein synthesis was decreased by NXF1 knockdown. Finally, overexpression of SRp20, a shuttling protein that binds to NXF1 and promotes NXF1 binding to RNA, also increased gag RNA loading onto polysomes and increased Pr65Gag synthesis. These experiments demonstrate that gammaretroviral pol sequences act in cis to recruit NXF1 and SRp20 to promote polysome loading of gag RNA and, thereby license the synthesis of Pr65Gag from unspliced mRNA.

Ability of Bottle Cap Color to Facilitate Accurate Patient-Physician Communication Regarding Medication Identity in Patients with Glaucoma.

PubMed

Dave, Pujan; Villarreal, Guadalupe; Friedman, David S; Kahook, Malik Y; Ramulu, Pradeep Y

2015-12-01

To determine the accuracy of patient-physician communication regarding topical ophthalmic medication use based on bottle cap color, particularly among individuals who may have acquired color vision deficiency from glaucoma. Cross-sectional, clinical study. Patients aged ≥18 years with primary open-angle, primary angle-closure, pseudoexfoliation, or pigment dispersion glaucoma, bilateral visual acuity of ≥20/400, and no concurrent conditions that may affect color vision. A total of 100 patients provided color descriptions of 11 distinct medication bottle caps. Color descriptors were then presented to 3 physicians. Physicians matched each color descriptor to the medication they thought the descriptor was describing. Frequency of patient-physician agreement, occurring when all 3 physicians accurately matched the color descriptor to the correct medication. Multivariate regression models evaluated whether patient-physician agreement decreased with degree of better-eye visual field (VF) damage, color descriptor heterogeneity, or color vision deficiency, as determined by the Hardy-Rand-Rittler (HRR) score and Lanthony D15 color confusion index (D15 CCI). Subjects had a mean age of 69 (±11) years, with VF mean deviation of -4.7 (±6.0) and -10.9 (±8.4) decibels (dB) in the better- and worse-seeing eyes, respectively. Patients produced 102 unique color descriptors to describe the colors of the 11 bottle caps. Among individual patients, the mean number of medications demonstrating agreement was 6.1/11 (55.5%). Agreement was less than 15% for 4 medications (prednisolone acetate [generic], betaxolol HCl [Betoptic; Alcon Laboratories Inc., Fort Worth, TX], brinzolamide/brimonidine [Simbrinza; Alcon Laboratories Inc.], and latanoprost [Xalatan; Pfizer, Inc., New York, NY]). Lower HRR scores and higher D15 CCI (both indicating worse color vision) were associated with greater VF damage (P < 0.001). Extent of color vision deficiency and color descriptor heterogeneity significantly predicted agreement in multivariate models (odds of agreement = 0.90 per 1 point decrement in HRR score, P < 0.001; odds of agreement = 0.30 for medications exhibiting high heterogeneity [≥11 descriptors], P = 0.007). Physician understanding of patient medication use based solely on bottle cap color is frequently incorrect, particularly in patients with glaucoma who may have color vision deficiency. Errors based on communication using bottle cap color alone may be common and could lead to confusion and harm. Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Headache, idiopathic intracranial hypertension and slipped capital femoral epiphysis during growth hormone treatment: a safety update from the KIGS database.

PubMed

Darendeliler, Feyza; Karagiannis, Georgios; Wilton, Patrick

2007-01-01

Several uncommon adverse effects may be related to growth hormone (GH) treatment. Three potential side effects, headache, idiopathic intracranial hypertension (IIH) and slipped capital femoral epiphysis (SCFE), will be discussed. Data from 57,968 children in the KIGS (Pfizer International Growth Study database) were analyzed to determine the effects of recombinant human GH (Genotropin) on these side effects. The diagnostic groups were idiopathic GH deficiency (IGHD) (n = 27,690), congenital GHD (CGHD) (n = 2,547), craniopharyngioma (n = 1,155), cranial tumours (n = 2,203), Turner syndrome (TS) (n = 6,092), idiopathic short stature (ISS) (n = 5,286), small for gestational age (SGA) (n = 2,973), chronic renal insufficiency (CRI) (n = 1,753) and Prader-Willi syndrome (PWS) (n = 1,368). Total incidence (per 100,000 treatment years) of headache was 793.5 (n = 569). The incidence was significantly higher in the groups of patients with craniopharyngiomas, CGHD and cranial tumours than in the other diagnostic groups (p < 0.05 for all). IIH occurred in 41 children resulting in a total incidence (per 100,000 treatment years) of 27.7. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (12.2) than in those with TS (56.4) (p = 0.0004), CGHD (54.5) (p = 0.0064), PWS (68.3) (p = 0.0263) and CRI (147.8) (p < 0.001). No cases of IIH were reported in the ISS group of patients. The median duration from onset of GH therapy to IIH ranged from 0.01 to 1.3 years in various diagnostic groups. SCFE was observed in a total of 52 children resulting in a total incidence (per 100,000 treatment years) of 73.4. The incidence (per 100,000 treatment years) was significantly lower in patients with IGHD (18.3) and in those children with ISS (14.5) than in the TS (84.5), cranial tumours (86.1) and craniopharyngioma groups (120.5) (p < 0.05 for all). No cases of SCFE were reported in the SGA and PWS groups. The median duration from onset of GH therapy to SCFE ranged from 0.4 to 2.5 years. The incidences of IIH and SCFE in this analysis are lower than the values reported in previous KIGS analyses and comparable to other databases. Patients with TS, organic GHD, PWS and CRI seem to be more prone to these side effects.

Abnormal subchondral bone microstructure following steroid administration is involved in the early pathogenesis of steroid-induced osteonecrosis.

PubMed

Wang, L; Zhang, L; Pan, H; Peng, S; Zhao, X; Lu, W W

2016-01-01

Loss of bone microstructure integrity is thought to be related to osteonecrosis. But the relationship between the time when bone microstructure integrity loss appears and the onset of osteonecrosis has not yet been determined. Our study demonstrated abnormal changes of subchondral bone microstructure involved in the early pathogenesis of osteonecrosis. Using a rabbit model, we investigated the changes of subchondral bone microstructure following steroid administration to identify the onset of abnormal bone microstructure development in steroid-induced osteonecrosis. Fifty-five adult female Japanese White rabbits (mean body weight 3.5 kg; mean age 24 months) were used and randomly divided among three time points (3, 7, and 14 days) consisting of 15 rabbits each, received a single intramuscular injection of methylprednisolone acetate (MP; Pfizer Manufacturing Belgium NV) at a dose of 4 mg/kg, and a control group consisting of 10 rabbits was fed and housed under identical conditions but were not given steroid injections. A micro-CT scanner was applied to detect changes in the trabecular region of subchondral bone of excised femoral head samples. Parameters including bone volume fraction (BV/TV), bone surface (BS), trabecular bone pattern factor (Tb.Pf), trabecular thickness/number/separation (Tb.Th, Tb.N, and Tb.Sp), and structure model index (SMI) were evaluated using the software CTAn (SkyScan). After micro-CT scans, bilateral femoral heads were cut in the coronal plane at a thickness of 4 μm. The sections were then stained with haematoxylin-eosin and used for the diagnosis of osteonecrosis and the rate of development of osteonecrosis. The BV/TV, BS, Tb.Th and Tb.N demonstrated a time-dependent decline from 3, 7, and 14 days compared with the control group, while the Tb.Pf, Tb.Sp and SMI demonstrated an increase at 3, 7, and 14 days compared with the control group. For the histopathology portion, osteonecrosis was not seen 3 days after steroid treatment, but was present 7 days after treatment and was obvious 14 days after treatment. Furthermore, the rate of osteonecrosis appearing between 7 and 14 days was not significantly different. In addition, the presence and variation of BV/TV, BS, Tb.Pf, Tb.Th, Tb.N, and SMI demonstrated significant changes at 7 days compared with the control group except Tb.Sp (at 14 days) and this is the time when osteonecrosis is thought to occur in this model. This study demonstrated that osteonecrosis in rabbits is chronologically associated with changes in subchondral bone microstructure.

Using Performance-Based Risk-Sharing Arrangements to Address Uncertainty in Indication-Based Pricing.

PubMed

Yeung, Kai; Li, Meng; Carlson, Josh J

2017-10-01

The rise in pharmaceutical expenditures in recent years has increased health care payer interest in ensuring good value for the money. Indication-based pricing (IBP) sets separate, indication-specific prices paid to the manufacturer according to the expected efficacy of a drug in each of its indications. IBP allows payers to consistently pay for value across indications. While promising, a limitation of IBP as originally conceived is that efficacy estimates are typically based on clinical trial data, which may differ from real-world effectiveness. An outcomes guarantee is a type of performance-based risk-sharing arrangement that adjusts payments according to prospectively tracked outcomes. We suggest that an outcomes guarantee contract, which has been used by some payers, may be adapted to achieve indication-based prices supported by real-world effectiveness. To illustrate the potential of an outcomes guarantee to achieve indication-based prices aligned with real-world value, using a case study of trastuzumab for the treatment of metastatic breast and advanced gastric cancers. We estimated costs and outcomes under traditional IBP (i.e., expected value IBP) and outcomes guarantee frameworks and calculated incremental cost-effectiveness ratios (ICERs) comparing treatment with and without trastuzumab. Efficacy data came from pivotal trials, whereas effectiveness data came from observational studies. We adjusted trastuzumab prices in order to achieve target ICERs of $150,000 per quality-adjusted life-year under each framework and for each indication. To achieve the ICER target under traditional IBP, the unit price of trastuzumab using efficacy evidence was adjusted for metastatic breast and advanced gastric cancers from an average sales price of $9.17 per mg to $3.50 per mg and $0.93 per mg, respectively. Under an outcomes guarantee, the unit price of trastuzumab using effectiveness evidence was adjusted for metastatic breast cancer and advanced gastric cancer to $8.66 per mg and $0.20 per mg, respectively. Like expected value IBP, outcomes guarantee contracts can also vary payment based on indication. In addition, an outcomes guarantee can also reduce uncertainty regarding effectiveness and better align payment with the actual value of a treatment. No funding supported this study. Carlson reports consulting fees from Genentech, Pfizer, and Seattle Genetics. The other authors have no conflicts of interest to disclose. Study concept and design were contributed by Carlson, Yeung, and Li. Yeung, Carlson, and Li collected and analyzed the data. The manuscript was written primarily by Yeung, along with Carlson and Li, and revised by all the authors.

Persistent efficacy of a long acting injectable formulation of moxidectin against natural infestations of the sheep nasal bot (Oestrus ovis) in Spain.

PubMed

Rugg, Douglas; Ferrer, Luis Miguel; Sarasola, Patxi; Figueras, Luis; Lacasta, Delia; Liu, Bo; Bartram, David

2012-09-10

Cydectin(®) 2% LA Solution for Injection for Sheep (Pfizer Animal Health) is a long-acting (LA) formulation of moxidectin for the treatment and prevention of mixed infections of gastro-intestinal nematodes, respiratory nematodes and certain arthropod parasites in sheep. To evaluate the duration of persistent efficacy against nasal bots (Oestrus ovis), a natural exposure study was conducted in Spain during the summer of 2011. One hundred and twenty nasal bot-free, Rasa Aragonesa sheep were randomly allocated to eight groups of 15 animals each. On Day 0, four groups were treated at the recommended dose rate of 1 mg moxidectin/kg bodyweight. Four groups remained untreated as negative controls. All animals were held in nasal bot-proof housing except for exposure to natural challenge when one group of treated sheep and one of group of control animals were transferred to a local pasture at either 0-20, 20-40, 40-60, or 60-80 days after treatment. Following challenge, sheep were scored for clinical signs of bot infestation, necropsied and the heads sectioned for larval recovery. Nasal bot larvae were retrieved from 7 to 11 control sheep following each exposure period indicating that adult bots were active throughout the study. In the first challenge up to 20 days after treatment, when sheep were slaughtered immediately after exposure, the majority of larvae were first instar (L1) and only 3 of the 15 control sheep were infested with second instars (L2). There was 100% efficacy against L2 and 38.1% reduction in the number of live L1 in the treated sheep but mean counts were not significantly different between treatment and control groups (P ≥ 0.05). For the subsequent exposure periods 20-80 days after treatment (necropsies 7-9 days after challenge), 6-10 sheep were infested with L1 and 9-11 control sheep were infested with L2 and third instars (L3). There was negligible efficacy against L1, but treatment with moxidectin resulted in 100% control of L2 and L3. These results are consistent with the biology of nasal bots and control with a systemic agent, as the slower growing L1 have limited feeding and are therefore less susceptible to systemic parasiticides. The study demonstrated that the persistent efficacy of this long-acting injectable formulation of moxidectin protects against the development of active O. ovis infestations for at least 80 days after treatment. Copyright © 2012 Elsevier B.V. All rights reserved.

Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis.

PubMed

Nissen, Steven E; Yeomans, Neville D; Solomon, Daniel H; Lüscher, Thomas F; Libby, Peter; Husni, M Elaine; Graham, David Y; Borer, Jeffrey S; Wisniewski, Lisa M; Wolski, Katherine E; Wang, Qiuqing; Menon, Venu; Ruschitzka, Frank; Gaffney, Michael; Beckerman, Bruce; Berger, Manuela F; Bao, Weihang; Lincoff, A Michael

2016-12-29

The cardiovascular safety of celecoxib, as compared with nonselective nonsteroidal antiinflammatory drugs (NSAIDs), remains uncertain. Patients who required NSAIDs for osteoarthritis or rheumatoid arthritis and were at increased cardiovascular risk were randomly assigned to receive celecoxib, ibuprofen, or naproxen. The goal of the trial was to assess the noninferiority of celecoxib with regard to the primary composite outcome of cardiovascular death (including hemorrhagic death), nonfatal myocardial infarction, or nonfatal stroke. Noninferiority required a hazard ratio of 1.12 or lower, as well as an upper 97.5% confidence limit of 1.33 or lower in the intention-to-treat population and of 1.40 or lower in the on-treatment population. Gastrointestinal and renal outcomes were also adjudicated. A total of 24,081 patients were randomly assigned to the celecoxib group (mean [±SD] daily dose, 209±37 mg), the naproxen group (852±103 mg), or the ibuprofen group (2045±246 mg) for a mean treatment duration of 20.3±16.0 months and a mean follow-up period of 34.1±13.4 months. During the trial, 68.8% of the patients stopped taking the study drug, and 27.4% of the patients discontinued follow-up. In the intention-to-treat analyses, a primary outcome event occurred in 188 patients in the celecoxib group (2.3%), 201 patients in the naproxen group (2.5%), and 218 patients in the ibuprofen group (2.7%) (hazard ratio for celecoxib vs. naproxen, 0.93; 95% confidence interval [CI], 0.76 to 1.13; hazard ratio for celecoxib vs. ibuprofen, 0.85; 95% CI, 0.70 to 1.04; P<0.001 for noninferiority in both comparisons). In the on-treatment analysis, a primary outcome event occurred in 134 patients in the celecoxib group (1.7%), 144 patients in the naproxen group (1.8%), and 155 patients in the ibuprofen group (1.9%) (hazard ratio for celecoxib vs. naproxen, 0.90; 95% CI, 0.71 to 1.15; hazard ratio for celecoxib vs. ibuprofen, 0.81; 95% CI, 0.65 to 1.02; P<0.001 for noninferiority in both comparisons). The risk of gastrointestinal events was significantly lower with celecoxib than with naproxen (P=0.01) or ibuprofen (P=0.002); the risk of renal events was significantly lower with celecoxib than with ibuprofen (P=0.004) but was not significantly lower with celecoxib than with naproxen (P=0.19). At moderate doses, celecoxib was found to be noninferior to ibuprofen or naproxen with regard to cardiovascular safety. (Funded by Pfizer; ClinicalTrials.gov number, NCT00346216 .).

Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial

PubMed Central

Griffin, Simon J; Borch-Johnsen, Knut; Davies, Melanie J; Khunti, Kamlesh; Rutten, Guy EHM; Sandbæk, Annelli; Sharp, Stephen J; Simmons, Rebecca K; van den Donk, Maureen; Wareham, Nicholas J; Lauritzen, Torsten

2011-01-01

Summary Background Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial treatment after diagnosis by screening. Methods In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40–69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice's study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00237549. Findings Primary endpoint data were available for 3055 (99·9%) of 3057 screen-detected patients. The mean age was 60·3 (SD 6·9) years and the mean duration of follow-up was 5·3 (SD 1·6) years. Improvements in cardiovascular risk factors (HbA1c and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7·2% (13·5 per 1000 person-years) in the intensive treatment group and 8·5% (15·9 per 1000 person-years) in the routine care group (hazard ratio 0·83, 95% CI 0·65–1·05), and of all-cause mortality 6·2% (11·6 per 1000 person-years) and 6·7% (12·5 per 1000 person-years; 0·91, 0·69–1·21), respectively. Interpretation An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death. Funding National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck. PMID:21705063

Consensus on Recording Deep Endometriosis Surgery: the CORDES statement.

PubMed

Vanhie, A; Meuleman, C; Tomassetti, C; Timmerman, D; D'Hoore, A; Wolthuis, A; Van Cleynenbreugel, B; Dancet, E; Van den Broeck, U; Tsaltas, J; Renner, S P; Ebert, A D; Carmona, F; Abbott, J; Stepniewska, A; Taylor, H; Saridogan, E; Mueller, M; Keckstein, J; Pluchino, N; Janik, G; Zupi, E; Minelli, L; Cooper, M; Dunselman, G; Koh, C; Abrao, M S; Chapron, C; D'Hooghe, T

2016-06-01

Which essential items should be recorded before, during and after endometriosis surgery and in clinical outcome based surgical trials in patients with deep endometriosis (DE)? A DE surgical sheet (DESS) was developed for standardized reporting of the surgical treatment of DE and an international expert consensus proposal on relevant items that should be recorded in surgical outcome trials in women with DE. Surgery is an important treatment for symptomatic DE. So far, data have been reported in such a way that comparison of different surgical techniques is impossible. Therefore, we present an international expert proposal for standardized reporting of surgical treatment and surgical outcome trials in women with DE. International expert consensus based on a systematic review of literature. Taking into account recommendations from Consolidated Standards of Reporting Trials (CONSORT), the Innovation Development Exploration Assessment and Long-term Study (IDEAL), the Initiative on Methods, Measurement and Pain Assessment in Clinical trials (IMMPACT) and the World Endometriosis Research Foundation Phenome and Biobanking Harmonisation Project (WERF EPHect), a systematic literature review on surgical treatment of DE was performed and resulted in a proposal for standardized reporting, adapted by contributions from eight members of the multidisciplinary Leuven University Hospitals Endometriosis Care Program, from 18 international experts and from audience feedback during three international meetings. We have developed the DESS to record in detail the surgical procedures for DE, and an international consensus on pre-, intra- and post-operative data that should be recorded in surgical outcome trials on DE. The recommendations in this paper represent a consensus among international experts based on a systematic review of the literature. For several items and recommendations, high-quality RCTs were not available. Further research is needed to validate and evaluate the recommendations presented here. This international expert consensus for standardized reporting of surgical treatment in women with DE, based on a systematic literature review and international consensus, can be used as a guideline to record and report surgical management of patients with DE and as a guideline to design, execute, interpret and compare clinical trials in this patient population. None of the authors received funding for the development of this paper. M.A. reports personal fees and non-financial support from Bayer Pharma outside the submitted work; H.T. reports a grant from Pfizer and personal fees for being on the advisory board of Perrigo, Abbvie, Allergan and SPD. N/A. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cytomegalovirus chimeric epitope vaccine supplemented with PF03512676 (CMVPepVax) in allogeneic hematopoietic stem cell transplantation: viremia, immunogenicity and survival outcomes in a randomised phase 1b trial

PubMed Central

Nakamura, Ryotaro; La Rosa, Corinna; Longmate, Jeffrey; Drake, Jennifer; Slape, Cynthia; Zhou, Qiao; Lampa, Melanie G.; O'Donnell, Margaret; Cai, Ji-Lian; Farol, Len; Salhotra, Amandeep; Snyder, David S.; Aldoss, Ibrahim; Forman, Stephen J.; Miller, Jeffrey S.; Zaia, John A.; Diamond, Don J.

2016-01-01

Summary Background Cytomegalovirus (CMV) seropositive recipients of allogeneic hematopoietic cell transplantation (HCT) are at risk for CMV reactivation. Stimulating viral immunity by vaccination may achieve CMV viremia control, without the need for antivirals. The aim of the trial is to assess safety, immunogenicity, and possible clinical benefit of CMVPepVax vaccine in HCT recipients. Methods In this randomised, open-label phase 1b trial, HCT recipients were enrolled at a single USA transplant center. Eligible patients were CMV seropositive, HLA A*0201-positive, 18–75 years, receiving HCT from matched related or unrelated donors. Patients were reassessed on day 28 post-HCT for eligibility, and 36 patients were randomised either to the vaccine (VA) or observation arm (OA), in blocks stratified by CMV donor serostatus. CMVPepVax was administered subcutaneously on days 28 and 56. CMVPepVax is a chimeric peptide composed of a cytotoxic CD8 T-cell epitope from CMV-pp65, and a tetanus T-helper epitope. It is formulated with the adjuvant PF03512676 (Pfizer Inc) a Toll-like receptor 9 agonist, which augments cellular immunity. The primary outcome was safety; secondary outcomes included immunogenicity, prevention of CMV reactivation, and clinical outcomes. Statistical analyses included all 36 randomized patients and were performed as per protocol. This study is registered as NCT01588015@www.clinicaltrials.gov. This trial is closed to accrual and a final analysis is presented in this report. Findings Between October 31, 2012, and November 5, 2014, 36 HCT recipients were randomised into the study. CMVPepVax was administered to 18 patients, with no adverse effect on HCT or rate of acute GVHD, and no unexpected adverse events. One serious adverse event (grade 1 fever) was attributed to CMVPepVax vaccination and resolved within 48 hours. Higher relapse free survival (1 versus 7 events, logrank p=0·015), a 2 fold increase in CMV-pp65 CD8 T cells during the first 100 days post-HCT (p=0·025), less CMV reactivation (1 versus 6 events, logrank p=0·039) and usage of antivirals (15 versus 263 days, p=0·03) were found in VA compared to OA recipients. Interpretation The results demonstrate safety and immunogenicity of CMVPepVax, and the prospect of significant clinical benefits that warrant testing in a phase 2 trial. PMID:26853648

Medicine as a corporate enterprise, patient welfare centered profession, or patient welfare centered professional enterprise?

PubMed

Singh, Ajai; Singh, Shakuntala

2005-11-01

There is an alarming trend in the field of medicine, whose portents are ominous but do not seem to shake the complacency and merry making doing the rounds.The wants of the medical man have multiplied beyond imagination. The cost of organizing conferences is no longer possible on delegate fees. The bottom-line is: Crores for a Conference Millions for a Mid-Term. However, the problem is that sponsors keep a discreet but careful tab on docs. All in all, costs of medicines escalate, and quality medical care becomes a luxury. The whole brunt of this movement is borne by the patient.Companies like GlaxoSmithKline, Bayer, Pfizer, Bristol-Myers Squibb, AstraZeneca, Schering-Plough, Abbott Labs, TAP Pharmaceuticals, Wyeth and Merck have paid millions of dollars each as compensation in the last few years. The financial condition of many pharmaceutical majors is not buoyant either. Price deflation, increased Rand D spending, and litigation costs are the main reasons. In the future, the messy lawsuits situation would no longer be restricted to industry. It would involve academia and practising doctors as well. Indian pharma industry captains, who were busy raking in the profits at present, would also come under the scanner. If nothing else, it means industry and docs will have to sit down and do some soul searching.Both short and long-term measures will have to be put into place. Short-term measures involve reduction in i) pharma spending over junkets and trinkets; ii) hype over 'me too' drugs; iii) manipulation of drug trials; iv) getting pliant researchers into drug trials; iv) manipulation of Journal Editors to publish positive findings about their drug trials and launches; v) and for Indian Pharma, to conduct their own unbiased clinical trial of the latest drug projected as a blockbuster in the West, before pumping in their millions.The long-term measures are related to the way biomedical advance is to be charted. We have to decide whether medicine is to become a corporate enterprise or remain a patient welfare centered profession. A third approach involves an eclectic resolution of the two. Such amount of patient welfare as also ensures profit, and such amount of profit as also ensures patient welfare is to be forwarded. For, profit, without patient welfare, is blind. And patient welfare, without profit, is lame. According to this approach, medicine becomes a patient welfare centered professional enterprise.The various ramifications of each of these approaches are discussed in this monograph.

The efficacy of a combined oral formulation of derquantel-abamectin against anthelmintic resistant gastro-intestinal nematodes of sheep in the UK.

PubMed

Geurden, Thomas; Hodge, Andrew; Noé, Laura; Winstanley, Dana; Bartley, David J; Taylor, Mike; Morgan, Colin; Fraser, Sarah J; Maeder, Steven; Bartram, David

2012-10-26

The objective of the present studies was to evaluate the efficacy of a combined formulation (Startect(®) Dual Active Oral Solution for Sheep, Pfizer Animal Health) of derquantel (DQL) and abamectin (ABA) for the treatment of: (1) sheep experimentally infected with a moxidectin (MOX)-resistant isolate of Teladorsagia circumcincta, and (2) multi-drug resistant gastrointestinal nematode parasites under UK field conditions. In the first study, a total of 40 animals were allocated into 4 treatment groups, and were either left untreated or treated with DQL+ABA, MOX or ABA. Faecal samples were collected on days 1-5 and on day 7 after treatment to examine the reduction in faecal egg excretion and to evaluate the egg viability. On day 14 post treatment all animals were euthanised for abomasal worm counts. There was a 100% reduction in geometric mean worm counts for the DQL+ABA treated animals compared to the untreated control animals (P<0.0001), whereas the percentage reduction in worm counts for the MOX- (P>0.05) and ABA-treated (P=0.0004) animals was 12.4% and 71.8%, respectively. The data from the egg hatch assay (EHA) indicated that in the MOX-treated and the ABA-treated animals, the majority of the eggs hatched after treatment. In the field study, performed on four farms, animals were allocated into 6 groups of 11-15 animals each in order to conduct a faecal egg count reduction test (FECRT), based on arithmetic mean egg counts. One group of animals remained untreated, whereas the other animals were treated with DQL+ABA, MOX, fenbendazole (FBZ), levamisole (LV) or ivermectin (IVM). On each of the farms the reduction in egg excretion after treatment with FBZ, LV or IVM was below 95.0%, indicating anthelmintic resistance. The efficacy of DQL+ABA ranged from 99.1 to 100%, yielding significantly lower egg counts compared to the untreated control group (P ≤ 0.003). For MOX the egg counts were significantly (P ≤ 0.003) lower compared to the untreated group at each farm, with reductions varying from 98.2 to 100%. The post-treatment copro-cultures for larva identification indicated that T. circumcincta was the most abundant worm species after treatment (52-99% of the larvae). The results of these studies confirm the high efficacy of the DQL+ABA combination formulation against anthelmintic resistant nematodes in the UK. Copyright © 2012 Elsevier B.V. All rights reserved.

Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations

PubMed Central

2010-01-01

Background Numerous pen devices are available to administer recombinant Human Growth Hormone (rhGH), and both patients and health plans have varying issues to consider when selecting a particular product and device for daily use. Therefore, the present study utilized multi-dimensional product analysis to assess potential time involvement, required weekly administration steps, and utilization costs relative to daily rhGH administration. Methods Study objectives were to conduct 1) Time-and-Motion (TM) simulations in a randomized block design that allowed time and steps comparisons related to rhGH preparation, administration and storage, and 2) a Cost Minimization Analysis (CMA) relative to opportunity and supply costs. Nurses naïve to rhGH administration and devices were recruited to evaluate four rhGH pen devices (2 in liquid form, 2 requiring reconstitution) via TM simulations. Five videotaped and timed trials for each product were evaluated based on: 1) Learning (initial use instructions), 2) Preparation (arrange device for use), 3) Administration (actual simulation manikin injection), and 4) Storage (maintain product viability between doses), in addition to assessment of steps required for weekly use. The CMA applied micro-costing techniques related to opportunity costs for caregivers (categorized as wages), non-drug medical supplies, and drug product costs. Results Norditropin® NordiFlex and Norditropin® NordiPen (NNF and NNP, Novo Nordisk, Inc., Bagsværd, Denmark) took less weekly Total Time (p < 0.05) to use than either of the comparator products, Genotropin® Pen (GTP, Pfizer, Inc, New York, New York) or HumatroPen® (HTP, Eli Lilly and Company, Indianapolis, Indiana). Time savings were directly related to differences in new package Preparation times (NNF (1.35 minutes), NNP (2.48 minutes) GTP (4.11 minutes), HTP (8.64 minutes), p < 0.05)). Administration and Storage times were not statistically different. NNF (15.8 minutes) and NNP (16.2 minutes) also took less time to Learn than HTP (24.0 minutes) and GTP (26.0 minutes), p < 0.05). The number of weekly required administration steps was also least with NNF and NNP. Opportunity cost savings were greater in devices that were easier to prepare for use; GTP represented an 11.8% drug product savings over NNF, NNP and HTP at time of study. Overall supply costs represented <1% of drug costs for all devices. Conclusions Time-and-motion simulation data used to support a micro-cost analysis demonstrated that the pen device with the greater time demand has highest net costs. PMID:20377905

Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations.

PubMed

Nickman, Nancy A; Haak, Sandra W; Kim, Jaewhan

2010-04-08

Numerous pen devices are available to administer recombinant Human Growth Hormone (rhGH), and both patients and health plans have varying issues to consider when selecting a particular product and device for daily use. Therefore, the present study utilized multi-dimensional product analysis to assess potential time involvement, required weekly administration steps, and utilization costs relative to daily rhGH administration. Study objectives were to conduct 1) Time-and-Motion (TM) simulations in a randomized block design that allowed time and steps comparisons related to rhGH preparation, administration and storage, and 2) a Cost Minimization Analysis (CMA) relative to opportunity and supply costs. Nurses naïve to rhGH administration and devices were recruited to evaluate four rhGH pen devices (2 in liquid form, 2 requiring reconstitution) via TM simulations. Five videotaped and timed trials for each product were evaluated based on: 1) Learning (initial use instructions), 2) Preparation (arrange device for use), 3) Administration (actual simulation manikin injection), and 4) Storage (maintain product viability between doses), in addition to assessment of steps required for weekly use. The CMA applied micro-costing techniques related to opportunity costs for caregivers (categorized as wages), non-drug medical supplies, and drug product costs. Norditropin(R) NordiFlex and Norditropin(R) NordiPen (NNF and NNP, Novo Nordisk, Inc., Bagsvaerd, Denmark) took less weekly Total Time (p < 0.05) to use than either of the comparator products, Genotropin(R) Pen (GTP, Pfizer, Inc, New York, New York) or HumatroPen(R) (HTP, Eli Lilly and Company, Indianapolis, Indiana). Time savings were directly related to differences in new package Preparation times (NNF (1.35 minutes), NNP (2.48 minutes) GTP (4.11 minutes), HTP (8.64 minutes), p < 0.05)). Administration and Storage times were not statistically different. NNF (15.8 minutes) and NNP (16.2 minutes) also took less time to Learn than HTP (24.0 minutes) and GTP (26.0 minutes), p < 0.05). The number of weekly required administration steps was also least with NNF and NNP. Opportunity cost savings were greater in devices that were easier to prepare for use; GTP represented an 11.8% drug product savings over NNF, NNP and HTP at time of study. Overall supply costs represented <1% of drug costs for all devices. Time-and-motion simulation data used to support a micro-cost analysis demonstrated that the pen device with the greater time demand has highest net costs.

Two-way WKB Approximation Applied to GPR - COST Action TU1208

NASA Astrophysics Data System (ADS)

Prokopovich, Igor; Popov, Alexei; Marciniak, Marian; Pajewski, Lara

2016-04-01

The main goal of subsurface radio wave probing consists in reconstruction of the shape and the electrical properties of buried objects in material media. For this purpose the knowledge of the laws of EM pulse excitation and propagation in non-uniform subsurface medium is required, as well as the methods and algorithms of solving the inverse problem. Two ways of treating this problem exist. On the one hand, one can describe EM wave propagation by solving the Maxwell's equations with finite difference methods implemented in computer codes. However, when solving inverse problems, pure numerical algorithms require huge amount of calculation and, as a consequence, long calculation time. In this respect, more promising are analytical approaches. Here, we apply couple wave theory ("two-way WKB" approximation) to the problem of subsurface wave propagation. The derived formulas can be used in GPR design and for fast data processing of the experimental data. We start from the 1D model problem of GPR probing. Classical WKB method [1] allows one to describe wave propagation through non-uniform media with slowly varying dielectric permittivity. A principal shortcoming of this approximation is that it does not take into account backward reflection from permittivity gradients. Consequently, WKB method as such can not be used for the purposes of GPR sounding. An extension of this approximation consists in solving two coupled WKB-type equations by iterations. This approach properly describes backward reflections and provides good accuracy in a wide frequency range [2]. In our previous work [3] a time-domain counterpart of the Bremmer-Brekhovkikh approximation has been derived and applied to a 1D inverse problem of subsurface medium probing by an ultra-wide band EM pulse. In order to convert this approach into a practical GPR algorithm, a more realistic model is required: 2D or 3D propagation from a localized source with the effects of wave divergence and refraction taken into account. In this work we study bistatic EM pulse probing of a horizontally layered medium in a 2D case. Coupled WKB equations set describing both forward and backward waves are derived and solved analytically. The comparison of our semi-analytical solutions with numerical calculations by gprMax software [4] demonstrates a good agreement, being hundreds of times faster than the letter. Our numerical results explain the protracted return pulses in the low-frequency GPR data. As an example, we discuss the experimental data obtained during the GPR mission in search of a big fragment of Chelyabinsk meteorite under a thick silt layer at the bottom of Chebarcul' Lake [5]. Acknowledgement The Authors are grateful to the European Cooperation in Science and Technology (www.cost.eu) facilitating this work by a Short-Term Scientific Missions (STSM) within the framework of the Action TU1208 "Civil engineering applications of Ground Penetrating Radar" (www.GPRadar.eu). References 1. H. Bremmer "Propagation of electromagnetic waves", in Handbuch der Physik, S. Flugge, Ed. Berlin-Goettingen-Heidelberg: Springer, 1958, pp. 423-639 2. L.M. Brekhovskikh, Waves in Stratified Media (in Russian). Moscow: USSR Academy of Sciences, 1957. 3. V.A.Vinogradov, V.V. Kopeikin, A.V. Popov, "An Approximate Solution of 1D Inverse Problem", in Proc. 10th Internat. Conf. on GPR, 21-24 June, 2004, Delft, The Netherlands 4. A. Giannopoulos, "Modelling ground penetrating radar by GprMax", Construction and Building Materials, vol. 19, no. 10, pp. 755-762, 2005, doi: 10.1016/j.conbuildmat.2005.06.007 5. V. V. Kopeikin , V. D. Kuznetsov, P. A. Morozov, A. V. Popov et al., "Ground penetrating radar investigation of the supposed fall site of a fragment of the Chelyabinsk meteorite in Lake Chebarkul'", Geochemistry International, vol. 51, no. 7, pp. 575-582, 2013, doi: 10.1134/S0016702913070112

Medicinal chemistry of antischistosomal drugs: Praziquantel and oxamniquine.

PubMed

da Silva, Vinícius Barros Ribeiro; Campos, Bruna Rafaella Koresch Leiva; de Oliveira, Jamerson Ferreira; Decout, Jean-Luc; do Carmo Alves de Lima, Maria

2017-07-01

Neglected tropical diseases (NTDs) are a group of diseases that, besides prevailing in poverty conditions, contribute to the maintenance of social inequality, being a strong barrier to a country development. Schistosomiasis, a NTD, is a tropical and subtropical disease caused by the trematode Schistosoma mansoni (Africa, Middle East, Caribbean, Brazil, Venezuela, Suriname), japonicum (China, Indonesia, the Philippines), mekongi (several districts of Cambodia and the Lao People's Democratic Republic), intercalatum and guianensis (areas of tropical rainforests in Central Africa) and hematobium (Middle East Africa, Corsica, France) whose adult forms inhabit the mesenteric vessels of the host, while the intermediate forms are found in the aquatic gastropod snails of the genus Biomphalaria. Currently, praziquantel (PZQ) is the first line drug chosen for the treatment of schistosomiasis according to the World Health Organization (WHO) Model List of Essential Medicines, 2015. PZQ chemotherapy is considered to be the most important development for decades in the treatment of schistosomiasis. Beside the PZQ, oxamniquine (OXA) has been first described in 1969 and launched in Brazil by Pfizer under the name of Mansil® for oral administration. It has a lower cost when compared to PZQ, being active in the intestinal and hepatosplenic infections caused exclusively by S. mansoni, single species in Brazil. Both PZQ and OXA have limitations, as low efficacy in the treatment of acute schistosomiasis, low activity against S. mansoni in immature stages and resistance or tolerance, which is the reason why further research are still necessary for the development of a second generation of antischistosomal drugs. For the development of new PZQ analogs, three main strategies can be adopted: (a) synthesis and evaluation of PZQ analogues; (b) rational design of new pharmacophores; (c) discovery of new active compounds from screening programs on a large scale. Such (b) approach is difficult as the target of PZQ still unknown, the synthesis of new active analogues is possible from delineation of structure-activity relationships for PZQ. Thus, we proposed for a review article an accurate analysis of PZQ and OXA medicinal properties and uses, focusing on the pharmacochemical aspects of both drugs through 178 bibliographic references. The mechanisms of action will be discussed, with the latest information available in the literature (for the first time in the case of the oxamniquine). Cases of resistance are also discussed. As both drugs are available as a racemic mixture the biological impact of their stereochemistry to activity and side effects are reviewed. The results obtained for the combination of PZQ and artemisinin derivatives against immature worms are also introduced in the discussion. Using the information about more than 200 PZQ new derivatives synthetized during almost 35years since its discovery, a deep structure-activity relationship (SAR) is also proposed in this study. Copyright © 2017 Elsevier Ltd. All rights reserved.

Paying for Cures: How Can We Afford It? Managed Care Pharmacy Stakeholder Perceptions of Policy Options to Address Affordability of Prescription Drugs.

PubMed

Yeung, Kai; Suh, Kangho; Basu, Anirban; Garrison, Louis P; Bansal, Aasthaa; Carlson, Josh J

2017-10-01

High-priced medications with curative potential, such as the newer hepatitis C therapies, have contributed to the recent growth in pharmaceutical expenditure. Despite the obvious benefits, health care decision makers are just beginning to grapple with questions of how to value and pay for curative therapies that may feature large upfront cost, followed by health benefits that are reaped over a patient's lifespan. Alternative policy options have been proposed to promote high value and financially sustainable use of these therapies. It is unclear which policy options would be most acceptable to health care payer and biomedical manufacturer stakeholders. To (a) briefly review pharmaceutical policy options to address health system affordability and (b) assess the acceptability of alternative policy options to health care payers and biomedical manufacturers before and after an Academy of Managed Care Pharmacy (AMCP) continuing pharmacy education (CPE) session. We searched MEDLINE and Cochran databases for pharmaceutical policy options addressing affordability. With input from a focus group of managed care professionals, we developed CPE session content and an 8-question survey focusing on the most promising policy options. We fielded the survey before and after the CPE session, which occurred as part of the 2016 AMCP Annual Meeting. We first conducted a chi-squared goodness-of-fit test to assess response distributions. Next, we tested how responses differed before and after by using an ordered logit and a multinomial logit to model Likert scale and unordered responses, respectively. Although risk-sharing payments over time remained the most favorable choice before (37%) and after (35%) the CPE session, this choice was closely followed by HealthCoin after the session, which increased in favorability from 4% to 33% of responses (P = 0.001). About half of the respondents (54%) indicated that legislative change is the most significant barrier to the implementation of any policy. As high-cost curative drugs reach the market, managed care stakeholders need information from a balanced education source regarding alternative policies to address affordability. We found that after the AMCP CPE session, risk-sharing payments over time and HealthCoin were the most favorable options. No funding was provided for this research. Carlson reports consulting fees from Genentech, Pfizer, and Seattle Genetics. The other authors have nothing to disclose. Study concept and design were contributed by Yeung, Garrison, and Carlson. Yeung collected the data, which were interpreted by Yeung and Basu. The manuscript was written by Yeung, Suh, and Bansal and revised by Yeung. A portion of this research was presented at the Academy of Managed Care & Specialty Pharmacy Annual Meeting as a continuing education session entitled "Paying for Cures: How Can We Afford It?" on April 20, 2016, in San Francisco, California.

Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial.

PubMed

Fleischmann, Roy; Mysler, Eduardo; Hall, Stephen; Kivitz, Alan J; Moots, Robert J; Luo, Zhen; DeMasi, Ryan; Soma, Koshika; Zhang, Richard; Takiya, Liza; Tatulych, Svitlana; Mojcik, Christopher; Krishnaswami, Sriram; Menon, Sujatha; Smolen, Josef S

2017-07-29

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than -13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI -6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (-6 [-14 to 3]) or tofacitinib and methotrexate (-8 [-16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Pfizer Inc. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exubera. Inhale therapeutic systems.

PubMed

Bindra, Sanjit; Cefalu, William T

2002-05-01

Inhale, in colaboration with Pfizer and Aventis Pharma (formerly Hoechst Marion Roussel; HMR), is developing an insulin formulation utilizing its pulmonary delivery technology for macromolecules for the potential treatment of type I and II diabetes. By July 2001, the phase III program had been completed and the companies had begun to assemble data for MAA and NDA filings; however, it was already clear at this time that additional data might be required for filing. By December 2001, it had been decided that the NDA should include an increased level of controlled, long-term pulmonary safety data in diabetic patients and a major study was planned to be completed in 2002, with the NDA filed thereafter (during 2002). US-05997848 was issued to Inhale Therapeutic Systems in December 1999, and corresponds to WO-09524183, filed in February 1995. Equivalent applications have appeared to date in Australia, Brazil, Canada, China, Czech Republic, Europe, Finland, Hungary, Japan, Norway, New Zealand, Poland and South Africa. This family of applications is specific to pulmonary delivery of insulin. In February 1999, Lehman Brothers gave this inhaled insulin a 60% probability of reaching market, with a possible launch date of 2001. The analysts estimated peak sales at $3 billion in 2011. In May 2000, Aventis predicted that estimated peak sales would be in excess of $1 billion. In February 2000, Merrill Lynch expected product launch in 2002 and predicted that it would be a multibillion-dollar product. Analysts Merril Lynch predicted, in September and November 2000, that the product would be launched by 2002, with sales in that year of e75 million, rising to euro 500 million in 2004. In April 2001, Merrill Lynch predicted that filing for this drug would occur in 2001. Following the report of the potential delay in regulatory filing, issued in July 2001, Deutsche Banc Alex Brown predicted a filing would take place in the fourth quarter of 2002 and launch would take place in the first quarter of 2003. In August 2001, Lehman Brothers predicted that launch would take place in the first half of 2002 and that the product would make sales of $475 million in 2003, rising to $875 million in 2004. In the same month, Deutsche Bank predicted that there would be worldwide sales of $50 million in 2003, rising to $400 million in 2005. At this time, analysts at Credit Suisse predicted a launch of the product in 2003, with sales of $70 million in that year, rising to $550 million in 2005. By October 2001, Deutsche Bank predicted sales of $50 million in 2004 and $250 million in 2005. In September 2001, Morgan Stanley predicted sales of $500 million in 2002, rising to $1250 million in 2006.

Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): a double-blind, randomised, placebo-controlled trial.

PubMed

Sierra-Madero, Juan G; Ellenberg, Susan S; Rassool, Mohammed S; Tierney, Ann; Belaunzarán-Zamudio, Pablo F; López-Martínez, Alondra; Piñeirúa-Menéndez, Alicia; Montaner, Luis J; Azzoni, Livio; Benítez, César Rivera; Sereti, Irini; Andrade-Villanueva, Jaime; Mosqueda-Gómez, Juan L; Rodriguez, Benigno; Sanne, Ian; Lederman, Michael M

2014-11-01

Immune reconstitution inflammatory syndrome (IRIS) is a common complication of antiretroviral therapy (ART) in patients with HIV. IRIS is associated with an increased risk of admission to hospital and death. We assessed whether CCR5 blockade with maraviroc reduces the risk of IRIS. The CADIRIS study was a double-blind, randomised, placebo-controlled trial that recruited participants from five clinical sites in Mexico and one in South Africa and followed them for 1 year. Patients were eligible if they were adults with HIV, who were naive to ART, had CD4 count lower than 100 cells per μL and HIV RNA greater than 1000 copies per mL. Participants were randomly assigned (1:1) by permuted block randomisation to receive either maraviroc (600 mg twice daily) or placebo in addition to an ART regimen that included tenofovir, emtricitabine, and efavirenz for 48 weeks. Patients, care providers, and members of the research team were masked to treatment allocation. Clinical and laboratory evaluations were done at baseline, and weeks 2, 4, 8, 12, 16, 24, 48, and 60. The primary outcome was time to an IRIS event by 24 weeks. All patients who were randomly assigned contributed to the primary time-to-event analysis from the date of ART initiation until week 24, the time of an IRIS event or death. This trial is registered with ClinicalTrials.gov, number NCT00988780. Between Dec 10, 2009, and Jan 17, 2012, we screened 362 patients; of whom 279 met the inclusion criteria and three refused to participate; thus 276 participants were randomly assigned (140 to receive maraviroc and 136 to receive placebo). 64 (23%) patients had IRIS events, 33 (24%) in the maraviroc group and 31 (23%) in the placebo group (p=0·74). No difference in the time to IRIS events was noted between the treatment groups (HR 1·08, 95% CI 0·66-1·77; log-rank test p=0·74). 37 participants (26%) in the maraviroc group had grade 3 or 4 adverse events compared with 24 (18%) in placebo group; p=0·072); 25 (18%) in the maraviroc group and 21 (15%) in the placebo group had serious treatment emergent adverse events (p=0·63). Maraviroc had no significant effect on development of IRIS after ART initiation. Inclusion of this CCR5 inhibitor in an initial treatment regimen does not confer a meaningful protection from the occurrence of IRIS in people with advanced HIV infection. Pfizer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Diabetes area participation analysis: a review of companies and targets described in the 2008 - 2010 patent literature.

PubMed

Carpino, Philip A; Goodwin, Bryan

2010-12-01

Type 2 diabetes is a chronic disease characterized by the development of insulin resistance, impaired pancreatic β-cell function and, ultimately, hyperglycemia. The disease is highly associated with obesity and it is thought that the inappropriate deposition of lipid in tissues such as liver and muscle contributes to a reduction in insulin sensitivity which, in turn, places a burden on the β-cell to secrete more insulin to achieve normoglycemia. Over an extended period of time, this can result in β-cell failure and diminished glycemic control. When poorly managed, type 2 diabetes increases the risk of developing both microvascular and macrovascular complications, including retinopathy, nephropathy and coronary artery disease. The number of Americans with diabetes has approached 24 million in 2007 and the prevalence of the disease is projected to increase with the sedentary lifestyles and high caloric diets that are common today. First-line treatment for the disease involves lifestyle modifications and, if unsuccessful, pharmacotherapy to control symptoms. Anti-diabetic drugs belonging to several mechanistic classes are available (e.g., insulin secretagogues, insulin sensitizers, insulin mimetics and DPP IV inhibitors); however, many of these drugs lose their effectiveness over time, are not well-tolerated in some patients or may have suboptimal risk:benefit ratios. The search for new anti-diabetic drugs has continued to attract considerable interest from both academia and the pharmaceutical industry. An analysis of 2008 - 2010 patent applications claiming diabetes as an indication has been undertaken. An understanding of: i) the pharmaceutical companies that have filed patent applications in the anti-diabetes area during 2008 - 2010; ii) the different pharmacological targets under investigation and the patent activity around such targets; iii) some of the targets in the research portfolios of selected companies; iv) chemical structures of compounds that modulate emerging targets and v) the pharmacological rationale underlying several targets with the largest patent counts. Type 2 diabetes is a complex disease with many potential points of intervention for pharmacotherapy. A majority of anti-diabetic patent applications claim chemical matter for just eight targets which include five enzymes, a GPCR, a family of nuclear hormone receptors and a class of sodium-dependent glucose co-transporters (11β-HSD1, DGAT1, DPP IV, glucokinase, GPR119, PPAR-α, -δ, -γ, SGLT1 and SGLT2, and stearoyl-CoA desaturase 1 (SCD1)). The major pharmaceutical companies are all pursuing some combination of these top eight targets. Several companies stand out for the breadth of new targets under investigation (e.g., F. Hoffmann-La Roche, Merck & Co., Pfizer, Takeda Pharmaceuticals, Sanofi-Aventis).

Prevalence of and Factors Associated with Clostridium difficile Co-infection Among Patients with Candidemia, United States, 2014–2016

PubMed Central

Tsay, Sharon; Benedict, Kaitlin; Beldavs, Zintars G; Farley, Monica M; Harrison, Lee H; Schaffner, William; Gerth, Taryn; Chiller, Tom; Vallabhaneni, Snigdha

2017-01-01

Abstract Background Candidemia and Clostridium difficile infection (CDI) are two common healthcare-associated infections (HAIs) and share risk factors such as antibiotic use and prolonged hospitalization. CDI and CDI treatment disrupt gut microbial diversity, allowing Candida overgrowth and translocation to the bloodstream. We describe CDI co-infection among patients with candidemia. Methods Population-based surveillance for candidemia was conducted through CDC’s Emerging Infections Program during 2014–2016. A case of candidemia was defined as a blood culture positive for Candida species collected from a surveillance area resident. Demographic and medical information, including occurrence of CDI was collected. We defined co-infection as CDI within 90 days of candidemia and performed bivariable analysis to assess factors associated with co-infection. Results Among 2129 cases of candidemia, 190 (9%) had CDI co-infection; 116 (5%) had CDI in the 90 days before candidemia (median: 10 days) and 60 (3%) had CDI following candidemia (median: 8 days). The median age of those with CDI-candidemia co-infection was 61 years and 100 (53%) were male. Compared with candidemia alone, the odds of CDI-candidemia co-infection was significantly greater for patients of black race (OR 1.41, 95% CI 1.05–1.90), those with diabetes (OR 1.68, 1.24–2.27), pancreatitis (OR 1.91, 1.01–3.61), or solid organ transplant (OR 4.15, 2.09–8.22). Those with co-infection had higher odds of certain healthcare exposures: hemodialysis (OR 2.27, 1.57–3.28), hospital stay in the past 90 days (OR 1.9, 1.37–2.64), ICU admission in the past 14 days (OR 1.78, 1.20–2.66), and central venous catheter (CVC) at the time of candidemia (OR 1.71, 1.19–2.46). There were no significant differences in 30-day mortality or in type of Candida species, although C. parapsilosis was less common in the co-infection group (8% vs. 13%). Conclusion Nearly one in ten patients with candidemia also had CDI co-infection. Black race, certain underlying conditions, hemodialysis, previous hospitalization, ICU stay, and the presence of a CVC were associated with co-infection. Clinicians should be vigilant for coinfection of CDI and candidemia, particularly in situations with associated risk factors. Disclosures W. Schaffner, Pfizer: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Novavax: Consultant, Consulting fee; Dynavax: Consultant, Consulting fee; Sanofi-pasteur: Consultant, Consulting fee; GSK: Consultant, Consulting fee; Seqirus: Consultant, Consulting fee

Metabolizable protein supply modulated the acute-phase response following vaccination of beef steers.

PubMed

Moriel, P; Arthington, J D

2013-12-01

Our objective was to evaluate the effects of MP supply, through RUP supplementation, on the acute-phase response of beef steers following vaccination. On d 0, Brangus-crossbred steers (n = 24; 173 ± 31 kg; 175 ± 16 d of age) were randomly assigned to receive 1 of 3 isocaloric diets formulated to provide 85, 100, and 115% of the daily MP requirements of a beef steer gaining 0.66 kg of BW daily. Diets were limit-fed at 1.8% of BW (DM basis) and individually provided to steers once daily (0800 h) from d 0 to 29. Steers were weighed on d 0 and 29, following a 12-h period of feed and water withdrawal. On d 7, steers were vaccinated against Mannheimia haemolytica (OneShot, Pfizer), and blood samples were collected on d 0, 7, 8, 10, 14, 21, and 30. Plasma metabolites were analyzed as repeated measures using the MIXED procedure of SAS. Final BW and ADG were similar (P ≥ 0.50) among treatments (mean = 184 ± 9 kg and 0.5 ± 0.08 kg/d, respectively). Effects of time were detected (P < 0.01) for plasma concentrations of all acute-phase proteins, which peaked between d 7 to 14, returning to baseline concentrations by d 29. Treatment effects were not detected (P ≥ 0.19) for plasma concentrations of acid-soluble protein, albumin, fibrinogen, IGF-1 and serum amyloid-A. Plasma concentrations of total protein (TP) and plasma urea nitrogen (PUN) increased (P ≤ 0.05) with increasing supply of MP (87.1, 89.6, and 90.1 ± 1.09 mg TP/mL and 6.1, 8.3, and 10.3 ± 0.41 mg PUN/dL for 85, 100, and 115% MP steers, respectively). From d 10 to 29, steers provided 115% MP had less (P < 0.001) plasma concentrations of ceruloplasmin than steers fed 85 and 100% MP, which had similar plasma ceruloplasmin concentrations. On d 14, plasma concentrations of haptoglobin were greatest (P ≤ 0.06) for steers fed 115% MP, intermediate for 100% MP, and least for 85% MP (0.98, 0.71 and 0.44 ± 0.099 mg/mL, respectively). On d 10, plasma concentrations of creatinine were greater (P = 0.01) for steers fed 115 vs. 85% MP, and intermediate for steers fed 100% MP (1.63, 1.28, and 1.50 ± 0.099 mg/dL, respectively). Thus, steers provided increasing metabolizable protein had greater plasma concentrations of haptoglobin, creatinine, total protein and PUN following vaccination against M. haemolytica.

Tranexamic acid for treatment of women with post-partum haemorrhage in Nigeria and Pakistan: a cost-effectiveness analysis of data from the WOMAN trial.

PubMed

Li, Bernadette; Miners, Alec; Shakur, Haleema; Roberts, Ian

2018-02-01

Sub-Saharan Africa and southern Asia account for almost 85% of global maternal deaths from post-partum haemorrhage. Early administration of tranexamic acid, within 3 h of giving birth, was shown to reduce the risk of death due to bleeding in women with post-partum haemorrhage in the World Maternal Antifibrinolytic (WOMAN) trial. We aimed to assess the cost-effectiveness of early administration of tranexamic acid for treatment of post-partum haemorrhage. For this economic evaluation we developed a decision model to assess the cost-effectiveness of the addition of tranexamic acid to usual care for treatment of women with post-partum haemorrhage in Nigeria and Pakistan. We used data from the WOMAN trial to inform model parameters, supplemented by estimates from the literature. We estimated costs (calculated in 2016 US$), life-years, and quality-adjusted life-years (QALYs) with and without tranexamic acid, calculated incremental cost-effectiveness ratios (ICERs), and compared these to threshold values in each country. Costs were assessed from the health-care provider perspective and discounted at 3% per year in the base case analysis. We did a series of one-way sensitivity analyses and probabilistic sensitivity analysis to assess the robustness of the results to parameter uncertainty. Early treatment of post-partum haemorrhage with tranexamic acid generated an average gain of 0·18 QALYs at an additional cost of $37·12 per patient in Nigeria and an average gain of 0·08 QALYs at an additional cost of $6·55 per patient in Pakistan. The base case ICER results were $208 per QALY in Nigeria and $83 per QALY in Pakistan. These ICERs were below the lower bound of the cost-effectiveness threshold range in both countries. The ICERs were most sensitive to uncertainty in parameter inputs for the relative risk of death due to bleeding with tranexamic acid, the discount rate, the cost of the drug, and the baseline probability of death due to bleeding. Early treatment of post-partum haemorrhage with tranexamic acid is highly cost-effective in Nigeria and Pakistan, and is likely to be cost-effective in countries in sub-Saharan Africa and southern Asia with a similar baseline risk of death due to bleeding. London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation. Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial.

PubMed

Derks, Marloes G M; Blok, Erik J; Seynaeve, Caroline; Nortier, Johan W R; Kranenbarg, Elma Meershoek-Klein; Liefers, Gerrit-Jan; Putter, Hein; Kroep, Judith R; Rea, Daniel; Hasenburg, Annette; Markopoulos, Christos; Paridaens, Robert; Smeets, Jan B E; Dirix, Luc Y; van de Velde, Cornelis J H

2017-09-01

After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4-8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5-3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0-10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65-69) for the exemestane group and 67% (65-69) for the sequential group (hazard ratio 0·96, 0·88-1·05; p=0·39). The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Pfizer, Dutch Cancer Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.

PubMed

Ridker, Paul M; Revkin, James; Amarenco, Pierre; Brunell, Robert; Curto, Madelyn; Civeira, Fernando; Flather, Marcus; Glynn, Robert J; Gregoire, Jean; Jukema, J Wouter; Karpov, Yuri; Kastelein, John J P; Koenig, Wolfgang; Lorenzatti, Alberto; Manga, Pravin; Masiukiewicz, Urszula; Miller, Michael; Mosterd, Arend; Murin, Jan; Nicolau, Jose C; Nissen, Steven; Ponikowski, Piotr; Santos, Raul D; Schwartz, Pamela F; Soran, Handrean; White, Harvey; Wright, R Scott; Vrablik, Michal; Yunis, Carla; Shear, Charles L; Tardif, Jean-Claude

2017-04-20

Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).

Indian vaccine innovation: the case of Shantha Biotechnics

PubMed Central

2011-01-01

Background Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than $1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million. Methods The case study and grounded research method was used to illustrate how the globalization of healthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines. Sources including interviews, literature analysis, and on-site observations were combined to conduct a robust examination of Shantha's evolution as a major provider of vaccines for global health indications. Results Shantha's ability to become a significant global vaccine manufacturer and achieve international valuation and market success appears to have been made possible by focusing first on the local health needs of India. How Shantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha identified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor. Second, Shantha persistently sought investments and partnerships from non-traditional and international sources including the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in innovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable vaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification by the World Health Organization and generated interest from large pharmaceutical companies in its contract research services. These two sources of revenue allowed Shantha to continue to invest in health innovation relevant to the developing world. Conclusions The Shantha case study underscores the important role the private sector can play in global health and access to medicines. Home-grown companies in the developing world are becoming a source of low-cost, locally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market forces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis' acquisition of Shantha reveals that even large pharmaceutical companies based in the developed world have recognized the importance of meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into private sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the developing world. PMID:21507259

Indian vaccine innovation: the case of Shantha Biotechnics.

PubMed

Chakma, Justin; Masum, Hassan; Perampaladas, Kumar; Heys, Jennifer; Singer, Peter A

2011-04-20

Although the World Health Organization had recommended that every child be vaccinated for Hepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant Hepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination. Shantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need domestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than $1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In 2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a valuation of USD$784 million. The case study and grounded research method was used to illustrate how the globalization of healthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines. Sources including interviews, literature analysis, and on-site observations were combined to conduct a robust examination of Shantha's evolution as a major provider of vaccines for global health indications. Shantha's ability to become a significant global vaccine manufacturer and achieve international valuation and market success appears to have been made possible by focusing first on the local health needs of India. How Shantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha identified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor. Second, Shantha persistently sought investments and partnerships from non-traditional and international sources including the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in innovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable vaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification by the World Health Organization and generated interest from large pharmaceutical companies in its contract research services. These two sources of revenue allowed Shantha to continue to invest in health innovation relevant to the developing world. The Shantha case study underscores the important role the private sector can play in global health and access to medicines. Home-grown companies in the developing world are becoming a source of low-cost, locally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market forces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis' acquisition of Shantha reveals that even large pharmaceutical companies based in the developed world have recognized the importance of meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into private sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the developing world.

Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial.

PubMed

Davidson, Andrew J; Disma, Nicola; de Graaff, Jurgen C; Withington, Davinia E; Dorris, Liam; Bell, Graham; Stargatt, Robyn; Bellinger, David C; Schuster, Tibor; Arnup, Sarah J; Hardy, Pollyanna; Hunt, Rodney W; Takagi, Michael J; Giribaldi, Gaia; Hartmann, Penelope L; Salvo, Ida; Morton, Neil S; von Ungern Sternberg, Britta S; Locatelli, Bruno Guido; Wilton, Niall; Lynn, Anne; Thomas, Joss J; Polaner, David; Bagshaw, Oliver; Szmuk, Peter; Absalom, Anthony R; Frawley, Geoff; Berde, Charles; Ormond, Gillian D; Marmor, Jacki; McCann, Mary Ellen

2016-01-16

Preclinical data suggest that general anaesthetics affect brain development. There is mixed evidence from cohort studies that young children exposed to anaesthesia can have an increased risk of poor neurodevelopmental outcome. We aimed to establish whether general anaesthesia in infancy has any effect on neurodevelopmental outcome. Here we report the secondary outcome of neurodevelopmental outcome at 2 years of age in the General Anaesthesia compared to Spinal anaesthesia (GAS) trial. In this international assessor-masked randomised controlled equivalence trial, we recruited infants younger than 60 weeks postmenstrual age, born at greater than 26 weeks' gestation, and who had inguinal herniorrhaphy, from 28 hospitals in Australia, Italy, the USA, the UK, Canada, the Netherlands, and New Zealand. Infants were randomly assigned (1:1) to receive either awake-regional anaesthesia or sevoflurane-based general anaesthesia. Web-based randomisation was done in blocks of two or four and stratified by site and gestational age at birth. Infants were excluded if they had existing risk factors for neurological injury. The primary outcome of the trial will be the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) Full Scale Intelligence Quotient score at age 5 years. The secondary outcome, reported here, is the composite cognitive score of the Bayley Scales of Infant and Toddler Development III, assessed at 2 years. The analysis was as per protocol adjusted for gestational age at birth. A difference in means of five points (1/3 SD) was predefined as the clinical equivalence margin. This trial is registered with ANZCTR, number ACTRN12606000441516 and ClinicalTrials.gov, number NCT00756600. Between Feb 9, 2007, and Jan 31, 2013, 363 infants were randomly assigned to receive awake-regional anaesthesia and 359 to general anaesthesia. Outcome data were available for 238 children in the awake-regional group and 294 in the general anaesthesia group. In the as-per-protocol analysis, the cognitive composite score (mean [SD]) was 98.6 (14.2) in the awake-regional group and 98.2 (14.7) in the general anaesthesia group. There was equivalence in mean between groups (awake-regional minus general anaesthesia 0.169, 95% CI -2.30 to 2.64). The median duration of anaesthesia in the general anaesthesia group was 54 min. For this secondary outcome, we found no evidence that just less than 1 h of sevoflurane anaesthesia in infancy increases the risk of adverse neurodevelopmental outcome at 2 years of age compared with awake-regional anaesthesia. Australia National Health and Medical Research Council (NHMRC), Health Technologies Assessment-National Institute for Health Research UK, National Institutes of Health, Food and Drug Administration, Australian and New Zealand College of Anaesthetists, Murdoch Childrens Research Institute, Canadian Institute of Health Research, Canadian Anesthesiologists' Society, Pfizer Canada, Italian Ministry of Heath, Fonds NutsOhra, and UK Clinical Research Network (UKCRN). Copyright © 2016 Elsevier Ltd. All rights reserved.

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

PubMed

Mease, Philip; Hall, Stephen; FitzGerald, Oliver; van der Heijde, Désirée; Merola, Joseph F; Avila-Zapata, Francisco; Cieślak, Dorota; Graham, Daniela; Wang, Cunshan; Menon, Sujatha; Hendrikx, Thijs; Kanik, Keith S

2017-10-19

Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs). In this 12-month, double-blind, active-controlled and placebo-controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5-mg dose taken orally twice daily (107 patients), tofacitinib at a 10-mg dose taken orally twice daily (104), adalimumab at a 40-mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5-mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10-mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. ACR20 response rates at month 3 were 50% in the 5-mg tofacitinib group and 61% in the 10-mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ-DI score was -0.35 in the 5-mg tofacitinib group and -0.40 in the 10-mg tofacitinib group, as compared with -0.18 in the placebo group (P=0.006 for the comparison of the 5-mg dose with placebo; P<0.001 for the comparison of the 10-mg dose with placebo); the score change was -0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5-mg tofacitinib group, 71% in the 10-mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5-mg tofacitinib dose, and 64% in the placebo group that switched to the 10-mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668 .).

Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study.

PubMed

Talmud, Philippa J; Shah, Sonia; Whittall, Ros; Futema, Marta; Howard, Philip; Cooper, Jackie A; Harrison, Seamus C; Li, Kawah; Drenos, Fotios; Karpe, Frederik; Neil, H Andrew W; Descamps, Olivier S; Langenberg, Claudia; Lench, Nicholas; Kivimaki, Mika; Whittaker, John; Hingorani, Aroon D; Kumari, Meena; Humphries, Steve E

2013-04-13

Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles. In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hôpital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C-raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII. We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0.90 [SD 0.23]) was strongly associated with LDL-C concentration (p=1.4 x 10(-77); R(2)=0.11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0 [SD 0.21]) than did WHII controls (p=4.5 x 10(-16)), as did the mutation-negative Belgian patients (0.99 [0.19]; p=5.2 x 10(-20)). The score was also higher in UK (0.95 [0.20]; p=1.6 x 10(-5)) and Belgian (0.92 [0.20]; p=0.04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles. In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry. Copyright © 2013 Elsevier Ltd. All rights reserved.

Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: a phase 1 safety and pharmacokinetics study.

PubMed

Martinelli, Giovanni; Oehler, Vivian G; Papayannidis, Cristina; Courtney, Rachel; Shaik, M Naveed; Zhang, Xiaoxi; O'Connell, Ashleigh; McLachlan, Karen R; Zheng, Xianxian; Radich, Jerald; Baccarani, Michele; Kantarjian, Hagop M; Levin, Wendy J; Cortes, Jorge E; Jamieson, Catriona

2015-08-01

Activation of the Hedgehog signalling pathway contributes to cancer progression and the development of myeloid leukaemia stem cell therapeutic resistance. We aimed to identify the maximum tolerated dose (MTD) and the recommended phase 2 dose of the selective Hedgehog antagonist PF-04449913 in myeloid malignancies. We undertook an open-label, dose-finding, standard 3+3 design phase 1 study of PF-04449913 in adult patients with acute myeloid leukaemia, chronic myeloid leukaemia, chronic myelomonocytic leukaemia, myelodysplastic syndrome, or myelofibrosis who were refractory, resistant, or intolerant to previous treatments, at three centres in the USA and one in Italy. Patients who had newly diagnosed, untreated disease were included if they were not eligible for standard treatment options or if standard treatments were not deemed appropriate. Patients received PF-04449913 once daily continuously until disease progression, unacceptable toxic effects, or patient withdrawal for up to 12 28-day cycles. Additional cycles were given if patients showed evidence of clinical benefit. The starting dose was 5 mg and was increased by 100% until the first dose-limiting toxic effect (DLT) and by 50% thereafter, in keeping with a 3+3 clinical trial statistical design. The primary endpoint was first-cycle DLTs. Secondary endpoints were safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. This trial is registered with ClinicalTrials.gov, number NCT00953758. Between March 24, 2010, and Sept 7, 2012, 47 patients were enrolled and included in the study: 28 with acute myeloid leukaemia, six with myelodysplastic syndrome, five with chronic myeloid leukaemia (two with chronic-phase and three with blast-phase disease), one with chronic myelomonocytic leukaemia, and seven with myelofibrosis. Patients received PF-04449913 once daily at 5 mg (n=3), 10 mg (n=3), 20 mg (n=4), 40 mg (n=4), 80 mg (n=8), 120 mg (n=3), 180 mg (n=3), 270 mg (n=5), 400 mg (n=9), and 600 mg (n=5). Two patients experienced DLTs (one each in the 80 mg and 600 mg dose groups). The MTD for PF-04449913 was established to be 400 mg once daily. Of the 47 patients enrolled, 28 (60%) experienced treatment-related adverse events, three of which were grade 4 in severity. The most common treatment-related adverse events included dysgeusia (13 [28%] patients), decreased appetite (nine [19%]), and alopecia (seven [15%]). None of the 15 deaths reported were treatment related. Pharmacokinetics seemed to be dose proportional. The mean half-life was 23·9 h (SD 14·0) in the MTD group. Some suggestion of clinical activity was noted in 23 (49%) of 47 patients with haematological malignancies. Based on these results, the recommended phase 2 dose was 200 mg or lower once daily. Based on these findings, PF-04449913 is being tested in phase 2 studies in patients with myelodysplastic syndrome, acute myeloid leukaemia, and myelofibrosis. Pfizer. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Changing Epidemiology of Invasive Pneumococcal Disease Among the Indigenous and Non-indigenous Population of Northwestern Ontario, Canada, from 2006 Through 2015 and Emergence of Non-vaccine Serotypes

PubMed Central

Dalcin, Daniel; Sieswerda, Lee; Ulanova, Marina

2017-01-01

Abstract Background Rates of invasive pneumococcal disease (IPD) among indigenous populations remain substantially higher than their non-indigenous counterparts. The goal of this study was to analyze the epidemiology and demographic features of IPD in northwestern Ontario (NWO) among the indigenous and non-indigenous population in the context of recent changes in the provincial pneumococcal vaccination programs. Methods Two databases were used to identify cases of IPD in NWO: Thunder Bay Regional Health Sciences Centre and the Thunder Bay District Health Unit. Adult patients with a diagnosis of IPD at the TBRHSC from January 1, 2006 to December 31, 2015 had their medical charts retrospectively reviewed; TBDHU data contained only serotype, age, and gender data. Results Table 1. Number of IPD cases and case fatality rate by indigenous status at the TBRHSC, 2006–2015 # of cases # of deaths year indigenous non-indigenous total indigenous non-indigenous total 2006 3 7 10 0 0 0 2007 0 8 8 0 1 1 2008 5 11 16 0 1 1 2009 8 20 28 2 0 2 2010 5 17 22 0 2 2 2011 6 22 28 1 1 2 2012 3 8 11 0 1 1 2013 10 12 22 1 3 4 2014 10 11 21 0 0 0 2015 3 13 16 0 2 2 total 53 129 182 4 11 15 53 of 182 (29.0%) of patients were indigenous. 35 of 53 (66.0%) of indigenous patients were immunocompromised, whereas 38 of 129 (29.5%) of non-indigenous patients were immunocompromised and the difference was statistically significant (P < 0.001, by chi square test). 35 of 73 (48.0%) of immunocompromised patients were indigenous. Table 2. Serotype distribution of Streptococcus pneumoniae causing IPD in northwestern Ontario, Canada, 2006–2015 (includes both TBRHSC + TBDHU data). year PCV7 PCV13 PCV23 non-vaccine serotypes unknown serotypes total 2006 0 0 0 0 26 26 2007 1 0 2 1 12 16 2008 2 2 5 4 14 27 2009 3 12 9 3 16 43 2010 0 7 8 4 12 31 2011 2 10 12 4 9 37 2012 0 2 11 8 4 25 2013 0 3 21 2 8 34 2014 1 2 9 3 8 23 2015 1 0 7 6 9 23 total 10 38 84 35 118 285 The proportion of non-vaccine serotypes has increased, on average, by 16% per year (P = 0.024, 95% CI: 1.02, 1.32). Conclusion High rates of IPD were found to occur among immunocompromised indigenous adults in NWO. Our findings identify a vulnerable cohort of the population that would benefit from pneumococcal vaccination coverage. The proportion of non-vaccine serotypes causing IPD has increased during the 10-year observation period. Disclosures M. Ulanova, Pfizer: Grant Investigator, Grant recipient

Dacomitinib versus erlotinib in patients with advanced-stage, previously treated non-small-cell lung cancer (ARCHER 1009): a randomised, double-blind, phase 3 trial.

PubMed

Ramalingam, Suresh S; Jänne, Pasi A; Mok, Tony; O'Byrne, Kenneth; Boyer, Michael J; Von Pawel, Joachim; Pluzanski, Adam; Shtivelband, Mikhail; Docampo, Lara Iglesias; Bennouna, Jaafar; Zhang, Hui; Liang, Jane Q; Doherty, Jim P; Taylor, Ian; Mather, Cecile B; Goldberg, Zelanna; O'Connell, Joseph; Paz-Ares, Luis

2014-11-01

Dacomitinib is an irreversible pan-EGFR family tyrosine kinase inhibitor. Findings from a phase 2 study in non-small cell lung cancer showed favourable efficacy for dacomitinib compared with erlotinib. We aimed to compare dacomitinib with erlotinib in a phase 3 study. In a randomised, multicentre, double-blind phase 3 trial in 134 centres in 23 countries, we enrolled patients who had locally advanced or metastatic non-small-cell lung cancer, progression after one or two previous regimens of chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and presence of measurable disease. We randomly assigned patients in a 1:1 ratio to dacomitinib (45 mg/day) or erlotinib (150 mg/day) with matching placebo. Treatment allocation was masked to the investigator, patient, and study funder. Randomisation was stratified by histology (adenocarcinoma vs non-adenocarcinoma), ethnic origin (Asian vs non-Asian and Indian sub-continent), performance status (0-1 vs 2), and smoking status (never-smoker vs ever-smoker). The coprimary endpoints were progression-free survival per independent review for all randomly assigned patients, and for all randomly assigned patients with KRAS wild-type tumours. The study has completed accrual and is registered with ClinicalTrials.gov, number NCT01360554. Between June 22, 2011, and March 12, 2013, we enrolled 878 patients and randomly assigned 439 to dacomitinib (256 KRAS wild type) and 439 (263 KRAS wild type) to erlotinib. Median progression-free survival was 2·6 months (95% CI 1·9-2·8) in both the dacomitinib group and the erlotinib group (stratified hazard ratio [HR] 0·941, 95% CI 0·802-1·104, one-sided log-rank p=0·229). For patients with wild-type KRAS, median progression-free survival was 2·6 months for dacomitinib (95% CI 1·9-2·9) and erlotinib (95% CI 1·9-3·0; stratified HR 1·022, 95% CI 0·834-1·253, one-sided p=0·587). In patients who received at least one dose of study drug, the most frequent grade 3-4 adverse events were diarrhoea (47 [11%] patients in the dacomitinib group vs ten [2%] patients in the erlotinib group), rash (29 [7%] vs 12 [3%]), and stomatitis (15 [3%] vs two [<1%]). Serious adverse events were reported in 52 (12%) patients receiving dacomitinib and 40 (9%) patients receiving erlotinib. Irreversible EGFR inhibition with dacomitinib was not superior to erlotinib in an unselected patient population with advanced non-small-cell lung cancer or in patients with KRAS wild-type tumours. Further study of irreversible EGFR inhibitors should be restricted to patients with activating EGFR mutations. Pfizer. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study.

PubMed

Castaigne, Sylvie; Pautas, Cécile; Terré, Christine; Raffoux, Emmanuel; Bordessoule, Dominique; Bastie, Jean-Noel; Legrand, Ollivier; Thomas, Xavier; Turlure, Pascal; Reman, Oumedaly; de Revel, Thierry; Gastaud, Lauris; de Gunzburg, Noémie; Contentin, Nathalie; Henry, Estelle; Marolleau, Jean-Pierre; Aljijakli, Ahmad; Rousselot, Philippe; Fenaux, Pierre; Preudhomme, Claude; Chevret, Sylvie; Dombret, Hervé

2012-04-21

The results of the addition of gemtuzumab ozogamicin, an anti-CD33 antibody conjugate, to the standard treatment for patients with acute myeloid leukaemia in phase 3 trials were contradictory. We investigated whether the addition of low fractionated-dose gemtuzumab ozogamicin to standard front-line chemotherapy would improve the outcome of patients with this leukaemia without causing excessive toxicity. In a phase 3, open-label study, undertaken in 26 haematology centres in France, patients aged 50-70 years with previously untreated de novo acute myeloid leukaemia were randomly assigned with a computer-generated sequence in a 1:1 ratio with block sizes of four to standard treatment (control group) with or without five doses of intravenous gemtuzumab ozogamicin (3 mg/m(2) on days 1, 4, and 7 during induction and day 1 of each of the two consolidation chemotherapy courses). The primary endpoint was event-free survival (EFS). Secondary endpoints were relapse-free (RFS), overall survival (OS), and safety. Analysis was by intention to treat. This study is registered with EudraCT, number 2007-002933-36. 280 patients were randomly assigned to the control (n=140) and gemtuzumab ozogamicin groups (n=140), and 139 patients were analysed in each group. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group (odds ratio 1·46, 95% CI 0·20-2·59; p=0·25). At 2 years, EFS was estimated as 17·1% (10·8-27·1) in the control group versus 40·8% (32·8-50·8) in the gemtuzumab ozogamicin group (hazard ratio 0·58, 0·43-0·78; p=0·0003), OS 41·9% (33·1-53·1) versus 53·2% (44·6-63·5), respectively (0·69, 0·49-0·98; p=0·0368), and RFS 22·7% (14·5-35·7) versus 50·3% (41·0-61·6), respectively (0·52, 0·36-0·75; p=0·0003). Haematological toxicity, particularly persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group than in the control group (22 [16%] vs 4 [3%]; p<0·0001), without an increase in the risk of death from toxicity. The use of fractionated lower doses of gemtuzumab ozogamicin allows the safe delivery of higher cumulative doses and substantially improves outcomes in patients with acute myeloid leukaemia. The findings warrant reassessment of gemtuzumab ozogamicin as front-line therapy for acute myeloid leukaemia. Wyeth (Pfizer). Copyright © 2012 Elsevier Ltd. All rights reserved.

The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study.

PubMed

Hijazi, Ziad; Oldgren, Jonas; Lindbäck, Johan; Alexander, John H; Connolly, Stuart J; Eikelboom, John W; Ezekowitz, Michael D; Held, Claes; Hylek, Elaine M; Lopes, Renato D; Siegbahn, Agneta; Yusuf, Salim; Granger, Christopher B; Wallentin, Lars

2016-06-04

The benefit of oral anticoagulation in atrial fibrillation is based on a balance between reduction in ischaemic stroke and increase in major bleeding. We aimed to develop and validate a new biomarker-based risk score to improve the prognostication of major bleeding in patients with atrial fibrillation. We developed and internally validated a new biomarker-based risk score for major bleeding in 14,537 patients with atrial fibrillation randomised to apixaban versus warfarin in the ARISTOTLE trial and externally validated it in 8468 patients with atrial fibrillation randomised to dabigatran versus warfarin in the RE-LY trial. Plasma samples for determination of candidate biomarker concentrations were obtained at randomisation. Major bleeding events were centrally adjudicated. The predictive values of biomarkers and clinical variables were assessed with Cox regression models. The most important variables were included in the score with weights proportional to the model coefficients. The ARISTOTLE and RE-LY trials are registered with ClinicalTrials.gov, numbers NCT00412984 and NCT00262600, respectively. The most important predictors for major bleeding were the concentrations of the biomarkers growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and haemoglobin, age, and previous bleeding. The ABC-bleeding score (age, biomarkers [GDF-15, cTnT-hs, and haemoglobin], and clinical history [previous bleeding]) score yielded a higher c-index than the conventional HAS-BLED and the newer ORBIT scores for major bleeding in both the derivation cohort (0·68 [95% CI 0·66-0·70] vs 0·61 [0·59-0·63] vs 0·65 [0·62-0·67], respectively; ABC-bleeding vs HAS-BLED p<0·0001 and ABC-bleeding vs ORBIT p=0·0008). ABC-bleeding score also yielded a higher c-index score in the the external validation cohort (0·71 [95% CI 0·68-0·73] vs 0·62 [0·59-0·64] for HAS-BLED vs 0·68 [0·65-0·70] for ORBIT; ABC-bleeding vs HAS-BLED p<0·0001 and ABC-bleeding vs ORBIT p=0·0016). A modified ABC-bleeding score using alternative biomarkers (haematocrit, cTnI-hs, cystatin C, or creatinine clearance) also outperformed the HAS-BLED and ORBIT scores. The ABC-bleeding score, using age, history of bleeding, and three biomarkers (haemoglobin, cTn-hs, and GDF-15 or cystatin C/CKD-EPI) was internally and externally validated and calibrated in large cohorts of patients with atrial fibrillation receiving anticoagulation therapy. The ABC-bleeding score performed better than HAS-BLED and ORBIT scores and should be useful as decision support on anticoagulation treatment in patients with atrial fibrillation. BMS, Pfizer, Boehringer Ingelheim, Roche Diagnostics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Involvement of AMPK, IKβα-NFκB and eNOS in the sildenafil anti-inflammatory mechanism in a demyelination model.

PubMed

Nunes, Ana Karolina Santana; Rapôso, Catarina; Rocha, Sura Wanessa Santos; Barbosa, Karla Patrícia de Sousa; Luna, Rayana Leal de Almeida; da Cruz-Höfling, Maria Alice; Peixoto, Christina Alves

2015-11-19

Sildenafil (Viagra®) has recently been found to have a neuroprotective effect, which occurs through the inhibition of inflammation and demyelination in the cerebellum. However, the mechanism of action of sildenafil remains unknown. AMPK, the regulatory protein of the lipid and glucose metabolism, plays a protective role by activating the eNOS enzyme. The production of a nanomolar concentration of NO by eNOS has an anti-inflammatory effect through the cGMP signaling pathway and plays an important role in the regulation of the nuclear transcription factor (NFkB), preventing the expression of inflammatory genes. The present study investigated whether AMPK-eNOS-NO-cGMP-IКβα-NFkB is involved in the mechanism of action of sildenafil in a cuprizone-demyelination model. Neuroinflammation and demyelination induced by cuprizone in rodents have been widely used as a model of MS. In the present study, five male C57BL/6 mice (7-10 weeks old) were used. Over a four week period, the groups received: cuprizone (CPZ) 0.2% mixed in feed; CPZ in the diet, combined with the administration of sildenafil (Viagra®, Pfizer, 25mg/kg) orally in drinking water, starting concurrently (sild-T0) or 15 days (sild-T15) after the start of CPZ. Control animals received pure food and water. The cerebella of the mice were dissected and processed for immunohistochemistry, immunofluorescence (frozen), western blotting and dosage of cytokines (Elisa). CPZ induced an increase in the expression of GFAP, IL-1β TNF-α, total NFkB and inactive AMPK, and prompt microglia activation. CPZ also induced a reduction of IKβα. The administration of sildenafil reduced the expression of the pro-inflammatory cytokines IL-1β and TNF-α and increased the expression of the anti-inflammatory cytokine IL-10. In addition, the administration of sildenafil reduced expression of GFAP, NFkB, inactive AMPK and iNOS, and increased IKβα. Interestingly, sildenafil also reduced levels of NGF. In general, the sild-T0 group was more effective than sild-T15 in improving clinical status and promoting the control of neuroinflammation. The present study offers evidence that sildenafil has anti-inflammatory and neuroprotective effects, which are probably achieved through modulation of AMPK-IKβα-NFκB signaling. In addition, eNOS may play a role in the sildenafil neuroprotective mechanism, contributing to the activation of AMPK. However, other pathways such as MAPK-NFkB and the downstream proteins AMPK (AMPK-SIRT1-NFκB) should also be further investigated. An understanding of these mechanisms of action is critical for the clinical use of sildenafil to control neuroinflammation in neurodegenerative diseases such as MS. Copyright © 2015 Elsevier B.V. All rights reserved.

Patent Pooling for Promoting Access to Antiretroviral Drugs (ARVs) – A Strategic Option for India

PubMed Central

Satyanarayana, Kanikaram; Srivastava, Sadhana

2010-01-01

The current HIV/AIDS scenario in India is quite grim with an estimated 2.4 million people living with HIV/AIDS (PLHA) in 2008, just behind South Africa and Nigeria. The anti-retroviral drugs (ARVs) remain the main stay of global HIV/AIDS treatment. Over 30 ARVs (single and FDCs) available under six categories viz., NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), Protease inhibitors, the new Fusion inhibitors, Entry inhibitors-CCR5 co-receptor antagonists and HIV integrase strand transfer inhibitors. The major originator companies for these ARVs are: Abbott, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Gilead, GlaxoSmithKline (GSK), Merck, Pfizer, Roche, and Tibotec. Beginning with zidovidine in 1987, all the drugs are available in the developed countries. In India, about 30 ARVs are available as generics manufactured by Aurobindo, Hyderabad, Andhra Pradesh; Cipla Limited, Goa; Emcure Pharmaceuticals, Pune, Maharashtra; Hetero Drugs, Hyderabad, Andhra Pradesh; Macleods Pharmaceuticals, Daman; Matrix Laboratories, Nashik, Maharashtra; Ranbaxy, Sirmour, Himachal Pradesh; and Strides Arcolab, Bangalore, Karnataka. The National AIDS Control Organization (NACO) set up in 1992 by the Govt. of India provides free ARVs to HIV positive patients in India since 2004. The drugs available in India include both single drugs and FDCs covering both first line and second line ARVs. Even while there are claims of stabilization of the disease load, there is still huge gap of those who require ARVs as only about 150,000 PLHA receive the ARVs from the Govt. and other sources. Access to ARVs therefore is still a cause of serious concern ever since India became fully Trade Related Aspects of Intellectual Property Rights (TRIPS)-complaint in 2005. Therefore, the Indian pharmaceutical companies cannot make generics for those for drugs introduced post-2005 due to product patent regime. Other concerns include heat stable, other better formulations and second line ARVs for adults and more drugs and formulations for paediatric groups, that are still to be widely available in India and other developing countries. To examine whether strong intellectual property (IP) protection systems are to be considered important barriers for the limited or lack of access to ARVs, we studied the patent profile of the ARVs of the originator companies within and outside India. We could record 93 patents in the United States Patent & Trademark Office (USPTO). The originator companies have been also aggressively filing and enforcing patents in India. There have been a few efforts by companies like Gilead and GSK to grant licenses to generic manufacturers in developing countries, ostensibly to promote access to ARVs through lower (two-tier) pricing. These steps are considered as too little and too late. There is an urgent need to look for alternative strategies to promote access to ARVs both linked to and independent of IPRs. Patent pooling as a viable strategy mooted by the UNITAID should be seriously explored to promote access to ARVs. India is ideally suited for trying out the patent pool strategy as most of the global requirement of affordable ARV drugs for HIV/AIDS treatment is sourced from Indian generic companies. PMID:20148091

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

PubMed Central

Gulley, James L.; Rajan, Arun; Spigel, David R.; Iannotti, Nicholas; Chandler, Jason; Wong, Deborah J. L.; Leach, Joseph; Edenfield, W. Jeff; Wang, Ding; Grote, Hans Juergen; von Heydebreck, Anja; Chin, Kevin; Cuillerot, Jean-Marie; Kelly, Karen

2017-01-01

Background Avelumab, a fully human IgG1 immune checkpoint inhibitor targeting programmed death ligand 1 (PD-L1), has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours. Here, we assessed avelumab treatment in patients with advanced, platinum-treated non-small cell lung cancer (NSCLC). Methods In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 sites in the United States. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or nonsquamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary endpoint was safety and tolerability. Secondary endpoints included best overall response, progression-free survival, overall survival, and clinical activity associated with PD-L1 expression. Responses were evaluated using RECIST v1.1, and analyses of antitumour activity and safety were performed in all patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov (NCT01772004); enrolment in this cohort is closed and the trial is ongoing. Findings Between 10 September 2013 and 24 June 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (interquartile range [first and third quartiles], 7·2–11·9 months). The most common treatment-related adverse events of any grade were fatigue (n=46; 25%), infusion-related reaction (n=38; 21%), and nausea (n=23; 13%). Grade ≥3 treatment-related adverse events occurred in 23 of 184 patients (13%); the most common were infusion-related reaction (n=4; 2%), elevated lipase (n=3; 2%), constipation (n=2; 1%), and dyspnoea (n=2; 1%). 16 of 184 patients (9%) had a serious adverse event related to treatment with avelumab, with infusion-related reaction (4 [2%]) and dyspnoea (2 [1%]) occurring in more than one patient. Immune-related treatment-related events occurred in 22 patients (12%). The confirmed objective response rate, regardless of PD-L1 status, was 12% (95% CI, 8–18), including one complete response and 21 partial responses. Seventy patients had stable disease, for an overall disease-control rate of 50%. Interpretation Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or resistant NSCLC, providing a rationale for additional studies of avelumab in this disease setting. Funding Merck KGaA, Darmstadt, Germany and Pfizer, Inc, New York, USA. PMID:28373005

Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial

PubMed Central

Rini, Brian I; Melichar, Bohuslav; Ueda, Takeshi; GrÜnwald, Viktor; Fishman, Mayer N; Arranz, José A; Bair, Angel H; Pithavala, Yazdi K; Andrews, Glen I; Pavlov, Dmitri; Kim, Sinil; Jonasch, Eric

2014-01-01

Summary Background Population pharmacokinetic data suggest axitinib plasma exposure correlates with efficacy in metastatic renal-cell carcinoma. Axitinib dose titration might optimise exposure and improve outcomes. We prospectively assessed the efficacy and safety of axitinib dose titration in previously untreated patients with metastatic renal-cell carcinoma. Methods In this randomised, double-blind, multicentre, phase 2 study, patients were enrolled from 49 hospitals and outpatient clinics in the Czech Republic, Germany, Japan, Russia, Spain, and USA. Patients with treatment-naive metastatic renal-cell carcinoma received axitinib 5 mg twice daily during a 4 week lead-in period. Those patients with blood pressure 150/90 mm Hg or lower, no grade 3 or 4 treatment-related toxic effects, no dose reductions, and no more than two antihypertensive drugs for 2 consecutive weeks were stratified by Eastern Cooperative Oncology Group performance status (0 vs 1), and then randomly assigned (1:1) to either masked titration with axitinib to total twice daily doses of 7 mg, and then 10 mg, if tolerated, or placebo titration. Patients who did not meet these criteria continued without titration. The primary objective was comparison of the proportion of patients achieving an objective response between randomised groups. Safety analyses were based on all patients who received at least one dose of axitinib. This ongoing trial is registered with ClinicalTrials.gov, number NCT00835978. Findings Between Sept 2, 2009, and Feb 28, 2011, we enrolled 213 patients, of whom 112 were randomly assigned to either the axitinib titration group (56 patients) or the placebo titration group (56 patients). 91 were not eligible for titration, and ten withdrew during the lead-in period. 30 patients (54%, 95% CI 40–67) in the axitinib titration group had an objective response, as did 19 patients (34%, 22–48]) in the placebo titration group (one-sided p=0·019). 54 (59%, 95% CI 49–70) of non-randomised patients achieved an objective response. Common grade 3 or worse, all-causality adverse events in treated patients were hypertension (ten [18%] of 56 in the axitinib titration group vs five [9%] of 56 in the placebo titration group vs 45 [49%] of 91 in the non-randomised group), diarrhoea (seven [13%] vs two [4%] vs eight [9%]), and decreased weight (four [7%] vs three [5%] vs six [7%]). One or more all-causality serious adverse events were reported in 15 (27%) patients in the axitinib titration group, 13 (23%) patients in the placebo titration group, and 35 (38%) non-randomised patients. The most common serious adverse events in all 213 patients were disease progression and dehydration (eight each [4%]), and diarrhoea, vomiting, pneumonia, and decreased appetite (four each [2%]). Interpretation The greater proportion of patients in the axitinib titration group achieving an objective response supports the concept of individual axitinib dose titration in selected patients with metastatic renal-cell carcinoma. Axitinib shows clinical activity with a manageable safety profile in treatment-naive patients with this disease. Funding Pfizer Inc. PMID:24140184

The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial.

PubMed

Roberts, Ian; Shakur, Haleema; Afolabi, Adefemi; Brohi, Karim; Coats, Tim; Dewan, Yashbir; Gando, Satoshi; Guyatt, Gordon; Hunt, B J; Morales, Carlos; Perel, Pablo; Prieto-Merino, David; Woolley, Tom

2011-03-26

The aim of the CRASH-2 trial was to assess the effects of early administration of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Tranexamic acid significantly reduced all-cause mortality. Because tranexamic acid is thought to exert its effect through inhibition of fibrinolysis, we undertook exploratory analyses of its effect on death due to bleeding. The CRASH-2 trial was undertaken in 274 hospitals in 40 countries. 20,211 adult trauma patients with, or at risk of, significant bleeding were randomly assigned within 8 h of injury to either tranexamic acid (loading dose 1 g over 10 min followed by infusion of 1 g over 8 h) or placebo. Patients were randomly assigned by selection of the lowest numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Both participants and study staff (site investigators and trial coordinating centre staff ) were masked to treatment allocation. We examined the effect of tranexamic acid on death due to bleeding according to time to treatment, severity of haemorrhage as assessed by systolic blood pressure, Glasgow coma score (GCS), and type of injury. All analyses were by intention to treat. The trial is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258, and South African Clinical Trial Register/Department of Health DOH-27-0607-1919. 10,096 patients were allocated to tranexamic acid and 10,115 to placebo, of whom 10,060 and 10,067, respectively, were analysed. 1063 deaths (35%) were due to bleeding. We recorded strong evidence that the effect of tranexamic acid on death due to bleeding varied according to the time from injury to treatment (test for interaction p<0.0001). Early treatment (≤1 h from injury) significantly reduced the risk of death due to bleeding (198/3747 [5.3%] events in tranexamic acid group vs 286/3704 [7.7%] in placebo group; relative risk [RR] 0.68, 95% CI 0.57-0.82; p<0.0001). Treatment given between 1 and 3 h also reduced the risk of death due to bleeding (147/3037 [4.8%] vs 184/2996 [6.1%]; RR 0.79, 0.64-0.97; p=0.03). Treatment given after 3 h seemed to increase the risk of death due to bleeding (144/3272 [4.4%] vs 103/3362 [3.1%]; RR 1.44, 1.12-1.84; p=0.004). We recorded no evidence that the effect of tranexamic acid on death due to bleeding varied by systolic blood pressure, Glasgow coma score, or type of injury. Tranexamic acid should be given as early as possible to bleeding trauma patients. For trauma patients admitted late after injury, tranexamic acid is less effective and could be harmful. UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation. Copyright © 2011 Elsevier Ltd. All rights reserved.

Efficacy and safety of additional 200-mg dose of celecoxib in adult patients with postoperative pain following extraction of impacted third mandibular molar: a multicenter, randomized, double-blind, placebo-controlled, phase II study in Japan.

PubMed

Saito, Ken'ichi; Kaneko, Akihiro; Machii, Katsuyuki; Ohta, Hiroyoshi; Ohkura, Masayuki; Suzuki, Makoto

2012-02-01

Although third mandibular molar extraction is a widely used and validated model of acute pain for evaluating analgesic efficacy, a large proportion of patients experience moderate or severe pain following this procedure and require analgesia. Current treatment options have been associated with safety concerns and alternative therapies are sought. Our aim was to assess the efficacy and safety of an additional 200-mg dose of celecoxib, administered 5 to 12 hours after an initial 400-mg dose of the drug for the treatment of moderate or severe acute pain following extraction of an impacted third mandibular molar. This was a multicenter, randomized, double-blind, placebo-controlled, Phase II study. Patients experiencing moderate or severe pain within 1 to 2 hours following extraction of an impacted third mandibular molar received an initial 400-mg dose of celecoxib. Patients requiring additional analgesia were subsequently randomized to receive either an additional 200-mg dose of celecoxib or placebo 5 to 12 hours after the initial dose. The study was designed and conducted by Pfizer Inc. for approval of celecoxib in Japan for the indication of acute pain. The primary end point was the patient's impression of efficacy (4-category global evaluation scale). Secondary efficacy end points included pain intensity on a 4-category pain intensity scale, pain intensity on a 100-mm visual analog scale (VAS), and the pain intensity difference (100-mm VAS). In an exploratory analysis, use of rescue medication was evaluated. Primary and secondary end points were analyzed using the full analysis set. Assessment of the safety profile included a physical examination, measurement of pulse rate and blood pressure, standard 12-lead ECG, and laboratory tests. A total of 69 patients (celecoxib, 42/64 [65.6%]; placebo, 27/58 [46.6%]) received the additional dose of study medication; all completed the study without the need for rescue medication. A significantly higher proportion of patients in the celecoxib 200 mg group (41/64 [64.1%]) compared with the placebo group (15/58 [25.9%]) rated the study medication as "good" or "excellent" ≥ 2 hours after the additional dose (P < 0.0001). Pain intensity (VAS) 2 hours after the additional dose was significantly higher in the placebo group than in the celecoxib 200 mg group (P = 0.0003). The reduction in pain intensity from baseline to 2 hours after the additional dose of study medication was also significantly greater in the celecoxib 200 mg group than in the placebo group (P < 0.0001). The incidence of treatment-related, all-cause adverse events was slightly lower in patients receiving celecoxib 200 mg (20.3%) compared with placebo (31.0%). Overall, an additional 200-mg dose of celecoxib was well tolerated and efficacious in reducing the pain associated with extraction of an impacted third mandibular molar in the study population. ClinicalTrials.gov identifier: NCT01062113. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Patent Pooling for Promoting Access to Antiretroviral Drugs (ARVs) - A Strategic Option for India.

PubMed

Satyanarayana, Kanikaram; Srivastava, Sadhana

2010-01-19

The current HIV/AIDS scenario in India is quite grim with an estimated 2.4 million people living with HIV/AIDS (PLHA) in 2008, just behind South Africa and Nigeria. The anti-retroviral drugs (ARVs) remain the main stay of global HIV/AIDS treatment. Over 30 ARVs (single and FDCs) available under six categories viz., NRTIs (nucleoside reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), Protease inhibitors, the new Fusion inhibitors, Entry inhibitors-CCR5 co-receptor antagonists and HIV integrase strand transfer inhibitors. The major originator companies for these ARVs are: Abbott, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Gilead, GlaxoSmithKline (GSK), Merck, Pfizer, Roche, and Tibotec. Beginning with zidovidine in 1987, all the drugs are available in the developed countries. In India, about 30 ARVs are available as generics manufactured by Aurobindo, Hyderabad, Andhra Pradesh; Cipla Limited, Goa; Emcure Pharmaceuticals, Pune, Maharashtra; Hetero Drugs, Hyderabad, Andhra Pradesh; Macleods Pharmaceuticals, Daman; Matrix Laboratories, Nashik, Maharashtra; Ranbaxy, Sirmour, Himachal Pradesh; and Strides Arcolab, Bangalore, Karnataka. The National AIDS Control Organization (NACO) set up in 1992 by the Govt. of India provides free ARVs to HIV positive patients in India since 2004. The drugs available in India include both single drugs and FDCs covering both first line and second line ARVs. Even while there are claims of stabilization of the disease load, there is still huge gap of those who require ARVs as only about 150,000 PLHA receive the ARVs from the Govt. and other sources. Access to ARVs therefore is still a cause of serious concern ever since India became fully Trade Related Aspects of Intellectual Property Rights (TRIPS)-complaint in 2005. Therefore, the Indian pharmaceutical companies cannot make generics for those for drugs introduced post-2005 due to product patent regime. Other concerns include heat stable, other better formulations and second line ARVs for adults and more drugs and formulations for paediatric groups, that are still to be widely available in India and other developing countries. To examine whether strong intellectual property (IP) protection systems are to be considered important barriers for the limited or lack of access to ARVs, we studied the patent profile of the ARVs of the originator companies within and outside India. We could record 93 patents in the United States Patent & Trademark Office (USPTO). The originator companies have been also aggressively filing and enforcing patents in India. There have been a few efforts by companies like Gilead and GSK to grant licenses to generic manufacturers in developing countries, ostensibly to promote access to ARVs through lower (two-tier) pricing. These steps are considered as too little and too late. There is an urgent need to look for alternative strategies to promote access to ARVs both linked to and independent of IPRs. Patent pooling as a viable strategy mooted by the UNITAID should be seriously explored to promote access to ARVs. India is ideally suited for trying out the patent pool strategy as most of the global requirement of affordable ARV drugs for HIV/AIDS treatment is sourced from Indian generic companies.

Increasing incidence and importance of HIV/AIDS and gonorrhea among men aged >/= 50 years in the US in the era of erectile dysfunction therapy.

PubMed

Karlovsky, Matthew; Lebed, Brett; Mydlo, Jack H

2004-01-01

With the advent of effective pharmacotherapy for erectile dysfunction, the risk of sexually transmitted diseases is a possible consequence, especially in the older population. We wanted to review the incidence of sexually transmitted diseases in the older population in an attempt to correlate this with the advent of these new drugs. Publicly available information on the incidence of HIV, AIDS and gonorrhea was retrieved from the websites of the Centers for Disease Control (CDC), the State of Florida Department of Health, the Senior HIV Intervention Project and the National Association on HIV Over Fifty. National case incidences of HIV and AIDS in men between 1996 and 2000 were examined for trends. National and Florida state trends were compared and, in Florida, Palm Beach, Broward and Dade counties in particular were selected because of their traditionally large retiree population. In addition, the national and Florida state incidences of gonorrheal infection were examined for trends. Statistics on national sildenafil (Viagra) prescriptions were obtained via a personal communication with a regional healthcare representative from Pfizer. According to the CDC, at the end of 1998 >10% of new AIDS cases nationally were in individuals aged >50 years. In the late 1990s, new AIDS cases rose faster in middle-aged and older adults than in people aged >40 years. Many of the newly diagnosed cases of AIDS may have contracted HIV before the age of 50 years; however, many individuals are newly becoming infected above the age of 50 years. Of the reported AIDS cases in 1996 in individuals aged >/= 50 years, 48% were aged 50-54 years, 26% were aged 55-59 years, 14% were aged 60-64 years and 12% were aged >/= 65 years; 84% of these cases were male, and blacks accounted for the greatest proportion of cases (43%). In the US, 7.5 million prescriptions for sildenafil were written in 1998, 9.5 million in 1999, 12 million in 2000 and 15.5 million in 2001. The age breakdown for these prescriptions was as follows: 40-49 years, 23%; 50-59 years, 35%; and 60-69 years, 25%. The past decade saw rises in heterosexual transmission of HIV and i.v. drug use, especially in the population aged >50 years. The CDC reports that the incidence of new HIV infection is stabilizing in men aged 30-39 years and even falling in men aged 20-29 years. Gonorrhea is well known to increase infectivity for HIV and other STDs. Although the rates of gonorrhea infection fell throughout the early 1990s, they increased by 9% between 1997 and 1999. The number of sildenafil prescriptions has increased by almost 80% over the last few years. Although there may be multiple contributory factors for these findings, to our knowledge this is the first paper in the urologic literature to examine such trends in the older male population, especially in the light of newly available medications for erectile dysfunction.

Ability and Use of Comparative Effectiveness Research by P&T Committee Members and Support Staff: A 1-Year Follow-up.

PubMed

Augustine, Jill; Warholak, Terri L; Hines, Lisa E; Sun, Diana; Brown, Mary; Hurwitz, Jason; Taylor, Ann M; Brixner, Diana; Cobaugh, Daniel J; Schlaifer, Marissa; Malone, Daniel C

2016-06-01

In recent years, comparative effectiveness tools and methods have evolved to assist health care decision makers in identifying optimal therapies. In-person training programs on comparative effectiveness research may be helpful in understanding and applying this information. To provide a follow-up assessment of the use of comparative effectiveness research (CER) in the pharmacy and therapeutics (P&T) committee decision-making process, using information collected from participants 1 year after attending a live continuing education program, in which participants were taught about CER designs and how to access available CER resources through the Agency for Healthcare Research and Quality (AHRQ) Effective Health Care (EHC) Program. A retrospective, cross-sectional questionnaire was developed and mailed to 2 groups of individuals: CER workshop attendees and interested nonattendees (expressing an interest in attending a workshop but did not attend for unknown reasons). The questionnaire asked respondents to indicate personal and organizational use of CER in the decision-making process. Participants were asked to indicate whether their knowledge, ability, and use of CER studies increased since participating in the program. Data were analyzed using nonparametric tests to compare the responses of attendees and nonattendees, as well as overall reliability of the instrument. A total of 164 respondents completed the questionnaire (63 attendees and 101 nonattendees; overall response rate = 44%). The majority of respondents were pharmacists (n = 157, 95.7%) and were affiliated with a hospital (n = 106, 64.6%). Proportions of attendees and nonattendees differed significantly in the use of EHC research reviews/reports (45% and 28%, respectively; P = 0.02) and EHC executive summaries of research reviews/reports (48% and 29%, respectively; P = 0.01). At 1-year follow-up, the majority of attendees reported an increase ("somewhat" or "very much") in knowledge of CER (91.5%), ability to use CER (83.0%), and use of CER studies (58.7%). Health professionals attending a continuing education CER program reported higher use of EHC CER materials compared with nonattendees. Additionally, attendees reported increased use of CER in clinical decision making. A continuing education program such as this may provide an effective avenue for introducing CER methods and resources to the P&T committee and clinical decision-making processes. This project was supported by grant number R18HS019220 from the Agency of Healthcare Research and Quality. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Agency of Healthcare Research and Quality. Augustine has stock in Pfizer. The authors declared no other potential conflicts of interest associated with this study. Study concept and design were primarily contributed by Malone, along with Warholak, Hines, Brown, Hurwitz, and Taylor. Warholak, Hines, Brown, Hurwitz, and Taylor collected the data, assisted by Malone, Brixner, Cobaugh, and Schlaifer. Data interpretation was performed by Malone and Augustine, with assistance from the other authors. The manuscript was written primarily by Augustine, with assistance from Malone, Sun, Warholak, Hines, Brown, Hurwitz, and Taylor. Malone revised the manuscript, assisted by Warholak, Hines, Brown, Hurwitz, Taylor, Brixner, Cobaugh, and Schlaifer.

Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial.

PubMed

Easton, J Donald; Lopes, Renato D; Bahit, M Cecilia; Wojdyla, Daniel M; Granger, Christopher B; Wallentin, Lars; Alings, Marco; Goto, Shinya; Lewis, Basil S; Rosenqvist, Mårten; Hanna, Michael; Mohan, Puneet; Alexander, John H; Diener, Hans-Christoph

2012-06-01

In the ARISTOTLE trial, the rate of stroke or systemic embolism was reduced by apixaban compared with warfarin in patients with atrial fibrillation (AF). Patients with AF and previous stroke or transient ischaemic attack (TIA) have a high risk of stroke. We therefore aimed to assess the efficacy and safety of apixaban compared with warfarin in prespecified subgroups of patients with and without previous stroke or TIA. Between Dec 19, 2006, and April 2, 2010, patients were enrolled in the ARISTOTLE trial at 1034 clinical sites in 39 countries. 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalised ratio 2·0-3·0). The median duration of follow-up was 1·8 years (IQR 1·4-2·3). The primary efficacy outcome was stroke or systemic embolism, analysed by intention to treat. The primary safety outcome was major bleeding in the on-treatment population. All participants, investigators, and sponsors were masked to treatment assignments. In this subgroup analysis, we estimated event rates and used Cox models to compare outcomes in patients with and without previous stroke or TIA. The ARISTOTLE trial is registered with ClinicalTrials.gov, number NTC00412984. Of the trial population, 3436 (19%) had a previous stroke or TIA. In the subgroup of patients with previous stroke or TIA, the rate of stroke or systemic embolism was 2·46 per 100 patient-years of follow-up in the apixaban group and 3·24 in the warfarin group (hazard ratio [HR] 0·76, 95% CI 0·56 to 1·03); in the subgroup of patients without previous stroke or TIA, the rate of stroke or systemic embolism was 1·01 per 100 patient-years of follow-up with apixaban and 1·23 with warfarin (HR 0·82, 95% CI 0·65 to 1·03; p for interaction=0·71). The absolute reduction in the rate of stroke and systemic embolism with apixaban versus warfarin was 0·77 per 100 patient-years of follow-up (95% CI -0·08 to 1·63) in patients with and 0·22 (-0·03 to 0·47) in those without previous stroke or TIA. The difference in major bleeding with apixaban compared with warfarin was 1·07 per 100 patient-years (95% CI 0·09-2·04) in patients with and 0·93 (0·54-1·32) in those without previous stroke or TIA. The effects of apixaban versus warfarin were consistent in patients with AF with and without previous stroke or TIA. Owing to the higher risk of these outcomes in patients with previous stroke or TIA, the absolute benefits of apixaban might be greater in this population. Bristol-Myers Squibb and Pfizer. Copyright © 2012 Elsevier Ltd. All rights reserved.

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Martin, Miguel; Holmes, Frankie A; Ejlertsen, Bent; Delaloge, Suzette; Moy, Beverly; Iwata, Hiroji; von Minckwitz, Gunter; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Tomašević, Zorica; Denduluri, Neelima; Šeparović, Robert; Gokmen, Erhan; Bashford, Anna; Ruiz Borrego, Manuel; Kim, Sung-Bae; Jakobsen, Erik Hugger; Ciceniene, Audrone; Inoue, Kenichi; Overkamp, Friedrich; Heijns, Joan B; Armstrong, Anne C; Link, John S; Joy, Anil Abraham; Bryce, Richard; Wong, Alvin; Moran, Susan; Yao, Bin; Xu, Feng; Auerbach, Alan; Buyse, Marc; Chan, Arlene

2017-12-01

ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events. Wyeth, Pfizer, and Puma Biotechnology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.

PubMed

Patel, Manish R; Ellerton, John; Infante, Jeffrey R; Agrawal, Manish; Gordon, Michael; Aljumaily, Raid; Britten, Carolyn D; Dirix, Luc; Lee, Keun-Wook; Taylor, Mathew; Schöffski, Patrick; Wang, Ding; Ravaud, Alain; Gelb, Arnold B; Xiong, Junyuan; Rosen, Galit; Gulley, James L; Apolo, Andrea B

2018-01-01

The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Merck KGaA, and Pfizer Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.

PubMed

Gulley, James L; Rajan, Arun; Spigel, David R; Iannotti, Nicholas; Chandler, Jason; Wong, Deborah J L; Leach, Joseph; Edenfield, W Jeff; Wang, Ding; Grote, Hans Juergen; Heydebreck, Anja von; Chin, Kevin; Cuillerot, Jean-Marie; Kelly, Karen

2017-05-01

Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. Merck KGaA and Pfizer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial.

PubMed

Choueiri, Toni K; Larkin, James; Oya, Mototsugu; Thistlethwaite, Fiona; Martignoni, Marcella; Nathan, Paul; Powles, Thomas; McDermott, David; Robbins, Paul B; Chism, David D; Cho, Daniel; Atkins, Michael B; Gordon, Michael S; Gupta, Sumati; Uemura, Hirotsugu; Tomita, Yoshihiko; Compagnoni, Anna; Fowst, Camilla; di Pietro, Alessandra; Rini, Brian I

2018-04-01

The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54-100) of six patients in the dose-finding phase and 26 (53%, 38-68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44-71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Pfizer and Merck. Copyright © 2018 Elsevier Ltd. All rights reserved.

Assessment of dexrazoxane as a cardioprotectant in doxorubicin-treated children with high-risk acute lymphoblastic leukaemia: long-term follow-up of a prospective, randomised, multicentre trial.

PubMed

Lipshultz, Steven E; Scully, Rebecca E; Lipsitz, Stuart R; Sallan, Stephen E; Silverman, Lewis B; Miller, Tracie L; Barry, Elly V; Asselin, Barbara L; Athale, Uma; Clavell, Luis A; Larsen, Eric; Moghrabi, Albert; Samson, Yvan; Michon, Bruno; Schorin, Marshall A; Cohen, Harvey J; Neuberg, Donna S; Orav, E John; Colan, Steven D

2010-10-01

Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia (ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m² doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m² dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00165087. 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: -0·82, 95% CI -1·31 to -0·33; end-systolic dimension: 0·57, 0·21-0·93) but not for those who also received dexrazoxane (-0·41, -0·88 to 0·06; 0·15, -0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46-0·48) and thickness-to-dimension ratio (0·66, 0·64-0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24-2·11), but not in boys (-0·10, -0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44-1·85), but not in boys (0·19, -0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3-12·1), event-free survival was 77% (95% CI 67-84) for children in the doxorubicin-alone group, and 76% (67-84) for children in the doxorubicin plus dexrazoxane group (p=0·99). Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis. Copyright © 2010 Elsevier Ltd. All rights reserved.

Presence of human papillomavirus in semen in relation to semen quality.

PubMed

Luttmer, Roosmarijn; Dijkstra, Maaike G; Snijders, Peter J F; Hompes, Peter G A; Pronk, Divera T M; Hubeek, Isabelle; Berkhof, Johannes; Heideman, Daniëlle A M; Meijer, Chris J L M

2016-02-01

Is the presence of human papillomavirus (HPV) in semen associated with impairment of semen quality? In a large cohort of males seeking fertility evaluation, no associations were observed between seminal HPV presence and semen parameters. HPV is commonly detected in semen samples. Whether the presence of HPV is related to impairment of semen quality, remains unclear. This cross-sectional study included a cohort of 430 males. Male partners in couples seeking fertility evaluation provided one semen sample per person. Semen samples were tested for HPV-DNA using GP5+/6+-PCR. Sperm concentration was counted and motility was assessed in a Makler counting chamber at a magnification of ×200. The presence of antisperm antibodies was assessed by a mixed agglutination reaction (MAR)-test. Overall HPV was detected in 14.9% (64/430) of semen samples, including 2.1% (9/430) that contained both high-risk (hr) HPV and low-risk (lr) HPV types, 8.8% (38/430) with exclusively hrHPV types and 4.0% (17/430) with exclusively lrHPV types. The presence of HPV in semen was not associated with the age of the participants, seminal pH, semen volume, total sperm count, sperm concentration, progressive motility or the presence of antisperm antibodies. This study did not observe an association between HPV presence in semen and impairment of semen quality. However, we cannot exclude an effect of seminal HPV on early embryo development and clinical reproductive outcomes. As HPV is frequently present in semen, screening of donor semen for HPV should be considered to prevent iatrogenic cervical HPV infections in the recipient. However our findings do not support standardized HPV testing of semen in the diagnostic work-up of subfertile couples. This study was sponsored by an unrestricted grant of Stichting Researchfonds Pathology Amsterdam, the Netherlands. P.J.F.S. has been on the speakers bureau of Roche, Gen-Probe, Abbott, Qiagen and Seegene and has been a consultant for Crucell B.V. J.B. has been on the speakers bureau of Qiagen and has been a consultant for Roche, DDL Diagnostic Laboratory, GlaxoSmithKline and Merck. D.A.M.H. has been member of the scientific advisory boards of Amgen and Pfizer, and has been on the speakers bureau of Hologic/Gen-Probe. C.J.L.M.M. has been on the speakers bureau of GlaxoSmithKline, Qiagen, Merck, Roche, Menarini and Seegene, has served occasionally on the scientific advisory board of GlaxoSmithKline, Qiagen, Merck, Roche and Genticel, and has occasionally been a consultant for Qiagen. Formerly, C.J.L.M.M. was a minority shareholder of Delphi Biosciences, which bankrupted in 2014. C.J.L.M.M. is a minority shareholder of Diassay B.V. P.J.F.S., D.A.M.H. and C.J.L.M.M. have minority stake in Self-Screen B.V., a spin-off company of VU University Medical Center. R.L., M.G.D., P.G.A.H., D.T.M.P., and I.H. do not have any conflicts of interest to disclose. Not applicable. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Proceedings of Synthetic Biology: Engineering, Evolution and Design (SEED) Conference 2015

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silver, Pamela; Flach, Evan

Synthetic Biology is an emerging discipline that seeks to accelerate the process of engineering biology. As such, the tools are broadly applicable to application areas, including chemicals and biofuels, materials, medicine and agriculture. A characteristic of the field is to look holistically at cellular design, from sensing and genetic circuitry to the manipulation of cellular processes and actuators, to controlling metabolism, to programming multicellular behaviors. Further, the types of cells that are manipulated are broad, from in vitro systems to microbes and fungi to mammalian and plant cells and living animals. Many of the projects in synthetic biology seek tomore » move biochemical functions across organisms. The field is highly interdisciplinary with faculty and students spread across departments that focus on engineering (biological, chemical, electrical, mechanical, civil, computer science) and basic science (biology and systems biology, chemistry, physics). While there have been many one-off workshops and meeting on synthetic biology, the 2014 Synthetic Biology: Engineering, Evolution and Design (SEED) was the first of an annual conference series that serves as a reliable place to pull together the involved disciplines in order to organize and exchange advances in the science and technology in the field. Further, the SEED conferences have a strong focus on industry, with many companies represented and actively participating. A number of these companies have started major efforts in synthetic biology including large companies (e.g., Pfizer, Novartis, Dow, Dupont, BP, Total), smaller companies have recently gone public (e.g., Amyris, Gevo, Intrexon), and many start-ups (e.g., Teslagen, Refactored Materials, Pivot, Genomatica). There are a number of loosely affiliated Synthetic Biology Centers, including ones at MIT, Boston University, UCSD, UCSF, UC-Berkeley, Imperial College, Oxford, and ETH. SEED 2015 will serve as the primary meeting at which international synthetic biology centers and related infrastructure (synthesis/software/foundries) meet to discuss technology, standards, and education. SEED2015 will be the second in an annual series of meeting held to bring researchers from industry and academia in the area of Synthetic Biology. The first SEED conference was highly successful, attracting 285 attendees with varying backgrounds from academia, industry and government. The SEED series provides leadership in the development of the field of synthetic biology and serves to broaden the participants in the field by appealing to broad sectors in industry and providing a means for young investigators and those outside of the field to participate. Further, the series closely integrates with groups such as the SBCC to provide a means by which the synthetic biology community can communicate with policy makers. Further, we will pursue making the meeting the center for the exchange of educational materials as centers for synthetic biology emerge globally. Proceedings will be published each year in the journal ACS Synthetic Biology. After each SEED meeting, surveys are distributed to assess the success of the conference and to help guide changes year-to-year. The diverse application areas further extend the expertise needed from people in areas such as plant biology, agriculture and soil science, environmental science, medicine, and the chemical industry. These areas could have a widespread impact on society in a number of ways. For example, the CRISPR/Cas9 system that serves to immunize bacteria from phage has provided the fundamental chemistry that is used to edit the genomes of diverse organisms, including human stem cells, crop plants, and livestock animals.« less

Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis.

PubMed

Saleheen, Danish; Haycock, Philip C; Zhao, Wei; Rasheed, Asif; Taleb, Adam; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Akhtar, Saba; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Mallick, Nadeem Hayyat; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-Ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Frossard, Philippe; Tsimikas, Sotirios; Witztum, Joseph L; Marcovina, Santica; Sandhu, Manjinder; Rader, Daniel J; Danesh, John

2017-07-01

The lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease. In this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease. The PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90-0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05-1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94-0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07-1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS. Human genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart disease. Lipoprotein(a)-lowering interventions could be preferentially effective in reducing the risk of coronary heart disease in individuals with smaller apolipoprotein(a) isoforms. British Heart Foundation, US National Institutes of Health, Fogarty International Center, Wellcome Trust, UK Medical Research Council, UK National Institute for Health Research, and Pfizer. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.

Relationship between maternal asthma, its severity and control and abortion.

PubMed

Blais, Lucie; Kettani, Fatima-Zohra; Forget, Amélie

2013-04-01

Are women with asthma, and more specifically those with severe or uncontrolled asthma, at higher risk of spontaneous and induced abortions? Pregnant women with asthma, notably when uncontrolled, are at higher risk of spontaneous abortion. Only one study has examined the association between asthma and spontaneous and induced abortions and revealed a modest increase in the risk of spontaneous abortions, particularly in women with more severe asthma and those with previous exacerbations, and a marginal decrease in the risk of induced abortions. A cohort of pregnancies from asthmatic (n = 15,107) and non-asthmatic (n = 34,331) women was reconstructed by linking three administrative databases from Quebec (Canada), between 1992 and 2002. The cohort included 7870 spontaneous abortions, 14,596 induced abortions and 26,972 live births. Pregnant women with and without asthma were analyzed. Asthma was defined by at least one asthma diagnosis and one dispensed prescription for an asthma medication in the 2 years prior to or during pregnancy. Asthma severity and control were assessed using validated indexes in the year before the 20th week of pregnancy or the termination of the pregnancy. Logistic polytomous regression models were used to estimate the relationship between asthma and asthma severity and control on the risk of abortion, while adjusting for potential confounders. The prevalence of spontaneous and induced abortions was 15.9 and 29.5%, respectively. Maternal asthma was associated with an increased risk of a spontaneous abortion [odds ratio (OR) = 1.41; 95% confidence interval (CI): 1.33-1.49] and a decreased risk of induced abortions (OR = 0.92; 0.88-0.97). No association was observed between asthma severity and abortion, while uncontrolled asthma increased the risk of a spontaneous abortion by 26% (95% CI: 14-41%) and the risk of induced abortions by 11% (95% CI: 1-21%). It is possible that the study results were confounded by imbalances between groups in variables that are not recorded in the databases, but that are known to be associated with spontaneous abortions, such as alcohol consumption, obesity or maternal smoking. However, we performed sensitivity analyses which revealed that these factors are unlikely to explain the observed increased risk for a spontaneous abortion. It is also possible that women with asthma are more likely to have abortions recorded in the databases, because subjects with a chronic disease tend to visit a physician more often than those without asthma. Therefore, our odds estimates for these outcomes may be overestimated when asthmatic women were compared with non-asthmatic women. A further limitation of the study is that it would have been more appropriate to measure the severity and control of asthma only during the pregnancy. Our cohort is less representative of women in the upper socio-economic level. This is not a threat to internal validity, but it could limit the external validity if the impact of asthma on the risk of abortion differed according to the socio-economic status of the mother. Despite the absence of supporting data, this possibility cannot be completely excluded. This study was funded by the Canadian Institutes of Health Research and Genentech. L.B. received research grants from Astra-Zeneca, Pfizer, sanofi-aventis, Novartis and Merck for research projects and co-chairs the Astra-Zeneca Endowment Pharmaceutical Chair in Respiratory Health. F.Z.K and A.F. have no competing interests to declare.

Neo-angiogenesis metabolic biomarker of tumor-genesis tracking by infrared joystick contact imaging in personalized homecare system

NASA Astrophysics Data System (ADS)

Szu, Harold; Hoekstra, Philip; Landa, Joseph; Vydelingum, Nadarajen A.

2014-05-01

We describe an affordable, harmless, and administrative (AHA) metabolic biomarker (MBM) for homecare cancer screening. It may save hundreds of thousands of women's and thousands of men's lives every year from breast cancer and melanoma. The goal is to increase the specificity of infrared (IR) imagery to reduce the false alarm rate (FAR). The patient's hands are immersed in icy cold water, about 11oC, for 30 seconds. We then compare two IR images, taken before and after the cold stimulus, and the difference reveals an enhanced signal and noise ratio (SNR) at tumorigenesis sites since the contraction of capillaries under cold challenge is natural to healthy capillaries, except those newly built capillaries during angiogenesis (Folkman, Nature 1995). Concomitant with the genome and the phenome (molecular signaling by phosphor-mediate protein causing inflammation by platelet activating factor (PAF) that transform cells from benign to malignant is the amplification of nitric oxide (NO) syntheses, a short-lived reactive oxygen species (ROS) that dilates regional blood vessels; superseding normal autonomic nervous system regulation. A rapidly growing tumor site might implicate accumulation of ROS, for which NO can rapidly stretch the capillary bed system usually having thinning muscular lining known as Neo-Angiogenesis (NA) that could behave like Leaky In-situ Faucet Effect (LIFE) in response to cold challenge. To emphasize the state of art knowledge of NA, we mentioned in passing the first generation of an anticapillary growth drug, Avastin by Genetech; it is an antibody protein that is injected for metastasis, while the second generation drug; Sorafenib by Bayers (2001) and Sutent by Pfizer (2000) both target molecular signaling loci to block receptor associated tyrosine kinase induced protein phosphorylation in order to reverse the angiogenesis. Differentiating benign from malignant in a straightforward manner is required to achieve the wellness protocol, yet would become prohibitively expensive and impossible to follow through. For example, given the probability of detection (PD) about 0.1% over unspecified number of years (e.g. menopause years for breast cancer), one might need hundred thousand volunteers. We suggested a Time Reversal Invariant Paradigm (TRIP) (a private communication with Vatican) for gathering equivalent cancer symptom imagery from recovery histories of dozens of patients. We further mixed it with few % of recovered/non-sick cases for negative controls. Creating Virtual images and running videos of these, frame by frame, in two directions (forward and backward in time) resulted in identical Receiver Operation Characteristics (ROC) for both the computer Aided Target Recognition (AiTR) algorithm and the human radiological experts; namely PD versus FAR within the standard deviation; even though the physiology could be entirely different. Such a TRIP would be true taken by any memory-less instantaneous imagery devices (IR, ultrasound, X-rays, MRI excluding magnetic hysteresis memory). In summary, such an affordable, harmless, and administrative, neo-angiogenesis metabolic biomarker can help monitor the transitioning from benign to malignant states of high-risk home alone seniors and also monitor the progress of home alone seniors treatment at home. Therefore, Smartphone equipped with a day camera having IR spectral filtering for a contact self imaging called joystick, when augmented with AHA NA MBM, may be suited for HAS homecare.

Budget Impact of Adding Ivabradine to Standard of Care in Patients with Chronic Systolic Heart Failure in the United States.

PubMed

Borer, Jeffrey S; Kansal, Anuraag R; Dorman, Emily D; Krotneva, Stanimira; Zheng, Ying; Patel, Harshali K; Tavazzi, Luigi; Komajda, Michel; Ford, Ian; Böhm, Michael; Kielhorn, Adrian

2016-09-01

Heart failure (HF) costs $21 billion annually in direct health care costs, 80% of which is directly attributable to hospitalizations. The SHIFT clinical study demonstrated that ivabradine plus standard of care (SoC) reduced HF-related and all-cause hospitalizations compared with SoC alone. To estimate the budget impact of ivabradine from a U.S. commercial payer perspective. A budget impact model estimated the per-member-per month (PMPM) impact of introducing ivabradine to existing formularies by comparing a reference scenario (SoC) and a new drug scenario (ivabradine + SoC) in hypothetical 1 million-member commercial and Medicare Advantage plans. In both scenarios, U.S. claims data were used for the reference cumulative annual rates of hospitalizations (HF, non-HF cardiovascular [CV], and non-CV), and hospitalization rates were adjusted using SHIFT data. The model controlled for mortality risk using SHIFT and U.S. life table data, and hospitalization costs were obtained from U.S. claims data: HF-related = $37,507; non-HF CV = $28,951; and non-CV = $17,904. The annualized wholesale acquisition cost of ivabradine was $4,500, with baseline use for this new drug at 2%, increasing 2% per year. Based on the approved U.S. indication, approximately 2,000 commercially insured patients from a 1 million-member commercial plan were eligible to receive ivabradine. Ivabradine resulted in a PMPM cost savings of $0.01 and $0.04 in years 1 and 3 of the core model, respectively. After including the acquisition price for ivabradine, the model showed a decrease in total costs in the commercial ($991,256 and $474,499, respectively) and Medicare populations ($13,849,262 and $4,280,291, respectively) in year 1. This decrease was driven by ivabradine's reduction in hospitalization rates. For the core model, the estimated pharmacy-only PMPM in year 1 was $0.01 for the commercial population and $0.24 for the Medicare Advantage population. Adding ivabradine to SoC led to lower average annual treatment costs. The negative PMPM budget impact indicates that ivabradine is an affordable option for U.S. payers. This study was funded by Amgen. Patel is employed by Amgen; Kielhorn was employed by Amgen at the time of the study but is no longer affiliated with Amgen. Borer, Böhm, Ford, and Komajda have received scientific support, consultative fees, and/or speakers honoraria from Servier and Amgen in connection with SHIFT, the trial underlying this analysis. Borer also has received consultative fees from Celladon, Pfizer, ARMGO, Cardiorentis, Novartis, and Takeda USA. Kansal, Dorman, Krotneva, and Zheng are employees of Evidera, which was hired to assist with this study. Tavazzi has received research grants and consultation fees from Servier in connection with this study and has had advisory board memberships with Boston Scientific, Servier, Cardiorentis, Medtronic, St. Jude Medical, and CVie Therapeutics. Study concept and design were contributed by Dorman and Keilhorn, along with the other authors. Tavazzi, Komajda, Ford, BÖhm, and Borer oversaw collection of the data. Tavazzi, Komajda, Ford, BÖhm, and Borer (along with Karl Swedberg) formed the Executive Committee of SHIFT, the trial underlying this analysis. The manuscript was written by Kansal, along with the other authors, and revised by Borer and Patel, with assistance from the other authors.

Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry.

PubMed

Tomson, Torbjörn; Battino, Dina; Bonizzoni, Erminio; Craig, John; Lindhout, Dick; Perucca, Emilio; Sabers, Anne; Thomas, Sanjeev V; Vajda, Frank

2018-06-01

Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the eight most commonly used antiepileptic drugs in monotherapy. We did a longitudinal, prospective cohort study based on the EURAP international registry. We included data from pregnancies in women who were exposed to antiepileptic drug monotherapy at conception, prospectively identified from 42 countries contributing to EURAP. Follow-up data were obtained after each trimester, at birth, and 1 year after birth. The primary objective was to compare the risk of major congenital malformations assessed at 1 year after birth in offspring exposed prenatally to one of eight commonly used antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, topiramate, and valproate) and, whenever a dose dependency was identified, to compare the risks at different dose ranges. Logistic regression was used to make direct comparisons between treatments after adjustment for potential confounders and prognostic factors. Between June 20, 1999, and May 20, 2016, 7555 prospective pregnancies met the eligibility criteria. Of those eligible, 7355 pregnancies were exposed to one of the eight antiepileptic drugs for which the prevalence of major congenital malformations was 142 (10·3%) of 1381 pregnancies for valproate, 19 (6·5%) of 294 for phenobarbital, eight (6·4%) of 125 for phenytoin, 107 (5·5%) of 1957 for carbamazepine, six (3·9%) of 152 for topiramate, ten (3·0%) of 333 for oxcarbazepine, 74 (2·9%) of 2514 for lamotrigine, and 17 (2·8%) of 599 for levetiracetam. The prevalence of major congenital malformations increased with the dose at time of conception for carbamazepine (p=0·0140), lamotrigine (p=0·0145), phenobarbital (p=0·0390), and valproate (p<0·0001). After adjustment, multivariable analysis showed that the prevalence of major congenital malformations was significantly higher for all doses of carbamazepine and valproate as well as for phenobarbital at doses of more than 80 mg/day than for lamotrigine at doses of 325 mg/day or less. Valproate at doses of 650 mg/day or less was also associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (odds ratio [OR] 2·43, 95% CI 1·30-4·55; p=0·0069). Carbamazepine at doses of more than 700 mg/day was associated with increased risk of major congenital malformations compared with levetiracetam at doses of 250-4000 mg/day (OR 2·41, 95% CI 1·33-4·38; p=0·0055) and oxcarbazepine at doses of 75-4500 mg/day (2·37, 1·17-4·80; p=0·0169). Different antiepileptic drugs and dosages have different teratogenic risks. Risks of major congenital malformation associated with lamotrigine, levetiracetam, and oxcarbazepine were within the range reported in the literature for offspring unexposed to antiepileptic drugs. These findings facilitate rational selection of these drugs, taking into account comparative risks associated with treatment alternatives. Data for topiramate and phenytoin should be interpreted cautiously because of the small number of exposures in this study. Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, UCB, the Netherlands Epilepsy Foundation, and Stockholm County Council. Copyright © 2018 Elsevier Ltd. All rights reserved.

Crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumours with and without anaplastic lymphoma kinase gene alterations (European Organisation for Research and Treatment of Cancer 90101 CREATE): a multicentre, single-drug, prospective, non-randomised phase 2 trial.

PubMed

Schöffski, Patrick; Sufliarsky, Jozef; Gelderblom, Hans; Blay, Jean-Yves; Strauss, Sandra J; Stacchiotti, Silvia; Rutkowski, Piotr; Lindner, Lars H; Leahy, Michael G; Italiano, Antoine; Isambert, Nicolas; Debiec-Rychter, Maria; Sciot, Raf; Van Cann, Thomas; Marréaud, Sandrine; Nzokirantevye, Axelle; Collette, Sandra; Wozniak, Agnieszka

2018-06-01

An inflammatory myofibroblastic tumour (IMFT) is a rare mesenchymal neoplasm characterised by anaplastic lymphoma kinase (ALK) gene rearrangements. We assessed the activity and safety of crizotinib, a tyrosine kinase inhibitor, targeting ALK in patients with advanced IMFT either with or without ALK alterations. We did a multicentre, biomarker-driven, single-drug, non-randomised, open-label, two-stage phase 2 trial (European Organisation for Research and Treatment of Cancer 90101 CREATE) at 13 study sites (five university hospitals and eight specialty clinics) in eight European countries (Belgium, France, Germany, Italy, Netherlands, Poland, Slovakia, and the UK). Eligible participants were patients aged at least 15 years with a local diagnosis of advanced or metastatic IMFT deemed incurable with surgery, radiotherapy, or systemic therapy; measurable disease; an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, renal, and liver function. Central reference pathology was done for confirmation of the diagnosis, and ALK positivity or negativity was assessed centrally using immunohistochemistry and fluorescence in-situ hybridisation based on archival tumour tissue and defined as ALK immunopositivity or rearrangements in at least 15% of tumour cells. Eligible ALK-positive and ALK-negative patients received oral crizotinib 250 mg twice per day administered on a continuous daily dosing schedule (the duration of each treatment cycle was 21 days) until documented disease progression, unacceptable toxicity, or patient refusal. If at least two of the first 12 eligible and assessable ALK-positive patients achieved a confirmed complete or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, a maximum of 35 patients were to be enrolled. If at least six ALK-positive patients achieved a confirmed response, the trial would be deemed successful. The primary endpoint was the proportion of patients who achieved an objective response (ie, a complete or partial response) as per RECIST 1.1, with response confirmation assessed by the local investigator every other cycle. Activity and safety endpoints were analysed in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01524926. Between Oct 3, 2012, and April 12, 2017, we recruited and treated 20 eligible participants, 19 of whom were assessable for the primary endpoint. Median follow-up was 863 days (IQR 358-1304). Six of 12 ALK-positive patients (50%, 95% CI 21·1-78·9) and one of seven ALK-negative patients (14%, 0·0-57·9) achieved an objective response. The most common treatment-related adverse events in the 20 participants were nausea (11 [55%]), fatigue (9 [45%]), blurred vision (nine [45%]), vomiting (seven [35%]), and diarrhoea (seven [35%]). Eight serious adverse events occurred in five patients: pneumonia, fever of unknown cause, a heart attack with increased creatinine and possible sepsis, an abdominal abscess with acute renal insufficiency, and a QT prolongation. With 50% of participants with ALK-positive tumours achieving an objective response, crizotinib met the prespecified criteria for success in this trial. The results presented here support the rationale for inhibiting ALK in patients with IMFT. Crizotinib could be considered as the standard of care for patients with locally advanced or metastatic ALK-positive IMFT who do not qualify for curative surgery. The European Organisation for Research and Treatment of Cancer and Pfizer. Copyright © 2018 Elsevier Ltd. All rights reserved.

The effect of internal teat sealant products (Teatseal and Orbeseal) on intramammary infection, clinical mastitis, and somatic cell counts in lactating dairy cows: a meta-analysis.

PubMed

Rabiee, A R; Lean, I J

2013-01-01

The objective of this study was to assess the efficacy of internal teat sealant products containing bismuth subnitrate (Teatseal and Orbeseal; Pfizer Animal Health, West Ryde, Australia) when used alone, or in the presence of antibiotic dry cow therapy (ADCT), before or at drying off on the incidence of new intramammary infections (IMI), clinical mastitis, and milk somatic cell count (SCC) during lactation. The literature search identified 18 English-language publications on the use of Teatseal in dairy cattle. A total of 12 studies with 17 subtrials or comparisons including 13 positive control subtrials (internal teat sealant and ADCT vs. ADCT) and 4 negative control subtrials (internal teat sealant vs. untreated) examining IMI were included in the analysis. Internal teat sealants, alone or in the presence of ADCT, reduced the risk of acquiring new IMI after calving by 25% [risk ratio (RR)=0.75; 95% confidence interval (CI): 0.67 to 0.83]. Internal teat sealants reduced the risk of IMI by 73% compared with untreated cows (RR=0.27; 95% CI: 0.13 to 0.55). The results of both meta-analyses of IMI, with positive and negative controls, were heterogeneous [I(2) (a statistic that describes the proportion of total variation in study effect estimates that is due to heterogeneity)=65.4 and 92.1%]. No farm or cow factors studied significantly contributed to the heterogeneity of the results. A total of 16 studies (21 subtrials), including 14 positive control subtrials and 7 negative control subtrials, examining clinical mastitis were included in the analysis. Internal teat sealants alone and in the presence of ADCT reduced the risk of clinical mastitis after calving in lactating cows by 29% (RR=0.71; 95% CI: 0.62 to 0.82), and 48% (RR=0.52; 95% CI: 0.37 to 0.75), respectively. The results of the meta-analysis on clinical mastitis with positive controls were homogeneous (I(2)=33.6%), whereas the results of studies with negative controls were heterogeneous (I(2)=60.4%). No farm or cow factors studied that had sufficient data to evaluate significantly contributed to the heterogeneity of the results. The estimated linear score (LS) of milk SCC after calving in published studies (n=3) and for studies that provided raw data (n=2), was significantly lower for cattle treated with internal teat sealants and ADCT in 3 studies than for cattle treated with internal teat sealants only. The estimated LS of pooled raw data of 3 studies from 32 herds showed that the LS of cows treated with internal teat sealant and ADCT was not significantly different than those treated with ADCT only. This study found that the application of internal teat sealants in the presence of ADCT or the use of internal teat sealants alone at dry off significantly reduced the incidence of IMI and clinical mastitis in lactating dairy cows compared with respective control groups. Further studies are needed to investigate the effect of internal teat sealants on postpartum milk SCC in lactating dairy cows. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Trends in underlying causes of death in people with HIV from 1999 to 2011 (D:A:D): a multicohort collaboration.

PubMed

Smith, Colette J; Ryom, Lene; Weber, Rainer; Morlat, Philippe; Pradier, Christian; Reiss, Peter; Kowalska, Justyna D; de Wit, Stephane; Law, Matthew; el Sadr, Wafaa; Kirk, Ole; Friis-Moller, Nina; Monforte, Antonella d'Arminio; Phillips, Andrew N; Sabin, Caroline A; Lundgren, Jens D

2014-07-19

With the advent of effective antiretroviral treatment, the life expectancy for people with HIV is now approaching that seen in the general population. Consequently, the relative importance of other traditionally non-AIDS-related morbidities has increased. We investigated trends over time in all-cause mortality and for specific causes of death in people with HIV from 1999 to 2011. Individuals from the Data collection on Adverse events of anti-HIV Drugs (D:A:D) study were followed up from March, 1999, until death, loss to follow-up, or Feb 1, 2011, whichever occurred first. The D:A:D study is a collaboration of 11 cohort studies following HIV-1-positive individuals receiving care at 212 clinics in Europe, USA, and Australia. All fatal events were centrally validated at the D:A:D coordinating centre using coding causes of death in HIV (CoDe) methodology. We calculated relative rates using Poisson regression. 3909 of the 49,731 D:A:D study participants died during the 308,719 person-years of follow-up (crude incidence mortality rate, 12.7 per 1000 person-years [95% CI 12.3-13.1]). Leading underlying causes were: AIDS-related (1123 [29%] deaths), non-AIDS-defining cancers (590 [15%] deaths), liver disease (515 [13%] deaths), and cardiovascular disease (436 [11%] deaths). Rates of all-cause death per 1000 person-years decreased from 17.5 in 1999-2000 to 9.1 in 2009-11; we saw similar decreases in death rates per 1000 person-years over the same period for AIDS-related deaths (5.9 to 2.0), deaths from liver disease (2.7 to 0.9), and cardiovascular disease deaths (1.8 to 0.9). However, non-AIDS cancers increased slightly from 1.6 per 1000 person-years in 1999-2000 to 2.1 in 2009-11 (p=0.58). After adjustment for factors that changed over time, including CD4 cell count, we detected no decreases in AIDS-related death rates (relative rate for 2009-11 vs 1999-2000: 0.92 [0.70-1.22]). However, all-cause (0.72 [0.61-0.83]), liver disease (0.48 [0.32-0.74]), and cardiovascular disease (0.33 [0.20-0.53) death rates still decreased over time. The percentage of all deaths that were AIDS-related (87/256 [34%] in 1999-2000 and 141/627 [22%] in 2009-11) and liver-related (40/256 [16%] in 1999-2000 and 64/627 [10%] in 2009-11) decreased over time, whereas non-AIDS cancers increased (24/256 [9%] in 1999-2000 to 142/627 [23%] in 2009-11). Recent reductions in rates of AIDS-related deaths are linked with continued improvement in CD4 cell count. We hypothesise that the substantially reduced rates of liver disease and cardiovascular disease deaths over time could be explained by improved use of non-HIV-specific preventive interventions. Non-AIDS cancer is now the leading non-AIDS cause and without any evidence of improvement. Oversight Committee for the Evaluation of Metabolic Complications of HAART, with representatives from academia, patient community, US Food and Drug Administration, European Medicines Agency and consortium of AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F Hoffmann-La Roche, and Janssen Pharmaceuticals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

PubMed

Atkins, Michael B; Plimack, Elizabeth R; Puzanov, Igor; Fishman, Mayer N; McDermott, David F; Cho, Daniel C; Vaishampayan, Ulka; George, Saby; Olencki, Thomas E; Tarazi, Jamal C; Rosbrook, Brad; Fernandez, Kathrine C; Lechuga, Mariajose; Choueiri, Toni K

2018-03-01

Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). Pfizer Inc. Copyright © 2018 Elsevier Ltd. All rights reserved.

Tectonic-erosion coupling? The erosional response to India-Asia collision

NASA Astrophysics Data System (ADS)

Najman, Y.; Henderson, A.; Jenks, D.; Parrish, R.; Horstwood, M.; Foster, G. L.; Green, O.

2009-04-01

In order to use the detrital record as an archive of hinterland evolution, we need to understand the erosional response to tectonics. Collision of India and Asia at ca 50 Ma [1 and refs therein] resulted in the subsequent development of the Himalayan orogen. What was the erosional response to this event? Most basins into which Himalayan detritus may have been deposited have now been researched at least at reconnaissance level. The conclusion reached is that, as yet, there appears to be no evidence of substantial detritus eroded from the southern flanks of the rising Himalayan mountain belt prior to ~40 Ma, 10 My after collision. In the Indus suture zone basin, detritus is predominantly sourced from the Trans-Himalayan arc of the northern, Asian plate, rather than the Himalaya to the south [2, 3]. In the peripheral foreland basin, the oldest substantial Himalayan-derived detritus is dated at <40 Ma [4]. To the west, in the Katawaz remnant ocean basin and offshore Indus Fan, earliest Himalayan derived deposits are poorly dated, insubstantial, and/or predominantly derived from north of the suture zone rather than the rising Himalayan thrust belt to the south [5, 6]. In the east, earliest Himalayan-derived material is dated at 38 Ma in the Bengal remnant ocean basin [7], and "post-Paleocene" in the Bengal Fan [8 and refs therein]. Paleogene sediments of the Sunda Arc accretionary prism, originally thought to be offscraped Himalayan-derived Bengal Fan [9, 10] are now shown to be predominantly derived from the arc to the east [11, 12]. What could be reason for this ~10 My delay between collision and first documented products of erosion from the mountain belt? The delay has been explained by suggesting collision occurred considerably later than commonly believed [13]. However, this is at variance with provenance data which show that material of Asian origin was deposited on the Indian plate by 50 Ma [14, 15] A second possibility is that Palaeogene Himalayan-derived detritus may lie beneath the overthrust fold-thrust belt. A third possibility is that the time gap does in fact represent a true delayed response to erosion after collision. This idea is consistent with the evidence of a transition from slow to exponentially increasing accumulation rates in offshore basins adjacent to the Himalaya around the start of the Oligocene. A 10 million year delayed response to erosion following India-Asia collision has been ascribed to either climatic causes or subdued topography in the early stages of collision, the result of a number of proposed mechanisms [16-18]. Given the bedrock evidence for metamorphism in the Himalaya that requires early crustal thickening [19, 20], we would favour those models that allow early crustal thickening, but retard erosion or uplift, if indeed early erosion was negligible. Such a study illustrates how the detrital record can inform and constrain models of crustal deformation, but also serves to show how incomplete our understanding of the principles of tectonic-erosion coupling currently stand. 1. Hodges, K.V.. GSA Bull, 2000. 112 p. 324-350. 2. Henderson, A., et al., (abstr). EGU 2009; this conference.. 3. Wu, F.Y., et al Tectonics, 2007. 26. 4. Najman, Y., et al., Nature, 2001. 410(6825): p. 194-197. 5. Clift, P.D., et al., GSA Bull, 2001. 113: p. 1039-1051. 6. Qayyum, M., et al. GSA Bull, 2001. 113: p. 320-332. 7. Najman, Y., et al., EPSL, 2008. 273: p. 1-14. 8. Curray, J.R. et al. Marine & Petrol. Geol., 2003. 19: p. 1191-1223. 9. Curray, J.R., J. Asian Earth Sci., 2005. 25: p. 187-232. 10. Curray, J.R., et al., AAPG Memoir, J.. Watkins, Ed.. 1979. p. 189-198. 11. Allen, R., et al., GSA Spec. Pap, A. Draut & P.D. Clift, Eds. 2008. p. 223-255. 12. Allen, R., et al., J. Geol. Soc. London, 2008. 165: p. 1045-1057. 13. Aitchison, J.C., J.R. Ali, and A.M. Davis, J. Geophys. Res., 2007. 112: p. B05423. 14. Critelli, S. & E. Garzanti, Sed. Geol, 1994. 89: p. 265-284. 15. Jenks, D., et al., (abstr.). EGU 2009; this conference. 16. Guillot, S., et al., G3 2003. 4: p. 1064. 17. Kohn, M.J. & C.D. Parkinson, Geology, 2002. 30: p. 591-594. 18. Metivier, F., et al., Geophys J. Internat, 1999. 137: p. 280-318. 19. Foster, G., et al., EPSL, 2000. 181: p. 327-340. 20. Vance, D. & N. Harris, Geology, 1999. 27: p. 395-398.

Seasonal and spatial contrasts of sedimentary organic carbon in floodplain lakes of the central Amazon basin.

NASA Astrophysics Data System (ADS)

Sobrinho, Rodrigo; Kim, Jung-Hyun; Abril, Gwenaël; Zell, Claudia; Moreira-Turcq, Patricia; Mortillaro, Jean-Michel; Meziane, Tarik; Damsté, Jaap; Bernardes, Marcelo

2014-05-01

Three-quarters of the area of flooded land in the world are temporary wetlands (Downing, 2009), which play a significant role in the global carbon cycle(Einsele et al., 2001; Cole et al., 2007; Battin et al., 2009; Abril et al., 2013). Previous studies of the Amazonian floodplain lakes (várzeas), one important compartment of wetlands, showed that the sedimentation of organic carbon (OC) in the floodplain lakes is strongly linked to the periodical floods and to the biogeography from upstream to downstream(Victoria et al., 1992; Martinelli et al., 2003). However, the main sources of sedimentary OC remain uncertain. Hence, the study of the sources of OC buried in floodplain lake sediments can enhance our understanding of the carbon balance of the Amazon ecosystems. In this study, we investigated the seasonal and spatial pattern of sedimentary organic matter in five floodplain lakes of the central Amazon basin (Cabaliana, Janauaca, Canaçari, Miratuba, and Curuai) which have different morphologies, hydrodynamics and vegetation coverage. Surface sediments were collected in four hydrological seasons: low water (LW), rising water (RW), high water (HW) and falling water (FW) in 2009 and 2010. We investigated commonly used bulk geochemical tracers such as C:N ratio and stable isotopic composition of organic carbon (δ13COC). These results were compared with lignin-phenol parameters as an indicator of vascular plant detritus (Hedges and Ertel, 1982) and branched glycerol dialkyl glycerol tetraethers (brGDGTs) to trace the soil OC from land to the aquatic settings (Hopmans et al., 2004). Our data showed that during the RW and FW seasons, the concentration of lignin and brGDGTs were higher in comparison to other seasons. Our study also indicated that floodplain lake sediments primarily consisted of a mixture of C3 plant detritus and soil OC. However, a downstream increase in C4 plant-derived OC contribution was observed along the gradient of increasingly open waters, i.e. from upstream to downstream. We also identify the OC contribution from the seasonally flooded forests, i.e. temporary wetlands as the most important source of sedimentary OC in floodplain lakes. Accordingly, we attribute temporal and spatial difference in sedimentary OC composition to the hydrological connectivity between the Amazon River and its floodplain lakes and thus between the surrounding forests and the floodplain lakes. References: Abril, G., J.-M.Martinez, Artigas, L.F., Moreira-Turcq, P., Benedetti, M.P., Vidal, L., Meziane, T., Kim, J.-H., Bernardes, M.C., Savoye, N., Deborde, J., Albéric, P., Souza, M.F.L., Souza, E.L., Roland, F. Amazon River carbon dioxide outgassing fuelled by wetlands. Nature accepted (2013). Battin, T.J., Luyssaert, S., Kaplan, L.A., Aufdenkampe, A.K., Richter, A., Tranvik, L.J., 2009. The boundless carbon cycle. Nature Geoscience 2, 598 - 600 (2009). Cole, J.J., Prairie, Y.T., Caraco, N.F., McDowell, W.H., Tranvik, L.J., Striegl, R.G., Duarte, C.M., Kortelainen, P., Downing, J.A., Middelburg, J.J., Melack, J. Plumbing the Global Carbon Cycle: Integrating Inland Waters into the Terrestrial Carbon Budget. Ecosystems 10, 171 - 184 (2007). Downing, J. A. Global limnology: up-scaling aquatic services and processes to planet Earth. Verh Internat Verein Limnol 30, 1149.-1166 (2009). Einsele, G., Yan, J., Hinderer, M. Atmospheric carbon burial in modern lake basins and its significance for the global carbon budget. Global and Planetary Change 30, 167 - 195 (2001). Hedges, J.I., Ertel, J.R. Characterization of Lignin by Gas Capillary Chromatography of Cupric Oxide Oxidation Products. Analitical Chemistry 54, 174-178 (1982). Hopmans, E.C., Weijers, J.W.H., Schefu, E., Herfort, L., Damste, J.S.S., Schouten, S.,. A novel proxy for terrestrial organic matter in sediments based on branched and isoprenoid tetraether lipids. Earth and Planetary Science Letters 224, 107 - 116 (2004). Martinelli, L.A., Victoria, R.L., Camargo, P.B.d., Piccolo, M.d.C., Mertes, L., Richey, J.E., Devol, A.H., Forsberg, B.R.. Inland variability of carbon-nitrogen concentrations and d13C in Amazon floodplain (várzea) vegetation and sediment. Hydrol. Process. 17, 1419-1430 (2003). Victoria, R.L., Martinelli, L.A., Trivelin, P.C.O., Matsui, E., Forsberg, B.R., Richey, J.E., Devol, A.H.. The use of stable isotopes in studies of nutrient cycling: Carbon Isotope composition of Amazon varzea sediments. Biotropica 24, 240-249 (1992).

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-01-01

Summary Background Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Methods Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m2) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). Findings 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60–71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23–184). Median follow-up was 43 months (IQR 30–60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79–1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66–0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69–0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3–5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Interpretation Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Funding Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research. PMID:26719232

It is important to note that RWD will never replace the more traditional and more robust RCT data; however, the emerging trend is to incorporate data that are more generalizable. Introduction.

PubMed

Mullins, C Daniel; Sanchez, Robert J

2011-01-01

The Patient Protection and Affordable Care Act brought considerable attention to comparative effectiveness research (CER).   To (a) suggest best practices for conducting and reporting CER using "real-world data" (RWD), (b) describe some of the data and infrastructure requirements for conducting CER using RWD, (c) identify statistical challenges with the analysis of nonrandomized studies and suggest appropriate techniques to address those challenges, (d) recognize the value of patient-reported outcomes in CER, (e) encourage the incorporation of observational data into randomized controlled studies, and (f) highlight the importance of incorporating payers in industry-sponsored research.  The first article in this supplement, "Something old, something new…" provides a policy perspective on the recent evolution of CER. It reviews the historical context, discusses the "promise and fear" of CER, and then describes the new role of the Patient-Centered Outcomes Research Institute (PCORI) in defining and sponsoring CER. The second paper, "Ten Commandments," proposes a series of tenets for planning, conducting, and reporting CER done with RWD. Oriented for basic-to-intermediate researchers, it combines standard scientific research principles with considerations specific to nonrandomized, RWD studies. The third article, "Infrastructure Requirements," points out that effective use of secondary data requires addressing major methodological and infrastructural issues, including development of analytical tools to readily access and analyze data, formulation of guidelines to enhance quality and transparency, establishment of data standards, and creation of data warehouses that respect the privacy and confidentiality of patients. It identifies gaps that must be filled to address the underlying issues, with emphasis on data standards, data quality assurance, data warehouses, computing environment, and protection of privacy and confidentiality. The fourth paper, "Statistical Issues," discusses how the validity of analytic results from observational studies is adversely impacted by biases that may be introduced due to lack of randomization. It reviews some of the methodological challenges that arise in the analysis of data from nonrandomized studies, with particular emphasis on the limitations of traditional approaches and potential solutions from recent methodological developments. The fifth paper, "Considerations on the Use of Patient Reported Outcomes (PROs)," describes how PRO data can play a critical role in guiding patients, health care providers, payers, and policy makers in making informed decisions regarding patient-centered treatment from among alternative options and technologies and have been noted as such by PCORI. However, collection and interpretation of such data within the context of CER have not yet been fully established. It discusses some challenges with including PROs in CER initiatives, provides a framework for their effective use, and proposes several areas for future research. Lastly, "Developing a Collaborative Study Protocol…" indicates that there is the potential, the desire, and the capability for payers to be involved in CER studies, combining elements of their own observational data with prospective studies. It describes a case example of a payer, a pharmaceutical company, and a research organization collaborating on a prospective study to examine the effect of prior authorization for pregabalin on health care costs to the payer.   Researchers at Pfizer routinely conduct CER-type studies. In this supplement, we have proposed some approaches that we believe are useful in developing certain kinds of evidence and have described some of our experiences. Our experiences also make us acutely aware of the limitations of approaches and data sources that have been used for CER studies and suggest that there is a need to further develop methods that are most useful for answering CER questions.

AMCP Partnership Forum: FDAMA Section 114-Improving the Exchange of Health Care Economic Data.

PubMed

2016-07-01

The Food and Drug Administration Modernization Act (FDAMA) of 1997 included Section 114 as a regulatory safe harbor with the goal of increasing the dissemination of health care economic information (HCEI) to those responsible for formulary decision making. HCEI is typically not included within FDA-approved labeling. Although it has been nearly 20 years since passage and enactment of Section 114, proactive distribution of HCEI has been underutilized by biopharmaceutical companies partly because of (a) vague wording in the statute and (b) the absence of FDA-implementing regulations. Consequently, companies and health care decisions makers have had to speculate about the scope of the provisions. As a result, the biopharmaceutical industry has significant concerns about stepping over the line when using the safe harbor. Also, payers and other "payer-like" decision makers (e.g., self-funded corporate insurers) who are trying to make appropriate coverage and utilization decisions are demanding this information but are not receiving it because of the uncertainties in the statute. Considering this renewed interest by multiple stakeholders regarding the need for revisions and/or guidance pertaining to Section 114, the Academy of Managed Care Pharmacy held a partnership forum on March 1-2, 2016, with a diverse group of health care stakeholders to provide the FDA with considerations for disseminating a guidance document on current thinking for the sharing of HCEI with health care decision makers. Forum participants represented the managed care industry, biopharmaceutical industry, health care providers, pharmacoeconomic experts, policy experts, and patient advocacy groups with specific expertise in the development, use, and dissemination of HCEI. The multistakeholder group represented the key professionals and entities affected by the provisions of Section 114 and present the collective credibility necessary for Congress and the FDA to modernize and operationalize the safe harbor by using the consensus recommendations developed during the forum. Speakers, panelists, and attendees focused on 4 terms in Section 114 that remain open to interpretation by companies and enforcement bodies: (1) the scope of HCEI, (2) the scope of "formulary committee or similar entity," (3) the definition of "competent and reliable scientific evidence (CRSE)," and (4) the parameters of how information "directly relates to an approved indication." Based on the forum results, it was recommended that the safe harbor for companies' proactive dissemination of information under Section 114 should include health care decision makers beyond health plan formulary committees, including organizations, or individuals in their role in an organization, who make health care decisions for patient populations. Recommendations also suggested expansion to organizations that evaluate HCEI or develop value frameworks and compendia and individuals in such organizations. Forum participants also recommended that HCEI be truthful, and not misleading, and be based on the expertise of professionals in the relevant area. HCEI must also be developed and disclosed in a transparent, reproducible, and accurate manner. Forum participants also discussed and agreed on the types of information, format, and processes by which managed care pharmacy and other health care decision makers seek to receive HCEI from biopharmaceutical companies. Finally, participants encouraged the FDA, Congress, and other stakeholders to find ways to ensure that patients or their representative organizations have appropriate access to a full range of information about their medications and that information related to the medication pipeline is communicated to appropriate stakeholders in a timely manner. The AMCP Partnership Forum on FDAMA Section 114-Improving the Exchange of Pharmacoeconomic Data and the development of this proceedings document were supported by AbbVie, Amgen, Boehringer Ingelheim Pharmaceuticals, Merck & Co., National Pharmaceutical Council, Pharmaceutical Research and Manufacturers of America, Precision for Value, Pfizer, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and participated in revising and approving the manuscript.

Adherence to Rivaroxaban, Dabigatran, and Apixaban for Stroke Prevention in Incident, Treatment-Naïve Nonvalvular Atrial Fibrillation.

PubMed

Brown, Joshua D; Shewale, Anand R; Talbert, Jeffery C

2016-11-01

Non-vitamin K antagonist oral anticoagulants (NOACs) are widely used for prevention of stroke secondary to nonvalvular atrial fibrillation (NVAF). Increased use of NOACs is partially a result of simplified regimens compared with warfarin, which has been associated with poor adherence and persistence to therapy. Few studies have assessed adherence to NOACs, especially using contemporary data now that multiple NOACs are available. To evaluate adherence to NOACs in a cohort of newly diagnosed NVAF patients who are commercially insured. Incident, treatment-naïve NVAF patients were identified in 2013 from a large claims database. Patients were included who initiated rivaroxaban, dabigatran, or apixaban within 30 days after diagnosis. Subjects were required to have 12 months of pre-index information to assess demographic and clinical characteristics (comorbidities, CHA 2 DS 2 -VASc, and HAS-BLED scores). Adherence to the index medication and adherence to any oral anticoagulant was assessed using proportion of days covered (PDC) at 3, 6, and 9 months. The number of switches and gaps in therapy were also evaluated. Analyses were stratified by stroke risk scores, and a logistic regression model was used to control for factors that may predict high adherence (PDC ≥ 0.80). A total of 3,455 rivaroxaban, 1,264 dabigatran, and 504 apixaban users were included with no major clinical or demographic differences between groups. At 3, 6, and 9 months of follow-up, dabigatran had lower adherence (PDC = 0.77, 0.67, and 0.62) compared with rivaroxaban (PDC = 0.84, 0.75, and 0.70; P < 0.001) and apixaban (PDC = 0.82, 0.75, and 0.71; P < 0.001), as well as nearly twice the number of switches to either other anticoagulants or antiplatelet therapy. At 9 months, 55.0% of rivaroxaban initiators had PDC ≥ 0.80, which was comparable with 56.8% for apixaban and significantly greater than 46.7% for dabigatran (P < 0.001). Adherence was higher overall as stroke risk increased and showed dabigatran had consistently lower adherence compared with the other NOACs. Overall adherence to any oral anticoagulants, allowing for switches to another NOAC or warfarin, was not dependent on the index medication (9-month PDC = 0.74, 0.71, and 0.74 for rivaroxaban, dabigatran, and apixaban initiators). Adjusted analyses showed that increasing age and comorbid hypertension and diabetes were associated with higher adherence. Compared with rivaroxaban, dabigatran initiators had nearly 30% lower odds of being adherent to their index medication, and no differences were observed between apixaban and rivaroxaban. At 9 months, there were no differences between NOACs for overall adherence to oral anticoagulants. In this real-world analysis of adherence to NOACs, rivaroxaban and apixaban had favorable profiles compared with dabigatran, and rivaroxaban appeared to have higher overall adherence among the NOACs. Clinicians and managed care organizations should consider the implications of lower adherence on clinical outcomes as well as quality assessment. The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1TR000117. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Brown reports receiving a training fellowship from Human and Pfizer. Study concept and design were contributed by Brown and Shewale. Talbert took the lead in data collection, along with Brown, and data interpretation was primarily performed by Brown, along with Shewale. The manuscript was written primarily by Brown, along with Shewale, and revised by all the authors.

Celecoxib plus hormone therapy versus hormone therapy alone for hormone-sensitive prostate cancer: first results from the STAMPEDE multiarm, multistage, randomised controlled trial

PubMed Central

James, Nicholas D; Sydes, Matthew R; Mason, Malcolm D; Clarke, Noel W; Anderson, John; Dearnaley, David P; Dwyer, John; Jovic, Gordana; Ritchie, Alastair WS; Russell, J Martin; Sanders, Karen; Thalmann, George N; Bertelli, Gianfilippo; Birtle, Alison J; O'Sullivan, Joe M; Protheroe, Andrew; Sheehan, Denise; Srihari, Narayanan; Parmar, Mahesh KB

2012-01-01

Summary Background Long-term hormone therapy alone is standard care for metastatic or high-risk, non-metastatic prostate cancer. STAMPEDE—an international, open-label, randomised controlled trial—uses a novel multiarm, multistage design to assess whether the early additional use of one or two drugs (docetaxel, zoledronic acid, celecoxib, zoledronic acid and docetaxel, or zoledronic acid and celecoxib) improves survival in men starting first-line, long-term hormone therapy. Here, we report the preplanned, second intermediate analysis comparing hormone therapy plus celecoxib (arm D) with hormone therapy alone (control arm A). Methods Eligible patients were men with newly diagnosed or rapidly relapsing prostate cancer who were starting long-term hormone therapy for the first time. Hormone therapy was given as standard care in all trial arms, with local radiotherapy encouraged for newly diagnosed patients without distant metastasis. Randomisation was done using minimisation with a random element across seven stratification factors. Patients randomly allocated to arm D received celecoxib 400 mg twice daily, given orally, until 1 year or disease progression (including prostate-specific antigen [PSA] failure). The intermediate outcome was failure-free survival (FFS) in three activity stages; the primary outcome was overall survival in a subsequent efficacy stage. Research arms were compared pairwise against the control arm on an intention-to-treat basis. Accrual of further patients was discontinued in any research arm showing safety concerns or insufficient evidence of activity (lack of benefit) compared with the control arm. The minimum targeted activity at the second intermediate activity stage was a hazard ratio (HR) of 0·92. This trial is registered with ClinicalTrials.gov, number NCT00268476, and with Current Controlled Trials, number ISRCTN78818544. Findings 2043 patients were enrolled in the trial from Oct 17, 2005, to Jan 31, 2011, of whom 584 were randomly allocated to receive hormone therapy alone (control group; arm A) and 291 to receive hormone therapy plus celecoxib (arm D). At the preplanned analysis of the second intermediate activity stage, with 305 FFS events (209 in arm A, 96 in arm D), there was no evidence of an advantage for hormone therapy plus celecoxib over hormone therapy alone: HR 0·98 (95% CI 0·90–1·06). 2-year FFS was 51% (95% CI 46–56) in arm A and 51% (95% CI 43–58) in arm D. There was no evidence of differences in the incidence of adverse events between groups (events of grade 3 or higher were noted at any time in 123 [23%, 95% CI 20–27] patients in arm A and 64 [25%, 19–30] in arm D). The most common grade 3–5 events adverse effects in both groups were endocrine disorders (55 [11%] of patients in arm A vs 19 [7%] in arm D) and musculoskeletal disorders (30 [6%] of patients in arm A vs 15 [6%] in arm D). The independent data monitoring committee recommended stopping accrual to both celecoxib-containing arms on grounds of lack of benefit and discontinuing celecoxib for patients currently on treatment, which was endorsed by the trial steering committee. Interpretation Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone therapy for high-risk prostate cancer, and we do not recommend its use in this setting. Accrual continues seamlessly to the other research arms and follow-up of all arms will continue to assess effects on overall survival. Funding Cancer Research UK, Pfizer, Novartis, Sanofi-Aventis, Medical Research Council (London, UK). PMID:22452894

Oral anticoagulants for primary prevention, treatment and secondary prevention of venous thromboembolic disease, and for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis and cost-effectiveness analysis.

PubMed

Sterne, Jonathan Ac; Bodalia, Pritesh N; Bryden, Peter A; Davies, Philippa A; López-López, Jose A; Okoli, George N; Thom, Howard Hz; Caldwell, Deborah M; Dias, Sofia; Eaton, Diane; Higgins, Julian Pt; Hollingworth, Will; Salisbury, Chris; Savović, Jelena; Sofat, Reecha; Stephens-Boal, Annya; Welton, Nicky J; Hingorani, Aroon D

2017-03-01

Warfarin is effective for stroke prevention in atrial fibrillation (AF), but anticoagulation is underused in clinical care. The risk of venous thromboembolic disease during hospitalisation can be reduced by low-molecular-weight heparin (LMWH): warfarin is the most frequently prescribed anticoagulant for treatment and secondary prevention of venous thromboembolism (VTE). Warfarin-related bleeding is a major reason for hospitalisation for adverse drug effects. Warfarin is cheap but therapeutic monitoring increases treatment costs. Novel oral anticoagulants (NOACs) have more rapid onset and offset of action than warfarin, and more predictable dosing requirements. To determine the best oral anticoagulant/s for prevention of stroke in AF and for primary prevention, treatment and secondary prevention of VTE. Four systematic reviews, network meta-analyses (NMAs) and cost-effectiveness analyses (CEAs) of randomised controlled trials. Hospital (VTE primary prevention and acute treatment) and primary care/anticoagulation clinics (AF and VTE secondary prevention). Patients eligible for anticoagulation with warfarin (stroke prevention in AF, acute treatment or secondary prevention of VTE) or LMWH (primary prevention of VTE). NOACs, warfarin and LMWH, together with other interventions (antiplatelet therapy, placebo) evaluated in the evidence network. Efficacy  Stroke, symptomatic VTE, symptomatic deep-vein thrombosis and symptomatic pulmonary embolism. Safety  Major bleeding, clinically relevant bleeding and intracranial haemorrhage. We also considered myocardial infarction and all-cause mortality and evaluated cost-effectiveness. MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library, reference lists of published NMAs and trial registries. We searched MEDLINE and PREMEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. The stroke prevention in AF review search was run on the 12 March 2014 and updated on 15 September 2014, and covered the period 2010 to September 2014. The search for the three reviews in VTE was run on the 19 March 2014, updated on 15 September 2014, and covered the period 2008 to September 2014. Two reviewers screened search results, extracted and checked data, and assessed risk of bias. For each outcome we conducted standard meta-analysis and NMA. We evaluated cost-effectiveness using discrete-time Markov models. Apixaban (Eliquis ® , Bristol-Myers Squibb, USA; Pfizer, USA) [5 mg bd (twice daily)] was ranked as among the best interventions for stroke prevention in AF, and had the highest expected net benefit. Edoxaban (Lixiana ® , Daiichi Sankyo, Japan) [60 mg od (once daily)] was ranked second for major bleeding and all-cause mortality. Neither the clinical effectiveness analysis nor the CEA provided strong evidence that NOACs should replace postoperative LMWH in primary prevention of VTE. For acute treatment and secondary prevention of VTE, we found little evidence that NOACs offer an efficacy advantage over warfarin, but the risk of bleeding complications was lower for some NOACs than for warfarin. For a willingness-to-pay threshold of > £5000, apixaban (5 mg bd) had the highest expected net benefit for acute treatment of VTE. Aspirin or no pharmacotherapy were likely to be the most cost-effective interventions for secondary prevention of VTE: our results suggest that it is not cost-effective to prescribe NOACs or warfarin for this indication. NOACs have advantages over warfarin in patients with AF, but we found no strong evidence that they should replace warfarin or LMWH in primary prevention, treatment or secondary prevention of VTE. These relate mainly to shortfalls in the primary data: in particular, there were no head-to-head comparisons between different NOAC drugs. Calculating the expected value of sample information to clarify whether or not it would be justifiable to fund one or more head-to-head trials. This study is registered as PROSPERO CRD42013005324, CRD42013005331 and CRD42013005330. The National Institute for Health Research Health Technology Assessment programme.

Efficacy and safety of varenicline for smoking cessation in people living with HIV in France (ANRS 144 Inter-ACTIV): a randomised controlled phase 3 clinical trial.

PubMed

Mercié, Patrick; Arsandaux, Julie; Katlama, Christine; Ferret, Samuel; Beuscart, Aurélie; Spadone, Christian; Duvivier, Claudine; Reynes, Jacques; Wirth, Nathalie; Moinot, Laetitia; Bénard, Antoine; Zucman, David; Duval, Xavier; Molina, Jean-Michel; Spire, Bruno; Fagard, Catherine; Chêne, Geneviève

2018-03-01

Tobacco smoking is common in people living with HIV, but high-quality evidence on interventions for smoking cessation is not available in this population. We aimed to assess the efficacy and safety of varenicline with counselling to aid smoking cessation in people living with HIV. The ANRS 144 Inter-ACTIV randomised, parallel, double-blind, multicentre, placebo-controlled phase 3 trial was done at 30 clinical hospital sites in France. People living with HIV who had smoked at least ten cigarettes per day for 1 year or longer, were motivated to stop smoking, were not dependent on another psychoactive substance, and had no history of depression or suicide attempt were eligible. Using a computer-generated randomisation sequence, we allocated (1:1) the patients to receive either varenicline titrated to two 0·5 mg doses twice daily or placebo twice daily for 12 weeks, plus face-to-face counselling. Patients and investigators were masked to treatment group allocation. Patients who were not abstinent at week 24 were offered open-label varenicline for 12 additional weeks. The primary outcome was the proportion of smokers continuously abstinent from week 9 to week 48. Smoking status was confirmed by carbon monoxide in exhaled air. Primary analyses were done in both the intention-to-treat (ITT) population and modified ITT (mITT) population, which comprised all patients who took at least one tablet of their assigned study treatment. The safety analyses were done in the mITT population. The trial is registered at ClinicalTrials.gov, number NCT00918307. The trial status is complete. From Oct 26, 2009, to Dec 20, 2012, of 303 patients assessed for eligibility, 248 patients were randomly assigned to the varenicline group (n=123) or the placebo group (n=125). After randomisation, one participant initially assigned to the placebo group was excluded from the ITT analysis for a regulatory reason (no French health-care coverage). 102 patients in the varenicline group and 111 patients in the placebo group received at least one dose of their assigned treatment and were included in the mITT analysis. In the ITT analysis, varenicline was associated with a higher proportion of patients achieving continuous abstinence over the study period (week 9-48): 18 (15%, 95% CI 8-21) of 123 in the varenicline group versus eight (6%, 2-11) of 124 in the placebo group, adjusted odds ratio (OR) 2·5 (95% CI 1·0-6·1; p=0·041). In the mITT analysis, varenicline was also associated with higher continuous abstinence: 18 (18%, 95% CI 10-25) of 102 versus eight (7%, 2-12) of 111 in the placebo group (adjusted OR 2·7, 95% CI 1·1-6·5; p=0·029). The incidence of depression was 2·4 per 100 person-years (95% CI 0·6-9·5; two [2%] of 102) in the varenicline group and 12·4 per 100 person-years (95% CI 6·9-22·5; 11 [10%] of 111) in the placebo group. 14 (7%) of 213 participants had 18 cardiovascular events: six (6%) of 102 people in the varenicline group and eight (7%) of 111 people in the placebo group. Varenicline is safe and efficacious for smoking cessation in people living with HIV and should be recommended as the standard of care. The French National Institute for Health and Medical Research (INSERM)-French National Agency for Research on AIDS and Viral Hepatitis (ANRS) and Pfizer. Copyright © 2018 Elsevier Ltd. All rights reserved.

Economic Impact of Above-Label Dosing with Etanercept, Adalimumab, or Ustekinumab in Patients with Psoriasis.

PubMed

Feldman, Steven R; Zhao, Yang; Zhou, Huanxue; Herrera, Vivian; Tian, Haijun; Li, Yunfeng

2017-05-01

Patients with moderate-to-severe psoriasis may be treated with above-label doses of biologics in an attempt to optimize outcomes. Dose escalation will have an effect on the cost of treatment. To examine costs related to above-label use of etanercept, adalimumab, and ustekinumab among patients with moderate-to-severe psoriasis. A retrospective study was performed using a large U.S. claims database. Patients were included in the study if they were aged ≥ 18 years with a diagnosis of psoriasis (excluding psoriatic arthritis) and had at least 1 medication fill for etanercept, adalimumab, or ustekinumab between January 1, 2011, and June 30, 2012. In addition, patients were required to have continuous enrollment for 12 months before, and 18 months after, the first biologic use (index biologic) during the maintenance period (defined as the period following the induction period in which each agent was titrated to its recommended maintenance dose per label) and at least 1 prescription filled for the index biologic during the 18 months after the maintenance period. Extensive above-label use was defined as taking an above-label dose (at least 10% higher than indicated in the label) for ≥ 180 days over a 12-month period following the maintenance period. Percentages of patients with extensive above-label use, mean number of days of above-label use, and additional costs associated with extensive above-label use (abovelabel cost minus on-label cost) were examined. The study included 3,310 patients who started treatment with etanercept (n = 1,443), adalimumab (n = 1,447), or ustekinumab (n = 420). Extensive above-label use occurred in 20.0% of etanercept patients, 2.6% of adalimumab patients, and 14.8% of ustekinumab patients. The mean duration of extensive above-label use was roughly similar for the 3 biologics (mean days [±SD]: 282 [±55] for etanercept, 279 [±57] for adalimumab, and 305 [±43] for ustekinumab). Additional annual costs per patient because of extensive above-label use were $19,458 for etanercept, $18,972 for adalimumab, and $21,045 for ustekinumab. Total additional annual costs were $5,623,362 for etanercept, $701,964 for adalimumab, and $1,304,790 for ustekinumab. Psoriasis patients treated with etanercept, adalimumab, or ustekinumab had extensive above-label use over the 12-month follow-up period, which subsequently led to higher costs. Novartis Pharmaceuticals Corporation sponsored this study and the resultant publication. BioScience Communications provided medical writing and editorial support, which was also funded by Novartis Pharmaceuticals Corporation. Feldman was engaged by Novartis Pharmaceuticals as a paid clinical expert and scientific advisor for this study. He has received research support and speaking and/or consulting fees from AbbVie, Advance Medical, Amgen, Anacor, Astellas, Baxter, Boehringer Ingelheim, Caremark, Celgene, Eli Lilly, Galderma, GSK/Stiefel, Informa, Janssen, LEO Pharma, Merck, Merz, Mylan, National Biological, National Psoriasis Foundation, Pfizer, Qurient, Suncare Research, UpToDate, and Valeant; is the founder and majority owner of www.DrScore.com ; and is founder and part owner of Causa Research. Zhao, Herrera, Tian, and Li are employees of Novartis Pharmaceuticals. Zhou is a paid consultant for Novartis Pharmaceuticals and is an employee of KMK Consulting. Study concept and design were contributed by Feldman, Zhao, Herrera, and Li. Zhou and Li were responsible for data collection. Data were interpreted by Feldman and Zhao, with assistance from Zhou, Herrera, Tian, and Li. The manuscript was written primarily by Feldman and Zhao, with assistance from Zhou and Li. The manuscript was revised by Feldman and Zhao, assisted by Zhou, Herrera, Tian, and Li. Portions of this work were presented at the 34th Anniversary Fall Clinical Dermatology Conference in Las Vegas, Nevada, October 1-4, 2015.

Pregabalin for decreasing pancreatic pain in chronic pancreatitis.

PubMed

Gurusamy, Kurinchi Selvan; Lusuku, Charnelle; Davidson, Brian R

2016-02-02

Chronic abdominal pain is one of the major symptoms in people with chronic pancreatitis. The role of pregabalin in people with chronic pancreatic pain due to chronic pancreatitis is uncertain. To assess the benefits and harms of pregabalin in people with chronic abdominal pain due to chronic pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2015, issue 6, and MEDLINE, EMBASE, Science Citation Index Expanded, trials registers until June 2015. We also searched the references of included trials to identify further trials. We considered only randomised controlled trials (RCT) performed in people with chronic pancreatic pain due to chronic pancreatitis, irrespective of language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) with RevMan 5, based on intention-to-treat analysis. Only one study, funded by Pfizer, met the inclusion criteria for the review. A total of 64 participants (with chronic pain due to chronic pancreatitis) were randomly assigned to receive escalating doses of pregabalin (150 mg per day to 600 mg per day; 34 participants) or matching placebo (30 participants). Participants received pregabalin or placebo for three weeks on an outpatient basis; the outcomes were measured at the end of the treatment (i.e. three weeks from commencement of treatment). Potential participants taking concomitant analgesic medication and expected to stay on a stable regime during the trial were allowed to enter the study. This trial was at low risk of bias. The overall quality of evidence was low or moderate.Only the short-term outcomes were available in this trial. The medium and long-term outcomes, number of work days lost, and length of hospital stay due to admissions for pain control were not available. This trial found that the changes in opiate use (MD -26.00 mg; 95% CI -47.36 to -4.64; participants = 64; moderate-quality evidence), and pain score percentage changes from baseline (MD -12.00; 95% CI -21.82 to -2.18; participants = 64; moderate-quality evidence) were better in participants taking pregabalin compared to those taking placebo. This trial also found that there were more adverse events in participants taking pregabalin compared to those taking placebo (RR 1.71; 95% CI 1.20 to 2.43; participants = 64). The differences between pregabalin and placebo were imprecise for short-term health-related quality of life measured with the EORTC CLQ-30 questionnaire (MD 11.40; 95% CI -3.28 to 26.08; participants = 64; moderate-quality evidence), proportion of people with serious adverse events (RR 1.76; 95% CI 0.35 to 8.96; participants = 64; low-quality evidence), and proportion of people requiring hospital admissions (RR 0.44; 95% CI 0.04 to 4.62; participants = 64; low quality evidence). Based on low- to moderate-quality evidence, short-term use of pregabalin decreases short-term opiate use, and short-term pain scores, but increases the adverse events compared to placebo, in people with chronic pain due to chronic pancreatitis. The clinical implication of the decreases in short-term opiate use and short-term pain scores is not known.Future trials assessing the role of pregabalin in decreasing chronic pain in chronic pancreatitis should assess the medium- or long-term effects of pregabalin and should include outcomes such as, quality of life, treatment-related adverse events, number of work days lost, number of hospital admissions, and the length of hospital stay, in addition to pain scores, to assess the clinical and socioeconomic impact.

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

PubMed

James, Nicholas D; Sydes, Matthew R; Clarke, Noel W; Mason, Malcolm D; Dearnaley, David P; Spears, Melissa R; Ritchie, Alastair W S; Parker, Christopher C; Russell, J Martin; Attard, Gerhardt; de Bono, Johann; Cross, William; Jones, Rob J; Thalmann, George; Amos, Claire; Matheson, David; Millman, Robin; Alzouebi, Mymoona; Beesley, Sharon; Birtle, Alison J; Brock, Susannah; Cathomas, Richard; Chakraborti, Prabir; Chowdhury, Simon; Cook, Audrey; Elliott, Tony; Gale, Joanna; Gibbs, Stephanie; Graham, John D; Hetherington, John; Hughes, Robert; Laing, Robert; McKinna, Fiona; McLaren, Duncan B; O'Sullivan, Joe M; Parikh, Omi; Peedell, Clive; Protheroe, Andrew; Robinson, Angus J; Srihari, Narayanan; Srinivasan, Rajaguru; Staffurth, John; Sundar, Santhanam; Tolan, Shaun; Tsang, David; Wagstaff, John; Parmar, Mahesh K B

2016-03-19

Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research. Copyright © 2016 James et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.

PubMed

Shaw, Alice T; Felip, Enriqueta; Bauer, Todd M; Besse, Benjamin; Navarro, Alejandro; Postel-Vinay, Sophie; Gainor, Justin F; Johnson, Melissa; Dietrich, Jorg; James, Leonard P; Clancy, Jill S; Chen, Joseph; Martini, Jean-François; Abbattista, Antonello; Solomon, Benjamin J

2017-12-01

Most patients with anaplastic lymphoma kinase (ALK)-rearranged or ROS proto-oncogene 1 (ROS1)-rearranged non-small-cell lung cancer (NSCLC) are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops, commonly within the CNS. This study aimed to analyse the safety, efficacy, and pharmacokinetic properties of lorlatinib, a novel, highly potent, selective, and brain-penetrant ALK and ROS1 TKI with preclinical activity against most known resistance mutations, in patients with advanced ALK-positive or ROS1-positive NSCLC. In this international multicentre, open-label, single-arm, first-in-man phase 1 dose-escalation study, eligible patients had advanced ALK-positive or ROS1-positive NSCLC and were older than 18 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate end-organ function. Lorlatinib was administered orally to patients at doses ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily, with a minimum of three patients receiving each dose. For some patients, tumour biopsy was done before lorlatinib treatment to identify ALK resistance mutations. Safety was assessed in patients who received at least one dose of lorlatinib; efficacy was assessed in the intention-to-treat population (patients who received at least one dose of study treatment and had either ALK or ROS1 rearrangement). The primary endpoint was dose-limiting toxicities during cycle 1 according to investigator assessment; secondary endpoints included safety, pharmacokinetics, and overall response. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01970865. Between Jan 22, 2014, and July 10, 2015, 54 patients received at least one dose of lorlatinib, including 41 (77%) with ALK-positive and 12 (23%) with ROS1-positive NSCLC; one patient had unconfirmed ALK and ROS1 status. 28 (52%) patients had received two or more TKIs, and 39 (72%) patients had CNS metastases. The most common treatment-related adverse events among the 54 patients were hypercholesterolaemia (39 [72%] of 54 patients), hypertriglyceridaemia (21 [39%] of 54 patients), peripheral neuropathy (21 [39%] of 54 patients), and peripheral oedema (21 [39%] of 54 patients). One dose-limiting toxicity occurred at 200 mg (the patient did not take at least 16 of 21 prescribed total daily doses in cycle 1 because of toxicities attributable to study drug, which were grade 2 neurocognitive adverse events comprising slowed speech and mentation and word-finding difficulty). No maximum tolerated dose was identified. The recommended phase 2 dose was selected as 100 mg once daily. For ALK-positive patients, the proportion of patients who achieved an objective response was 19 (46%) of 41 patients (95% CI 31-63); for those who had received two or more TKIs, the proportion of patients with an objective response was 11 (42%) of 26 patients (23-63). In ROS1-positive patients, including seven crizotinib-pretreated patients, an objective response was achieved by six (50%) of 12 patients (95% CI 21-79). In this phase 1, dose-escalation study, lorlatinib showed both systemic and intracranial activity in patients with advanced ALK-positive or ROS1-positive NSCLC, most of whom had CNS metastases and had previously had two or more TKI treatments fail. Therefore, lorlatinib might be an effective therapeutic strategy for patients with ALK-positive NSCLC who have become resistant to currently available TKIs, including second-generation ALK TKIs, and is being investigated in a phase 3 randomised controlled trial comparing lorlatinib to crizotinib (ClinicalTrials.gov, NCT03052608). Pfizer. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

PubMed

Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A; Moy, Beverly; Iwata, Hiroji; Harvey, Vernon J; Robert, Nicholas J; Silovski, Tajana; Gokmen, Erhan; von Minckwitz, Gunter; Ejlertsen, Bent; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Buyse, Marc; Gore, Ira; Smith, John; Harker, Graydon; Masuda, Norikazu; Petrakova, Katarina; Zotano, Angel Guerrero; Iannotti, Nicholas; Rodriguez, Gladys; Tassone, Pierfrancesco; Wong, Alvin; Bryce, Richard; Ye, Yining; Yao, Bin; Martin, Miguel

2016-03-01

Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70 invasive disease-free survival events had occurred in patients in the neratinib group versus 109 events in those in the placebo group (stratified hazard ratio 0·67, 95% CI 0·50-0·91; p=0·0091). The 2-year invasive disease-free survival rate was 93·9% (95% CI 92·4-95·2) in the neratinib group and 91·6% (90·0-93·0) in the placebo group. The most common grade 3-4 adverse events in patients in the neratinib group were diarrhoea (grade 3, n=561 [40%] and grade 4, n=1 [<1%] vs grade 3, n=23 [2%] in the placebo group), vomiting (grade 3, n=47 [3%] vs n=5 [<1%]), and nausea (grade 3, n=26 [2%] vs n=2 [<1%]). QT prolongation occurred in 49 (3%) patients given neratinib and 93 (7%) patients given placebo, and decreases in left ventricular ejection fraction (≥grade 2) in 19 (1%) and 15 (1%) patients, respectively. We recorded serious adverse events in 103 (7%) patients in the neratinib group and 85 (6%) patients in the placebo group. Seven (<1%) deaths (four patients in the neratinib group and three patients in the placebo group) unrelated to disease progression occurred after study drug discontinuation. The causes of death in the neratinib group were unknown (n=2), a second primary brain tumour (n=1), and acute myeloid leukaemia (n=1), and in the placebo group were a brain haemorrhage (n=1), myocardial infarction (n=1), and gastric cancer (n=1). None of the deaths were attributed to study treatment in either group. Neratinib for 12 months significantly improved 2-year invasive disease-free survival when given after chemotherapy and trastuzumab-based adjuvant therapy to women with HER2-positive breast cancer. Longer follow-up is needed to ensure that the improvement in breast cancer outcome is maintained. Wyeth, Pfizer, Puma Biotechnology. Copyright © 2016 Elsevier Ltd. All rights reserved.

Patterns of Adherence to Oral Atypical Antipsychotics Among Patients Diagnosed with Schizophrenia.

PubMed

MacEwan, Joanna P; Forma, Felicia M; Shafrin, Jason; Hatch, Ainslie; Lakdawalla, Darius N; Lindenmayer, Jean-Pierre

2016-11-01

Poor medication adherence contributes to negative treatment response, symptom relapse, and hospitalizations in schizophrenia. Many health plans use claims-based measures like medication possession ratios or proportion of days covered (PDC) to measure patient adherence to antipsychotics. Classifying patients solely on the basis of a single average PDC measure, however, may mask clinically meaningful variations over time in how patients arrive at an average PDC level. To model patterns of medication adherence evolving over time for patients with schizophrenia who initiated treatment with an oral atypical antipsychotic and, based on these patterns, to identify groups of patients with different adherence behaviors. We analyzed health insurance claims for patients aged ≥ 18 years with schizophrenia and newly prescribed oral atypical antipsychotics in 2007-2013 from 3 U.S. insurance claims databases: Truven MarketScan (Medicaid and commercial) and Humana (Medicare). Group-based trajectory modeling (GBTM) was used to stratify patients into groups with distinct trends in adherence and to estimate trends for each group. The response variable was the probability of adherence (defined as PDC ≥ 80%) in each 30-day period after the patient initiated antipsychotic therapy. GBTM proceeds from the premise that there are multiple distinct adherence groups. Patient demographics, health status characteristics, and health care resource use metrics were used to identify differences in patient populations across adherence trajectory groups. Among the 29,607 patients who met the inclusion criteria, 6 distinct adherence trajectory groups emerged from the data: adherent (33%); gradual discontinuation after 3 months (15%), 6 months (7%), and 9 months (5%); stop-start after 6 months (15%); and immediate discontinuation (25%). Compared to patients 18-24 years of age in the adherent group, patients displaying a stop-start pattern after 6 months had greater odds of having a history of drug abuse (OR = 1.46; 95% CI = 1.26-1.66; P < 0.001), alcohol abuse (OR = 1.34; 95% CI = 1.14-1.53; P< 0.001), and a codiagnosis of major depressive disorder (OR = 1.24; 95% CI = 1.05-1.44; P < 0.001) and were less likely to be aged 35-54 years (OR = 0.66; 95% CI = 0.46-0.85; P < 0.001). Longitudinal medication adherence patterns can be expressed as distinct trajectories associated with specific patient characteristics and health care utilization patterns. We found 6 distinct patterns of adherence to antipsychotics over 12 months. Patients in different groups may warrant different types of clinical interventions to prevent hospitalizations, longer hospital stays, and increased clinical complexity. For example, clinicians may consider regular home visits, assertive community treatment, and other related interventions for patients at high risk of immediate discontinuation. Health plans should consider supplementing claims-based adherence measures with new technologies that are able to track patient adherence patterns over time. Otsuka Pharmaceutical Development & Commercialization provided support for this research. MacEwan and Shafrin are employees of Precision Health Economics, which was contracted by Otsuka Pharmaceutical Development & Commercialization to conduct this study. Lakdawalla is the Chief Scientific Officer and a founding partner of Precision Health Economics. Forma is an employee of Otsuka Pharmaceutical Development & Commercialization. Hatch is a former employee of Otsuka Pharmaceutical Development & Commercialization and is a current employee of ODH, Inc. Lindenmayer has received grant/research support from Janssen, Lilly, AstraZeneca, Johnson & Johnson, Pfizer, BMS, Otsuka, Dainippon, and Roche and is a consultant for Janssen, Lilly, Merck, Shire, and Lundbeck. Portions of this study were presented as a poster at the American Society of Clinical Psychopharmacology Annual Meeting in Miami Beach, Florida; June 23, 2015; and at the 28th Annual U.S. Psychiatric and Mental Health Congress; San Diego, California; September 12, 2015. Study concept and design were contributed by Forma, Ladkawalla, MacEwan, and Shafrin, along with Hatch and Lindenmayer. MacEwan, Shafrin, Forma, and Lakdawalla collected the data, along with Hatch and Lindenmayer. Data interpretation was performed by Hatch, Lindenmayer, MacEwan, and Shafrin, assisted by Forma and Lakdawalla. The manuscript was written and revised by MacEwan, Forma, and Shafrin, along with Hatch Lakdawalla, and Lindenmayer.

Effect of ADRB2 polymorphisms on the efficacy of salmeterol and tiotropium in preventing COPD exacerbations: a prespecified substudy of the POET-COPD trial.

PubMed

Rabe, Klaus F; Fabbri, Leonardo M; Israel, Elliot; Kögler, Harald; Riemann, Kathrin; Schmidt, Hendrik; Glaab, Thomas; Vogelmeier, Claus F

2014-01-01

The effect of β2-adrenergic receptor (ADRB2) polymorphisms on the treatment response to longacting bronchodilators in chronic obstructive pulmonary disease (COPD) is unclear. We aimed to establish whether ADRB2 polymorphisms differentially affected COPD exacerbation outcomes in response to tiotropium versus salmeterol. We did a prespecified analysis of the ADRB2 polymorphisms Arg16Gly and Gln27Glu within the 1 year randomised, double-blind, double-dummy, parallel-group Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD) trial, comparing the effects of treatment with tiotropium or salmeterol on exacerbations in 7376 patients with COPD. One blood sample was collected for pharmacogenetic testing from each patient who elected to participate in the substudy. Random assignment of patients to treatment groups was not stratified according to genotypes. Genomic DNA was extracted from whole-blood specimens and samples were genotyped for the two SNPs, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu). All assays were done in technical duplicates and 10% of samples that were randomly chosen were repeated as technical duplicates in a second independent genotyping process. Our primary endpoint was the risk of a first exacerbation of COPD based on time to first exacerbation data. An exacerbation of COPD was defined as the increase or new onset of more than one symptom of COPD (cough, sputum, wheezing, dyspnoea, or chest tightness), with at least one of the symptoms lasting for 3 days or more and needing treatment with antibiotics or systemic glucocorticoids (moderate exacerbations), or admission to hospital (severe exacerbations). POET-COPD is registered with ClinicalTrials.gov, number NCT00563381. 5125 patients gave informed consent for genotyping. The distributions of ADRB2 genotypes were well matched among groups. Polymorphisms at aminoacid 27 did not affect exacerbation outcomes. In the salmeterol group, patients with Arg16Arg genotype had a significantly reduced exacerbation risk compared with patients with Arg16Gly (p=0·0130) and Gly16Gly (p=0·0018) genotypes (proportion of patients with at least one exacerbation was 32·3% in Arg16Arg, 39·8% in Arg16Gly, and 42·1% in Gly16Gly). By contrast, exacerbation risk was not modified by polymorphisms at aminoacid 16 in the tiotropium group. The effect of the Arg16Gly polymorphism on treatment response to salmeterol was dependent on the use of inhaled corticosteroids (ICS). In patients untreated with ICS at baseline, Arg16Gly and Arg16Arg genotypes were associated with significantly prolonged time to first exacerbation compared with Gly16Gly (vs Arg16Gly p=0·0164; Arg16Arg p=0·0316; proportion of patients with at least one exacerbation was 28·3% in Arg16Arg, 31·6% in Arg16Gly, and 39·2% in Gly16Gly), whereas in patients on ICS at baseline, only the Arg16Arg genotype was associated with significantly prolonged time to first exacerbation compared with Gly16Gly (p=0·0198; not Arg16Gly p=0·64; proportion of patients with at least one exacerbation was 35·9% in Arg16Arg, 46·7% in Arg16Gly, and 44·8% in Gly16Gly). The respiratory disorders, in particular worsening of COPD, were the most common serious adverse events. Patients with the Arg16Arg genotype had better exacerbation outcomes in response to salmeterol than Gly16Gly and Arg16Gly genotypes, suggesting a potential differential Arg16Gly genotype effect on treatment response to longacting β-agonists (LABAs). However, the use of ADRB2 polymorphisms for predicting LABA treatment response is still limited and further prospective validation will be needed to advance the mechanistic understanding of β-adrenergic polymorphisms and their association with clinical features of COPD. Boehringer Ingelheim and Pfizer. Copyright © 2014 Elsevier Ltd. All rights reserved.

The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.

PubMed

Finn, Richard S; Crown, John P; Lang, Istvan; Boer, Katalin; Bondarenko, Igor M; Kulyk, Sergey O; Ettl, Johannes; Patel, Ravindranath; Pinter, Tamas; Schmidt, Marcus; Shparyk, Yaroslav; Thummala, Anu R; Voytko, Nataliya L; Fowst, Camilla; Huang, Xin; Kim, Sindy T; Randolph, Sophia; Slamon, Dennis J

2015-01-01

Palbociclib (PD-0332991) is an oral, small-molecule inhibitor of cyclin-dependent kinases (CDKs) 4 and 6 with preclinical evidence of growth-inhibitory activity in oestrogen receptor-positive breast cancer cells and synergy with anti-oestrogens. We aimed to assess the safety and efficacy of palbociclib in combination with letrozole as first-line treatment of patients with advanced, oestrogen receptor-positive, HER2-negative breast cancer. In this open-label, randomised phase 2 study, postmenopausal women with advanced oestrogen receptor-positive and HER2-negative breast cancer who had not received any systemic treatment for their advanced disease were eligible to participate. Patients were enrolled in two separate cohorts that accrued sequentially: in cohort 1, patients were enrolled on the basis of their oestrogen receptor-positive and HER2-negative biomarker status alone, whereas in cohort 2 they were also required to have cancers with amplification of cyclin D1 (CCND1), loss of p16 (INK4A or CDKN2A), or both. In both cohorts, patients were randomly assigned 1:1 via an interactive web-based randomisation system, stratified by disease site and disease-free interval, to receive continuous oral letrozole 2.5 mg daily or continuous oral letrozole 2.5 mg daily plus oral palbociclib 125 mg, given once daily for 3 weeks followed by 1 week off over 28-day cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Accrual to cohort 2 was stopped after an unplanned interim analysis of cohort 1 and the statistical analysis plan for the primary endpoint was amended to a combined analysis of cohorts 1 and 2 (instead of cohort 2 alone). The study is ongoing but closed to accrual; these are the results of the final analysis of progression-free survival. The study is registered with the ClinicalTrials.gov, number NCT00721409. Between Dec 22, 2009, and May 12, 2012, we randomly assigned 165 patients, 84 to palbociclib plus letrozole and 81 to letrozole alone. At the time of the final analysis for progression-free survival (median follow-up 29.6 months [95% CI 27.9-36.0] for the palbociclib plus letrozole group and 27.9 months [25.5-31.1] for the letrozole group), 41 progression-free survival events had occurred in the palbociclib plus letrozole group and 59 in the letrozole group. Median progression-free survival was 10.2 months (95% CI 5.7-12.6) for the letrozole group and 20.2 months (13.8-27.5) for the palbociclib plus letrozole group (HR 0.488, 95% CI 0.319-0.748; one-sided p=0.0004). In cohort 1 (n=66), median progression-free survival was 5.7 months (2.6-10.5) for the letrozole group and 26.1 months (11.2-not estimable) for the palbociclib plus letrozole group (HR 0.299, 0.156-0.572; one-sided p<0.0001); in cohort 2 (n=99), median progression-free survival was 11.1 months (7.1-16.4) for the letrozole group and 18.1 months (13.1-27.5) for the palbociclib plus letrozole group (HR 0.508, 0.303-0.853; one-sided p=0.0046). Grade 3-4 neutropenia was reported in 45 (54%) of 83 patients in the palbociclib plus letrozole group versus one (1%) of 77 patients in the letrozole group, leucopenia in 16 (19%) versus none, and fatigue in four (4%) versus one (1%). Serious adverse events that occurred in more than one patient in the palbociclib plus letrozole group were pulmonary embolism (three [4%] patients), back pain (two [2%]), and diarrhoea (two [2%]). No cases of febrile neutropenia or neutropenia-related infections were reported during the study. 11 (13%) patients in the palbociclib plus letrozole group and two (2%) in the letrozole group discontinued the study because of adverse events. The addition of palbociclib to letrozole in this phase 2 study significantly improved progression-free survival in women with advanced oestrogen receptor-positive and HER2-negative breast cancer. A phase 3 trial is currently underway. Pfizer. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

PubMed

Jones-Hughes, Tracey; Snowsill, Tristan; Haasova, Marcela; Coelho, Helen; Crathorne, Louise; Cooper, Chris; Mujica-Mota, Ruben; Peters, Jaime; Varley-Campbell, Jo; Huxley, Nicola; Moore, Jason; Allwood, Matt; Lowe, Jenny; Hyde, Chris; Hoyle, Martin; Bond, Mary; Anderson, Rob

2016-08-01

End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. This study is registered as PROSPERO CRD42014013189. The National Institute for Health Research Health Technology Assessment programme.

Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial.

PubMed

Lai, Zhi-Wei; Kelly, Ryan; Winans, Thomas; Marchena, Ivan; Shadakshari, Ashwini; Yu, Julie; Dawood, Maha; Garcia, Ricardo; Tily, Hajra; Francis, Lisa; Faraone, Stephen V; Phillips, Paul E; Perl, Andras

2018-03-24

Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6-15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p<0·001) and the mean total BILAG index score decreased from 28·4 (12·4) at enrolment to 17·4 (10·7) after 12 months of treatment (p<0·001). The mean daily dose of prednisone required to control disease activity decreased from 23·7 mg (SD 9·6) to 7·2 mg (2·3; p<0·001) after 12 months of treatment. Sirolimus expanded CD4 + CD25 + FoxP3 + regulatory T cells and CD8 + memory T-cell populations and inhibited interleukin-4 and interleukin-17 production by CD4 + and CD4 - CD8 - double-negative T cells after 12 months. CD8 + memory T cells were selectively expanded in SRI-responders. Patient liver function and lymphocyte counts were unchanged. Although HDL-cholesterol (Z=-2·50, p=0·012), neutrophil counts (Z=-1·92, p=0·054), and haemoglobin (Z=-2·83, p=0·005) were moderately reduced during treatment, all changes occurred within a range that was considered safe. Platelet counts were slightly elevated during treatment (Z=2·06, p=0·0400). These data show that a progressive improvement in disease activity is associated with correction of pro-inflammatory T-cell lineage specification in patients with active systemic lupus erythematosus during 12 months of sirolimus treatment. Follow-up placebo-controlled clinical trials in diverse patient populations are warranted to further define the role of mTOR blockade in treatment of systemic lupus erythematosus. Pfizer, the National Institutes of Health, and the Central New York Community Foundation. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

PubMed Central

Jones-Hughes, Tracey; Snowsill, Tristan; Haasova, Marcela; Coelho, Helen; Crathorne, Louise; Cooper, Chris; Mujica-Mota, Ruben; Peters, Jaime; Varley-Campbell, Jo; Huxley, Nicola; Moore, Jason; Allwood, Matt; Lowe, Jenny; Hyde, Chris; Hoyle, Martin; Bond, Mary; Anderson, Rob

2016-01-01

BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme. PMID:27578428

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

PubMed Central

Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Crathorne, Louise; Cooper, Chris; Varley-Campbell, Jo; Mujica-Mota, Ruben; Coelho, Helen; Huxley, Nicola; Lowe, Jenny; Dudley, Jan; Marks, Stephen; Hyde, Chris; Bond, Mary; Anderson, Rob

2016-01-01

BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013544. FUNDING The National Institute for Health Research HTA programme. PMID:27557331

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

PubMed

Haasova, Marcela; Snowsill, Tristan; Jones-Hughes, Tracey; Crathorne, Louise; Cooper, Chris; Varley-Campbell, Jo; Mujica-Mota, Ruben; Coelho, Helen; Huxley, Nicola; Lowe, Jenny; Dudley, Jan; Marks, Stephen; Hyde, Chris; Bond, Mary; Anderson, Rob

2016-08-01

End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. This study is registered as PROSPERO CRD42014013544. The National Institute for Health Research HTA programme.

Alpha-2 agonists for sedation of mechanically ventilated adults in intensive care units: a systematic review.

PubMed

Cruickshank, Moira; Henderson, Lorna; MacLennan, Graeme; Fraser, Cynthia; Campbell, Marion; Blackwood, Bronagh; Gordon, Anthony; Brazzelli, Miriam

2016-03-01

Care of critically ill patients in intensive care units (ICUs) often requires potentially invasive or uncomfortable procedures, such as mechanical ventilation (MV). Sedation can alleviate pain and discomfort, provide protection from stressful or harmful events, prevent anxiety and promote sleep. Various sedative agents are available for use in ICUs. In the UK, the most commonly used sedatives are propofol (Diprivan(®), AstraZeneca), benzodiazepines [e.g. midazolam (Hypnovel(®), Roche) and lorazepam (Ativan(®), Pfizer)] and alpha-2 adrenergic receptor agonists [e.g. dexmedetomidine (Dexdor(®), Orion Corporation) and clonidine (Catapres(®), Boehringer Ingelheim)]. Sedative agents vary in onset/duration of effects and in their side effects. The pattern of sedation of alpha-2 agonists is quite different from that of other sedatives in that patients can be aroused readily and their cognitive performance on psychometric tests is usually preserved. Moreover, respiratory depression is less frequent after alpha-2 agonists than after other sedative agents. To conduct a systematic review to evaluate the comparative effects of alpha-2 agonists (dexmedetomidine and clonidine) and propofol or benzodiazepines (midazolam and lorazepam) in mechanically ventilated adults admitted to ICUs. We searched major electronic databases (e.g. MEDLINE without revisions, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and Cochrane Central Register of Controlled Trials) from 1999 to 2014. Evidence was considered from randomised controlled trials (RCTs) comparing dexmedetomidine with clonidine or dexmedetomidine or clonidine with propofol or benzodiazepines such as midazolam, lorazepam and diazepam (Diazemuls(®), Actavis UK Limited). Primary outcomes included mortality, duration of MV, length of ICU stay and adverse events. One reviewer extracted data and assessed the risk of bias of included trials. A second reviewer cross-checked all the data extracted. Random-effects meta-analyses were used for data synthesis. Eighteen RCTs (2489 adult patients) were included. One trial at unclear risk of bias compared dexmedetomidine with clonidine and found that target sedation was achieved in a higher number of patients treated with dexmedetomidine with lesser need for additional sedation. The remaining 17 trials compared dexmedetomidine with propofol or benzodiazepines (midazolam or lorazepam). Trials varied considerably with regard to clinical population, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded outcome assessors. Compared with propofol or benzodiazepines (midazolam or lorazepam), dexmedetomidine had no significant effects on mortality [risk ratio (RR) 1.03, 95% confidence interval (CI) 0.85 to 1.24, I (2) = 0%; p = 0.78]. Length of ICU stay (mean difference -1.26 days, 95% CI -1.96 to -0.55 days, I (2) = 31%; p = 0.0004) and time to extubation (mean difference -1.85 days, 95% CI -2.61 to -1.09 days, I (2) = 0%; p < 0.00001) were significantly shorter among patients who received dexmedetomidine. No difference in time to target sedation range was observed between sedative interventions (I (2) = 0%; p = 0.14). Dexmedetomidine was associated with a higher risk of bradycardia (RR 1.88, 95% CI 1.28 to 2.77, I (2) = 46%; p = 0.001). Trials varied considerably with regard to participants, type of comparators, dose of sedative agents, outcome measures and length of follow-up. Overall, risk of bias was generally high or unclear. In particular, few trials blinded assessors. Evidence on the use of clonidine in ICUs is very limited. Dexmedetomidine may be effective in reducing ICU length of stay and time to extubation in critically ill ICU patients. Risk of bradycardia but not of overall mortality is higher among patients treated with dexmedetomidine. Well-designed RCTs are needed to assess the use of clonidine in ICUs and identify subgroups of patients that are more likely to benefit from the use of dexmedetomidine. This study is registered as PROSPERO CRD42014014101. The National Institute for Health Research Health Technology Assessment programme. The Health Services Research Unit is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates.

Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

PubMed

Cristofanilli, Massimo; Turner, Nicholas C; Bondarenko, Igor; Ro, Jungsil; Im, Seock-Ah; Masuda, Norikazu; Colleoni, Marco; DeMichele, Angela; Loi, Sherene; Verma, Sunil; Iwata, Hiroji; Harbeck, Nadia; Zhang, Ke; Theall, Kathy Puyana; Jiang, Yuqiu; Bartlett, Cynthia Huang; Koehler, Maria; Slamon, Dennis

2016-04-01

In the PALOMA-3 study, the combination of the CDK4 and CDK6 inhibitor palbociclib and fulvestrant was associated with significant improvements in progression-free survival compared with fulvestrant plus placebo in patients with metastatic breast cancer. Identification of patients most suitable for the addition of palbociclib to endocrine therapy after tumour recurrence is crucial for treatment optimisation in metastatic breast cancer. We aimed to confirm our earlier findings with this extended follow-up and show our results for subgroup and biomarker analyses. In this multicentre, double-blind, randomised phase 3 study, women aged 18 years or older with hormone-receptor-positive, HER2-negative metastatic breast cancer that had progressed on previous endocrine therapy were stratified by sensitivity to previous hormonal therapy, menopausal status, and presence of visceral metastasis at 144 centres in 17 countries. Eligible patients-ie, any menopausal status, Eastern Cooperative Oncology Group performance status 0-1, measurable disease or bone disease only, and disease relapse or progression after previous endocrine therapy for advanced disease during treatment or within 12 months of completion of adjuvant therapy-were randomly assigned (2:1) via a centralised interactive web-based and voice-based randomisation system to receive oral palbociclib (125 mg daily for 3 weeks followed by a week off over 28-day cycles) plus 500 mg fulvestrant (intramuscular injection on days 1 and 15 of cycle 1; then on day 1 of subsequent 28-day cycles) or placebo plus fulvestrant. The primary endpoint was investigator-assessed progression-free survival. Analysis was by intention to treat. We also assessed endocrine therapy resistance by clinical parameters, quantitative hormone-receptor expression, and tumour PIK3CA mutational status in circulating DNA at baseline. This study is registered with ClinicalTrials.gov, NCT01942135. Between Oct 7, 2013, and Aug 26, 2014, 521 patients were randomly assigned, 347 to fulvestrant plus palbociclib and 174 to fulvestrant plus placebo. Study enrolment is closed and overall survival follow-up is in progress. By March 16, 2015, 259 progression-free-survival events had occurred (145 in the fulvestrant plus palbociclib group and 114 in the fulvestrant plus placebo group); median follow-up was 8·9 months (IQR 8·7-9·2). Median progression-free survival was 9·5 months (95% CI 9·2-11·0) in the fulvestrant plus palbociclib group and 4·6 months (3·5-5·6) in the fulvestrant plus placebo group (hazard ratio 0·46, 95% CI 0·36-0·59, p<0·0001). Grade 3 or 4 adverse events occurred in 251 (73%) of 345 patients in the fulvestrant plus palbociclib group and 38 (22%) of 172 patients in the fulvestrant plus placebo group. The most common grade 3 or 4 adverse events were neutropenia (223 [65%] in the fulvestrant plus palbociclib group and one [1%] in the fulvestrant plus placebo group), anaemia (ten [3%] and three [2%]), and leucopenia (95 [28%] and two [1%]). Serious adverse events (all causalities) occurred in 44 patients (13%) of 345 in the fulvestrant plus palbociclib group and 30 (17%) of 172 patients in the fulvestrant plus placebo group. PIK3CA mutation was detected in the plasma DNA of 129 (33%) of 395 patients for whom these data were available. Neither PIK3CA status nor hormone-receptor expression level significantly affected treatment response. Fulvestrant plus palbociclib was associated with significant and consistent improvement in progression-free survival compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, hormone-receptor expression level, and PIK3CA mutational status. The combination could be considered as a therapeutic option for patients with recurrent hormone-receptor-positive, HER2-negative metastatic breast cancer that has progressed on previous endocrine therapy. Pfizer. Copyright © 2016 Elsevier Ltd. All rights reserved.

AMCP Partnership Forum: Enabling the Exchange of Clinical and Economic Information Pre-FDA Approval.

PubMed

2017-01-01

Current federal laws and FDA regulations have significantly restricted the sharing of clinical and health economic information on biopharmaceuticals that have yet to receive FDA approval. Over the past several years, organizations that make health care coverage decisions, including those that set copayments, premiums, and formulary placement, have expressed a need for receiving this information before approval, as long as appropriate safeguards exist to prevent this information from reaching unintended entities. Population health decision makers have indicated that waiting until FDA approval is often too late for the critical planning, budgeting, and forecasting associated with health benefit design, especially given the recent influx of high-cost medications and scrutiny for better evaluation and preparation. Recognizing that securities laws restrict the disclosure of nonpublic information and may need to be amended, permissible early dissemination would allow population health decision makers to incorporate clinical and economic information for pipeline drugs or expanded indications into financial forecasting for the following year's plan. Access to this information is needed 12-18 months before FDA approval when organizations are deciding on terms of coverage and budgetary assumptions for state health insurance rate filings, Medicare and Medicaid bids, contracts with health care purchasers, and other financial arrangements. The need for exchange of clinical economic information before FDA approval was first introduced at a previous Academy of Managed Care (AMCP) forum in March 2016, which addressed section 114 of the Food and Drug Administration Modernization Act and the communication of such information after FDA approval. To address preapproval information specifically, AMCP convened a Partnership Forum on September 13-14, 2016. This forum included a diverse group of stakeholders representing managed care, the biopharmaceutical industry, providers, patients, health economists, academia, and others. The multistakeholder group represented the key professionals and entities affected by the federal laws and FDA regulations that restrict the sharing of preapproval information and the collective credibility necessary for proposing this new communication process. Forum participants primarily focused on 6 items of discussion: (1) creating and defining new terms for how biopharmaceutical manufacturers may provide clinical and economic information 12-18 months before FDA approval; (2) defining the clinical and scientific standards that this information should meet; (3) determining which entities should have access to this information and the value to each; (4) the format and process by which this information should be disseminated; (5) developing definitions for existing terms referenced in current laws, regulations, or guidance documents that would need to be modernized to align with the identified new term; and (6) providing safeguards to prevent this information from reaching unintended entities. Forum participants selected "preapproval information exchange" (PIE) as the correct term to describe this proposed new communication process and to be inclusive of data from pivotal phase III clinical trials, pharmaco-economic data, and patient-reported outcomes, as well as other relevant items, including anticipated indications, place in therapy, and routes of administration. Stakeholders agreed that PIE should be truthful, non-misleading, and include a broad range of information to meet the needs of population health decision makers and health care technology evolution. Recipients of PIE would be limited to population health decision makers who need this information for coverage decisions. The format and process for PIE disseminated should allow for a bidirectional exchange between manufacturers and population health decision makers but should not be proscribed in legislation. Furthermore, new legislative language may be beneficial, since PIE is a novel category of information. New legislation could provide a safe harbor and clarity that PIE does not violate preapproval promotion and the Federal Food, Drug, and Cosmetic Act and its regulations. The AMCP Partnership Forum on Enabling the Exchange of Clinical and Economic Data Pre-FDA Approval and the development of this proceedings document were supported by AbbVie, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Celgene, Intarcia Therapeutics, Eli Lilly and Company, GlaxoSmithKline, Merck, National Pharmaceutical Council, Novo Nordisk, Pfizer, Pharmaceutical Research and Manufacturers of America, Precision for Value, Sanofi, Takeda Pharmaceuticals, U.S.A., and Xcenda. All sponsors participated in the forum and in revising and approving the manuscript.

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.

PubMed

2017-05-27

Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65-1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52-0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88-1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial.

PubMed

Ueki, Kohjiro; Sasako, Takayoshi; Okazaki, Yukiko; Kato, Masayuki; Okahata, Sumie; Katsuyama, Hisayuki; Haraguchi, Mikiko; Morita, Ai; Ohashi, Ken; Hara, Kazuo; Morise, Atsushi; Izumi, Kazuo; Ishizuka, Naoki; Ohashi, Yasuo; Noda, Mitsuhiko; Kadowaki, Takashi

2017-12-01

Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions. In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45-69 years with hypertension, dyslipidaemia, or both, and an HbA 1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA 1c <6·9% [52·0 mmol/mol], blood pressure <130/80 mm Hg, LDL cholesterol <120 mg/dL [or 100 mg/dL in patients with a history of coronary artery disease]) or intensive therapy (HbA 1c <6·2% [44·3 mmol/mol], blood pressure <120/75 mm Hg, LDL cholesterol <80 mg/dL [or 70 mg/dL in patients with a history of coronary artery disease]). Randomisation was done using a computer-generated, dynamic balancing method, stratified by sex, age, HbA 1c , and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976. Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3-9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA 1c , systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p<0·0001). The primary outcome occurred in 109 patients in the intensive therapy group and in 133 patients in the conventional therapy group (hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·094). In a post-hoc breakdown of the composite outcome, frequencies of all-cause mortality (HR 1·01, 95% CI 0·68-1·51; p=0·95) and coronary events (myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angioplasty; HR 0·86, 0·58-1·27; p=0·44) did not differ between groups, but cerebrovascular events (stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting) were significantly less frequent in the intensive therapy group (HR 0·42, 0·24-0·74; p=0·002). Apart from non-severe hypoglycaemia (521 [41%] patients in the intensive therapy group vs 283 [22%] in the conventional therapy group, p<0·0001) and oedema (193 [15%] vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups. Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes. Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda. Copyright © 2017 Elsevier Ltd. All rights reserved.

Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency.

PubMed

Latremouille-Viau, Dominick; Guerin, Annie; Gagnon-Sanschagrin, Patrick; Dea, Katherine; Cohen, Benjamin G; Joseph, George J

2017-02-01

Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios. Adult patients newly diagnosed with CML who started TKI firstline therapy were identified from U.S. administrative claims data (2010-2015). TKI adherence (medication possession ratio [MPR]), number of inpatient days, emergency room (ER) visits, outpatient service days, and mean costs per HRU event were measured during the first year of CML treatment. Direct and indirect effects of qPCR test frequency were estimated using multivariate regression models. Subsequently, an economic model was developed to assess the overall effect of varying qPCR test frequency on HRU and associated costs during the first year of CML treatment under different clinical practice scenarios; the scenario reported is the increase from 1 to 2 qPCR tests. Of the 1,431 patients included, 36% had no qPCR tests, the average qPCR test frequency was 1.6, and the average MPR was 0.86 during the first year of CML treatment. The direct effect of increasing qPCR test frequency by 1 was associated with 13.0% fewer inpatient days (adjusted incidence rate ratio [adjusted IRR] = 0.87; P = 0.010); 8.3% fewer ER visits (adjusted IRR = 0.92; P = 0.043); and 3.0% more outpatient service days (adjusted IRR = 1.03; P = 0.002). Each increase of 1 test was associated with an increase in TKI adherence by 2.2 percentage points (adjusted MPR difference = 0.022; P < 0.001). When considering the indirect effect of qPCR test frequency through TKI adherence, an increase of 1 qPCR test combined with an increase in TKI adherence by 2.2 percentage points was associated with a greater reduction of inpatient days from 13.0% to 15.2%, ER visits from 8.3% to 8.6%, and a smaller increase of outpatient service days from 3.0% to 2.6%. Based on the economic model, an increase from 1 to 2 qPCR tests, considering the increase in TKI adherence, was associated with a reduction of 0.87 (95% CI = -1.49, -0.18) inpatient days and 0.06 (95% CI = -0.12, 0.05) ER visits, an increase of 0.98 (95% CI = 0.25, 1.60) outpatient service days and a cost savings of $2,918 (95% CI = -5,213, -349) per patient per year. Closer alignment with the monitoring guidelines' recommended qPCR test frequency and better adherence to TKIs were associated with lower HRU and medical service costs. Managed care initiatives to increase qPCR test frequency and TKI adherence might benefit from an enhanced reduction because of the interaction between both factors. This study was funded by Novartis Pharmaceuticals, which was involved in all stages of the study and in the decision to submit the report for publication. Latremouille-Viau, Guerin, Gagnon-Sanschagrin, and Dea are employees of Analysis Group, which received consulting fees from Novartis Pharmaceuticals for work on this study. Joseph is an employee of Novartis Pharmaceuticals and owns stock in Amgen and Pfizer. Cohen was an employee of Novartis Pharmaceuticals at the time of this study. Portions of this study were presented online (beginning May 20, 2016) as part of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on June 3-7, 2016, and as a poster at the American Society of Hematology (ASH) Annual Meeting in San Diego, California, on December 3-6, 2016. Study concept and design were contributed by Latremouille-Viau and Guerin, along with the other authors. Gagnon-Sanschagrin and Dea took the lead in data collection, assisted by the other authors, and data interpretation was performed by Cohen and Joseph, along with the other authors. The manuscript was written by Latremouille-Viau, along with the other authors, and revised by Joseph, along with the other authors.

Cognitive and neuroimaging features and brain β-amyloidosis in individuals at risk of Alzheimer's disease (INSIGHT-preAD): a longitudinal observational study.

PubMed

Dubois, Bruno; Epelbaum, Stephane; Nyasse, Francis; Bakardjian, Hovagim; Gagliardi, Geoffroy; Uspenskaya, Olga; Houot, Marion; Lista, Simone; Cacciamani, Federica; Potier, Marie-Claude; Bertrand, Anne; Lamari, Foudil; Benali, Habib; Mangin, Jean-François; Colliot, Olivier; Genthon, Remy; Habert, Marie-Odile; Hampel, Harald

2018-04-01

Improved understanding is needed of risk factors and markers of disease progression in preclinical Alzheimer's disease. We assessed associations between brain β-amyloidosis and various cognitive and neuroimaging parameters with progression of cognitive decline in individuals with preclinical Alzheimer's disease. The INSIGHT-preAD is an ongoing single-centre observational study at the Salpêtrière Hospital, Paris, France. Eligible participants were age 70-85 years with subjective memory complaints but unimpaired cognition and memory (Mini-Mental State Examination [MMSE] score ≥27, Clinical Dementia Rating score 0, and Free and Cued Selective Reminding Test [FCSRT] total recall score ≥41). We stratified participants by brain amyloid β deposition on 18 F-florbetapir PET (positive or negative) at baseline. All patients underwent baseline assessments of demographic, cognitive, and psychobehavioural, characteristics, APOE ε4 allele carrier status, brain structure and function on MRI, brain glucose-metabolism on 18 F-fluorodeoxyglucose ( 18 F-FDG) PET, and event-related potentials on electroencephalograms (EEGs). Actigraphy and CSF investigations were optional. Participants were followed up with clinical, cognitive, and psychobehavioural assessments every 6 months, neuropsychological assessments, EEG, and actigraphy every 12 months, and MRI, and 18 F-FDG and 18 F-florbetapir PET every 24 months. We assessed associations of amyloid β deposition status with test outcomes at baseline and 24 months, and with clinical status at 30 months. Progression to prodromal Alzheimer's disease was defined as an amnestic syndrome of the hippocampal type. From May 25, 2013, to Jan 20, 2015, we enrolled 318 participants with a mean age of 76·0 years (SD 3·5). The mean baseline MMSE score was 28·67 (SD 0·96), and the mean level of education was high (score >6 [SD 2] on a scale of 1-8, where 1=infant school and 8=higher education). 88 (28%) of 318 participants showed amyloid β deposition and the remainder did not. The amyloid β subgroups did not differ for any psychobehavioural, cognitive, actigraphy, and structural and functional neuroimaging results after adjustment for age, sex, and level of education More participants positive for amyloid β deposition had the APOE ε4 allele (33 [38%] vs 29 [13%], p<0·0001). Amyloid β 1-42 concentration in CSF significantly correlated with mean 18 F-florbetapir uptake at baseline (r=-0·62, p<0·0001) and the ratio of amyloid β 1-42 to amyloid β 1-40 (r=-0·61, p<0·0001), and identified amyloid β deposition status with high accuracy (mean area under the curve values 0·89, 95% CI 0·80-0·98 and 0·84, 0·72-0·96, respectively). No difference was seen in MMSE (28·3 [SD 2·0] vs 28·9 [1·2], p=0·16) and Clinical Dementia Rating scores (0·06 [0·2] vs 0·05 [0·3]; p=0·79) at 30 months (n=274) between participants positive or negative for amyloid β. Four participants (all positive for amyloid β deposition at baseline) progressed to prodromal Alzheimer's disease. They were older than other participants positive for amyloid β deposition at baseline (mean 80·2 years [SD 4·1] vs 76·8 years [SD 3·4]) and had greater 18 F-florbetapir uptake at baseline (mean standard uptake value ratio 1·46 [SD 0·16] vs 1·02 [SD 0·20]), and more were carriers of the APOE ε4 allele (three [75%] of four vs 33 [39%] of 83). They also had mild executive dysfunction at baseline (mean FCSRT free recall score 21·25 [SD 2·75] vs 29·08 [5·44] and Frontal Assessment Battery total score 13·25 [1·50] vs 16·05 [1·68]). Brain β-amyloidosis alone did not predict progression to prodromal Alzheimer's disease within 30 months. Longer follow-up is needed to establish whether this finding remains consistent. Institut Hospitalo-Universitaire and Institut du Cerveau et de la Moelle Epinière (IHU-A-ICM), Ministry of Research, Fondation Plan Alzheimer, Pfizer, and Avid. Copyright © 2018 Elsevier Ltd. All rights reserved.

World Endometriosis Society consensus on the classification of endometriosis.

PubMed

Johnson, Neil P; Hummelshoj, Lone; Adamson, G David; Keckstein, Jörg; Taylor, Hugh S; Abrao, Mauricio S; Bush, Deborah; Kiesel, Ludwig; Tamimi, Rulla; Sharpe-Timms, Kathy L; Rombauts, Luk; Giudice, Linda C

2017-02-01

What is the global consensus on the classification of endometriosis that considers the views of women with endometriosis? We have produced an international consensus statement on the classification of endometriosis through systematic appraisal of evidence and a consensus process that included representatives of national and international, medical and non-medical societies, patient organizations, and companies with an interest in endometriosis. Classification systems of endometriosis, developed by several professional organizations, traditionally have been based on lesion appearance, pelvic adhesions, and anatomic location of disease. One system predicts fertility outcome and none predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis. A consensus meeting, in conjunction with pre- and post-meeting processes, was undertaken. A consensus meeting was held on 30 April 2014 in conjunction with the World Endometriosis Society's 12th World Congress on Endometriosis. Rigorous pre- and post-meeting processes, involving 55 representatives of 29 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement. A total of 28 consensus statements were made. Of all, 10 statements had unanimous consensus, however none of the statements was made without expression of a caveat about the strength of the statement or the statement itself. Two statements did not achieve majority consensus. The statements covered women's priorities, aspects of classification, impact of low resources, as well as all the major classification systems for endometriosis. Until better classification systems are developed, we propose a classification toolbox (that includes the revised American Society for Reproductive Medicine and, where appropriate, the Enzian and Endometriosis Fertility Index staging systems), that may be used by all surgeons in each case of surgery undertaken for women with endometriosis. We also propose wider use of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project surgical and clinical data collection tools for research to improve classification of endometriosis in the future, of particular relevance when surgery is not undertaken. This consensus process differed from that of formal guideline development, although based on the same available evidence. A different group of international experts from those participating in this process may have yielded subtly different consensus statements. This is the first time that a large, global, consortium-representing 29 major stake-holding organizations, from 19 countries - has convened to systematically evaluate the best available evidence on the classification of endometriosis and reach consensus. In addition to 21 international medical organizations and companies, representatives from eight national endometriosis organizations were involved, including lay support groups, thus generating and including input from women who suffer from endometriosis in an endeavour to keep uppermost the goal of optimizing quality of life for women with endometriosis. The World Endometriosis Society convened and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Mauricio Abrao is an advisor to Bayer Pharma, and a consultant to AbbVie and AstraZeneca; G David Adamson is the Owner of Advanced Reproductive Care Inc and Ziva and a consultant to Bayer Pharma, Ferring, and AbbVie; Deborah Bush has received travel grants from Fisher & Paykel Healthcare and Bayer Pharmaceuticals; Linda Giudice is a consultant to AbbVie, Juniper Pharmaceutical, and NextGen Jane, holds research grant from the NIH, is site PI on a clinical trial sponsored by Bayer, and is a shareholder in Merck and Pfizer; Lone Hummelshoj is an unpaid consultant to AbbVie; Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; Jörg Keckstein has received a travel grant from AbbVie; Ludwig Kiesel is a consultant to Bayer Pharma, AbbVie, AstraZeneca, Gedeon Richter, and Shionogi, and holds a research grant from Bayer Pharma; Luk Rombauts is an advisor to MSD, Merck Serono, and Ferring, and a shareholder in Monash IVF. The following have declared that they have nothing to disclose: Kathy Sharpe Timms; Rulla Tamimi; Hugh Taylor. N/A. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Impact of a Patient Support Program on Patient Adherence to Adalimumab and Direct Medical Costs in Crohn's Disease, Ulcerative Colitis, Rheumatoid Arthritis, Psoriasis, Psoriatic Arthritis, and Ankylosing Spondylitis.

PubMed

Rubin, David T; Mittal, Manish; Davis, Matthew; Johnson, Scott; Chao, Jingdong; Skup, Martha

2017-08-01

AbbVie provides a free-to-patient patient support program (PSP) to assist adalimumab-treated patients with medication costs, nurse support, injection training, pen disposal, and medication reminders. The impact of these services on patient adherence to adalimumab and direct medical costs associated with autoimmune disease has not been assessed. To quantify the relationship between participation in a PSP and outcomes (adalimumab adherence, persistence, and direct medical costs) in patients initiating adalimumab treatment. A longitudinal, retrospective, cohort study was conducted using patient-level data from the PSP combined with Symphony Health Solutions administrative claims data for patients initiating adalimumab between January 2008 and June 2014. The sample included patients aged ≥ 18 years with a diagnosis of Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis who were biologic-naïve before initiation of adalimumab. Patients who enrolled in the PSP (PSP cohort) were matched to those who did not enroll (non-PSP cohort) based on age, sex, year of treatment initiation, comorbidities, diagnosis, and initiation at a specialty pharmacy. For the PSP cohort, the index date was assigned as the earliest date of PSP enrollment, and time to enrollment following adalimumab initiation was used to assign index dates for the non-PSP cohort. All patients were required to have evidence of medical and pharmacy coverage for at least 6 months before and after their first adalimumab claim and at least 12 months after their index date. Adherence (proportion of days covered during the 12 months following PSP opt-in [index date]) was compared between cohorts using t-tests. Persistence was assessed using survival analysis of discontinuation rates. Medical costs for emergency department, inpatient, physician, and outpatient visits (all-cause and disease-related) and total costs (medical plus drug costs) were compared at 12 months following the index date using t-tests. A total of 2,386 patients were included in the study and were allocated to the PSP (n = 1,199) and non-PSP (n = 1,187) cohorts. Baseline characteristics were similar between cohorts. During the follow-up period, adalimumab adherence was 14% greater in the PSP cohort than for the non-PSP cohort (67.0% vs. 58.8%; P < 0.001). The discontinuation rate for adalimumab was 14% lower in the PSP cohort compared with the non-PSP cohort (39.7% vs. 46.2%; P = 0.001). Univariate analyses showed that PSP patients had 23% lower 12-month medical costs (excluding costs for biologic treatment) than did non-PSP patients ($18,322 vs. $23,679; P = 0.003). Disease-related medical costs were 22% lower for PSP than for non-PSP patients ($8,001 vs. $10,202; P = 0.045). Total costs were 10% lower for PSP than for non-PSP patients ($35,741 vs. $39,713; P = 0.030). Patient enrollment in the PSP was associated with greater adherence, improved persistence, and reduced medical (all-cause and disease-related) and total health care costs for patients receiving adalimumab therapy. Design, study conduct, and financial support for this study were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the abstract. All authors contributed to the development of the publication and maintained control over the final content. Rubin has received consulting fees or research support from AbbVie, Amgen, Emmi, Genentech, Ironwood, Janssen, Pfizer, Prometheus, Shire, and Takeda. Skup and Mittal are employees and stockholders of AbbVie. Chao was an employee of AbbVie at the time of the study and may hold AbbVie stock. Johnson and Davis are employees of Medicus Economics, which received payment from AbbVie to participate in this research. Study concept and design were contributed by Rubin, Mittal, Chao, and Skup, along with Davis and Johnson. Davis and Johnson took the lead in data collection, with assistance from the other authors, and data interpretation was performed by Rubin, Mittal, Chao, and Skup, with assistance from Davis and Johnson. All authors contributed to the writing and revision of the manuscript. The abstract for this study was published as Rubin DT, Skup M, Davis M, Johnson S, Chao J. Impact of AbbVie's patient support program on resource costs in Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis. J Manag Care Spec Pharm. 2015;21(Suppl 4a):S74-75 (poster presentation at Academy of Managed Care, 27th Annual Meeting and Expo; April 7-10, 2015; San Diego, CA) and as abstract 2339 in Arthritis Rheumatol. 2015;67(Suppl 10; poster presentation at American College of Rheumatology 2015 ACR/AHRP Annual Meeting; November 7-11, 2015; San Francisco, CA).

Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study.

PubMed

O'Donnell, Martin J; Chin, Siu Lim; Rangarajan, Sumathy; Xavier, Denis; Liu, Lisheng; Zhang, Hongye; Rao-Melacini, Purnima; Zhang, Xiaohe; Pais, Prem; Agapay, Steven; Lopez-Jaramillo, Patricio; Damasceno, Albertino; Langhorne, Peter; McQueen, Matthew J; Rosengren, Annika; Dehghan, Mahshid; Hankey, Graeme J; Dans, Antonio L; Elsayed, Ahmed; Avezum, Alvaro; Mondo, Charles; Diener, Hans-Christoph; Ryglewicz, Danuta; Czlonkowska, Anna; Pogosova, Nana; Weimar, Christian; Iqbal, Romaina; Diaz, Rafael; Yusoff, Khalid; Yusufali, Afzalhussein; Oguz, Aytekin; Wang, Xingyu; Penaherrera, Ernesto; Lanas, Fernando; Ogah, Okechukwu S; Ogunniyi, Adesola; Iversen, Helle K; Malaga, German; Rumboldt, Zvonko; Oveisgharan, Shahram; Al Hussain, Fawaz; Magazi, Daliwonga; Nilanont, Yongchai; Ferguson, John; Pare, Guillaume; Yusuf, Salim

2016-08-20

Stroke is a leading cause of death and disability, especially in low-income and middle-income countries. We sought to quantify the importance of potentially modifiable risk factors for stroke in different regions of the world, and in key populations and primary pathological subtypes of stroke. We completed a standardised international case-control study in 32 countries in Asia, America, Europe, Australia, the Middle East, and Africa. Cases were patients with acute first stroke (within 5 days of symptom onset and 72 h of hospital admission). Controls were hospital-based or community-based individuals with no history of stroke, and were matched with cases, recruited in a 1:1 ratio, for age and sex. All participants completed a clinical assessment and were requested to provide blood and urine samples. Odds ratios (OR) and their population attributable risks (PARs) were calculated, with 99% confidence intervals. Between Jan 11, 2007, and Aug 8, 2015, 26 919 participants were recruited from 32 countries (13 447 cases [10 388 with ischaemic stroke and 3059 intracerebral haemorrhage] and 13 472 controls). Previous history of hypertension or blood pressure of 140/90 mm Hg or higher (OR 2·98, 99% CI 2·72-3·28; PAR 47·9%, 99% CI 45·1-50·6), regular physical activity (0·60, 0·52-0·70; 35·8%, 27·7-44·7), apolipoprotein (Apo)B/ApoA1 ratio (1·84, 1·65-2·06 for highest vs lowest tertile; 26·8%, 22·2-31·9 for top two tertiles vs lowest tertile), diet (0·60, 0·53-0·67 for highest vs lowest tertile of modified Alternative Healthy Eating Index [mAHEI]; 23·2%, 18·2-28·9 for lowest two tertiles vs highest tertile of mAHEI), waist-to-hip ratio (1·44, 1·27-1·64 for highest vs lowest tertile; 18·6%, 13·3-25·3 for top two tertiles vs lowest), psychosocial factors (2·20, 1·78-2·72; 17·4%, 13·1-22·6), current smoking (1·67, 1·49-1·87; 12·4%, 10·2-14·9), cardiac causes (3·17, 2·68-3·75; 9·1%, 8·0-10·2), alcohol consumption (2·09, 1·64-2·67 for high or heavy episodic intake vs never or former drinker; 5·8%, 3·4-9·7 for current alcohol drinker vs never or former drinker), and diabetes mellitus (1·16, 1·05-1·30; 3·9%, 1·9-7·6) were associated with all stroke. Collectively, these risk factors accounted for 90·7% of the PAR for all stroke worldwide (91·5% for ischaemic stroke, 87·1% for intracerebral haemorrhage), and were consistent across regions (ranging from 82·7% in Africa to 97·4% in southeast Asia), sex (90·6% in men and in women), and age groups (92·2% in patients aged ≤55 years, 90·0% in patients aged >55 years). We observed regional variations in the importance of individual risk factors, which were related to variations in the magnitude of ORs (rather than direction, which we observed for diet) and differences in prevalence of risk factors among regions. Hypertension was more associated with intracerebral haemorrhage than with ischaemic stroke, whereas current smoking, diabetes, apolipoproteins, and cardiac causes were more associated with ischaemic stroke (p<0·0001). Ten potentially modifiable risk factors are collectively associated with about 90% of the PAR of stroke in each major region of the world, among ethnic groups, in men and women, and in all ages. However, we found important regional variations in the relative importance of most individual risk factors for stroke, which could contribute to worldwide variations in frequency and case-mix of stroke. Our findings support developing both global and region-specific programmes to prevent stroke. Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Health Research Board Ireland, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland (Sweden), AstraZeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MSD, Chest, Heart and Stroke Scotland, and The Stroke Association, with support from The UK Stroke Research Network. Copyright © 2016 Elsevier Ltd. All rights reserved.

Antihyperlipidemic Medication Treatment Patterns and Statin Adherence Among Patients with ASCVD in a Managed Care Plan After Release of the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol.

PubMed

Bellows, Brandon K; Olsen, Cody J; Voelker, Jennifer; Wander, Curtis

2016-08-01

The American College of Cardiology (ACC) and American Heart Association (AHA) released a new blood cholesterol treatment guideline in November 2013. It is unknown how the new recommendations have affected cholesterol medication use and adherence in a commercial health plan. To evaluate the effect of the 2013 guideline release on antihyperlipidemic treatment patterns and statin adherence in patients with atherosclerotic cardiovascular disease (ASCVD) compared with a historical control group. This study was a historical cohort analysis of adult patients (aged 21-75 years) with clinical ASCVD enrolled in a SelectHealth commercial health plan. Patients were included in the guideline implementation cohort if they had a medical claim with an ICD-9-CM diagnosis of ASCVD in the year before the November 2013 ACC/AHA guideline release. The index date was defined as the first outpatient medical claim with an ICD-9-CM for ASCVD in the first 6 months after the guideline was released. Patients were required to have continuous enrollment for ≥ 1 year before and after the index date. These same criteria were applied to patients exactly 4 years earlier to identify a historical control group. Patients meeting these criteria formed the antihyperlipidemic treatment patterns cohort. Of these, patients who also had ≥1 pharmacy claim for a statin in the 1-year pre- and post-index periods were included in the statin adherence cohort. Antihyperlipidemic treatment patterns were assessed using pharmacy claims for antihyperlipidemic medications in the 1-year pre- and post-index periods. Antihyperlipidemic medication claims were classified as a nonstatin cholesterol medication, low-intensity statin, moderate-intensity statin, or high-intensity statin. To address differences in pre-index antihyperlipidemic medications between the guideline implementation and historical control groups, patients were randomly matched 1:1 based on pre-index classification in a post hoc analysis. Post-index antihyperlipidemic classifications were compared between groups using a Stuart-Maxwell test. The change in mean statin adherence (proportion of days covered [PDC]) was compared within and between groups using paired and independent t-tests, respectively. The proportion of adherent patients (PDC ≥ 0.80) in the pre- and post-index periods was compared between groups using a chi-square test. A multivariable logistic regression was used to compare the likelihood of being adherent in the post-index period while controlling for pre-index adherence and other potential confounders. A total of 7,818 adult members with ASCVD in the index period and 1 year before the index period were identified. Of those, 1,841 patients met the criteria to be included in the analysis, and 1,526 patients were matched on antihyperlipidemic classification and included in the antihyperlipidemic treatment patterns analysis. Baseline characteristics were similar, although the guideline implementation group was younger (58.3 vs. 60.5 years, P < 0.001), and more were male (74.8% vs. 71.3%, P = 0.106) than the historical control group. In the matched cohort, there was a significant difference in the post-index antihyperlipidemic classification (P < 0.001), which appeared to be a result of the difference in nonstatin cholesterol medications (guideline 6.9% vs. historical 13.0%) and high-intensity statins (guideline 23.7% vs. historical 16.3%). Of the 1,841 patients in the antihyperlipidemic treatment patterns cohort, 919 patients met inclusion criteria for the statin adherence analysis. Although PDC decreased over time in both groups, significantly more patients in the guideline implementation group were adherent in the post-index period than the historical control group (66.5% vs. 57.3%, respectively; P = 0.005). Additionally, patients in the guideline implementation group were more likely than the historical control to be adherent in the post-index period when adjusting for potential confounders (OR = 1.49, 95% CI = 1.10-2.03; P = 0.011). Since the release of the updated ACC/AHA treatment guideline, more commercial health plan patients with ASCVD used high-intensity statins and fewer used nonstatin cholesterol medications than historical controls. Additionally, since the guideline release, more patients are adherent to statin therapy than historical controls. This study provides managed care organizations with valuable information regarding the effect of the 2013 ACC/AHA guideline. No outside funding or services were received for this work. Outside of the current study, Bellows has received research funding from Biogen Idec, Regeneron Pharmaceuticals, Myriad Genetic Laboratories, Shire Development, and Bristol-Myers Squibb and an honorariam from Avanir Pharmaceuticals. Voelker received summer intern support from Pfizer and the AMCP Foundation during the time of this study. The remaining authors have nothing to disclose. All authors contributed to study concept and design and to the revision of the manuscript. Bellows, Olsen, and Voelker collected the data, assisted by Wander; data interpretation was performed primarily by Bellows, along with Olsen and Voelker and assisted by Wander. The manuscript was primarily written by Bellows, along with the other authors.

[Early achievements of the Danish pharmaceutical industry-6 Pharmacia].

PubMed

Grevsen, Jørgen V; Kruse, Edith; Kruse, Poul R

2014-01-01

The article series provides a written and pictorial account of the Danish pharmaceutical industry's products from their introduction until about 1950. Part 6 deals with products from A/S Pharmacia. A/S Pharmacia was established in Copenhagen in 1922 as a Danish limited company by the enterprising pharmacist Edward Jacobsen. Pharmacia was not Jacobsen's first pharmaceutical company as previously he had established a pharmaceutical agency already in 1913 which in 1919 was reorganized to a limited company by the name of A/S Edward Jacobsen. This agency was later extended to include a production of generics. Jacobsen remained the co-owner and manager of Pharmacia until 1934 where he resigned and established another company, A/S Ejco, for the manufacture of generics. It is worth mentioning that already in 1911 a Swedish pharmaceutical company was established named AB Pharmacia. Today we do not know whether Edward Jacobsen knew about this Swedish company. Later on in 1936 AB Pharmacia and A/S Pharmacia made a contract concerning mutual market sharing, and a research cooperation was brought about between the two companies which resulted in an increase of turnover for A/S Pharmacia. In 1955 the cooperation between the two companies was increased as the Swedish company joined as principal shareholder with the purpose of continuing and developing the Danish company as an independent pharmaceutical company with its own research and development as well as manufacture, control and marketing. Therefore Pharmacia in Denmark was able to establish a synthesis factory in Koge and move the domicile to new premises in Hillered. In 1993 Pharmacia was presented in a printed matter as "The largest Nordic pharmaceutical company" as a result of the merger between the Swedish Kabi Pharmacia, formerly established by a merger between Kabi Vitrum and AB Pharmacia, and the Italian Farmitalia Carlo Erba. Only two years later in 1995 Pharmacia merged with the American pharmaceutical company The Upjohn Company under the name of Pharmacia & Upjohn. In 2000 this company was merged with the chemical group Monsanto under a new name, Pharmacia Corporation. Pharmacia Corporation was taken over by Pfizer in 2003. The early activities of A/S Pharmacia included not only the import of raw materials and ready-made articles, such as medicinal products, but also the manufacture of own medicinal products. This is not surprising considering the founder Edward Jacobsen's pharmaceutical career. Pharmacia's early manufacture of own medicinal products consisted mainly of generics, however, not only the expensive foreign medicinal products, but also any available Danish generics such as easily manufactured pharmacopeia products. It is thus worth mentioning that Pharmacia's own technological production capacity at that time was limited and required a cooperation with other (Danish) pharmaceutical companies. Pharmacia was able to produce tablet cores, but the sugarcoating had to be made by external business partners. Pharmacia was able to produce digitalis preparations, but the standardization of these had to be effected elsewhere. The total production of one of Pharmacia's products took place at an external business partner. Pharmacia was established at a time where the increasing use of industrially manufactured medicinal products, both Danish and foreign ones, had resulted in a considerable decrease in sales of pharmacy produced medicinal products. This had for a long time worried The Danish Association of Pharmacies, and this resulted in a reaction from the association, namely the DAK-products which by nature were produced in Denmark and thus became the most essential element in the fight against the industrially manufactured products--a fight which according to the association had to be fought with all legal means. Therefore The Danish Association of Pharmacies obviously reacted precipitated when in 1926 the association in writing stated that Pharmacia's products were not manufactured in Denmark in spite of the fact that they were labelled as such according to agreement with Landsforeningen Dansk Arbejde, i.e., The National Association Danish Work, which in 1925 allowed Pharmacia to use the labels of the association. The unemployment was high in the 1920'ies and increasing so when Pharmacia subsequently took legal action against the Association of Pharmacies and claimed that the statement was unjustified and might harm Pharmacia, it may indicate that the public of that time looked positively upon the manufacture and the use of Danish manufactured products. The Danish Association of Pharmacies lost the case as the claim according to the court was unjustified and thus unlawful. The suspicions of the association were not supported by facts, however, they were not either completely groundless. Following this The National Association Danish Work gave notice to terminate the contract with Pharmacia concerning the right to use the labels of the association. By expanding the cooperation and later on by merging with the Swedish Pharmacia AB the Danish A/S Pharmacia succeeded in continuing and developing a company where research, development and production of innovative medicinal products as well as of generics could take place in Denmark.

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase.

PubMed

Gupta, Ajay; Thompson, David; Whitehouse, Andrew; Collier, Tim; Dahlof, Bjorn; Poulter, Neil; Collins, Rory; Sever, Peter

2017-06-24

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Pfizer, Servier Research Group, and Leo Laboratories. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical signatures of life in modern stromatolites from Lake Alchichica, Mexico. Applications for the search of life on Mars

NASA Astrophysics Data System (ADS)

Navarro, Karina F.; Navarro-Gonzalez, Rafael; Alcocer, Javier; Escobar, Elva; Morales, Pedro; Cienfuegos, Edith; Coll, Patrice; Raulin, Francois; Stalport, Fabien; Cabane, Michel; Person, Alain; McKay, Chris

Stromatolites are one of the most important forms of fossil evidence for microbial life on early Earth (Schopf et al., 1971). They are formed when layers of microbial organisms at the shallow bottom of a lake or tide pool are periodically covered with sediment or precipitating salts (e.g. carbonate). The photosynthetic organisms that form the basis of the community must migrate through sediment toward the light in order to survive. If life emerged on Mars, it is possible that stromatolites were formed in lakes and marine lagoons. Recently the Mars Reconnaissance Orbiter mapping found a regional rock layer with near-infrared spectral characteristics that are consistent with the presence of magnesium carbonate in the Nili Fossae region (Ehlmann et al., 2008). The Nili Fossae is a fracture in the surface of Mars that has been eroded and partly filled in by sediments and clay-rich ejecta from a nearby crater. It is located at 22° N, 75° E and has an elevation of 0.6 km. The carbonate-bearing rocks outcrops in the Nili Fossae region could have formed in (1) the subsurface by groundwater percolating through fractures in the ultramafic rock and altering olivine or (2) in shallow lakes from waters enriched in Mg2+ relative to other cations by percolation through ultramafic olivine-bearing rocks. In the latter scenario, it is possible that these carbonate outcrops could have been deposited in association with microbial activity. The purpose of this work is to chemically characterize a modern stromatolite by thermal volatization (TV), a method that has been widely used in past missions (Viking and Phoenix) and will also be used in future missions (Mars Science Laboratory and ExoMars) in the search for life on Mars. Alchichica is a volcanic crater lake situated in an enclosed basin within the El Seco Valley at 19° 24' 13" N, 97° 24' 0" W, and 2.345 km above sea level in Mexico. It has an area of 1.81 km2 , a mean depth of 38.5 m and a maximum depth of 64 m. The lake is hyposaline (8.5-10 g l-1 ) and alkaline (pH 8.9-9.1 and alkalinity of 37 meq l-1 ) with sodium and chloride being the dominant ions but also with bicarbonate and carbonate ions. These conditions are favorable for active carbonate deposition that results in the formation of distinctive stromatolite structures in the littoral region of the lake. These structures generate extended submerged carbonaceous platforms down to a depth of 15 m that slope steeply to the bottom of the lake where soft sediments prevail (Escobar-Briones et al., 1998). The lake is populated by 18 species of cyanobacteria (Tavera and Komárek, 1996) which are the primary producers in the food web a of the lake fixing not only carbon (Escobar-Briones et al., 1998) but also nitrogen (Falcón eto al, 2002). The stromatolite samples were freeze-dried and then were finely grounded with an agate mor-tar mill for analyses. The mineral composition of the sample is essentially hydromagnesite (Mg5 (CO3 )4 (OH)2 , 4 H2 O)) with traces of quartz (SiO2 ) as determined by X-rays diffraction. This is also consistent with differential thermal analysis and thermal gravimetry of the sample. Analysis of the sample by TV-mass spectrometry (MS) using the Phoenix Lander Protocol (Navarro-González et al., 2009) indicates that the major volatile released is carbon dioxide a from 350 C to 1000° C with broad peaks centered at 400° C and 600° C. Organics are also re-° leased from 380° C to 750° C as monitored by a characteristic organic fragment with m/z=41 and that is attributed to the allyl cation: [CH2 CHCH2 ]+ . Analysis of the sample by TV-gas chromatography (GC)-MS using the Viking Lander Protocol but at 750° C (Navarro-González a et al., 2009) demonstrates that a complex suite of organics are released such as 1,3-butadiene, furan, propanal, 2-propenenitrile, 1,3 cyclopentadiene, 2-methyl-1,3-butadiene, propanenitrile, methylfuran, butanal, benzene, 1-methyl-cyclohexene, 1-H-pyrrole, pyridine, methylbenzene, 2,5-dimethylfuran, 4-methylpyridine, ethylbenzene, dimethylbenzene, styrene, methylbenze-neamine, 2,4-hexadienal, phenol, 3-methyl-2-cyclopenten-1-one, benzonitrile, cyclopropyliden-emethylbenzene, 2,3-dihydro-1-H-indene, 1-methylethenylbenzene, 3-methylphenol, and 1-propenyl-benzene. The carbon isotopic composition of the organic fraction of the stromatolites is deter-mined by a δ 13 C=-24.28 whereas the inorganic fraction, hydromagnesite, is determined by a δ 13 C=5.86. Our data shows two interesting chemical signatures that can used to detect extant life in Martian carbonates: (1) organics are not oxidized by mineral matrix during TV-MS and TV-GC-MS analysis; and (2) distinctive carbon isotopic fractionation occurs in the or-ganic and inorganic fraction of stromatolites. Future work should center on studying fossilized stromatolites to determine if these chemical signatures are lost with time. References: Ehlmann, B.L., Mustard, J.F., Murchie, S.L. Poulet, F., Bishop, J.L., Brown, A.J., Calvin, W.M., Clark, R.N., Des Marais, D.J., Milliken, R.E., Roach, L.H., Roush, T.L., Swayze, G.A., and Wray, J.J.: 2008, Orbital identification of carbonate-bearing rocks on Mars. Science 322, 1828-1832. Escobar-Briones, E., Alcocer, J., Cienfuegos, E., and Morales P.: 1998, Carbon stable isotopes ratios of pelagic and litoral communities in Alchichica crater-lake, Mexico, Internat J Salt Lake Res 7, 345-355. Falcón, L.I., Escobar-Briones, E., and Romero, D.: 2002, Nitrogen fixation patterns displayed by cyanobacterial consortia in Alchichica crater-lake, Mexico, Hydrobiol 467, 71-78. Navarro-González, R., Navarro, K.F., de la Rosa, J., Molina, P., Iñiguez, E., Miranda, L.D., a n Morales, P., Cienfuegos, E., Coll, P., Raulin, F., Amils, R. and McKay, C.P.: 2006. The limitations on organic detection in Mars-like soils by thermal volatilization-gas chromatography-MS and their implications for the Viking results. Proc Natl Acad Sci USA 103, 16089-16094. Navarro-González, R., Iñiguez, E., de la Rosa, J. and McKay, C.P.: 2009, Characterization of a n organics, microorganisms, desert soils and Mars-like soils by thermal volatilization coupled to mass spectrometry and their implications for the search of organics on Mars by Phoenix and future space missions. Astrobiology 9, 703-715, doi: 10.1089/ast.2008.0284. Schopf, J.W., Oehler, D.Z. Horodyski, R.J. and Kvenvolden K.A.:1971, Biogenicity and signif-icance of the oldest known stromatolites. J Paleontol 45, 477-485. Tavera, R., and Komárek J.: 1996, Cyanoprokaryotes in the volcanic lake of alchichica, Puebla a State, Mexico, Algological Studies 83, 511-538.

Low-Cost Generic Program Use by Medicare Beneficiaries: Implications for Medication Exposure Misclassification in Administrative Claims Data.

PubMed

Pauly, Nathan J; Talbert, Jeffery C; Brown, Joshua

2016-06-01

Administrative claims data are used for a wide variety of research and quality assurance purposes; however, they are prone to medication exposure misclassification if medications are purchased without using an insurance benefit. Low-cost generic drug programs (LCGPs) offered at major chain pharmacies are a relatively new and sparsely investigated source of exposure misclassification. LCGP medications are often purchased out of pocket; thus, a pharmacy claim may never be submitted, and the exposure may go unobserved in claims data. As heavy users of medications, Medicare beneficiaries have much to gain from the affordable medications offered through LCGPs. This use may put them at increased risk of exposure misclassification in claims data. Many high-risk medications (HRMs) and medications tracked for adherence and utilization quality metrics are available through LCGPs, and exposure misclassification of these medications may impact the quality assurance efforts reliant on administrative claims data. Presently, there is little information regarding the use of these programs among a geriatric population. To (a) quantify the prevalence of LCGP users in a nationally representative population of Medicare beneficiaries; (b) compare clinical and demographic characteristics of LCGP users and nonusers; (c) assess determinants of LCGP use and medications acquired through these programs; and (d) analyze patterns of LCGP use during the years 2007-2012. This study relied on data from the Medical Expenditure Panel Survey (MEPS) from 2007 to 2012. The first 3 objectives were completed with a cohort of individuals in the most recent MEPS panel, while the fourth objective was completed with a separate cohort composed of individuals who participated in MEPS from 2007 to 2012. Inclusion in either study cohort required that individuals were Medicare beneficiaries aged 65 years or greater, used at least 1 prescription drug during their 2-year panel period, and participated in all 5 rounds of data collection during their panel period. MEPS captures medication utilization by surveying individuals on current and previous medication use and verifies this information at the pharmacy level, so prescription fills can be observed irrespective of payment by an insurer or a filed claim. Pharmaceutical utilization was assessed at the individual level for each year of the study period, and LCGP use was recorded as a binary variable for each individual. An LCGP medication fill was identified if the total cost of the drug was paid out of pocket and matched the cost of medications listed on LCGP formularies available from major pharmacy retailers during these years. Cohort demographics and characteristics of interest included age, gender, race, employment status, marital status, family income level, education level, residence in a metropolitan statistical area, geographic region, prescription drug coverage, Medicare type, comorbidities, number of unique medications used, and number of medication fills. Comparisons were made between users and nonusers using chi-square and t-tests. Multivariable logistic regression was used to identify factors associated with LCGP use. From the most recent MEPS panel, 1,861 individuals were included in the study cohort, of which 53.5% were observed to be LCGP users. The 995 LCGP users in this cohort represented over 20 million Medicare beneficiaries who used LCGPs from 2011 to 2012. Significant differences between LCGP users and nonusers existed in terms of race, educational attainment, comorbidity burden, type of Medicare insurance, number of unique medications used, and number of medication fills. Each additional unique medication filled increased the odds of LCGP use by 12% (95% CI = 1.09-1.14). Individuals with insurance in addition to Medicare (i.e., Tricare/Veteran's Affairs or Medicaid) had less than half the odds of using LCGPs compared with those with Medicare or Medicare managed care insurance coverage only. The proportion of LCGP users and the proportion of LCGP fills out of all medications available through LCGPs increased from 2007 to 2012. There is a high rate of LCGP use among Medicare beneficiaries aged 65 years or greater. Claims-based research and quality assurance programs focusing on the benefits and harms of medications available through these programs are at risk of underestimating the true medication exposure in this population and should account for this possibility in sensitivity analyses. Managed care organizations should incentivize the reporting of LCGP medication use or make adjustments to generic medication benefit structures to more effectively capture true medication exposure. No direct sources of funding were used to conduct this study. Data acquisition was supported by the University of Kentucky Center for Clinical and Translational Science through funding from NIH NCATS grant #UL1TR000117. Brown is the Humana-Pfizer Research Fellow at the Institute for Pharmaceutical Outcomes & Policy at the University of Kentucky College of Pharmacy and is provided salary from these corporations. However, neither company provided any direct funding for the current study nor provided any input or guidance for the design, methods, or drafting of the manuscript. Pauly has no financial disclosures or conflicts of interest. Portions of these results were presented at the 20th International Society for Pharmacoeconomics and Outcomes Research International Meeting; May 16-20, 2015; Philadelphia, Pennsylvania. Study concept and design were primarily contributed by Brown, along with the other authors. Brown took the lead in data collection and interpretation, along with Pauly and Talbert. All authors participated in the writing and revision of the manuscript.

New ways of insulin delivery.

PubMed

Heinemann, L

2010-02-01

When Exubera (EXU), the first inhaled insulin formulation to make it through the clinical development process, was introduced to the market some years ago it was hoped that this would be the first in a series of novel insulin formulations applied by this route. In addition, it was hoped that inhaled insulin would pave the way for other alternative routes of insulin administration (ARIA), i.e. oral insulin, nasal insulin or transdermal insulin to mention only some of the different attempts that have been studied in the last 90 years. The failure of EXU, i.e. its withdrawal from the market due to insufficient market success, was followed by the cessation of nearly all other attempts to develop inhaled insulin formulations. Currently there is only one company (MannKind) which moves sturdily ahead with their Technosphere insulin. This company has submitted an NDA for their product recently and hopes to bring it to the market by the end of 2010 or early 2011. Even if the product is able to pass the approval hurdles in the USA and Europe, this does not guarantee that it will become a market success. Many diabetologists were sceptical about the need/advantages of inhaled insulin/EXU from the start and the introduction of this product has raised even more scepticism. Reports about 'side effects' (development of lung cancer in patients treated with EXU) of inhaled insulin are also not helpful, even if the causality of the appearance of cancer with this type of insulin therapy is not proven. One of the very negative consequences of stopping EXU are the huge financial losses to Pfizer. The managers in charge in other pharmaceutical companies and also most venture capitalists are reluctant to invest in ARIA nowadays. This in turn means that many of the small companies that try to develop new forms of insulin administration have issues when they try to find a big brother and/or sufficient financial support. Clearly the economic crisis has further aggravated this issue. One can foresee that with most new ways of insulin delivery the bioavailability/biopotency will be lower than with subcutaneous (SC) insulin administration. This in turn requires that more insulin has to be applied to induce the same metabolic (blood glucose lowering) effect in patients with diabetes. If the costs of insulin are of relevance for the price (this clearly depends on the source of insulin the individual company has to use) the price of the product will be higher relative to standard SC insulin therapy. The question is, clearly, what are the advantages of the new product? In times when SC insulin administration was painful and cumbersome it was clear that the ease of swallowing an insulin tablet was a good argument for many patients. With the invention of thin insulin needles that make the SC injection practically pain free in most cases, this argument of being 'convenient' becomes of limited relevance. However, for many patients (especially the public) the avoidance of 'injection' is an argument. The question is, how much is the patient (society) willing to pay for such a psychological 'advantage'? Most probably additional clear-cut clinical advantages must be demonstrable to convince the payers to reimburse a new product, especially when the price is higher than that of SC insulin. If, for example, postprandial glycaemic excursions are considerably better controlled because the pharmacodynamic (PD) effects are better than with SC injection of rapid-acting insulin analogues (this might be possible with inhaled Technosphere insulin), this would be a clinically relevant argument. Without such advantages, new products will have no market success. Most probably it will not be until one of the various ARIA developments (e.g. nasal insulin) makes it into a financially attractive product (sufficient return on investment) that more money will flow again in this area of research. The search for relevant articles about new ways to deliver insulin did not reveal very many, especially on clinical studies. However, it is fascinating to see that the imagination about improvements in existing ways to deliver insulin (e.g. insulin pens) and also about novel ways to improve insulin absorption (e.g. local heating of the injection site) is still there. At the same time the above-mentioned considerations (coming more from the viewpoint of pharmaceutical companies and more market oriented) appear not to be the focus of many scientists in pharmacological research institutes. Otherwise it is difficult to understand why every year a number of new oral insulin formulations are published in pharmacological journals, reporting impressive data from animal studies (mainly performed on rats), but only a very limited number of these are transferred to the clinical development process. It is well known that most drugs fail during the clinical development process and the resources of pharmaceutical companies that are willing to invest in, for example, oral insulin are very limited. Small companies tend to make a lot of smoke out of a little fire to gain access to these resources. Unfortunately, the limited financial resources also hamper the design and performance of pre-clinical experiments and clinical studies. The consequence is that many of the study results presented are inconclusive (to phrase it carefully). One good study that proves that a given approach works - or shows convincingly that it does not work - would be much better than a number of small studies. Sometimes one has the impression that this is done on purpose to show some activity and keep the company alive. Without a more stringent approach there is a high risk that many of the current developments will never make it into an available clinical product. These comments are not intended to be destructive but to strengthen a thorough scientific approach and to induce a more realistic view of the prospects: most probably an oral insulin pill will not be on the market next year! Nevertheless, this is the route of insulin administration where I would put my money (if I had enough). Also in this area of research it is not easy to make statements about which approaches are valid and will make it to a product. The fact that some large pharmaceutical companies are active in this area indicates that they also believe that oral insulin is the hottest candidate of the next ARIA that will come to the market.

Intermediate crust (IC); its construction at continent edges, distinctive epeirogenic behaviour and identification as sedimentary basins within continents: new light on pre-oceanic plate motions

NASA Astrophysics Data System (ADS)

Osmaston, Miles F.

2014-05-01

Introduction. The plate tectonics paradigm currently posits that the Earth has only two kinds of crust - continental and oceanic - and that the former may be stretched to form sedimentary basins or the latter may be modified by arc or collision until it looks continental. But global analysis of the dynamics of actual plate motions for the past 150 Ma indicates [1 - 3] that continental tectospheres must be immensely thicker and rheologically stiffer than previously thought; almost certainly too thick to be stretched with the forces available. In the extreme case of cratons, these tectospheric keels evidently extend to 600 km or more [2, 3]. This thick-plate behaviour is attributable, not to cooling but to a petrological 'stiffening' effect, associated with a loss of water-weakening of the mineral crystals, which also applies to the hitherto supposedly mobile LVZ below MORs [4, 5]. The corresponding thick-plate version of the mid-ocean ridge (MOR) process [6 - 8], replacing the divergent mantle flow model, has a deep, narrow wall-accreting axial crack which not only provides the seismic anisotropy beneath the flanks but also brings two outstanding additional benefits:- (i) why, at medium to fast spreading rates, MOR axes become straight and orthogonally segmented [6], (ii) not being driven by body forces, it can achieve the sudden jumps of axis, spreading-rate and direction widely present in the ocean-floor record. Furthermore, as we will illustrate, the crack walls push themselves apart at depth by a thermodynamic mechanism, so the plates are not being pulled apart. So the presence of this process at a continental edge would not imply the application of extensional force to the margin. Intermediate Crust (IC). In seeking to resolve the paradox that superficially extensional structures are often seen at margins we will first consider how this MOR process would be affected by the heavy concurrent sedimentation to be expected when splitting a mature continent. I reason that, by blocking the hydrothermal cooling widely seen along MOR axes this must inhibit the freezing-in of diagnostic spreading-type magnetic anomalies and would prolong magmagenesis to give a thicker-than-oceanic mafic crust. I have called this Intermediate Crust (IC) [9, 10], to distinguish it from Mature Continental Crust (MCC). Plate separation will continue to generate IC along the margins for as long/far as the sedimentation input is sufficient to have this effect. Transition to the MOR process will then follow. But if, contrary to the general plate tectonics assumption, based on body forces, plate separation ceases after a limited separation (or perhaps several in differing directions), without proceeding to the oceanic condition, the resulting IC areas will be incorporated within the continent [11]. Where does this lead us? With examples drawn from 40 years' study, I will contend that this is indeed the way the Earth has worked and that it offers potential plate kinematic explanation of the origin of the block-and-sedimentary basin layouts abundantly present in the non-craton areas of continents. I will show that in some cases the intricacy of block outlines and the precision with which they can be fitted together in a kinematically consistent manner rules out that this was purely by chance. The evidently meaningful character of those outlines means that they have been drawn by a narrow-crack separative mechanism which reflects that of our new MOR model. To provide a basis for such Plate Kinematic Analysis (PKA) we now link and compare some features of IC-formation at continental edges and of the crust of sedimentary basins. Characteristics of IC and of sedimentary basin crust (SBC). 1. IC basement, with expected seismic Vp around 6km/s, must look deceptively like that assigned to supposedly stretched MCC. 2. For thermodynamic reasons, the hydrous metamorphic content of deep MCC and of deeply subducted UHP slices of it gives them a big thermal epeirogenic sensitivity which IC lacks. Calculation [8, 9] shows that this type of process yields some 12-30 times more column density reduction per joule than does pure thermal expansivity. So IC and MCC are clearly distinguishable epeirogenically. 3. The mantle below forming IC will be similar thermally to that at under young oceanic crust (OC), which habitually subsides under water about 3km with age. If the water + OC is replaced with IC and isostasy is applied we get an IC thickness of around 27km, typical of SBC. 4. The magmatic generation of IC basement will incorporate many interlayers of (now dry) HT-metamorphosed sediment. At the sediment-deprived transition to the formation of OC with its intense hydrothermal cooling and rapid off-axis subsidence, this IC basement structure could be what we see as 'steeply dipping reflectors' (SDRs). 5. Multiple horizontal seismic reflectors, first extensively observed during the BIRPs programme in the British Isles region, were noted [10] as characteristic of the basement of SBC of western Europe, but were interpreted as shear zones denoting extension. Geologically it is unlikely that shear zones would be thick enough to cause such reflections. The layered structure of IC basement is the preferred interpretation. 6. In near-margin places where the sub-MCC mantle had a hydrous content, this, combined with the thermal volume-increase (2, above) of the MCC lower crust, can cause an oceanward-directed laccolith of both, beneath the upper crust of the margin, which therefore undergoes extensional tectonics, but which is not plate extension. This phenomenon has been recorded offshore Gabon and Galicia. In Gabon this laccolith is seen in seismics to have overthrust existing OC, showing that this was a thermally delayed response, some time after plate separation had got going. In conclusion. Intermediate crust (IC) is the product of the gross modification of the MOR process by the heavy sedimentation to be expected for a time after the onset of plate separation. IC areas thus created by limited plate separation events that did not proceed to oceans then become the floors of sedimentary basins, thus extending very precisely the study of plate relative motions - Plate Kinematic Analysis (PKA) - to much further into the past than is obtainable from the present ocean floor. Concurrent flood magmatism is induced where thermal upwarping at a fresh margin also splits the deep tectosphere of near-by craton. [1] Osmaston MF (2006) Global tectonic actions emanating from Arctic opening in the circumstances of a two-layer mantle and a thick-plate paradigm involving deep cratonic tectospheres: the Eurekan (Eocene) compressive motion of Greenland and other examples. In ICAM IV, Proc. 4th Internat. Conf. on Arctic Margins, 2003 (ed. R Scott & D Thurston). OCS Study MMS 2006-003, pp.105-124: Also on: http://www.mms.gov/alaska/icam. [2]Osmaston MF (2009) Deep cratonic keels and a 2-layer mantle? Tectonic basis for some far-reaching new insights on the dynamical properties of the Earth's mantle: example motions from Mediterranean, Atlantic-Arctic and India. EGU Gen. Assy 2009, GRA 11, EGU2009-6359 Session SM 6.2 (Solicited). [3] Osmaston MF (2012) Did clockwise rotation of Antarctica cause the break-up of Gondwanaland? An investigation in the 'deep-keeled cratons' frame for global dynamics. GRA 14, EGU2012-2170-1. [4] Karato S (1986) Does partial melting reduce the creep strength of the upper mantle? Nature 319, 309-310. [5] Hirth G & Kohlstedt DL (1996) Water in the oceanic upper mantle: implication for rheology, melt extraction, and the evolution of the lithosphere. EPSL 144, 93-108. [6] Osmaston MF (1995) A straightness mechanism for MORs: a new view of ocean plate genesis and evolution. In IUGG XXI , Boulder, Colorado. Abstracts A472. [7] Osmaston MF (2000) What goes on beneath MORs? A reassessment. In 31st IGC, Rio de Janeiro.Abstracts CD-ROM. General Symposium 4-1. [8] Osmaston M (2014 (submitted)) Mantle properties and the MOR process: a new and versatile model for mid-ocean ridges. GRA 16, EGU2014-1750 - Submitted to Session GD3.5. [9] Osmaston MF (2008) Basal subduction tectonic erosion (STE), butter mélanges and the construction and exhumation of HP-UHP belts: the Alps example and some comparisons. International Geology Review 50(8), 685-754 DOI: 10.2747/00206814.50.8.685. [10] Osmaston MF (2011) An introduction to Intermediate Crust (IC): its formation, epeirogenic character, and plate tectonics significance. TSG Ann. Mtg 2011, Durham University, Technical Programme p.45. [11] Osmaston MF (1973) Limited lithosphere separation as a main cause of continental basins, continental growth and epeirogeny. In Implications of continental drift to the Earth Sciences, Vol. 2 (ed. DH Tarling & SK Runcorn), pp. 649-674. Academic Press. [12] Meissner R et al (2006) Seismic lamination and anisotropy of the Lower Continental Crust. Tectonophysics 416, 81-99.

Recognition of Intermediate Crust (IC), its construction and its distinctive epeirogenic behaviour: an exciting new tool for plate kinematic analysis (PKA) of the Arctic margins and western Siberia

NASA Astrophysics Data System (ADS)

Osmaston, M. F.

2012-04-01

Identification of a microcontinental block within or near a continental margin raises two questions, addressed in this talk - How did it get there? What is the nature of the intervening crust? I will then illustrate briefly how, in the Arctic, the answers, although by no means restricted to that region, do seem to help us a lot to begin unravelling the ancient plate kinematics of its wide margins. The plate tectonics paradigm currently posits that the Earth has only two kinds of crust - continental and oceanic - and that the former may be stretched to form sedimentary basins or the latter may be modified by arc or collision until it looks continental. But global analysis of the dynamics of actual plate motions for the past 150 Ma indicates [1, 2, 3] that continental tectospheres must be immensely thicker than previously thought and almost certainly too thick to be stretched with the forces available. In the extreme case of cratons, these tectospheric keels may commonly extend to 600 km or more [3]. This thick-plate behaviour is attributable, not to cooling but to a petrological 'stiffening' effect, associated with a loss of water-weakening, which also applies to the LVZ below MORs [4, 5, 6]. The corresponding thick-plate version of the MOR process [1, 6] has a deep, narrow wall-accreting axial crack which inherently brings two outstanding additional benefits:- (i) why, at medium to fast spreading rates, MOR axes become straight and orthogonally segmented [7], (ii) not being driven by body forces, it can achieve the sudden jumps of axis, spreading-rate and direction widely recorded in mid-ocean and are necessary after generating the limited separations of microplates near margins. So in seeking the 'continent-ocean boundary' (COB) along passive margins, a site where stretching has often been invoked, we need instead to consider how this MOR process would be affected by the heavy concurrent sedimentation to be expected when splitting a continent. I reason that, by blocking the hydrothermal cooling, this must inhibit magnetic anomaly formation and prolong magmagenesis to give a thicker-than-oceanic mafic crust, which I have called Intermediate Crust (IC) [8, 9], to distinguish it from Mature Continental Crust (MCC). Seismologically, IC basement must look deceptively like that assigned to stretched MCC. For thermodynamic reasons [8, 9] the hydrous content of deep MCC and of deeply subducted UHP crustal slices gives them a big thermal epeirogenic sensitivity which IC lacks. The NE Atlantic offers an example of this distinction. Structurally, the MCC of Greenland and Norway must have been intimately juxtaposed by the Scandian collision, so it was concluded [9] that the crust of the Greenland-Norway continental shelves must mostly be IC of post-Scandian (early Devonian?) age, a character confirmed by their lack of epeirogenic response to laterally conducted heat from the opening N Atlantic, although drainage systems in Norway proper clearly show it. Geometrically, this separation appears to have changed direction sharply, the second and bigger stage also involving separation of Svalbard from near Tromsø, where it had provided northward continuation of a complete Caledonian transect, so it has an IC implication for much of the Barents Sea area (bar the Bjørnøya block). Moving quickly round to the NE side of Baltica, we can begin to trace the separative motions of the Novaya Zemlya - Pay Khoy (NZPK) strip of less-mature MCC, transverse to the Timanian belt, and the associated evolution of the Pechora basin system. In places, faulted IC/MCC epeirogenic contrasts seem to define the size and direction of the IC-generating separation with remarkable precision. A crucial opening-up of this analysis is provided by realizing that the Polar Ural stretch is not MCC, but is merely the huge 585 Ma Voykar-Synya ophiolite, with its metamorphics, resting on a now-crumpled boundary between IC of very different ages. For further understanding we need briefly to extend the analysis, first to the formation of the West Siberian Basin, the IC nature of whose crust (but not its low thermal epeirogenic sensitivity) has been obscured by Permo-Triassic addition of the Siberian flood basalts, and thence to the complicated MCC distribution seen in Khazakhstan. The pattern of the older elements of the latter appears to be a further, but more ancient, example of the plate dynamics evidence [1, 2, 3] for 'deep-keeled' cratons, in that, when they separate, horizontal inflows of mantle are induced which impinge on the lesser keels of MCC blocks in the region, potentially generating IC-floored basins in between them. In this way the geology which now lies between the Baltica and East Siberia cratons can in principle provide powerful constraints on the freedom with which palaeomagnetic data for them has been interpreted. A key element in this is that otherwise-missing components of the Timanian orogen are apparently to be found on the western edge of the Siberian platform. This means that the NZPK strip and Pechora Basin area were formed as part of the Timanian interplay between the then-roughly-parallel sides of the Baltica and Siberian cratons. A final step in this limited analysis suggests that the clockwise bending of northern Novaya Zemlya was the dextral consequence of the final (~2000 km) northwestward cratonic separation of Baltica plus NZPK etc. to form the IC of the West Siberian Basin during the 580-535 Ma interval. This may be older than any of the NZ rocks suitable for palaeomagnetic determination. Resolution of the conflict between this geologically and geometrically secured reconstruction and that prescribed palaeomagnetically for 'Rodinia' appears to lie in the possibility that at some point on the APWP there has been an inadvertent switch between following the N and the S pole, due to the habitual choosing of the lesser of two plate motion speeds during the interval between points on the curve. In that case some of the supposed assemblage will be geographically upside down in relation to the rest. Finally, a quick visit to the Chukchi-Bering-Alaska sector of the Arctic margin. Here, too, recognition of IC may provide a key. I suggest that northward emplacement of the Brooks Range Ophiolite at close to 170 Ma was swiftly followed by the (now) westward extraction of the Seward-Chukchi MCC assemblage to form, as IC, both the extensive Koyukuk basin system which lies south of Brooks Range and, ultimately, the Bering gap in the Pacific rim of cratonic keels, through which mantle to put at depth under the widening Eurasian Basin ocean floor has been drawn, initiating the Aleutian arc in the Palaeocene, trapping OC/IC behind it. I discuss a global reason for the initiation of the Bering gap, and its timing, in another session (GD6.1) of this meeting. [1] Osmaston M. F. (2006) Global tectonic actions emanating from Arctic opening in the circumstances of a two-layer mantle and a thick-plate paradigm involving deep cratonic tectospheres: the Eurekan (Eocene) compressive motion of Greenland and other examples. In, Proc. ICAM IV 2003 (ed. R. Scott & D. Thurston). OCS Study MMS 2006-003, pp.105-124: Also published on: http://www.mms.gov/alaska/icam [2] Osmaston M. F. (2007) Cratonic keels and a two-layer mantle tested: mantle expulsion during Arabia-Russia closure linked to westward enlargement of the Black Sea, formation of the Western Alps and subduction of the Tyrrhenian (not the Ionian) Sea. XXIV IUGG, Session JSS 011 Abstr #2105. http://www.iugg2007perugia.it/webbook/. [3] Osmaston M. F. (2009) Deep cratonic keels and a 2-layer mantle? Tectonic basis for some far-reaching new insights on the dynamical properties of the Earth's mantle: example motions from Mediterranean, Atlantic-Arctic and India. Geophys. Res. Abst. 11, EGU2009-6359 (Solicited). [4] Karato S. (1986) Does partial melting reduce the creep strength of the upper mantle? Nature 319, 309-310. [5] Hirth G. & Kohlstedt D. L. (1996) Water in the oceanic upper mantle: implication for rheology, melt extraction, and the evolution of the lithosphere. EPSL 144, 93-108. [6] Osmaston M. F. (2010) On the actual variety of plate dynamical mechanisms and how mantle evolution affected them through time, from core formation to the Indian collision. Geophys. Res. Abstr. 12, EGU2010-6101. [7] Osmaston M. F. (1995) A straightness mechanism for MORs: a new view of ocean plate genesis and evolution. In IUGG XXI Gen. Assy. Abstracts p. A472. [8] Osmaston M. F. (2011) An introduction to Intermediate Crust (IC): its formation, epeirogenic character, and plate tectonics significance. TSG Ann.Mtg. 2011, Durham University, Technical Programme p.45. [9] Osmaston M. F. (2008) Basal subduction tectonic erosion (STE), butter mélanges and the construction and exhumation of HP-UHP belts: the Alps example and some comparisons. Internat. Geol. Rev. 50(8), 685-754 DOI: 10.2747/00206814.50.8.685.

The applications of Complexity Theory and Tsallis Non-extensive Statistics at Solar Plasma Dynamics

NASA Astrophysics Data System (ADS)

Pavlos, George

2015-04-01

As the solar plasma lives far from equilibrium it is an excellent laboratory for testing complexity theory and non-equilibrium statistical mechanics. In this study, we present the highlights of complexity theory and Tsallis non extensive statistical mechanics as concerns their applications at solar plasma dynamics, especially at sunspot, solar flare and solar wind phenomena. Generally, when a physical system is driven far from equilibrium states some novel characteristics can be observed related to the nonlinear character of dynamics. Generally, the nonlinearity in space plasma dynamics can generate intermittent turbulence with the typical characteristics of the anomalous diffusion process and strange topologies of stochastic space plasma fields (velocity and magnetic fields) caused by the strange dynamics and strange kinetics (Zaslavsky, 2002). In addition, according to Zelenyi and Milovanov (2004) the complex character of the space plasma system includes the existence of non-equilibrium (quasi)-stationary states (NESS) having the topology of a percolating fractal set. The stabilization of a system near the NESS is perceived as a transition into a turbulent state determined by self-organization processes. The long-range correlation effects manifest themselves as a strange non-Gaussian behavior of kinetic processes near the NESS plasma state. The complex character of space plasma can also be described by the non-extensive statistical thermodynamics pioneered by Tsallis, which offers a consistent and effective theoretical framework, based on a generalization of Boltzmann - Gibbs (BG) entropy, to describe far from equilibrium nonlinear complex dynamics (Tsallis, 2009). In a series of recent papers, the hypothesis of Tsallis non-extensive statistics in magnetosphere, sunspot dynamics, solar flares, solar wind and space plasma in general, was tested and verified (Karakatsanis et al., 2013; Pavlos et al., 2014; 2015). Our study includes the analysis of solar plasma time series at three cases: sunspot index, solar flare and solar wind data. The non-linear analysis of the sunspot index is embedded in the non-extensive statistical theory of Tsallis (1988; 2004; 2009). The q-triplet of Tsallis, as well as the correlation dimension and the Lyapunov exponent spectrum were estimated for the SVD components of the sunspot index timeseries. Also the multifractal scaling exponent spectrum f(a), the generalized Renyi dimension spectrum D(q) and the spectrum J(p) of the structure function exponents were estimated experimentally and theoretically by using the q-entropy principle included in Tsallis non-extensive statistical theory, following Arimitsu and Arimitsu (2000, 2001). Our analysis showed clearly the following: (a) a phase transition process in the solar dynamics from high dimensional non-Gaussian SOC state to a low dimensional non-Gaussian chaotic state, (b) strong intermittent solar turbulence and anomalous (multifractal) diffusion solar process, which is strengthened as the solar dynamics makes a phase transition to low dimensional chaos in accordance to Ruzmaikin, Zelenyi and Milovanov's studies (Zelenyi and Milovanov, 1991; Milovanov and Zelenyi, 1993; Ruzmakin et al., 1996), (c) faithful agreement of Tsallis non-equilibrium statistical theory with the experimental estimations of: (i) non-Gaussian probability distribution function P(x), (ii) multifractal scaling exponent spectrum f(a) and generalized Renyi dimension spectrum Dq, (iii) exponent spectrum J(p) of the structure functions estimated for the sunspot index and its underlying non equilibrium solar dynamics. Also, the q-triplet of Tsallis as well as the correlation dimension and the Lyapunov exponent spectrum were estimated for the singular value decomposition (SVD) components of the solar flares timeseries. Also the multifractal scaling exponent spectrum f(a), the generalized Renyi dimension spectrum D(q) and the spectrum J(p) of the structure function exponents were estimated experimentally and theoretically by using the q-entropy principle included in Tsallis non-extensive statistical theory, following Arimitsu and Arimitsu (2000). Our analysis showed clearly the following: (a) a phase transition process in the solar flare dynamics from a high dimensional non-Gaussian self-organized critical (SOC) state to a low dimensional also non-Gaussian chaotic state, (b) strong intermittent solar corona turbulence and an anomalous (multifractal) diffusion solar corona process, which is strengthened as the solar corona dynamics makes a phase transition to low dimensional chaos, (c) faithful agreement of Tsallis non-equilibrium statistical theory with the experimental estimations of the functions: (i) non-Gaussian probability distribution function P(x), (ii) f(a) and D(q), and (iii) J(p) for the solar flares timeseries and its underlying non-equilibrium solar dynamics, and (d) the solar flare dynamical profile is revealed similar to the dynamical profile of the solar corona zone as far as the phase transition process from self-organized criticality (SOC) to chaos state. However the solar low corona (solar flare) dynamical characteristics can be clearly discriminated from the dynamical characteristics of the solar convection zone. At last we present novel results revealing non-equilibrium phase transition processes in the solar wind plasma during a strong shock event, which can take place in Solar wind plasma system. The solar wind plasma as well as the entire solar plasma system is a typical case of stochastic spatiotemporal distribution of physical state variables such as force fields ( ) and matter fields (particle and current densities or bulk plasma distributions). This study shows clearly the non-extensive and non-Gaussian character of the solar wind plasma and the existence of multi-scale strong correlations from the microscopic to the macroscopic level. It also underlines the inefficiency of classical magneto-hydro-dynamic (MHD) or plasma statistical theories, based on the classical central limit theorem (CLT), to explain the complexity of the solar wind dynamics, since these theories include smooth and differentiable spatial-temporal functions (MHD theory) or Gaussian statistics (Boltzmann-Maxwell statistical mechanics). On the contrary, the results of this study indicate the presence of non-Gaussian non-extensive statistics with heavy tails probability distribution functions, which are related to the q-extension of CLT. Finally, the results of this study can be understood in the framework of modern theoretical concepts such as non-extensive statistical mechanics (Tsallis, 2009), fractal topology (Zelenyi and Milovanov, 2004), turbulence theory (Frisch, 1996), strange dynamics (Zaslavsky, 2002), percolation theory (Milovanov, 1997), anomalous diffusion theory and anomalous transport theory (Milovanov, 2001), fractional dynamics (Tarasov, 2013) and non-equilibrium phase transition theory (Chang, 1992). References 1. T. Arimitsu, N. Arimitsu, Tsallis statistics and fully developed turbulence, J. Phys. A: Math. Gen. 33 (2000) L235. 2. T. Arimitsu, N. Arimitsu, Analysis of turbulence by statistics based on generalized entropies, Physica A 295 (2001) 177-194. 3. T. Chang, Low-dimensional behavior and symmetry braking of stochastic systems near criticality can these effects be observed in space and in the laboratory, IEEE 20 (6) (1992) 691-694. 4. U. Frisch, Turbulence, Cambridge University Press, Cambridge, UK, 1996, p. 310. 5. L.P. Karakatsanis, G.P. Pavlos, M.N. Xenakis, Tsallis non-extensive statistics, intermittent turbulence, SOC and chaos in the solar plasma. Part two: Solar flares dynamics, Physica A 392 (2013) 3920-3944. 6. A.V. Milovanov, Topological proof for the Alexander-Orbach conjecture, Phys. Rev. E 56 (3) (1997) 2437-2446. 7. A.V. Milovanov, L.M. Zelenyi, Fracton excitations as a driving mechanism for the self-organized dynamical structuring in the solar wind, Astrophys. Space Sci. 264 (1-4) (1999) 317-345. 8. A.V. Milovanov, Stochastic dynamics from the fractional Fokker-Planck-Kolmogorov equation: large-scale behavior of the turbulent transport coefficient, Phys. Rev. E 63 (2001) 047301. 9. G.P. Pavlos, et al., Universality of non-extensive Tsallis statistics and time series analysis: Theory and applications, Physica A 395 (2014) 58-95. 10. G.P. Pavlos, et al., Tsallis non-extensive statistics and solar wind plasma complexity, Physica A 422 (2015) 113-135. 11. A.A. Ruzmaikin, et al., Spectral properties of solar convection and diffusion, ApJ 471 (1996) 1022. 12. V.E. Tarasov, Review of some promising fractional physical models, Internat. J. Modern Phys. B 27 (9) (2013) 1330005. 13. C. Tsallis, Possible generalization of BG statistics, J. Stat. Phys. J 52 (1-2) (1988) 479-487. 14. C. Tsallis, Nonextensive statistical mechanics: construction and physical interpretation, in: G.M. Murray, C. Tsallis (Eds.), Nonextensive Entropy-Interdisciplinary Applications, Oxford Univ. Press, 2004, pp. 1-53. 15. C. Tsallis, Introduction to Non-Extensive Statistical Mechanics, Springer, 2009. 16. G.M. Zaslavsky, Chaos, fractional kinetics, and anomalous transport, Physics Reports 371 (2002) 461-580. 17. L.M. Zelenyi, A.V. Milovanov, Fractal properties of sunspots, Sov. Astron. Lett. 17 (6) (1991) 425. 18. L.M. Zelenyi, A.V. Milovanov, Fractal topology and strange kinetics: from percolation theory to problems in cosmic electrodynamics, Phys.-Usp. 47 (8), (2004) 749-788.

Is subduction really in the plate tectonics driving seat, or do two other global mechanisms do the driving? A review in the 'deep-keeled cratons' frame for global dynamics

NASA Astrophysics Data System (ADS)

Osmaston, M. F.

2012-04-01

Introduction. The title poses a question very like that of my talk in 2003 [1], concluding then that, as a driver, subduction comes 'a doubtful third'. My purpose here is to show that subsequent developments now cause even that limited status to be denied it with great assurance, except in a rare situation, of which there is no current example. The key point is that studies of subduction have been importantly mistaken as to the nature of the plate arriving for subduction. Deep-keeled cratons? The 'deep-keeled cratons' frame for global dynamics [2 - 5] is the result of seeking Earth-behaviour guidance on the following outside-the-box proposition:- "If cratons have tectospheric keels that reach or approach the 660 km discontinuity, AND the 660 level is an effective barrier to mantle circulation, then obviously (i) when two cratons separate, the upper mantle to put under the nascent ocean must arrive by a circuitous route and, conversely, (ii) if they approach one another, the mantle volume that was in between them must get extruded sideways." Remarkably it has turned out [2 - 5] that Earth dynamical behaviour for at least the past 150 Ma provides persuasive affirmation of both these expectations and that the explanation for the otherwise-unexpected immobility of subcratonic material to such depths is a petrological one which is also applicable to the behaviour of LVZ mantle below MORs [6 - 8]. Straight away this result has major consequences for the character of the plate arriving for subduction. First, to construct them, we need a 'thick-plate' (>100km?) model of the MOR process which recognizes that this LVZ immobility renders invalid the existing concept of divergent mantle flow below MORs. I show that my now not-so-new model [1, 8 - 10], based on a deep, narrrow, wall-accreting sub-axis crack, possesses outstandingly relevant properties, even appropriately dependent on spreading rate. Second, the oceanic plate arriving for subduction is no longer just the cooled mantle boundary layer habitually assumed, but its LVZ content gives it (i) residual heat content, (ii) corresponding buoyancy, and (iii) a flexural strength which demands a reconsideration of its mode of downbend, hitherto widely regarded as flexural, but still be able to explain outer rises and their differences. Solutions for (ii) and (iii) are convincingly supported by widespread exposure of the resulting rocks in the Alps, telling us how they and other UHP metamorphic mountain belts have been built [11]. I will illustrate the essential points. In particular, the buoyancy (ii) provides the upward mechanical contact essential for the shallow basal subduction tectonic erosion of the upper plate as preparation of thin imbricate crustal slices to subduct to UHP. And a seismologically supported through-plate step-faulting mode of downbend copes with the flexure problem (iii) and provides the tectonic erosion mechanism. In tackling these matters, important intrinsic properties of the materials are, notably:- (1) the thermal conductivity of non-migrating interstitial melt is >20 times less than its parent rock, so the LVZ heat is effectively trapped during the plate's journey across the ocean, only to be released when subduction raises the pressure and the melt freezes; (2) the garnet-to-spinel peridotite phase change, typically at 50 to 90 km depth, gives some 50 times more volume change per joule than pure expansivity, and it does so with the big force of solid-state recrystallization. This force is the crack-wall push-apart force provided by our thick-plate MOR model, which thereby develops at least an order more ridge push than the divergent flow model. We now consider the post-downbend evolution of the subducting plate, recognizing both the heat content of its ex-LVZ material and that, within the 2-layer mantle picture established by the plate dynamics of 'deep-keeled cratons' [2 - 5], there is no substantial mantle transport across the 660 km level. Examination of tomographic transects shows at once that in by far the majority of cases, the 'slab' signature begins to fade at some depth in the 180 - 350 km interval, but that a second high-Vp signature begins near 400 km and may continue far into the lower mantle. The fading, whose onset depth varies both with the age of the plate and with the subduction rate, is clearly due, not to slab drop-off, but to reheating of the slab component by its underlying ex-LVZ heat. In either case, reheating or drop-off, this invalidates slab pull as a reliable item in the tectonics toolkit. Instead, there is a thick-plate mechanism to provide back-arc opening in the presence of ridge-push [3, 11]. Slab-reheating may proceed to the stage of partially melting the interface oceanic crust. On experimental evidence, this will, at TZ depth, produce high-density, high-Vp stishovitic residues, lumps of which I see as causing the second high-Vp signature, as they shower through the 660 into the lower mantle. This interpretation escapes the slab-view paradox that the world's longest-lived young-plate subduction zone also has the world's biggest high-Vp signature in the lower mantle, whereas Izu-Bonin, subducting very old plate, has one of the smallest. Young-plate heat would surely melt more of the interface crust and generate more of the high-density residue. The early Proterozoic date at which this mantle layout replaced whole-mantle overturn is well shown by the behaviour of the mantle depletion index, epsilon Nd. At this point I conclude unhesitatingly that subduction is neither the, nor even one of the drivers of current plate motions, but is primarily driven by the powerful ridge-push from the thick-plate version of the MOR process. That push is what compresses the ocean plate if step-faulting at the downbend has temporarily locked subduction ('seismic coupling'), with the potential to release the energy for an M9 earthquake. But our system is dynamically incomplete. Ridge push cannot split a continent, so how does that occur? My original proposal [1] for that function was the long-term clockwise rotation of Antarctica and its coupling to the other plates. In another contribution at this meeting [12] the observational basis for its reality is now shown to be very strong. So the conclusion is that plate tectonics has only two primary drivers - this rotation and ridge push - subduction being a wholly passive consequence. [1] Osmaston M. F. (2003) What drives plate tectonics? Slab pull, ridge push or geomagnetic torque from the CMB? A new look at the old players vis-a-vis an exciting new one. XXIII IUGG, B129, Abstr. 016795-2. [2] Osmaston M. (2005) Interrelationships between large-scale plate motions as indicators of mantle structure: new constraints on mantle modelling and compositional layout. In 3rd Workshop on "Earth's mantle composition, structure and phase transitions". http://deep.earth.free.fr/participants.php. [3] Osmaston M. F. (2006) Global tectonic actions emanating from Arctic opening in the circumstances of a two-layer mantle and a thick-plate paradigm involving deep cratonic tectospheres: the Eurekan (Eocene) compressive motion of Greenland and other examples. In Proc. ICAM IV, 2003 (ed. R. Scott & D. Thurston). OCS Study MMS 2006-003, pp.105-124: Also at ; http://www.mms.gov/alaska/icam. [4] Osmaston M. F. (2007) Cratonic keels and a two-layer mantle tested: mantle expulsion during Arabia-Russia closure linked to westward enlargement of the Black Sea, formation of the Western Alps and subduction of the Tyrrhenian (not the Ionian) Sea. XXIV IUGG, Session JSS 011 Abstr #2105, http://www.iugg2007perugia.it/webbook/. [5] Osmaston M. F. (2009) Deep cratonic keels and a 2-layer mantle? Tectonic basis for some far-reaching new insights on the dynamical properties of the Earth's mantle: example motions from Mediterranean, Atlantic-Arctic and India. Geophys. Res.Abstr 11, EGU2009-6359 (Solicited). [6] Karato S. (1986) Does partial melting reduce the creep strength of the upper mantle? Nature 319, 309-310. [7] Hirth G. & Kohlstedt D. L. (1996) Water in the oceanic upper mantle: implication for rheology, melt extraction, and the evolution of the lithosphere. EPSL 144, 93-108. [8] Osmaston M. F. (2010) On the actual variety of plate dynamical mechanisms and how mantle evolution affected them through time, from core formation to the Indian collision. Geophys. Res. Abstr. 12, EGU2010-6101. [9] Osmaston M. F. (1995) A straightness mechanism for MORs: a new view of ocean plate genesis and evolution XXI IUGG, Abstracts p. A472. [10] Osmaston M. (2005) The ridge push mechanism of MORs as the agent of seismic coupling, tsunami, convergence partitioning and landward thrusting at subduction zones; insights on an interactive family of mostly-jerky mechanisms. IASPEI 2005 Gen. Assy, Santiago, Chile, Abstr. No 303. [11] Osmaston M. F. (2008) Basal subduction tectonic erosion (STE), butter mélanges and the construction and exhumation of HP-UHP belts: the Alps example and some comparisons. Internat. Geol. Rev. 50(8), 685-754 DOI: 10.2747/00206814.50.8.685. [12] Osmaston M. F. (2012) Did clockwise rotation of Antarctica cause the break-up of Gondwanaland? An investigation in the 'deep-keeled cratons' frame for global dynamics. GD6.1. Geophys. Res. Abstr. 14, EGU2012-2170.