The Biopharmaceutics Classification System: Subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC

PubMed Central

Tsume, Yasuhiro; Mudie, Deanna M.; Langguth, Peter; Amidon, Greg E.; Amidon, Gordon L.

2014-01-01

The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include subspecification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro–in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. PMID:24486482

State laser regulations: Arizona's approach and experience

NASA Astrophysics Data System (ADS)

Barat, Kenneth L.

1992-06-01

Approximately a dozen states have regulatory or statutory authority in the area of nonionizing radiation. With only half that number having established laser regulations. Examples are Texas, Florida, Arizona, Mass. many more are considering establishing such rules, such as N.J., Il., Neb. On the federal level, the Food and Drug Administration has been the most active entity. OSHA has just recently established laser safety guidelines for its inspection staff. In March of 1990 the State of Arizona enacted rules for the control of Nonionizing radiation. This fell under Article 14 of Tittle 12 of the Arizona Administrative Code, which is under the authority of the Arizona Radiation Regulatory Agency. The rules cover a wide range of nonionizing sources, but the major emphasis is in the area of laser devices. While all class lasers fall under Article 14, only Class IIIb and Class IV laser use facilities are required to be registered and inspected by the agency. The rules apply to all Class IIIb and Class IV laser users, meaning medical, industrial, entertainment, and also research facilities.

Establishing the pharmaceutical quality of Chinese herbal medicine: a provisional BCS classification.

PubMed

Fong, Sophia Y K; Liu, Mary; Wei, Hai; Löbenberg, Raimar; Kanfer, Isadore; Lee, Vincent H L; Amidon, Gordon L; Zuo, Zhong

2013-05-06

The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has received little attention in the area of Chinese herbal medicine (CHM). This is likely, in part, due to the presence of multiple active components as well as lack of standardization of CHM. In this report, we apply BCS classification to CHMs provisionally as a basis for establishing improved in vitro quality standards. Based on a top-200 drugs selling list in China, a total of 31 CHM products comprising 50 official active marker compounds (AMCs) were provisionally classified according to BCS. Information on AMC content and doses of these CHM products were retrieved from the Chinese Pharmacopoeia. BCS parameters including solubility and permeability of the AMCs were predicted in silico (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical properties of their AMCs is demonstrated to be feasible in the current study and can be used to provide a minimum set of quality standards. Our provisional results showed that 44% of the included AMCs were classified as Class III (high solubility, low permeability), followed by Class II (26%), Class I (18%), and Class IV (12%). A similar trend was observed when CHMs were classified in accordance with the BCS class of AMCs. Most (45%) of the included CHMs were classified as Class III, followed by Class II (16%), Class I (10%), and Class IV (6%); whereas 23% of the CHMs were of mixed class due to the presence of multiple individual AMCs with different BCS classifications. Moreover, about 60% of the AMCs were classified as high-solubility compounds (Class I and Class III), suggesting an important role for an in vitro dissolution test in setting quality control standards ensuring consistent biopharmaceutical quality for the commercially available CHM products. That is, provisionally, more than half of the AMCs of the top-selling CHMs included in this study would be candidates for a bioequivalence (BE) biowaiver, based on WHO recommendations and EMEA guidelines. Thus a dissolution requirement on these AMCs would represent a significant advance in the pharmaceutical quality of CHM today.

A benefit-risk assessment of class III antiarrhythmic agents.

PubMed

Brendorp, Bente; Pedersen, Oledyg; Torp-Pedersen, Christian; Sahebzadah, Naji; Køber, Lars

2002-01-01

With beta-blockers as the exception, increasing doubt is emerging on the value of antiarrhythmic drug therapy following a series of trials that have either shown no mortality benefit or even an excess mortality. Vaughan Williams class I drugs are generally avoided in patients with structural heart disease, and class IV drugs are avoided in heart failure. Unfortunately, arrhythmias are a growing problem due to an increase in the incidence of atrial fibrillation and sudden death. The population is becoming older and more patients survive for a longer time period with congestive heart failure, which again increases the frequency of both supraventricular as well as ventricular arrhythmias. Class III antiarrhythmic drugs act by blocking repolarising currents and thereby prolong the effective refractory period of the myocardium. This is believed to facilitate termination of re-entry tachyarrhythmias. This class of drugs is developed for treatment of both supraventricular and ventricular arrhythmias. Amiodarone, sotalol, dofetilide, and ibutilide are examples of class III drugs that are currently available. Amiodarone and sotalol have other antiarrhythmic properties in addition to pure class III action, which differentiates them from the others. However, all have potential serious adverse events. Proarrhythmia, especially torsade de pointes, is a common problem making the benefit-risk ratio of these drugs a key question. Class III drugs have been evaluated in different settings: primary and secondary prevention of ventricular arrhythmias and in treatment of atrial fibrillation or flutter. Based on existing evidence there is no routine indication for antiarrhythmic drug therapy other than beta-blockers in patients at high risk of sudden death. Subgroup analyses of trials with amiodarone and dofetilide suggest that patients with atrial fibrillation may have a mortality reduction with these drugs. However, this needs to be tested in a prospective trial. Similarly, subgroups that will benefit from prophylactic treatment with class III antiarrhythmic drugs may be found based on QT-intervals or - in the future - from genetic testing. Class III drugs are effective in converting atrial fibrillation to sinus rhythm and for the maintenance of sinus rhythm after conversion. This is currently by far the most important indication for this class of drugs. As defined by recent guidelines, amiodarone and dofetilide have their place as second-line therapy except for patients with heart failure where they are first line therapy being the only drugs where the safety has been documented for this group of high risk patients.

Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

PubMed

Madar, David J; Kopecka, Hana; Pireh, Daisy; Yong, Hong; Pei, Zhonghua; Li, Xiaofeng; Wiedeman, Paul E; Djuric, Stevan W; Von Geldern, Thomas W; Fickes, Michael G; Bhagavatula, Lakshmi; McDermott, Todd; Wittenberger, Steven; Richards, Steven J; Longenecker, Kenton L; Stewart, Kent D; Lubben, Thomas H; Ballaron, Stephen J; Stashko, Michael A; Long, Michelle A; Wells, Heidi; Zinker, Bradley A; Mika, Amanda K; Beno, David W A; Kempf-Grote, Anita J; Polakowski, James; Segreti, Jason; Reinhart, Glenn A; Fryer, Ryan M; Sham, Hing L; Trevillyan, James M

2006-10-19

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.

Multidisciplinary and multisetting team management programme in heart failure patients affects hospitalisation and costing.

PubMed

Piepoli, M F; Villani, G Q; Aschieri, D; Bennati, S; Groppi, F; Pisati, M S; Rosi, A; Capucci, A

2006-08-28

We evaluated whether multidisciplinary disease management programme developed with collaboration of physicians and nurses inside and outside general district hospital settings can affect clinical outcomes in heart failure population over a 12-month period. 571 patients hospitalised with CHF were referred to our unit and 509 patients agreed to participation. The intervention team included physicians and nurses from Internal Medicine and Cardiac Dept., and the patient's general practitioners. Contacts were on a pre-specified schedule, included a computerised programme of hospital visits and phone calls; in case of NYHA functional class III and IV patients, home visits were also planned. The median age of patients was 77.7+/-9 years (43.3% women). At baseline the percentage of patients with NYHA class III and IV was 56.0% vs. 26.0% after 12 months (P<0.05). Programme enrolment reduced total hospital admissions (82 vs. 190, -56%, P<0.05), number of patients hospitalised (62 vs. 146, 57%, P<0.05). All NYHA functional class benefited (class I=75%, class IV=67%), with reduction in the costing (-48%, P<0.05). Improvement in symptoms (-9.0+/-3.2) and signs (-5.2+/-3.1) scores was measured (P<0.01). Therapy optimisation was obtained by 20.5% increase in patients taking betablockade and 21.0% increase in those on anti-aldosterone drugs. Multidisciplinary approach to CHF management can improve clinical management, reducing hospitalisation rate and costing.

Testing for Drug Hypersensitivity Syndromes

PubMed Central

Rive, Craig M; Bourke, Jack; Phillips, Elizabeth J

2013-01-01

Adverse drug reactions are a common cause of patient morbidity and mortality. Type B drug reactions comprise only 20% of all drug reactions but they tend to be primarily immunologically mediated and less dependent on the drug’s pharmacological action and dose. Common Type B reactions seen in clinical practice are those of the immediate, IgE, Gell-Coombs Type I reactions, and the delayed, T-cell mediated, Type IV reactions. Management of these types of reactions, once they have occurred, requires careful consideration and recognition of the utility of routine diagnostic tests followed by ancillary specialised diagnostic testing. For Type I, IgE mediated reactions this includes prick/intradermal skin testing and oral provocation. For Type IV, T-cell mediated reactions this includes a variety of in vivo (patch testing) and ex vivo tests, many of which are currently mainly used in highly specialised research laboratories. The recent association of many serious delayed (Type IV) hypersensitivity reactions to specific drugs with HLA class I and II alleles has created the opportunity for HLA screening to exclude high risk populations from exposure to the implicated drug and hence prevent clinical reactions. For example, the 100% negative predictive value of HLA-B*5701 for true immunologically mediated abacavir hypersensitivity and the development of feasible, inexpensive DNA-based molecular tests has led to incorporation of HLA-B*5701 screening in routine HIV clinical practice. The mechanism by which drugs specifically interact with HLA has been recently characterised and promises to lead to strategies for pre-clinical screening to inform drug development and design. PMID:23592889

40 CFR 144.23 - Class IV wells.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 23 2011-07-01 2011-07-01 false Class IV wells. 144.23 Section 144.23... INJECTION CONTROL PROGRAM Authorization of Underground Injection by Rule § 144.23 Class IV wells. (a) Injection into existing Class IV wells is authorized for up to six months after approval or promulgation of...

40 CFR 144.23 - Class IV wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 24 2012-07-01 2012-07-01 false Class IV wells. 144.23 Section 144.23... INJECTION CONTROL PROGRAM Authorization of Underground Injection by Rule § 144.23 Class IV wells. (a) Injection into existing Class IV wells is authorized for up to six months after approval or promulgation of...

40 CFR 144.23 - Class IV wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 22 2010-07-01 2010-07-01 false Class IV wells. 144.23 Section 144.23... INJECTION CONTROL PROGRAM Authorization of Underground Injection by Rule § 144.23 Class IV wells. (a) Injection into existing Class IV wells is authorized for up to six months after approval or promulgation of...

A Novel Class of Bis- and Tris-Chelate Diam(m)inebis(dicarboxylato)platinum(IV) Complexes as Potential Anticancer Prodrugs

PubMed Central

Varbanov, Hristo P.; Göschl, Simone; Heffeter, Petra; Theiner, Sarah; Roller, Alexander; Jensen, Frank; Jakupec, Michael A.; Berger, Walter; Galanski, Markus; Keppler, Bernhard K.

2015-01-01

A novel class of platinum(IV) complexes of the type [Pt(Am)-(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models. PMID:25032896

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.

PubMed

Teixeira, M C; Carbone, C; Souto, E B

2017-10-01

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided. Copyright © 2017 Elsevier Ltd. All rights reserved.

Trends in oral drug bioavailability following bariatric surgery: examining the variable extent of impact on exposure of different drug classes

PubMed Central

Darwich, Adam S; Henderson, Kathryn; Burgin, Angela; Ward, Nicola; Whittam, Janet; Ammori, Basil J; Ashcroft, Darren M; Rostami-Hodjegan, Amin

2012-01-01

AIMS To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery. METHODS A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination. RESULTS No significant difference in the ‘post/pre surgery oral drug exposure ratio’ (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as ‘solubility limited’ displayed an overall reduction as compared with ‘freely soluble’ compounds, as well as an unaltered and increased ppR. CONCLUSION Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance. PMID:22463107

Treatment burden in patients with at least one class IV or V CFTR mutation.

PubMed

Dewulf, Jonas; Vermeulen, François; Wanyama, Simeon; Thomas, Muriel; Proesmans, Marijke; Dupont, Lieven; De Boeck, Kris

2015-12-01

CFTR mutations are grouped according to disease-causing mechanism. Several studies demonstrated that patients having at least one mutation of class IV/V, present with a milder phenotype, but little is known about their relative treatment burden. We compared treatment burden between patients with two class I, II, or III mutations and patients with at least one mutation of class IV/V in the 2010 database of the Belgian CF Registry. We calculated a "Treatment Burden Index" (TBI) by assigning long term therapies to categories low, medium and high intensity, for differential weighing in the total score. There were 779 patients with two known class I/II/III mutations and 94 patients with at least one class IV/V mutation. Compared to class I/II/III, class IV/V patients had a lower median number of clinic visits (4 vs. 5; P < 0.001), a lower risk of hospitalization (24.7% vs. 50.8%; P < 0.001) and intravenous antibiotic treatment (23.5% vs. 46.0%; P < 0.001) and a lower median TBI (6 vs. 9; P < 0.001). These differences remained significant when only class IV/V patients with pancreatic insufficiency (n = 31) were considered. This study clearly demonstrates the significantly lower treatment burden in patients with CF and at least one class IV/V mutation compared to patients with two class I/II/III mutations and contributes to providing better individual counseling at time of diagnosis. © 2015 Wiley Periodicals, Inc.

Strategies for reduction in the duration of intravenous drug use: Interest of drug tracers as quality indicators to improve intravenous to oral switch.

PubMed

Corny, Jennifer; Perreau, Simon; Thivilliers, Anne-Pauline; Leplay, Céline; Chevalier, Delphine; Beaussier, Hélène; Bézie, Yvonnick

2017-08-01

Intravenous (IV) to oral (PO) drug switch is a challenge for tertiary care institutions for several reasons: catheter-related infections, patient's pain and discomfort or higher costs, and overuse of IV drugs considered as an irrational use of medicines. The objective was to evaluate yearly acetaminophen and proton-pump inhibiters' (PPIs) IV/PO ratios from 2011 to 2015 and to determine their correlation with all drugs IV/PO ratios and their relevance as drug tracers. A secondary objective was to estimate costs savings associated with a IV to PO switch improvement. Data on IV and PO consumptions and impact on costs were presented to physicians yearly, followed by the development of a computerized tool and pharmaceutical validation of prescriptions. Intravenous and PO drug consumptions were extracted yearly for all drugs, acetaminophen, and PPIs from 2011-01-01 to 2015-12-31. Acetaminophen and PPIs' IV/PO ratios were compared to IV/PO consumptions for all drugs. Costs savings associated with this switch were calculated yearly by multiplying the difference in average cost per dose by the total number of doses delivered (fixed purchase prices, euros) for both routes. All drugs IV/PO ratio decreased every year to achieve a 16.3% reduction between 2011 and 2015. Acetaminophen and PPIs also decreased respectively by 35.5% and 16.5%. Same tendency of decrease of ratios year by year was noted for all drugs, PPIs, and acetaminophen. Savings for both acetaminophen and PPIs IV/PO switch were over 98 000€ for 5 years. This study demonstrated that acetaminophen IV/PO ratio, easily produced in routine, was a relevant tracer to follow IV/PO switch improvement as it was correlated with all drugs IV/PO ratio. Direct cost savings associated with IV/PO switch improvements were consequent and illustrate well the impact of our approach on the efficiency of therapeutics' management. © 2017 John Wiley & Sons, Ltd.

Aortic valve replacement in elderly patients.

PubMed

Glock, Y; Pecoul, R; Cerene, A; Laguerre, J; Puel, P

1984-01-01

The results for 62 consecutive patients aged 70 or more given aortic valve replacement (A.V.R.) between 1970 and 1982 are reported. All the patients were in the New York Heart Association (N.Y.H.A.) functional class III (29%) or IV (71%); 54.8% had angina and 30.6% had experienced syncope. Forty patients had aortic stenosis (A.S.), 10 had aortic regurgitation and 12 had mixed aortic valve disease. The operative myocardial infarction rate was 6.4%. Tilting disk valves were used. Eighty percent of the patients were anticoagulated with Warfarin whilst twenty percent received only antiplatelet drugs. All the patients were followed up for a mean period of 26 months; late mortality was 22.6% with 4.8% cardiac deaths. The thromboembolic rate was 1.6% and the disinsertion rate was 3.2%. Cerebral stroke was fatal in 3 cases in anticoagulated patients but the mechanism of the accident was not known. At the termination of the study 93% of surviving patients were in N.Y.H.A. class I or II. No patient was in class IV. The probability of five year survival is 71% for the entire group.

Cost-Effectiveness of Sacubitril-Valsartan in Patients With Heart Failure With Reduced Ejection Fraction.

PubMed

Sandhu, Alexander T; Ollendorf, Daniel A; Chapman, Richard H; Pearson, Steven D; Heidenreich, Paul A

2016-11-15

Sacubitril-valsartan therapy reduces cardiovascular mortality compared with enalapril therapy in patients with heart failure with reduced ejection fraction. To evaluate the cost-effectiveness of sacubitril-valsartan versus angiotensin-converting enzyme inhibitor therapy in patients with chronic heart failure. Markov decision model. Clinical trials, observational analyses, reimbursement data from the Centers for Medicare & Medicaid Services, drug pricing databases, and Centers for Disease Control and Prevention life tables. Patients at an average age of 64 years, New York Heart Association (NYHA) class II to IV heart failure, and left ventricular ejection fraction of 0.40 or less. Lifetime. Societal. Treatment with sacubitril-valsartan or lisinopril. Life-years, quality-adjusted life-years (QALYs), costs, heart failure hospitalizations, and incremental cost-effectiveness ratios. The sacubitril-valsartan group experienced 0.08 fewer heart failure hospitalization, 0.69 additional life-year, 0.62 additional QALY, and $29 203 in incremental costs, equating to a cost per QALY gained of $47 053. The cost per QALY gained was $44 531 in patients with NYHA class II heart failure and $58 194 in those with class III or IV heart failure. Sacubitril-valsartan treatment was most sensitive to the duration of improved outcomes, with a cost per QALY gained of $120 623 if the duration was limited to the length of the trial (median, 27 months). No variations in other parameters caused the cost to exceed $100 000 per QALY gained. The benefit of sacubitril-valsartan is based on a single clinical trial. Treatment with sacubitril-valsartan provides reasonable value in reducing cardiovascular mortality and morbidity in patients with NYHA class II to IV heart failure. U.S. Department of Veterans Affairs and Institute for Clinical and Economic Review.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole.

PubMed

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-03-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole - β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study.

Formulation of thermoresponsive and buccal adhesive in situ gel for treatment of oral thrush containing poorly water soluble drug bifonazole

PubMed Central

Patel, Dimendra; Patel, Dipti; Prajapati, Jatin; Patel, Umang; Patel, Vijay

2012-01-01

The aim of the present work is to formulate and evaluate in situ oral topical gels of poorly water soluble drug Bifonazole based on temperature induced systems for the treatment of oral candidiasis. Bifonazole is poorly water soluble and low permeable drug means it's belongs to BCS Class IV. Due to its poor water solubility, it necessary to enhance solubility in water by make complex with Beta- Cyclodextrin (Drug to βCyclo Dextrine ratio is 1:1). After in situ gel preparation done by using Poloxamer (10% and 15%w/w) along with carbopol 934 (0.2 to 1.0% w/w) and Bifonazole – β CD complex (1%w/w). The formulations were evaluated for physiochemical parameter, gelation Temperature, viscosity, gel strength, content uniformity mucoadhesive force, Diffusion Study. PMID:23066185

40 CFR 147.650 - State-administrative program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... CONTROL PROGRAMS Idaho § 147.650 State-administrative program—Class I, II, III, IV, and V wells. The UIC program for Class I, II, III, IV, and V wells in the State of Idaho, other than those on Indian lands, is the program administered by the Idaho Department of Water Resources, approved by EPA pursuant to...

Reliability of Use, Abuse, and Dependence of Four Types of Inhalants in Adolescents and Young Adults

PubMed Central

Ridenour, Ty A.; Bray, Bethany C.; Cottler, Linda B.

2007-01-01

Inhalants, as a class of drugs, consists of heterogeneous substances that include some of the most dangerous drugs on a per use basis. Research on inhalant abuse has lagged behind other drugs partly because of the need for a diagnostic instrument of different types of inhalants. This study was conducted to obtain reliability estimates for the new Substance Abuse Module DSM-IV inhalants diagnoses for four types of inhalants: aerosols, gases, nitrites, and solvents as well as different diagnostic configurations of inhalant use. Participants were 162 community sample adolescents or young adults (mean age = 20.3 years, SD = 2.4). Two-thirds of the sample was male and 83.3% was Caucasian. Kappas and intraclass correlation coefficients were computed to estimate test-retest reliabilities. Results suggested (a) abuse was more common than dependence (34.6% vs. 12.3%), (b) reliabilities of abuse criteria and diagnosis were good to excellent across subtypes, and (c) reliabilities of dependence criteria and diagnoses were poor to good across subtypes. Alternative configurations of DSM-IV criteria that were consistent with previous research on adolescents provided excellent reliabilities across subtypes of inhalants. Moreover, 11.1% of participants experienced inhalants withdrawal. PMID:17576041

40 CFR 147.2200 - State-administered program-Class I, III, IV, and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... the in situ combustion of coal are regulated by the Rail Road Commission of Texas under a separate UIC... program for Class I, III, IV, and V wells in the State of Texas, except for those wells on Indian lands... (SDWA). Notice of the original approval for Class I, III, IV, and V wells was published in the Federal...

40 CFR 147.2200 - State-administered program-Class I, III, IV, and V wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

... the in situ combustion of coal are regulated by the Rail Road Commission of Texas under a separate UIC... program for Class I, III, IV, and V wells in the State of Texas, except for those wells on Indian lands... (SDWA). Notice of the original approval for Class I, III, IV, and V wells was published in the Federal...

Mechanistic Physiologically Based Pharmacokinetic Modeling of the Dissolution and Food Effect of a Biopharmaceutics Classification System IV Compound-The Venetoclax Story.

PubMed

Emami Riedmaier, Arian; Lindley, David J; Hall, Jeffrey A; Castleberry, Steven; Slade, Russell T; Stuart, Patricia; Carr, Robert A; Borchardt, Thomas B; Bow, Daniel A J; Nijsen, Marjoleen

2018-01-01

Venetoclax, a selective B-cell lymphoma-2 inhibitor, is a biopharmaceutics classification system class IV compound. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to mechanistically describe absorption and disposition of an amorphous solid dispersion formulation of venetoclax in humans. A mechanistic PBPK model was developed incorporating measured amorphous solubility, dissolution, metabolism, and plasma protein binding. A middle-out approach was used to define permeability. Model predictions of oral venetoclax pharmacokinetics were verified against clinical studies of fed and fasted healthy volunteers, and clinical drug interaction studies with strong CYP3A inhibitor (ketoconazole) and inducer (rifampicin). Model verification demonstrated accurate prediction of the observed food effect following a low-fat diet. Ratios of predicted versus observed C max and area under the curve of venetoclax were within 0.8- to 1.25-fold of observed ratios for strong CYP3A inhibitor and inducer interactions, indicating that the venetoclax elimination pathway was correctly specified. The verified venetoclax PBPK model is one of the first examples mechanistically capturing absorption, food effect, and exposure of an amorphous solid dispersion formulated compound. This model allows evaluation of untested drug-drug interactions, especially those primarily occurring in the intestine, and paves the way for future modeling of biopharmaceutics classification system IV compounds. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Class IV polyhydroxyalkanoate (PHA) synthases and PHA-producing Bacillus.

PubMed

Tsuge, Takeharu; Hyakutake, Manami; Mizuno, Kouhei

2015-08-01

This review highlights the recent investigations of class IV polyhydroxyalkanoate (PHA) synthases, the newest classification of PHA synthases. Class IV synthases are prevalent in organisms of the Bacillus genus and are composed of a catalytic subunit PhaC (approximately 40 kDa), which has a PhaC box sequence ([GS]-X-C-X-[GA]-G) at the active site, and a second subunit PhaR (approximately 20 kDa). The representative PHA-producing Bacillus strains are Bacillus megaterium and Bacillus cereus; the nucleotide sequence of phaC and the genetic organization of the PHA biosynthesis gene locus are somewhat different between these two strains. It is generally considered that class IV synthases favor short-chain-length monomers such as 3-hydroxybutyrate (C4) and 3-hydroxyvalerate (C5) for polymerization, but can polymerize some unusual monomers as minor components. In Escherichia coli expressing PhaRC from B. cereus YB-4, the biosynthesized PHA undergoes synthase-catalyzed alcoholytic cleavage using endogenous and exogenous alcohols. This alcoholysis is thought to be shared among class IV synthases, and this reaction is useful not only for the regulation of PHA molecular weight but also for the modification of the PHA carboxy terminus. The novel properties of class IV synthases will open up the possibility for the design of new PHA materials.

Nutrient-dependent increased dendritic arborization of somatosensory neurons.

PubMed

Watanabe, Kaori; Furumizo, Yuki; Usui, Tadao; Hattori, Yukako; Uemura, Tadashi

2017-01-01

Suboptimal nutrition imposes developmental constraints on infant animals, which marshal adaptive responses to eventually become mature adults. Such responses are mounted at multiple levels from systemic to cellular. At the cellular level, the underlying mechanisms of cell proliferation control have been intensively studied. However, less is known about how growth of postmitotic and morphologically complex cells, such as neurons, is controlled by nutritional status. We address this question using Class I and Class IV dendritic arborization neurons in Drosophila larvae. Class IV neurons have been shown to sense nociceptive thermal, mechanical and light stimuli, whereas Class I neurons are proprioceptors. We reared larvae on diets with different protein and carbohydrate content throughout larval stages and examined how morphologies of Class I or Class IV neurons were affected. Dendritic arbors of Class IV neurons became more complex when larvae were reared on a low-yeast diet, which contains lower amounts of amino acids and other ingredients, compared to a high-yeast diet. In contrast, such low-yeast-dependent hyperarborization was not seen in Class I neurons. The physiological and metabolic implications of the hyperarborization phenotype are discussed in relation to a recent hypothesis that Class IV neurons sense protein-deficient stress and to our characterization of how the dietary yeast contents impacted larval metabolism. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

21 CFR 880.5025 - I.V. container.

Code of Federal Regulations, 2014 CFR

2014-04-01

... I.V. container. (a) Identification. An I.V. container is a container made of plastic or glass used... 21 Food and Drugs 8 2014-04-01 2014-04-01 false I.V. container. 880.5025 Section 880.5025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES...

21 CFR 880.5025 - I.V. container.

Code of Federal Regulations, 2013 CFR

2013-04-01

... I.V. container. (a) Identification. An I.V. container is a container made of plastic or glass used... 21 Food and Drugs 8 2013-04-01 2013-04-01 false I.V. container. 880.5025 Section 880.5025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES...

21 CFR 880.5025 - I.V. container.

Code of Federal Regulations, 2012 CFR

2012-04-01

... I.V. container. (a) Identification. An I.V. container is a container made of plastic or glass used... 21 Food and Drugs 8 2012-04-01 2012-04-01 false I.V. container. 880.5025 Section 880.5025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES...

21 CFR 880.5025 - I.V. container.

Code of Federal Regulations, 2011 CFR

2011-04-01

... I.V. container. (a) Identification. An I.V. container is a container made of plastic or glass used... 21 Food and Drugs 8 2011-04-01 2011-04-01 false I.V. container. 880.5025 Section 880.5025 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES...

Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medicines of Pakistan

PubMed Central

Shawahna, R.; Rahman, NU.

2011-01-01

Background and the purpose of the study Partition coefficients (log D and log P) and molecular surface area (PSA) are potential predictors of the intestinal permeability of drugs. The aim of this investigation was to evaluate and compare these intestinal permeability indicators. Methods Aqueous solubility data were obtained from literature or calculated using ACD/Labs and ALOGPS. Permeability data were predicted based on log P, log D at pH 6.0 (log D6.0), and PSA. Results Metoprolol's log P, log D6.0, and a PSA of <65 Å correctly predicted 55.9%, 50.8% and 54.2% of permeability classes, respectively. Labetalol's log P, log D6.0 and PSA correctly predicted 54.2%, 64.4% and 61% of permeability classes, respectively. Log D6.0 correlated well (81%) with Caco-2 permeability (Papp). Of the list of national essential medicines, 135 orally administered drugs were classified into biopharmaceutical classification system (BCS). Of these, 57 (42.2%), 28 (20.7%), 44 (32.6%), and 6 (4.4%) were class I, II, III and IV respectively. Conclusion Log D6.0 showed better prediction capability than log P. Metoprolol as permeability internal standard was more conservative than labetalol. PMID:22615645

Physicians' decision process for drug prescription and the impact of pharmaceutical marketing mix instruments.

PubMed

Campo, Katia; De Staebel, Odette; Gijsbrechts, Els; van Waterschoot, Walter

2005-01-01

This paper provides an in-depth, qualitative analysis of the physicians' decision process for drug prescription. Drugs in the considered therapeutic classes are mainly prescribed by specialists, treating patients with obligatory medical insurance, for a prolonged period of time. The research approach is specifically designed to capture the full complexity and sensitive nature of the physician's choice behavior, which appears to be more hybrid and less rational in nature than is often assumed in quantitative, model-based analyses of prescription behavior. Several interesting findings emerge from the analysis: (i) non-compensatory decision rules seem to dominate the decision process, (ii) consideration sets are typically small and change-resistant, (iii) drug cost is not a major issue for most physicians, (iv) detailing remains one of the most powerful pharmaceutical marketing instruments and is highly appreciated as a valuable and quick source of information, and (v) certain types of non-medical marketing incentives (such as free conference participation) may in some situations also influence drug choices.

[Preoperative risk assessment with the ASA classification. A prospective study of morbidity and mortality in various ASA classes in 2,937 patients in general surgery].

PubMed

Menke, H; John, K D; Klein, A; Lorenz, W; Junginger, T

1992-12-01

The value of ASA classification in assessment of perioperative risk, i.e. especially postoperative morbidity, was analyzed prospectively using the data of 2937 patients. The analysis took into account the criteria validity, reliability, and sensitivity. The incidence of post-operative morbidity after elective surgery rose from 3.9% in ASA class I to 36% in ASA class IV. Mortality was 0.6% in ASA class II, whereas 9.3% died in ASA class IV. Morbidity, mortality respectively, after emergency surgery was 10.2% in ASA class II compared to 69% in class IV, mortality 1.4% compared to 21.5%. Differences between the ASA classes were confirmed (p-value < 0.05) considering separate kinds of complications and different periods. Furthermore, ASA classification was a valuable reference to length of stay and severity of necessary therapy at the ICU.

Oral amiodarone: historical overview and development.

PubMed

Pollak, P T

1998-01-01

To review the historical development of amiodarone and the changing perceptions of the drug, and discuss its electrophysiologic, pharmacologic, and pharmacokinetic properties. Review of relevant literature. In the 1970s and 1980s a plethora of new antiarrhythmic agents, including amiodarone, was introduced. Amiodarone is predominately a class III antiarrhythmic, but also possesses class I, II, and IV effects. By 1977 it was described as the ideal antiarrhythmic agent. However, clinicians underestimated potential difficulties caused by misunderstanding its variable absorption, slow initial response at nonloading dosages, and extended half-life. Elevated dosages also produced frequent adverse effects. Thus, early enthusiasm for the drug's efficacy was gradually replaced by a focus on its toxicity. The 1990s witnessed reacceptance of the agent as more logical initial regimens and lower maintenance dosages decreased adverse effects, and amiodarone emerged as one of the few drugs effective in suppressing and preventing arrhythmias that does not increase mortality. Remaining challenges include delineation of an optimal oral regimen, identification of markers useful in clinical monitoring, and elucidation of the relationship between dose-tissue concentration and response and dose-toxicity associations. Amiodarone is an increasingly valuable component of today's antiarrhythmic therapy.

40 CFR 147.251 - EPA-administered program-Class I, III, IV and V wells and Indian lands.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., IV and V wells and Indian lands. 147.251 Section 147.251 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS California § 147.251 EPA-administered program—Class I, III, IV and V wells and...

40 CFR 147.301 - EPA-administered program-Class I, III, IV, V wells and Indian lands.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., IV, V wells and Indian lands. 147.301 Section 147.301 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Colorado § 147.301 EPA-administered program—Class I, III, IV, V wells and Indian...

40 CFR 147.251 - EPA-administered program-Class I, III, IV and V wells and Indian lands.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., IV and V wells and Indian lands. 147.251 Section 147.251 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS California § 147.251 EPA-administered program—Class I, III, IV and V wells and...

40 CFR 147.301 - EPA-administered program-Class I, III, IV, V wells and Indian lands.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., IV, V wells and Indian lands. 147.301 Section 147.301 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Colorado § 147.301 EPA-administered program—Class I, III, IV, V wells and Indian...

The Current Case of Quinolones: Synthetic Approaches and Antibacterial Activity.

PubMed

Naeem, Abdul; Badshah, Syed Lal; Muska, Mairman; Ahmad, Nasir; Khan, Khalid

2016-03-28

Quinolones are broad-spectrum synthetic antibacterial drugs first obtained during the synthesis of chloroquine. Nalidixic acid, the prototype of quinolones, first became available for clinical consumption in 1962 and was used mainly for urinary tract infections caused by Escherichia coli and other pathogenic Gram-negative bacteria. Recently, significant work has been carried out to synthesize novel quinolone analogues with enhanced activity and potential usage for the treatment of different bacterial diseases. These novel analogues are made by substitution at different sites--the variation at the C-6 and C-8 positions gives more effective drugs. Substitution of a fluorine atom at the C-6 position produces fluroquinolones, which account for a large proportion of the quinolones in clinical use. Among others, substitution of piperazine or methylpiperazine, pyrrolidinyl and piperidinyl rings also yields effective analogues. A total of twenty six analogues are reported in this review. The targets of quinolones are two bacterial enzymes of the class II topoisomerase family, namely gyrase and topoisomerase IV. Quinolones increase the concentration of drug-enzyme-DNA cleavage complexes and convert them into cellular toxins; as a result they are bactericidal. High bioavailability, relative low toxicity and favorable pharmacokinetics have resulted in the clinical success of fluoroquinolones and quinolones. Due to these superior properties, quinolones have been extensively utilized and this increased usage has resulted in some quinolone-resistant bacterial strains. Bacteria become resistant to quinolones by three mechanisms: (1) mutation in the target site (gyrase and/or topoisomerase IV) of quinolones; (2) plasmid-mediated resistance; and (3) chromosome-mediated quinolone resistance. In plasmid-mediated resistance, the efflux of quinolones is increased along with a decrease in the interaction of the drug with gyrase (topoisomerase IV). In the case of chromosome-mediated quinolone resistance, there is a decrease in the influx of the drug into the cell.

Psychometric modeling of abuse and dependence symptoms across six illicit substances indicates novel dimensions of misuse

PubMed Central

Clark, Shaunna L.; Gillespie, Nathan A.; Adkins, Daniel E.; Kendler, Kenneth S.; Neale, Michael C.

2015-01-01

Aims This study explored the factor structure of DSM III-R/IV symptoms for substance abuse and dependence across six illicit substance categories in a population-based sample of males. Method DSM III-R/IV drug abuse and dependence symptoms for cannabis, sedatives, stimulants, cocaine, opioids and hallucinogens from 4179 males born 1940-1970 from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders were analyzed. Confirmatory factor analyses tested specific hypotheses regarding the latent structure of substance misuse for a comprehensive battery of 13 misuse symptoms measured across six illicit substance categories (78 items). Results Among the models fit, the latent structure of substance misuse was best represented by a combination of substance-specific factors and misuse symptom-specific factors. We found no support for a general liability factor to illicit substance misuse. Conclusions Results indicate that liability to misuse illicit substances is drug class specific, with little evidence for a general liability factor. Additionally, unique dimensions capturing propensity toward specific misuse symptoms (e.g., tolerance, withdrawal) across substances were identified. While this finding requires independent replication, the possibility of symptom-specific misuse factors, present in multiple substances, raises the prospect of genetic, neurobiological and behavioral predispositions toward distinct, narrowly defined features of drug abuse and dependence. PMID:26517709

40 CFR 146.10 - Plugging and abandoning Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

...) The plugging and abandonment plan required in 40 CFR 144.51(o) and 144.52(a)(6) shall, in the case of... deems it necessary and feasible to insure adequate protection of USDWs. (b) Requirements for Class IV... with 40 CFR 144.23(b). (c) Requirements for Class V wells. (1) Prior to abandoning a Class V well, the...

40 CFR 146.10 - Plugging and abandoning Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2014 CFR

2014-07-01

...) The plugging and abandonment plan required in 40 CFR 144.51(o) and 144.52(a)(6) shall, in the case of... deems it necessary and feasible to insure adequate protection of USDWs. (b) Requirements for Class IV... with 40 CFR 144.23(b). (c) Requirements for Class V wells. (1) Prior to abandoning a Class V well, the...

40 CFR 146.10 - Plugging and abandoning Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2013 CFR

2013-07-01

...) The plugging and abandonment plan required in 40 CFR 144.51(o) and 144.52(a)(6) shall, in the case of... deems it necessary and feasible to insure adequate protection of USDWs. (b) Requirements for Class IV... with 40 CFR 144.23(b). (c) Requirements for Class V wells. (1) Prior to abandoning a Class V well, the...

Relationship between time to clinical response and outcomes among Pneumonia Outcomes Research Team (PORT) risk class III and IV hospitalized patients with community-acquired pneumonia who received ceftriaxone and azithromycin.

PubMed

Zasowski, Evan; Butterfield, Jill M; McNutt, Louise-Ann; Cohen, Jason; Cosler, Leon; Pai, Manjunath P; Gottwald, Joseph; Chen, Wen Zhen; Lodise, Thomas P

2014-07-01

Recent Food and Drug Administration (FDA) guidance endorses the use of an early clinical response endpoint as the primary outcome for community-acquired bacterial pneumonia (CABP) trials. While antibiotics will now be approved for CABP, in practice they will primarily be used to treat patients with community-acquired pneumonia (CAP). More importantly, it is unclear how achievement of the new FDA CABP early response endpoint translates into clinically applicable real-world outcomes for patients with CAP. To address this, a retrospective cohort study was conducted among adult patients who received ceftriaxone and azithromycin for CAP of Pneumonia Outcomes Research Team (PORT) risk class III and IV at an academic medical center. The clinical response was defined as clinical stability for 24 h with improvement in at least one pneumonia symptom and with no symptom worsening. A classification and regression tree (CART) was used to determine the delay in response time, measured in days, associated with the greatest risk of a prolonged hospital length of stay (LOS) and adverse outcomes (in-hospital mortality or 30-day CAP-related readmission). A total of 250 patients were included. On average, patients were discharged 2 days following the achievement of a clinical response. In the CART analysis, adverse clinical outcomes were higher among day 5 nonresponders than those who responded by day 5 (22.4% versus 6.9%, P = 0.001). The findings from this study indicate that time to clinical response, as defined by the recent FDA guidance, is a reasonable prognostic indicator of real-world effectiveness outcomes among hospitalized PORT risk class III and IV patients with CAP who received ceftriaxone and azithromycin. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

76 FR 58020 - Prescription Drug User Fee Act IV Information Technology Plan

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-19

...] Prescription Drug User Fee Act IV Information Technology Plan AGENCY: Food and Drug Administration, HHS. ACTION... information technology (IT) plan entitled ``PDUFA IV Information Technology Plan'' (updated plan) to achieve... Information Technology Plan.'' This plan will meet one of the performance goals agreed to under the 2007...

Trends in oral drug bioavailability following bariatric surgery: examining the variable extent of impact on exposure of different drug classes.

PubMed

Darwich, Adam S; Henderson, Kathryn; Burgin, Angela; Ward, Nicola; Whittam, Janet; Ammori, Basil J; Ashcroft, Darren M; Rostami-Hodjegan, Amin

2012-11-01

Changes to oral drug bioavailability have been observed post bariatric surgery. However, the magnitude and the direction of changes have not been assessed systematically to provide insights into the parameters governing the observed trends. Understanding these can help with dose adjustments. Analysis of drug characteristics based on a biopharmaceutical classification system is not adequate to explain observed trends in altered oral drug bioavailability following bariatric surgery, although the findings suggest solubility to play an important role. To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery. A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination. No significant difference in the 'post/pre surgery oral drug exposure ratio' (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as 'solubility limited' displayed an overall reduction as compared with 'freely soluble' compounds, as well as an unaltered and increased ppR. Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Evaluation of Intestinal Absorption and Bioavailability of a Bergenin-Phospholipid Complex Solid Dispersion in Rats.

PubMed

Gao, Haoshi; Wei, Yue; Xi, Long; Sun, Yuanyuan; Zhang, Tianhong

2018-05-01

Bergenin (BN) is a Biopharmaceutics Classification System class IV (BCS IV) drug with poor hydrophilicity and lipophilicity and is potentially eliminated by the efflux function of P-glycoprotein (P-gp). These factors may explain its low oral bioavailability. In the present study, a BN-phospholipid complex solid dispersion (BNPC-SD) was prepared by solvent evaporation and characterized based on differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, infrared diffraction, solubility, octanol-water partition coefficient, and in vitro dissolution. To investigate how P-gp can inhibit BN absorption in vivo, the P-gp inhibitor verapamil was co-administered with BNPC-SD to Sprague Dawley rats. By in situ single-pass intestinal perfusion, the membrane permeability of BN from BNPC-SD was higher than that of BN given alone and was improved further by co-administered verapamil. A pharmacokinetics study was done in Sprague Dawley rats, with plasma BN levels estimated by high-performance liquid chromatography. C max and AUC 0 → t values for BN were significantly higher for BNPC-SD than for BN given alone and were increased further by verapamil. Thus, the relative oral bioavailability of BNPC-SD as well as BNPC-SD co-administered with verapamil was 156.33 and 202.46%, respectively, compared with the value for BN given alone. These results showed that BNPC-SD can increase the oral bioavailability of BCS IV drugs.

Overview of phase IV clinical trials for postmarket drug safety surveillance: a status report from the ClinicalTrials.gov registry.

PubMed

Zhang, Xinji; Zhang, Yuan; Ye, Xiaofei; Guo, Xiaojing; Zhang, Tianyi; He, Jia

2016-11-23

Phase IV trials are often used to investigate drug safety after approval. However, little is known about the characteristics of contemporary phase IV clinical trials and whether these studies are of sufficient quality to advance medical knowledge in pharmacovigilance. We aimed to determine the fundamental characteristics of phase IV clinical trials that evaluated drug safety using the ClinicalTrials.gov registry data. A data set of 19 359 phase IV clinical studies registered in ClinicalTrials.gov was downloaded. The characteristics of the phase IV trials focusing on safety only were compared with those evaluating both safety and efficacy. We also compared the characteristics of the phase IV trials in three major therapeutic areas (cardiovascular diseases, mental health and oncology). Multivariable logistic regression was used to evaluate factors associated with the use of blinding and randomisation. A total of 4772 phase IV trials were identified, including 330 focusing on drug safety alone and 4392 evaluating both safety and efficacy. Most of the phase IV trials evaluating drug safety (75.9%) had enrolment <300 with 96.5% <3000. Among these trials, 8.2% were terminated or withdrawn. Factors associated with the use of blinding and randomisation included the intervention model, clinical specialty and lead sponsor. Phase IV trials evaluating drug safety in the ClinicalTrials.gov registry were dominated by small trials that might not have sufficient power to detect less common adverse events. An adequate sample size should be emphasised for phase IV trials with safety surveillance as main task. 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/.

40 CFR 147.2650 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... CONTROL PROGRAMS Puerto Rico § 147.2650 State-administered program—Class I, II, III, IV, and V wells. The Underground Injection Control Program for all classes of wells in the Commonwealth of Puerto Rico, other than those on Indian lands, is the program administered by Puerto Rico's Environmental Quality Board (EQB...

40 CFR 147.2650 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2011 CFR

2011-07-01

... CONTROL PROGRAMS Puerto Rico § 147.2650 State-administered program—Class I, II, III, IV, and V wells. The Underground Injection Control Program for all classes of wells in the Commonwealth of Puerto Rico, other than those on Indian lands, is the program administered by Puerto Rico's Environmental Quality Board (EQB...

40 CFR 147.2650 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2013 CFR

2013-07-01

... CONTROL PROGRAMS Puerto Rico § 147.2650 State-administered program—Class I, II, III, IV, and V wells. The Underground Injection Control Program for all classes of wells in the Commonwealth of Puerto Rico, other than those on Indian lands, is the program administered by Puerto Rico's Environmental Quality Board (EQB...

The first crystal structures of a family 19 class IV chitinase: the enzyme from Norway spruce.

PubMed

Ubhayasekera, Wimal; Rawat, Reetika; Ho, Sharon Wing Tak; Wiweger, Malgorzata; Von Arnold, Sara; Chye, Mee-Len; Mowbray, Sherry L

2009-10-01

Chitinases help plants defend themselves against fungal attack, and play roles in other processes, including development. The catalytic modules of most plant chitinases belong to glycoside hydrolase family 19. We report here x-ray structures of such a module from a Norway spruce enzyme, the first for any family 19 class IV chitinase. The bi-lobed structure has a wide cleft lined by conserved residues; the most interesting for catalysis are Glu113, the proton donor, and Glu122, believed to be a general base that activate a catalytic water molecule. Comparisons to class I and II enzymes show that loop deletions in the class IV proteins make the catalytic cleft shorter and wider; from modeling studies, it is predicted that only three N-acetylglucosamine-binding subsites exist in class IV. Further, the structural comparisons suggest that the family 19 enzymes become more closed on substrate binding. Attempts to solve the structure of the complete protein including the associated chitin-binding module failed, however, modeling studies based on close relatives indicate that the binding module recognizes at most three N-acetylglucosamine units. The combined results suggest that the class IV enzymes are optimized for shorter substrates than the class I and II enzymes, or alternatively, that they are better suited for action on substrates where only small regions of chitin chain are accessible. Intact spruce chitinase is shown to possess antifungal activity, which requires the binding module; removing this module had no effect on measured chitinase activity.

Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy

PubMed Central

Zhu, Caiying; Xiao, Jingjing; Tang, Ming; Feng, Hua; Chen, Wulian; Du, Ming

2017-01-01

The preparation of polymer therapeutics capable of controlled release of multiple chemotherapeutic drugs has remained a tough problem in synergistic combination cancer therapy. Herein, a novel dual-drug co-delivery system carrying doxorubicin (DOX) and platinum(IV) (Pt[IV]) was developed. An amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-AzPMA), was synthesized and used as a nanoscale drug carrier in which DOX and Pt(IV) could be packaged together. The copolymers were shell cross-linked by Pt(IV) prodrug via a click reaction. Studies on the in vitro drug release and cellular uptake of the dual-drug co-delivery system showed that the micelles were effectively taken up by the cells and simultaneously released drugs in the cells. Futhermore, the co-delivery polymer nanoparticles caused much higher cell death in HeLa and A357 tumor cells than either the free drugs or single-drug-loaded micelles at the same dosage, exhibiting a synergistic combination of DOX and Pt(IV). The results obtained with the shell cross-linked micelles based on an anticancer drug used as a cross-linking linkage suggested a promising application of the micelles for multidrug delivery in combination cancer therapy. PMID:28553108

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

PubMed

Meyers, Marvin J; Anderson, Elizabeth J; McNitt, Sarah A; Krenning, Thomas M; Singh, Megh; Xu, Jing; Zeng, Wentian; Qin, Limei; Xu, Wanwan; Zhao, Siting; Qin, Li; Eickhoff, Christopher S; Oliva, Jonathan; Campbell, Mary A; Arnett, Stacy D; Prinsen, Michael J; Griggs, David W; Ruminski, Peter G; Goldberg, Daniel E; Ding, Ke; Liu, Xiaorong; Tu, Zhengchao; Tortorella, Micky D; Sverdrup, Francis M; Chen, Xiaoping

2015-08-15

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease β-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 μM and 0.099 μM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study. Copyright © 2015 Elsevier Ltd. All rights reserved.

Trajectories of Substance Use Disorder in Youth After Detention: A 12-Year Longitudinal Study

PubMed Central

Welty, Leah J.; Hershfield, Jennifer A.; Abram, Karen M.; Han, Hongyun; Byck, Gayle R.; Teplin, Linda A.

2016-01-01

Objective Identify trajectories of substance use disorders (SUDs) in youth during the 12 years after detention, and how gender, race/ethnicity, and age at baseline predict trajectories. Method As part of the Northwestern Juvenile Project, a longitudinal study of 1,829 youth randomly sampled from detention in Chicago, Illinois, 1995–1998, participants were re-interviewed in the community or correctional facilities up to 9 times over 12 years. Independent interviewers assessed SUDs using the Diagnostic Interview Schedule for Children 2.3 (baseline) and the Diagnostic Interview Schedule IV (follow-ups). Primary outcome was a mutually exclusive 5-category typology of disorder: no SUD, alcohol alone, marijuana alone, comorbid alcohol and marijuana, or “other” illicit (“hard”) drug. We estimated trajectories using growth mixture models with a 3-category ordinal variable derived from the typology. Results During the 12-year follow-up, 19.6% of youth did not have an SUD. The remaining 81.4% were in 3 trajectory classes. Class 1 (24.5%), a bell-shaped trajectory, peaked 5 years after baseline when 42.7% had an SUD and 12.5% had comorbid/“other” illicit drug disorders. Class 2 (41.3%) had higher prevalence of SUD at baseline (73.8%). Although prevalence decreased over time, 23.5% had an SUD 12 years later. Class 3 (14.6%), the most serious and persistent trajectory, had the highest prevalence of comorbid/“other” illicit drug disorders—52.1% at baseline and 17.4% 12 years later. Males, Hispanics, non-Hispanic whites, and youth who were older at baseline (detention) had the worst outcomes. Conclusion Gender, race/ethnicity, and age at detention predict trajectories of SUDs in delinquent youth. Findings provide an empirical basis for child psychiatry to address health disparities and improve prevention. PMID:28117060

[A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy].

PubMed

Wang, Shan-Chun; Zeng, Li-Li; Ding, Yu-Yang; Zeng, Shao-Gao; Song, Hong-Rui; Hu, Wen-Hui; Xie, Hui

2014-01-01

Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.

Finite element analysis of maxillary bone stress caused by Aramany Class IV obturator prostheses.

PubMed

Miyashita, Elcio Ricardo; Mattos, Beatriz Silva Câmara; Noritomi, Pedro Yoshito; Navarro, Hamilton

2012-05-01

The retention of an Aramany Class IV removable partial dental prosthesis can be compromised by a lack of support. The biomechanics of this obturator prosthesis result in an unusual stress distribution on the residual maxillary bone. This study evaluated the biomechanics of an Aramany Class IV obturator prosthesis with finite element analysis and a digital 3-dimensional (3-D) model developed from a computed tomography scan; bone stress was evaluated according to the load placed on the prosthesis. A 3-D model of an Aramany Class IV maxillary resection and prosthesis was constructed. This model was used to develop a finite element mesh. A 120 N load was applied to the occlusal and incisal platforms corresponding to the prosthetic teeth. Qualitative analysis was based on the scale of maximum principal stress; values obtained through quantitative analysis were expressed in MPa. Under posterior load, tensile and compressive stresses were observed; the tensile stress was greater than the compressive stress, regardless of the bone region, and the greatest compressive stress was observed on the anterior palate near the midline. Under an anterior load, tensile stress was observed in all of the evaluated bone regions; the tensile stress was greater than the compressive stress, regardless of the bone region. The Aramany Class IV obturator prosthesis tended to rotate toward the surgical resection when subjected to posterior or anterior loads. The amount of tensile and compressive stress caused by the Aramany Class IV obturator prosthesis did not exceed the physiological limits of the maxillary bone tissue. (J Prosthet Dent 2012;107:336-342). Copyright © 2012 The Editorial Council of the Journal of Prosthetic Dentistry. Published by Mosby, Inc. All rights reserved.

49 CFR 572.127 - Test conditions and instrumentation.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Forces—Class 1000; (ii) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation—Class 60 (if used). (3) Thorax: (i) Rib acceleration—Class 1000; (ii) Spine and pendulum accelerations—Class...

49 CFR 572.127 - Test conditions and instrumentation.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Forces—Class 1000; (ii) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation—Class 60 (if used). (3) Thorax: (i) Rib acceleration—Class 1000; (ii) Spine and pendulum accelerations—Class...

49 CFR 572.127 - Test conditions and instrumentation.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Forces—Class 1000; (ii) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation—Class 60 (if used). (3) Thorax: (i) Rib acceleration—Class 1000; (ii) Spine and pendulum accelerations—Class...

49 CFR 572.127 - Test conditions and instrumentation.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Forces—Class 1000; (ii) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation—Class 60 (if used). (3) Thorax: (i) Rib acceleration—Class 1000; (ii) Spine and pendulum accelerations—Class...

49 CFR 572.127 - Test conditions and instrumentation.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Forces—Class 1000; (ii) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation—Class 60 (if used). (3) Thorax: (i) Rib acceleration—Class 1000; (ii) Spine and pendulum accelerations—Class...

Intravenous lysine clonixinate for the acute treatment of severe migraine attacks: a double-blind, randomized, placebo-controlled study.

PubMed

Krymchantowski, Abouch Valenty; Silva, Marcus Tulius T

2003-09-01

Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in the treatment of migraine. However, few commercially available NSAIDs can be administered IV. Lysine clonixinate (LC), an NSAID derived from nicotinic acid, has been proved effective in various algesic syndromes (eg, renal colic, muscular pain, nerve compression, odontalgia). The oral formulation of LC has been shown to be effective in the treatment of migraine of moderate severity. The aim of this study was to assess the efficacy and tolerability of the IV formulation of LC in the treatment of severe migraine. This double-blind, randomized, placebo-controlled, prospective study enrolled patients with severe migraine (without aura) as defined by the criteria of the International Headache Society. When patients presented to a neurology hospital with an outpatient headache unit (Instituto de Neurologia Deolindo Couto, Rio de Janeiro, Brazil) with a severe migraine attack that had lasted <4 hours, they were randomized to 1 of 2 groups (IV placebo [25 mL of 0.9% saline] or IV LC [21 mL of 0.9% saline plus 4 mL of LC 200 mg]). Headache intensity and adverse effects (AEs) were assessed before (0 minute) and 30, 60, and 90 minutes after study drug administration. Rescue medication was available 2 hours after study drug administration, and its use was compared between groups. Thirty-two patients (23 women, 9 men; mean [SD] age, 32 [2] years; range, 18-58 years) entered the study. Twenty-nine patients (21 women, 8 men; mean [SD] age, 32 [2] years; range, 18-56 years) completed the study. Three patients (all in the placebo group) did not complete the study (1 patient was unable to rate the pain severity after drug administration and 2 patients refused IV drug administration). Among study completers, 17 patients received LC and 12 placebo. At 30 minutes, 1 patient (8.3%) in the placebo group and 5 patients (29.4%) in the LC group were pain free; the between-group difference was not statistically significant. At 60 and 90 minutes, respectively, 3 (25.0%) and 5 (41.7%) patients in the placebo group and 12 (70.6%) and 14 (82.4%) patients in the LC group were pain free (P = 0.021 and P = 0.028 between groups at 60 and 90 minutes, respectively). Six patients (50.0%) in the placebo group and 1 patient (5.9%) in the LC group required rescue medication at 2 hours (P = 0.010 between groups). Three patients (25.0%) in the placebo group experienced AEs, including vomiting, dizziness, and malaise (1 patient [8.3%] each); 11 patients (64.7%) in the LC group experienced 1 AE, including burning pain at the injection site (5 patients [29.4%]), heartburn (4 patients [23.5%]), and dizziness and malaise (1 patient [5.9%] each) (P = 0.025). NSAIDs administered by the IV route cannot be used routinely in an outpatient environment, although an attempt to improve drugs in this class is clearly justified. This study demonstrated that IV LC was effective and well tolerated in the treatment of severe migraine attacks. This finding differs from results with the oral formulation, which is effective only in migraine of moderate severity.

Intravenous lysine clonixinate for the acute treatment of severe migraine attacks: a double-blind, randomized, placebo-controlled study☆

PubMed Central

Krymchantowski, Abouch Valenty; Silva, Marcus Tulius T

2003-01-01

Background Several nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be effective in the treatment of migraine. However, few commercially available NSAIDs can be administered IV. Lysine clonixinate (LC), an NSAID derived from nicotinic acid, has been proved effective in various algesic syndromes (eg, renal colic, muscular pain, nerve compression, odontalgia). The oral formulation of LC has been shown to be effective in the treatment of migraine of moderate severity. Objective The aim of this study was to assess the efficacy and tolerability of the IV formulation of LC in the treatment of severe migraine. Methods This double-blind, randomized, placebo-controlled, prospective study enrolled patients with severe migraine (without aura) as defined by the criteria of the International Headache Society. When patients presented to a neurology hospital with an outpatient headache unit (Instituto de Neurologia Deolindo Couto, Rio de Janeiro, Brazil) with a severe migraine attack that had lasted <4 hours, they were randomized to 1 of 2 groups (IV placebo [25 mL of 0.9% saline] or IV LC [21 mL of 0.9% saline plus 4 mL of LC 200 mg]). Headache intensity and adverse effects (AEs) were assessed before (0 minute) and 30, 60, and 90 minutes after study drug administration. Rescue medication was available 2 hours after study drug administration, and its use was compared between groups. Results Thirty-two patients (23 women, 9 men; mean [SD] age, 32 [2] years; range, 18–58 years) entered the study. Twenty-nine patients (21 women, 8 men; mean [SD] age, 32 [2] years; range, 18–56 years) completed the study. Three patients (all in the placebo group) did not complete the study (1 patient was unable to rate the pain severity after drug administration and 2 patients refused IV drug administration). Among study completers, 17 patients received LC and 12 placebo. At 30 minutes, 1 patient (8.3%) in the placebo group and 5 patients (29.4%) in the LC group were pain free; the between-group difference was not statistically significant. At 60 and 90 minutes, respectively, 3 (25.0%) and 5 (41.7%) patients in the placebo group and 12 (70.6%) and 14 (82.4%) patients in the LC group were pain free (P = 0.021 and P = 0.028 between groups at 60 and 90 minutes, respectively). Six patients (50.0%) in the placebo group and 1 patient (5.9%) in the LC group required rescue medication at 2 hours (P = 0.010 between groups). Three patients (25.0%) in the placebo group experienced AEs, including vomiting, dizziness, and malaise (1 patient [8.3%] each); 11 patients (64.7%) in the LC group experienced 1 AE, including burning pain at the injection site (5 patients [29.4%]), heartburn (4 patients [23.5%]), and dizziness and malaise (1 patient [5.9%] each) (P = 0.025). Conclusions NSAIDs administered by the IV route cannot be used routinely in an outpatient environment, although an attempt to improve drugs in this class is clearly justified. This study demonstrated that IV LC was effective and well tolerated in the treatment of severe migraine attacks. This finding differs from results with the oral formulation, which is effective only in migraine of moderate severity. PMID:24944400

49 CFR 572.146 - Test conditions and instrumentation.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Head acceleration—Class 1000 (2) Neck (i) Force—Class 1000 (ii) Moments—Class 600 (iii) Pendulum... acceleration—Class 1000 (ii) Spine and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv...

49 CFR 572.146 - Test conditions and instrumentation.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Head acceleration—Class 1000 (2) Neck (i) Force—Class 1000 (ii) Moments—Class 600 (iii) Pendulum... acceleration—Class 1000 (ii) Spine and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv...

49 CFR 572.146 - Test conditions and instrumentation.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Head acceleration—Class 1000 (2) Neck (i) Force—Class 1000 (ii) Moments—Class 600 (iii) Pendulum... acceleration—Class 1000 (ii) Spine and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv...

49 CFR 572.146 - Test conditions and instrumentation.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Head acceleration—Class 1000 (2) Neck (i) Force—Class 1000 (ii) Moments—Class 600 (iii) Pendulum... acceleration—Class 1000 (ii) Spine and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv...

49 CFR 572.146 - Test conditions and instrumentation.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Head acceleration—Class 1000 (2) Neck (i) Force—Class 1000 (ii) Moments—Class 600 (iii) Pendulum... acceleration—Class 1000 (ii) Spine and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv...

[New aspects of the molecular effect of anti-arrhythmia agents].

PubMed

Honerjäger, P

1990-04-01

Excitation propagation is mediated by the brief opening of voltage-dependent Na-channels in the plasma membranes of cells of the conduction system and working myocardium. The refractory period is a function of the re-availability of the Na-channel for renewed opening. Most antiarrhythmic agents block cardiac Na-channels and, consequently, affect the desired refractory period prolongation. At the same time, however, dependent on the concentration and the substance, they slow conduction; an effect which can facilitate reentry excitation in the injured heart. The Na-channel blocking drugs, class I antiarrhythmic agents, are distinguished from the beta-receptor blockers, class II, repolarizing prolonging drugs, class III, and the cardiac Ca-channel blocking drugs (class IV) (Table 1). MOLECULAR STRUCTURE OF THE CARDIAC NA-CHANNEL: Voltage-dependent Na-channels which have been structurally elucidated to date are glycoprotein macromolecules of about 2000 amino acids with a molecular weight of about 260,000. Beginning at the amino terminal, four consecutive homologous domains can be differentiated which are composed of six transmembranous segments each. The terminal portion of the chain as well as the connecting segments between the domains appear intracellular. There are important relationships between the molecular structure and the function of the Na-channel (Figure 1). On comparison of the primary structures of neuronal and cardiac Na-channels, domains I to IV as well as the connecting segment between domains III and IV, are nearly identical. Homology in all of the remaining molecular regions, in contrast, is less than 70%. These segments as well as the differing structure of the four S5-S6 connecting chains may be responsible for the varying functional response of the cardiac Na-channels. MOLECULAR SITE OF ACTION OF ANTIARRHYTHMIC AGENTS AT THE CARDIAC NA-CHANNEL: Since most antiarrhythmic agents are weak bases with pK values between 7.5 and 9.5, in the physiologic range of pH, they are present in part in the protonated, positively-charged form, in part as uncharged free base. It is assumed that the Na-channel of nerve and skeletal muscle has one receptor for local anesthetics at which both the protonated and the uncharged molecular forms bind. The receptor is thought to be located on the inner wall of the ion pore about half of the distance between the intracellular and the extracellular channel opening. The uncharged form of the Na-channel blocker penetrates directly from the lipid phase of the surrounding cell membrane, the protonated form only from the intracellular space during the short opening of the channel at the beginning of the action potential. Through binding on the receptor, the Na-channel is blocked. Dissociation of the molecular forms takes place in the same manner. The peptide region on which antiarrhythmic drugs bind, however, has not been identified. By means of the patch-clamp technique, it has been shown that on extracellular application of the quaternary lidocaine derivative QX-314 there is a rapid and marked reduction of Na-flux in cardiac Purkinje fibers in contrast to the effects at neuronal and skeletal muscle Na-channels. Intracellular application similarly leads to blockade but only in the course of repetitive depolarizations indicating that the cardiac Na-channel may have a second binding site for local anesthetics at the extracellular side.(ABSTRACT TRUNCATED AT 400 WORDS)

Lupus nephritis in Lebanon.

PubMed

Uthman, I W; Muffarij, A A; Mudawar, W A; Nasr, F W; Masri, A F

2001-01-01

This is a retrospective study of the clinicopathological characteristics of 50 systemic lupus erythematosus patients with nephritis who underwent a kidney biopsy and were admitted to the American University of Beirut Medical Center, in Lebanon, between 1979 and 1999. There were 43 females and seven males, with a median age of 24 y. Renal histology slides from these patients were assessed according to the World Health Organization classification, and were distributed as follows: class I (n = 3, 6%); class II (n = 14, 28%); class III (n = 11, 22%); class IV (n = 19, 38%); class V (n = 1, 2%); class VI (n = 2, 4%). All the patients received oral prednisone, in addition the following treatments were used: pulse intravenous (i.v.) cyclophosphamide (n = 23, 46%); azathioprine (n = 22, 44%); pulse i.v. steroids (n = 19, 38%); chloroquine sulfate (n = 17, 34%); methotrexate (n = 5, 10%); and plasmapheresis (n = 2, 4%). The median duration of follow-up was 5 y (range 1-33 y). On their last evaluation, out of 37 patients who were followed, 20 patients (54%) had controlled disease, eight patients (22%) were still on active medical treatment, four patients (11%) were on chronic hemodialysis, and five patients (13%) had died. Unlike three other Arab populations studies from Kuwait, United Arab Emirates and Saudi Arabia, where the most frequent histopathologic abnormality was class III, diffuse proliferative LN (class IV) was the most common type of lupus nephritis in Lebanon, similarly to reports from USA, France, Netherlands, South Africa, Thailand and Taiwan.

[Adherence to pharmaceutical guidance in patients over 85 years of age with chronic heart failure-stage C. Effects on 12-month mortality].

PubMed

Esteve Arríen, Ainhoa; Domínguez de Pablos, Gema; Minaya Saiz, Jesús

2009-01-01

To describe factors related to prescription on discharge of treatment for Chronic Heart Failure(CHF)-Stage C and to analyse whether this is related to 12month-mortality. Observational follow-up study of patients over 85 hospitalized during 2006/7 with Stage C-Chronic Heart Failure in an outskirt support hospital. Drug-prescription adherence was assessed according to the American Heart Society 2005-Guidelines and recommendations of the American Geriatrics Society-2007. A multivariate analysis of logistic regression was performed to obtain odds for 12-month mortality for each recommended therapy, adjusting by mortality risk factors. 104 patients aged 90+/-3yr were followed on discharge, 85% of which were women. NYHA-classes were distributed NYHA I-28,2%, II-37,9%, III-30,1%, IV-3,9%. Most frequently prescribed drugs were loop diuretics (83,3%) and IACEs/ARB (62%), and the less frequent beta-blockers (19,1%). IACEs/ARB were prescribed to those with lower functional impairment (p=0.04), and beta-blockers to those with worse NYHA class (p=0.02). All recommended prescriptions had a tendency to 12 month mortality risk reduction, even adjusted by age, functional status, co-morbidity, NYHA class and co-morbid atrial fibrillation, except for spironolactone (OR-1,8; IC95% 0,48-17,19). Treatment with CHF disease-modifying therapies except for spironolactone can reduce 12 month risk mortality, also in the oldest old. There exists room for improvement in frequency of drug prescription in this group of age.

Development of Platinum(iv) Complexes as Anticancer Prodrugs: the Story so Far

NASA Astrophysics Data System (ADS)

Wong, Daniel Yuan Qiang; Ang, Wee Han

2012-06-01

The serendipitous discovery of the antitumor properties of cisplatin by Barnett Rosenberg some forty years ago brought about a paradigm shift in the field of medicinal chemistry and challenged conventional thinking regarding the role of potentially toxic heavy metals in drugs. Platinum(II)-based anticancer drugs have since become some of the most effective and widely-used drugs in a clinician's arsenal and have saved countless lives. However, they are limited by high toxicity, severe side-effects and the incidence of drug resistance. In recent years, attention has shifted to stable platinum(IV) complexes as anticancer prodrugs. By exploiting the unique chemical and structural attributes of their scaffolds, these platinum(IV) prodrugs offer new strategies of targeting and killing cancer cells. This review summarizes the development of anticancer platinum(IV) prodrugs to date and some of the exciting strategies that utilise the platinum(IV) construct as targeted chemotherapeutic agents against cancer.

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2011 CFR

2011-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2013 CFR

2013-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2012 CFR

2012-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2014 CFR

2014-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

28 CFR 2.219 - Maximum terms of imprisonment and supervised release.

Code of Federal Regulations, 2010 CFR

2010-07-01

... other than above (e.g., marijuana/hashish), or schedule III drugs 3 years 2 years. If schedule IV drugs... PCP 5 years 3 years. If schedule I or II drugs other than above (e.g., marijuana, hashish....g., marijuana, hashish), or schedule III or IV drugs 3 years 2 years. If schedule V drugs 3 years 1...

Oxabicyclooctane-Linked Novel Bacterial Topoisomerase Inhibitors as Broad Spectrum Antibacterial Agents

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

Singh, Sheo B.; Kaelin, David E.; Wu, Jin

Bacterial resistance is eroding the clinical utility of existing antibiotics necessitating the discovery of new agents. Bacterial type II topoisomerase is a clinically validated, highly effective, and proven drug target. This target is amenable to inhibition by diverse classes of inhibitors with alternative and distinct binding sites to quinolone antibiotics, thus enabling the development of agents that lack cross-resistance to quinolones. Described here are novel bacterial topoisomerase inhibitors (NBTIs), which are a new class of gyrase and topo IV inhibitors and consist of three distinct structural moieties. The substitution of the linker moiety led to discovery of potent broad-spectrum NBTIsmore » with reduced off-target activity (hERG IC50 > 18 μM) and improved physical properties. AM8191 is bactericidal and selectively inhibits DNA synthesis and Staphylococcus aureus gyrase (IC50 = 1.02 μM) and topo IV (IC50 = 10.4 μM). AM8191 showed parenteral and oral efficacy (ED50) at less than 2.5 mg/kg doses in a S. aureus murine infection model. A cocrystal structure of AM8191 bound to S. aureus DNA-gyrase showed binding interactions similar to that reported for GSK299423, displaying a key contact of Asp83 with the basic amine at position-7 of the linker.« less

Optimized conditions for MDCK permeability and turbidimetric solubility studies using compounds representative of BCS classes I-IV.

PubMed

Taub, Mitchell E; Kristensen, Lisbeth; Frokjaer, Sven

2002-05-01

The solubility enhancing effects of various excipients, including their compatibility with in vitro permeability (P(app)) systems, was investigated using drugs representative of Biopharmaceutics Classification System (BCS) classes I-IV. Turbidimetric solubility determination using nephelometry and transport experiments using MDCK Strain I cell monolayers were employed. The highest usable concentration of each excipient [dimethyl sulfoxide (DMSO), ethanol, hydroxypropyl-beta-cyclodextrin (HPCD), and sodium taurocholate] was determined by monitoring apical (AP) to basolateral (BL) [14C]mannitol apparent permeability (P(app)) and the transepithelial electrical resistance (TEER) in transport experiments done at pH 6.0 and 7.4. The excipients were used in conjunction with compounds demonstrating relatively low aqueous solubility (amphotericin B, danazol, mefenamic acid, and phenytoin) in order to obtain a drug concentration >50 microM in the donor compartment. The addition of at least one of the selected excipients enhanced the solubility of the inherently poorly soluble compounds to >50 microM as determined via turbidimetric evaluation at pH 6.0 and 7.4. Ethanol and DMSO were found to be generally disruptive to the MDCK monolayer and were not nearly as useful as HPCD and sodium taurocholate. Sodium taurocholate (5 mM) was compatible with MDCK monolayers under all conditions investigated. Additionally, a novel in vitro system aimed at more accurately simulating in vivo conditions, i.e., a pH gradient (6.0 AP/7.4 BL), sodium taurocholate (5 mM, AP), and bovine serum albumin (0.25%, BL), was shown to generate more reliable P(app) values for compounds that are poorly soluble and/or highly protein bound.

Joint Counterdrug Operations

DTIC Science & Technology

1998-02-17

II-8 • Marijuana (Cannabis) Industry ................................................................................ II-9...High Intensity Drug Trafficking Areas ................................................................ III-26 • Organized Crime Drug Enforcement...IV-4 • Legal or Regulatory Considerations ....................................................................... IV-5 • Major

49 CFR 572.137 - Test conditions and instrumentation.

Code of Federal Regulations, 2011 CFR

2011-10-01

...—Class 1000 (2) Neck: (i) Forces—Class 1000 (ii) Moments—Class 600 (iii) Pendulum acceleration—Class 180... and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv) Forces—Class 1000 (v...—Class 180 (6) Femur forces and knee pendulum—Class 600 (n) Coordinate signs for instrumentation polarity...

49 CFR 572.137 - Test conditions and instrumentation.

Code of Federal Regulations, 2010 CFR

2010-10-01

...—Class 1000 (2) Neck: (i) Forces—Class 1000 (ii) Moments—Class 600 (iii) Pendulum acceleration—Class 180... and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv) Forces—Class 1000 (v...—Class 180 (6) Femur forces and knee pendulum—Class 600 (n) Coordinate signs for instrumentation polarity...

49 CFR 572.137 - Test conditions and instrumentation.

Code of Federal Regulations, 2013 CFR

2013-10-01

...—Class 1000 (2) Neck: (i) Forces—Class 1000 (ii) Moments—Class 600 (iii) Pendulum acceleration—Class 180... and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv) Forces—Class 1000 (v...—Class 180 (6) Femur forces and knee pendulum—Class 600 (n) Coordinate signs for instrumentation polarity...

49 CFR 572.137 - Test conditions and instrumentation.

Code of Federal Regulations, 2014 CFR

2014-10-01

...—Class 1000 (2) Neck: (i) Forces—Class 1000 (ii) Moments—Class 600 (iii) Pendulum acceleration—Class 180... and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv) Forces—Class 1000 (v...—Class 180 (6) Femur forces and knee pendulum—Class 600 (n) Coordinate signs for instrumentation polarity...

49 CFR 572.137 - Test conditions and instrumentation.

Code of Federal Regulations, 2012 CFR

2012-10-01

...—Class 1000 (2) Neck: (i) Forces—Class 1000 (ii) Moments—Class 600 (iii) Pendulum acceleration—Class 180... and pendulum accelerations—Class 180 (iii) Sternum deflection—Class 600 (iv) Forces—Class 1000 (v...—Class 180 (6) Femur forces and knee pendulum—Class 600 (n) Coordinate signs for instrumentation polarity...

Biochemistry of plant class IV chitinases and fungal chitinase-modifying proteins

USDA-ARS?s Scientific Manuscript database

Plant class IV chitinases have 2 domains, a small (3 kDa) amino-terminal domain with homology to carbohydrate binding peptides, and a larger (25 kDa) catalytic domain. The biological function of these chitinases is not known. But it is known that some pathogenic fungi secrete chitinase modifying pro...

Polyglycine hydrolases secreted by Pleosporineae fungi that target the linker region of plant class IV chitinases*

USDA-ARS?s Scientific Manuscript database

Chitinase modifying proteins (cmps) are fungal proteases that truncate plant class IV chitinases by cleaving near their amino termini. We previously described Fv-cmp, a fungalysin protease that cleaves a conserved glycine-cysteine bond within the hevein domain. Here we describe a new type of cmp—pol...

Alcoholytic Cleavage of Polyhydroxyalkanoate Chains by Class IV Synthases Induced by Endogenous and Exogenous Ethanol

PubMed Central

Hyakutake, Manami; Tomizawa, Satoshi; Mizuno, Kouhei; Abe, Hideki

2014-01-01

Polyhydroxyalkanoate (PHA)-producing Bacillus strains express class IV PHA synthase, which is composed of the subunits PhaR and PhaC. Recombinant Escherichia coli expressing PHA synthase from Bacillus cereus strain YB-4 (PhaRCYB-4) showed an unusual reduction of the molecular weight of PHA produced during the stationary phase of growth. Nuclear magnetic resonance analysis of the low-molecular-weight PHA revealed that its carboxy end structure was capped by ethanol, suggesting that the molecular weight reduction was the result of alcoholytic cleavage of PHA chains by PhaRCYB-4 induced by endogenous ethanol. This scission reaction was also induced by exogenous ethanol in both in vivo and in vitro assays. In addition, PhaRCYB-4 was observed to have alcoholysis activity for PHA chains synthesized by other synthases. The PHA synthase from Bacillus megaterium (PhaRCBm) from another subgroup of class IV synthases was also assayed and was shown to have weak alcoholysis activity for PHA chains. These results suggest that class IV synthases may commonly share alcoholysis activity as an inherent feature. PMID:24334666

Dispelling the myth of "smart drugs": cannabis and alcohol use problems predict nonmedical use of prescription stimulants for studying.

PubMed

Arria, Amelia M; Wilcox, Holly C; Caldeira, Kimberly M; Vincent, Kathryn B; Garnier-Dykstra, Laura M; O'Grady, Kevin E

2013-03-01

This study tested the hypothesis that college students' substance use problems would predict increases in skipping classes and declining academic performance, and that nonmedical use of prescription stimulants (NPS) for studying would occur in association with this decline. A cohort of 984 students in the College Life Study at a large public university in the US participated in a longitudinal prospective study. Interviewers assessed NPS; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) cannabis and alcohol use disorders; and frequency of skipping class. Semester grade point average (GPA) was obtained from the university. Control variables were race, sex, family income, high school GPA, and self-reported attention deficit hyperactivity disorder diagnosis. Longitudinal growth curve modeling of four annual data waves estimated the associations among the rates of change of cannabis use disorder, percentage of classes skipped, and semester GPA. The associations between these trajectories and NPS for studying were then evaluated. A second structural model substituted alcohol use disorder for cannabis use disorder. More than one-third (38%) reported NPS for studying at least once by Year 4. Increases in skipping class were associated with both alcohol and cannabis use disorder, which were associated with declining GPA. The hypothesized relationships between these trajectories and NPS for studying were confirmed. These longitudinal findings suggest that escalation of substance use problems during college is related to increases in skipping class and to declining academic performance. NPS for studying is associated with academic difficulties. Although additional research is needed to investigate causal pathways, these results suggest that nonmedical users of prescription stimulants could benefit from a comprehensive drug and alcohol assessment to possibly mitigate future academic declines. Copyright © 2012 Elsevier Ltd. All rights reserved.

Home inotropic therapy in advanced heart failure: cost analysis and clinical outcomes.

PubMed

Harjai, K J; Mehra, M R; Ventura, H O; Lapeyre, Y M; Murgo, J P; Stapleton, D D; Smart, F W

1997-11-05

This study was conducted to assess cost savings and clinical outcomes associated with the use of home i.v. inotropic therapy in patients with advanced (New York Heart Association [NYHA] class IV) heart failure. Retrospective analysis. Tertiary care referral center. Twenty-four patients (13 men, 11 women; age, 61+/-12 years) with left ventricular ejection fraction <30% and heart failure refractory to oral agents required home i.v. inotropic therapy for at least 4 consecutive weeks between May 1994 and April 1996. Inotropic agents used included dobutamine (n=20; dose, 5.0+/-2.2 microg/kg/min) or milrinone (n=7; dose, 0.53+/-0.05 microg/kg/min). Cost of care and clinical outcomes (hospital admissions, length of hospital stay, NYHA functional class) were compared during the period of inotropic therapy (study period) and the immediate preceding period of equal duration (control period). In comparison to the control period, the study period (3.9+/-2.7 months) was associated with a 16% reduction in cost, amounting to a calculated savings of $5,700 per patient or $1,465 per patient per month. Concomitantly, a decrease in the number of hospital admissions from 2.7+/-2.6 to 1.3+/-1.3 (p=0.056) and length of hospital stay from 20.9+/-12.7 to 5.5+/-5.4 days (p=0.0004) was observed with improvement in NYHA functional class from 4.0+/-0.0 to 2.7+/-0.9 (p<0.0001). Eight patients (38%) died after 2.8+/-1.7 months of home i.v. inotropic therapy. Home i.v. inotropic therapy reduces hospital admissions, length of stay, and cost of care and improves functional class in patients with advanced (NYHA class IV) heart failure.

Echoguided drug infiltration in chronic prostatitis: results of a multi-centre study.

PubMed

Guercini, Federico; Pajoncini, Cinzia; Bard, Robert; Fiorentino, Francesco; Bini, Vittorio; Costantini, Elisabetta; Porena, Massimo

2005-06-01

In chronic prostatitis there are many causes that may provoke a therapeutical failure of a systemic antibiotic treatment. At the moment a consensus has not been reached on the efficacy of the many therapeutical options that are available with not one of these approaches being efficacious in all patients. In our view the main causes of treatment failure are the well-known hurdle to antibiotic diffusion inside the glandular parenchyma associated with the so-called intraprostatic bacterial biofilms and the possible presence of local auto-immune reactions. Given this background, we tested ultrasound guided intraprostate infiltration of a cocktail of antibiotics and betamethasone, for a therapeutical options. 320 patients, referred to us because of symptoms indicative of chronic prostatitis, were enrolled in this study. The inclusion criteria were the severity of the symptoms and the failure of repeated cycles of antibiotics in the previous 12 months. At the initial consultation patients completed the NIH Prostatitis Symptoms Index (NIH-CPSI). All underwent: a) digital rectal examination (DRE), b) transrectal prostatic ultrasound scan (TRUS), c) uroflowmetry, d) cultures of first voiding and after prostatic massage urine and cultures of sperm for saprophytic and pathogen germs, yeasts and protozoa, e) DNA amplification with polymerase chain reaction (PCR) on urine and sperm, for Chlamydia trachomatis, Mycoplasmas (Ureaplasma urealyticum and Mycoplasma hominis), Gonococcus, HPV and HCV Patients on the basis of laboratory results received a cocktail of antibiotics associated with betamethasone. The cocktail was administered as prostate infiltration. Administration was repeated after 7 and 14 days. Final assessment of the efficacy of therapy included not only the NIH-CPSI scores but also the patient's subjective judgement expressed as a "percentage overall improvement". The percentage judgements were arbitrarily divided into 4 classes: 0-30% no improvement (Class I); 30-50% satisfactory improvement (Class II); 50-80% good improvement (Class III; 80-100% cured (Class IV). Statistical analysis of the results showed 68% of patients were included in the Class IV and 13% were no responders (Class I). In our opinion this is one of the more valid therapeutical approaches to chronic bacterial or abacterial prostatitis also if it requires more studies.

Injectable-antineoplastic-drug practices in Michigan hospitals.

PubMed

Cohen, I A; Newland, S J; Kirking, D M

1987-05-01

Practices related to parenteral (injectable) antineoplastic drugs (PADs) in Michigan hospitals were surveyed. All hospitals in Michigan were surveyed to assess compliance with American Society of Hospital Pharmacists (ASHP) and Occupational Safety and Health Administration (OSHA) recommendations related to PADs. Other PAD-related practice issues not covered within those guidelines were also studied. Surveys were mailed to the pharmacy directors of the state's 192 acute-care hospitals. Included were questions concerning policies and procedures for ordering, storing, preparing, handling, labeling, transporting, administering, and disposing of PADs. Questions concerning staff education, spill cleanup, and personnel issues were also included. A total of 169 questionnaires were returned, yielding a response rate of 88%. Of those respondents, 132 indicated that they prepare PAD doses for inpatients. Adherence rates were high for several of the PAD-preparation recommendations, including handwashing (97%) and gloving (98.5%). Rates for gowning (71.2%), labeling of PAD doses as biohazards (chemical hazards) (73.5%), and use of Class II biological-safety cabinets (71.2%) were less favorable. Practice areas with relatively poor adherence rates included use of plastic-backed absorbent pads under PAD preparation areas (53.8%), storing PADs separately from other drugs (48.5%), informing prospective employees of potential risks of handling PADs (36.4%), availability of spill kits (36.4%), and attaching and priming i.v. tubing before adding PADs to i.v. containers (5.4%). Many pharmacy departments in Michigan hospitals can substantially improve their adherence to ASHP and OSHA recommendations related to PADs.

Pharmacology of midazolam.

PubMed

Pieri, L; Schaffner, R; Scherschlicht, R; Polc, P; Sepinwall, J; Davidson, A; Möhler, H; Cumin, R; Da Prada, M; Burkard, W P; Keller, H H; Müller, R K; Gerold, M; Pieri, M; Cook, L; Haefely, W

1981-01-01

8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam, Ro 21-3981, Dormicum) is an imidazobenzodiazepine whose salts are soluble and stable in aqueous solution. It has a quick onset and, due to rapid metabolic inactivation, a rather short duration of action in all species studied. Midazolam has a similar pharmacologic potency and broad therapeutic range as diazepam. It produces all the characteristic effects of the benzodiazepine class, i.e., anticonvulsant, anxiolytic, sleep-inducing, muscle relaxant, and "sedative" effects. The magnitude of the anticonflict effect of midazolam is smaller than that of diazepam in rats and squirrel monkeys, probably because a more pronounced sedative component interferes with the increase of punished responses. In rodents, surgical anaesthesia is not attained with midazolam alone even in high i.v. doses, whereas this state is obtained in monkeys. The drug potentiates the effect of various central depressant agents. Midazolam is virtually free of effects on the cardiovascular system in conscious animals and produces only slight decreases in cardiac performance in dogs anaesthetized with barbiturates. No direct effects of the drugs on autonomic functions were found, however, stress-induced autonomic disturbances are prevented, probably by an effect on central regulatory systems. All animal data suggest the usefulness of midazolam as a sleep-inducer and i.v. anaesthetic of rapid onset and short duration.

49 CFR 572.155 - Test conditions and instrumentation.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation potentiometer response (if used)—CFC 60. (3) Thorax: (i) Spine and pendulum accelerations—Class 180; (ii) Shoulder forces—Class 600; (4...

49 CFR 572.155 - Test conditions and instrumentation.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation potentiometer response (if used)—CFC 60. (3) Thorax: (i) Spine and pendulum accelerations—Class 180; (ii) Shoulder forces—Class 600; (4...

49 CFR 572.155 - Test conditions and instrumentation.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation potentiometer response (if used)—CFC 60. (3) Thorax: (i) Spine and pendulum accelerations—Class 180; (ii) Shoulder forces—Class 600; (4...

49 CFR 572.155 - Test conditions and instrumentation.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation potentiometer response (if used)—CFC 60. (3) Thorax: (i) Spine and pendulum accelerations—Class 180; (ii) Shoulder forces—Class 600; (4...

49 CFR 572.155 - Test conditions and instrumentation.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) Moments—Class 600; (iii) Pendulum acceleration—Class 180; (iv) Rotation potentiometer response (if used)—CFC 60. (3) Thorax: (i) Spine and pendulum accelerations—Class 180; (ii) Shoulder forces—Class 600; (4...

Classification and Short-Term Course of DSM-IV Cannabis, Hallucinogen, Cocaine, and Opioid Disorders in Treated Adolescents

ERIC Educational Resources Information Center

Chung, Tammy; Martin, Christoper S.

2005-01-01

This study examined the latent class structure of Diagnostic and Statistical Manual of Mental Disorders (text rev.; DSM-IV; American Psychiatric Association, 2000) symptoms used to diagnose cannabis, hallucinogen, cocaine, and opiate disorders among 501 adolescents recruited from addictions treatment. Latent class results were compared with the…

40 CFR 147.2800 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 23 2011-07-01 2011-07-01 false State-administered program-Class I, II, III, IV, and V wells. 147.2800 Section 147.2800 Protection of Environment ENVIRONMENTAL PROTECTION... Federal Register effective July 31, 1985. (1) CNMI Environmental Protection Act, 2 CMC sections 3101, et...

40 CFR 147.2800 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 23 2014-07-01 2014-07-01 false State-administered program-Class I, II, III, IV, and V wells. 147.2800 Section 147.2800 Protection of Environment ENVIRONMENTAL PROTECTION... Federal Register effective July 31, 1985. (1) CNMI Environmental Protection Act, 2 CMC sections 3101, et...

40 CFR 147.2800 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 22 2010-07-01 2010-07-01 false State-administered program-Class I, II, III, IV, and V wells. 147.2800 Section 147.2800 Protection of Environment ENVIRONMENTAL PROTECTION... Federal Register effective July 31, 1985. (1) CNMI Environmental Protection Act, 2 CMC sections 3101, et...

40 CFR 147.2800 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 24 2012-07-01 2012-07-01 false State-administered program-Class I, II, III, IV, and V wells. 147.2800 Section 147.2800 Protection of Environment ENVIRONMENTAL PROTECTION... Federal Register effective July 31, 1985. (1) CNMI Environmental Protection Act, 2 CMC sections 3101, et...

40 CFR 147.2800 - State-administered program-Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 24 2013-07-01 2013-07-01 false State-administered program-Class I, II, III, IV, and V wells. 147.2800 Section 147.2800 Protection of Environment ENVIRONMENTAL PROTECTION... Federal Register effective July 31, 1985. (1) CNMI Environmental Protection Act, 2 CMC sections 3101, et...

Abundance of truncated and full-length ChitA and ChitB chitinases in healthy and diseased maize tissues

USDA-ARS?s Scientific Manuscript database

Chitinase modifying proteins, cmps, are secreted fungal proteases that combat plant defenses by truncating plant class IV chitinases. We initially discovered that ChitA and ChitB, two plant class IV chitinases that are abundant in developing and mature kernels of corn, are truncated by cmps during e...

Cloning and identification of Fv-cmp, a protease from Fusarium verticillioides that truncates Zea mays and Arabidopsis thaliana class IV chitinases

USDA-ARS?s Scientific Manuscript database

Chitinase modifying proteins (cmps) are proteases, secreted by fungal pathogens, that were originally identified as proteins that truncate class IV chitinases of maize during ear rot. Cmps from Bipolaris zeicola and Stenocarpella maydis have been characterized, but the identities of the proteases h...

40 CFR 147.2550 - State-administered program-Class I, III, IV and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Rules and Regulations, Wyoming Department of Environmental Quality, Chapter XXI: In Situ Mining... program for Class I, III, IV and V wells in the State of Wyoming, except those on Indian lands is the... section 1422 of the SDWA. Notice of this approval was published in the Federal Register on July 15, 1983...

40 CFR 147.2550 - State-administered program-Class I, III, IV and V wells.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Rules and Regulations, Wyoming Department of Environmental Quality, Chapter XXI: In Situ Mining... program for Class I, III, IV and V wells in the State of Wyoming, except those on Indian lands is the... section 1422 of the SDWA. Notice of this approval was published in the Federal Register on July 15, 1983...

[Microinvasive dental treatment in pre-school children].

PubMed

Korolenkova, M V

The aim of the study was to assess the efficiency of atraumatic restorative treatment (ART) with cavity preparation by means of dental endo motor. ART method was applied in 94 children (50 females and 44 males, 301 teeth treated) aged 21-96 months. Wireless dental endo motor (Endo Mate TC2, NSK, Japan) was used for cavity preparation. The cavities (102 (33.9%) class I, 156 (51.8%) class V, 20 (6.6%) class II, 18 (6%) class III and 5 (1.7%) class IV) were then filled with glass-ionomer cement (Fuji IX, GC, Japan). Success rate was assessed 3, 6, 12 and 18 months after treatment. Overall ART procedure success rate (good marginal fit, no occlusal wearing or restoration fractures) at 18-month follow up was 88.7% (267 fillings out of 301) with the highest survival in class I (96.1%) and class V (96.2%) restoration and poorest in class II (50%), class III (44.4%) and class IV (20%) restorations. Cavity preparation with wireless dental endo motor was well tolerated even by infants (12 children were younger than 24 months), as it is noiseless and significantly faster than conventional manual preparation. ART method with the use of dental endo motor showed good success rate and proved to be highly efficient in small and apprehensive children. The method, however, should be avoided in class III and IV cavities as the success rate is poor mostly because of restoration fractures.

Identifying cases of heroin toxicity where 6-acetylmorphine (6-AM) is not detected by toxicological analyses.

PubMed

Ellis, Ashley D; McGwin, Gerald; Davis, Gregory G; Dye, Daniel W

2016-09-01

Heroin has a half-life of 2-6 min and is metabolized too quickly to be detected in autopsy samples. The presence of 6-acetylmophine (6-AM) in urine, blood, or other samples is convincing evidence of heroin use by a decedent, but 6-AM itself has a half-life of 6-25 min before it is hydrolyzed to morphine, so 6-AM may not be present in sufficient concentration to detect in postmortem samples. Codeine is often present in heroin preparations as an impurity and is not a metabolite of heroin. Studies report that a ratio of morphine to codeine greater than one indicates heroin use. We hypothesize that the ratio of morphine to codeine in our decedents abusing drugs intravenously will be no different in individuals with 6-AM present than in individuals where no 6-AM is detected, and we report our study of this hypothesis. All accidental deaths investigated by the Jefferson County Coroner/Medical Examiner Office from 2010 to 2013 with morphine detected in blood samples collected at autopsy were reviewed. Five deaths where trauma caused or contributed to death were excluded from the review. The presence or absence of 6-AM and the concentrations of morphine and codeine were recorded for each case. The ratio of morphine to codeine was calculated for all decedents. Any individual in whom no morphine or codeine was detected in a postmortem sample was excluded from further study. Absence or presence of drug paraphernalia or evidence of intravascular (IV) drug use was documented in each case to identify IV drug users. The proportion of the IV drug users with and without 6-AM present in a postmortem sample was compared to the M/C ratio for the individuals. Of the 230 deaths included in the analysis, 103 IV drug users with quantifiable morphine and codeine in a postmortem sample were identified allowing for calculation of an M/C ratio. In these IV drug users, the M/C ratio was greater than 1 in 98 % of decedents. When controlling for the absence or presence of 6-AM there was no statistically significant difference in the proportion of IV drug users when compared to non IV drug users with an M/C ratio of greater than 1 (p = 1.000). The M/C ratio in IV drug users, if greater than 1, is seen in deaths due to heroin toxicity where 6-AM is detected in a postmortem sample. This study provides evidence that a M/C ratio greater than one in an IV drug user is evidence of a death due to heroin toxicity even if 6-AM is not detected in the blood. Using the M/C ratio, in addition to scene and autopsy findings, provides sufficient evidence to show heroin is the source of the morphine and codeine. Listing heroin as a cause or contributing factor in deaths with evidence of IV drug abuse and where the M/C ratio exceeds 1 will improve identification of heroin fatalities, which will allow better allocation of resources for public health initiatives.

Classification of natural products as sources of drugs according to the biopharmaceutics drug disposition classification system (BDDCS).

PubMed

Li, Ji; Larregieu, Caroline A; Benet, Leslie Z

2016-12-01

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products. Copyright © 2016 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Trajectories of Substance Use Disorder in Youth After Detention: A 12-Year Longitudinal Study.

PubMed

Welty, Leah J; Hershfield, Jennifer A; Abram, Karen M; Han, Hongyun; Byck, Gayle R; Teplin, Linda A

2017-02-01

To identify trajectories of substance use disorders (SUDs) in youth during the 12 years after detention and how gender, race/ethnicity, and age at baseline predict trajectories. As part of the Northwestern Juvenile Project, a longitudinal study of 1,829 youth randomly sampled from detention in Chicago, Illinois from 1995 through 1998, participants were reinterviewed in the community or correctional facilities up to 9 times over 12 years. Independent interviewers assessed SUDs using the Diagnostic Interview Schedule for Children 2.3 (baseline) and the Diagnostic Interview Schedule IV (follow-ups). Primary outcome was a mutually exclusive 5-category typology of disorder: no SUD, alcohol alone, marijuana alone, comorbid alcohol and marijuana, or "other" illicit ("hard") drug. Trajectories were estimated using growth mixture models with a 3-category ordinal variable derived from the typology. During the 12-year follow-up, 19.6% of youth did not have an SUD. The remaining 81.4% were in 3 trajectory classes. Class 1 (24.5%), a bell-shaped trajectory, peaked 5 years after baseline when 42.7% had an SUD and 12.5% had comorbid or "other" illicit drug disorders. Class 2 (41.3%) had a higher prevalence of SUD at baseline, 73.8%. Although prevalence decreased over time, 23.5% had an SUD 12 years later. Class 3 (14.6%), the most serious and persistent trajectory, had the highest prevalence of comorbid or "other" illicit drug disorders-52.1% at baseline and 17.4% 12 years later. Males, Hispanics, non-Hispanic whites, and youth who were older at baseline (detention) had the worst outcomes. Gender, race/ethnicity, and age at detention predict trajectories of SUDs in delinquent youth. Findings provide an empirical basis for child psychiatry to address health disparities and improve prevention. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene.

PubMed

Sholder, Gabriel; Creech, Amanda; Loechler, Edward L

2015-11-01

To bypass DNA damage, cells have Y-Family DNA polymerases (DNAPs). One Y-Family-class includes DNAP κ and DNAP IV, which accurately insert dCTP opposite N(2)-dG adducts, including from the carcinogen benzo[a]pyrene (BP). Another class includes DNAP η and DNAP V, which insert accurately opposite UV-damage, but inaccurately opposite BP-N(2)-dG. To investigate structural differences between Y-Family-classes, regions are swapped between DNAP IV (a κ/IV-class-member) and Dpo4 (a η/V-class-member); the kinetic consequences are evaluated via primer-extension studies with a BP-N(2)-dG-containing template. Four key structural elements are revealed. (1) Y-Family DNAPs have discreet non-covalent contacts between their little finger-domain (LF-Domain) and their catalytic core-domain (CC-Domain), which we call "non-covalent bridges" (NCBs). Arg37 and Arg38 in DNAP IV's CC-Domain near the active site form a non-covalent bridge (AS-NCB) by interacting with Glu251 and Asp252, respectively, in DNAP IV's LF-Domain. Without these interactions dATP/dGTP/dTTP misinsertions increase. DNAP IV's AS-NCB suppresses misinsertions better than Dpo4's equivalent AS-NCB. (2) DNAP IV also suppresses dATP/dGTP/dTTP misinsertions via a second non-covalent bridge, which is ∼8Å from the active site (Distal-NCB). Dpo4 has no Distal-NCB, rendering it inferior at dATP/dGTP/dTTP suppression. (3) dCTP insertion is facilitated by the larger minor groove opening near the active site in DNAP IV versus Dpo4, which is sensible given that Watson/Crick-like [dCTP:BP-N(2)-dG] pairing requires the BP-moiety to be in the minor groove. (4) Compared to Dpo4, DNAP IV has a smaller major groove opening, which suppresses dGTP misinsertion, implying BP-N(2)-dG bulk in the major groove during Hoogsteen syn-adduct-dG:dGTP pairing. In summary, DNAP IV has a large minor groove opening to enhance dCTP insertion, a plugged major groove opening to suppress dGTP misinsertion, and two non-covalent bridges (near and distal to the active site) to suppress dATP/dGTP/dTTP misinsertions; collectively these four structural features enhance DNAP IV's dNTP insertion fidelity opposite a BP-N(2)-dG adduct compared to Dpo4. Copyright © 2015 Elsevier B.V. All rights reserved.

[Coping with HIV infection and motivation for therapy in multi-drug dependent patients].

PubMed

Grube, M

1995-05-01

The intrapsychological process of working through the five stages of death in terminally ill patients (according to Kübler-Ross) was documented by videotaping semistructured interviews. There were 67 i.v. drug-dependent polytoxic HIV-positive inpatients. An inquiry was also made into their social niveau, the course of their addiction, the patients' legal status, and their previous experience with long-term therapy. Prevalent forms of working through the five stages of death could be established with reasonable reliability, and their influence could be determined on how the patients actually made use of offers of long-term therapy. The most important finding was that HIV-positive i.v. drug-addicted polytoxic patients started with a similar ratio of 1:3 in drug-free long-term therapy compared to HIV-negative i.v. drug-addicted polytoxic inpatients (n = 71). In the group of HIV-positive i.v. drug-addicted inpatients their individual means of psychologically working through their illness, their legal status and their previous experience with drug-free long-term therapy seem to be relevant factors in positive therapy motivation. This should be kept in mind when methadone programs are discussed.

Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices.

PubMed

Bajema, Ingeborg M; Wilhelmus, Suzanne; Alpers, Charles E; Bruijn, Jan A; Colvin, Robert B; Cook, H Terence; D'Agati, Vivette D; Ferrario, Franco; Haas, Mark; Jennette, J Charles; Joh, Kensuke; Nast, Cynthia C; Noël, Laure-Hélène; Rijnink, Emilie C; Roberts, Ian S D; Seshan, Surya V; Sethi, Sanjeev; Fogo, Agnes B

2018-04-01

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions. Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Examining the Stability of "DSM-IV" and Empirically Derived Eating Disorder Classification: Implications for "DSM-5"

ERIC Educational Resources Information Center

Peterson, Carol B.; Crow, Scott J.; Swanson, Sonja A.; Crosby, Ross D.; Wonderlich, Stephen A.; Mitchell, James E.; Agras, W. Stewart; Halmi, Katherine A.

2011-01-01

Objective: The purpose of this investigation was to derive an empirical classification of eating disorder symptoms in a heterogeneous eating disorder sample using latent class analysis (LCA) and to examine the longitudinal stability of these latent classes (LCs) and the stability of DSM-IV eating disorder (ED) diagnoses. Method: A total of 429…

Mathematical Relationships between Neuron Morphology and Neurite Growth Dynamics in Drosophila melanogaster Larva Class IV Sensory Neurons

NASA Astrophysics Data System (ADS)

Ganguly, Sujoy; Liang, Xin; Grace, Michael; Lee, Daniel; Howard, Jonathon

The morphology of neurons is diverse and reflects the diversity of neuronal functions, yet the principles that govern neuronal morphogenesis are unclear. In an effort to better understand neuronal morphogenesis we will be focusing on the development of the dendrites of class IV sensory neuron in Drosophila melanogaster. In particular we attempt to determine how the the total length, and the number of branches of dendrites are mathematically related to the dynamics of neurite growth and branching. By imaging class IV neurons during early embryogenesis we are able to measure the change in neurite length l (t) as a function of time v (t) = dl / dt . We found that the distribution of v (t) is well characterized by a hyperbolic secant distribution, and that the addition of new branches per unit time is well described by a Poisson process. Combining these measurements with the assumption that branching occurs with equal probability anywhere along the dendrite we were able to construct a mathematical model that provides reasonable agreement with the observed number of branches, and total length of the dendrites of the class IV sensory neuron.

The role of single immediate loading implant in long Class IV Kennedy mandibular partial denture.

PubMed

Mohamed, Gehan F; El Sawy, Amal A

2012-10-01

The treatment of long-span Kennedy class IV considers a prosthodontic challenge. This study evaluated the integrity of principle abutments in long Kennedy class IV clinically and radiographically, when rehabilitated with conventional metallic partial denture as a control group and mandibular partial overdentures supported with single immediately loaded implant in symphyseal as a study group. Twelve male patients were divided randomly allotted into two equal groups. First group patients received removable metallic partial denture, whereas in the second group, patients received partial overdentures supported with single immediately loaded implant in symphyseal region. The partial dentures design in both groups was the same. Long-cone paralleling technique and transmission densitometer were used at the time of denture insertion, 3, 6, and 12 months. Gingival index, bone loss, and optical density were measured for principle abutments during the follow-up. A significant reduction in bone loss and density were detected in group II comparing with group I. Gingival index had no significant change (p-value < 0.05). A single symphyseal implant in long span class IV Kennedy can play a pivotal role to improve the integrity of the principle abutments and alveolar bone support. © 2010 Wiley Periodicals, Inc.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration.

PubMed

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions.

Development of a stable low-dose aglycosylated antibody formulation to minimize protein loss during intravenous administration

PubMed Central

Morar-Mitrica, Sorina; Puri, Manasi; Beumer Sassi, Alexandra; Fuller, Joshua; Hu, Ping; Crotts, George; Nesta, Douglas

2015-01-01

The physical and chemical integrity of a biopharmaceutical must be maintained not only during long-term storage but also during administration. Specifically for the intravenous (i.v.) delivery of a protein drug, loss of stability can occur when the protein formulation is compounded with i.v. bag diluents, thus modifying the original composition of the drug product. Here we present the challenges associated with the delivery of a low-dose, highly potent monoclonal antibody (mAb) via the i.v. route. Through parallel in-use stability studies and conventional formulation development, a drug product was developed in which adsorptive losses and critical oxidative degradation pathways were effectively controlled. This development approach enabled the i.v. administration of clinical doses in the range of 0.1 to 0.5 mg total protein, while ensuring liquid drug product storage stability under refrigerated conditions. PMID:26073995

Latent class instrumental variables: A clinical and biostatistical perspective

PubMed Central

Baker, Stuart G.; Kramer, Barnett S.; Lindeman, Karen S.

2015-01-01

In some two-arm randomized trials, some participants receive the treatment assigned to the other arm as a result of technical problems, refusal of a treatment invitation, or a choice of treatment in an encouragement design. In some before-and-after studies, the availability of a new treatment changes from one time period to this next. Under assumptions that are often reasonable, the latent class instrumental variable (IV) method estimates the effect of treatment received in the aforementioned scenarios involving all-or-none compliance and all-or-none availability. Key aspects are four initial latent classes (sometimes called principal strata) based on treatment received if in each randomization group or time period, the exclusion restriction assumption (in which randomization group or time period is an instrumental variable), the monotonicity assumption (which drops an implausible latent class from the analysis), and the estimated effect of receiving treatment in one latent class (sometimes called efficacy, the local average treatment effect, or the complier average causal effect). Since its independent formulations in the biostatistics and econometrics literatures, the latent class IV method (which has no well-established name) has gained increasing popularity. We review the latent class IV method from a clinical and biostatistical perspective, focusing on underlying assumptions, methodological extensions, and applications in our fields of obstetrics and cancer research. PMID:26239275

Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and intensive care units.

PubMed

Maiguy-Foinard, Aurélie; Genay, Stéphanie; Lannoy, Damien; Barthélémy, Christine; Lebuffe, Gilles; Debaene, Bertrand; Odou, Pascal; Décaudin, Bertrand

2017-02-01

The aims are to identify critical parameters influencing the drug mass flow rate of infusion delivery to patients during multidrug infusion and to discuss their clinical relevance. A review of literature was conducted in January 2016 using Medline, Google Scholar, ScienceDirect, Web of Science and Scopus online databases. References relating to the accuracy of fluid delivery via gravity-flow intravenous (IV) infusion systems and positive displacement pumps, components of IV administration sets, causes of flow rate variability, potential complications due to flow rate variability, IV therapies especially at low flow rates and drug compatibilities were considered relevant. Several parameters impact the delivery of drugs and fluids by IV infusion. Among them are the components of infusion systems that particularly influence the flow rate of medications and fluids being delivered. By their conception, they may generate significant start-up delays and flow rate variability. Performing multidrug infusion requires taking into account two main points: the common dead volume of drugs delivered simultaneously with potential consequences on the accuracy and amount of drug delivery and the prevention of drug incompatibilities and their clinical effects. To prevent the potentially serious effects of flow rate variability on patients, clinicians should receive instruction on the fluid dynamics of an IV administration set and so be able to take steps to minimise flow rate changes during IV therapy. Copyright © 2016 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Decision-Making Under Risk, but Not Under Ambiguity, Predicts Pathological Gambling in Discrete Types of Abstinent Substance Users.

PubMed

Wilson, Michael J; Vassileva, Jasmin

2018-01-01

This study explored how different forms of reward-based decision-making are associated with pathological gambling (PG) among abstinent individuals with prior dependence on different classes of drugs. Participants had lifetime histories of either "pure" heroin dependence ( n = 64), "pure" amphetamine dependence ( n = 51), or polysubstance dependence ( n = 89), or had no history of substance dependence ( n = 133). Decision-making was assessed via two neurocognitive tasks: (1) the Iowa Gambling Task (IGT), a measure of decision-making under ambiguity (i.e., uncertain risk contingencies); and (2) the Cambridge Gambling task (CGT), a measure of decision-making under risk (i.e., explicit risk contingencies). The main effects of neurocognitive performance and drug class on PG (defined as ≥3 DSM-IV PG symptoms) as well as their interactional effects were assessed via multiple linear regression. Two CGT indices of decision-making under risk demonstrated positive main effects on PG. Interaction effects indicated that the effects of decision-making under risk on PG were largely consistent across participant groups. Notably, a linear relationship between greater CGT Risk-Taking and PG symptoms was not observed among amphetamine users, whereas IGT performance was selectively and positively associated with PG in polysubstance users. Overall, results indicate that reward-based decision-making under risk may represent a risk factor for PG across substance users, with some variations in these relationships influenced by specific class of substance of abuse.

Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A Review

NASA Astrophysics Data System (ADS)

Vadlamudi, Manoj Kumar; Dhanaraj, Sangeetha

2017-11-01

Nowadays most of the drug substances are coming into the innovation pipeline with poor water solubility. Here, the influence of excipients will play a significant role to improve the dissolution of poorly aqueous soluble compounds. The drug substance needs to be dissolved in gastric fluids to get the better absorption and bioavailability of an orally administered drug. Dissolution is the rate-controlling stage for drugs which controls the rate and degree of absorption. Usually, poorly soluble oral administrated drugs show a slower dissolution rate, inconsistent and incomplete absorption which can lead to lower bioavailability. The low aqueous solubility of BCS class II and IV drugs is a major challenge in the drug development and delivery process. Several technologies have been used in an attempt to progress the bioavailability of poorly water-soluble drug compounds which include solid dispersions, lipid-based formulations, micronization, solvent evaporation, co-precipitation, ordered mixing, liquid-solid compacts, solvent deposition inclusion complexation, and steam aided granulation. In fact, most of the technologies require excipient as a carrier which plays a significant role in improving the bioavailability using Hypromellose acetate succinate, Cyclodextrin, Povidone, Copovidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Crospovidone, Starch, Dimethylacetamide, Polyethylene glycol, Sodium lauryl sulfate, Polysorbate, Poloxamer. Mesoporous silica and so on. This review deliberates about the excipients significance on bioavailability enhancement of drug products in a single platform along with pragmatically proved applications so that user can able to select the right excipients as per the molecule.

Intravenous Vancomycin Associated With the Development of Nephrotoxicity in Patients With Class III Obesity.

PubMed

Choi, Yookyung Christy; Saw, Stephen; Soliman, Daniel; Bingham, Angela L; Pontiggia, Laura; Hunter, Krystal; Chuang, Linda; Siemianowski, Laura A; Ereshefsky, Benjamin; Hollands, James M

2017-11-01

A consensus statement recommends initial intravenous (IV) vancomycin dosing of 15-20 mg/kg every 8- 24 hours, with an optional 25- to 30-mg/kg loading dose. Although some studies have shown an association between weight and the development of vancomycin-associated nephrotoxicity, results have been inconsistent. To evaluate the correlation between incidence of nephrotoxicity associated with weight-based IV vancomycin dosing strategies in nonobese and obese patients. This retrospective cohort study evaluated hospitalized adult patients admitted who received IV vancomycin. Patients were stratified into nonobese (body mass index [BMI] <25 kg/m 2 ), obesity class I and II (BMI 30-39.9kg/m 2 ), and obesity class III (BMI≥40 kg/m 2 ) groups; patients who were overweight but not obese were excluded. Incidence of nephrotoxicity and serum vancomycin trough concentrations were evaluated. Of a total of 62 documented cases of nephrotoxicity (15.1%), 13 (8.7%), 23 (14.3%), and 26 (26.3%) cases were observed in nonobese, obesity class I and II, and obesity class III groups, respectively ( P=0.002). Longer durations of therapy ( P<0.0001), higher initial maintenance doses in both total milligrams/day ( P=0.0137) and milligrams/kilogram ( P=0.0307), and any trough level >20 mg/L ( P<0.0001) were identified as predictors of development of nephrotoxicity. Concomitant administration of piperacillin/tazobactam, diuretics, and IV contrast were associated with development of nephrotoxicity ( P<0.005, all). Patients with class III obesity were 3-times as likely to develop nephrotoxicity when compared with nonobese patients (odds ratio [OR]=2.99; CI=1.12-7.94) and obesity class I and II patients (OR=3.14; CI=1.27-7.75). Obesity and other factors are associated with a higher risk of vancomycin-associated nephrotoxicity.

Digitized Speech Characteristics in Patients with Maxillectomy Defects.

PubMed

Elbashti, Mahmoud E; Sumita, Yuka I; Hattori, Mariko; Aswehlee, Amel M; Taniguchi, Hisashi

2017-12-06

Accurate evaluation of speech characteristics through formant frequency measurement is important for proper speech rehabilitation in patients after maxillectomy. This study aimed to evaluate the utility of digital acoustic analysis and vowel pentagon space for the prediction of speech ability after maxillectomy, by comparing the acoustic characteristics of vowel articulation in three classes of maxillectomy defects. Aramany's classifications I, II, and IV were used to group 27 male patients after maxillectomy. Digital acoustic analysis of five Japanese vowels-/a/, /e/, /i/, /o/, and /u/-was performed using a speech analysis system. First formant (F1) and second formant (F2) frequencies were calculated using an autocorrelation method. Data were plotted on an F1-F2 plane for each patient, and the F1 and F2 ranges were calculated. The vowel pentagon spaces were also determined. One-way ANOVA was applied to compare all results between the three groups. Class II maxillectomy patients had a significantly higher F2 range than did Class I and Class IV patients (p = 0.002). In contrast, there was no significant difference in the F1 range between the three classes. The vowel pentagon spaces were significantly larger in class II maxillectomy patients than in Class I and Class IV patients (p = 0.014). The results of this study indicate that the acoustic characteristics of maxillectomy patients are affected by the defect area. This finding may provide information for obturator design based on vowel articulation and defect class. © 2017 by the American College of Prosthodontists.

Pretest Differences in Drug-Related Variables among Intact College Classes: Implications for Outcome Evaluation in Drug Education.

ERIC Educational Resources Information Center

Gonzalez, Gerardo M.; Haney, Michael L.

1992-01-01

Identified significant pretest differences in drug-related variables in college students from alcohol and drug education class (n=99), stress management class (n=44), and social problems class (n=80). Higher levels of alcohol and drug abuse among students in drug abuse course suggests student users are possibly being attracted to course as means…

Magnetic Nanoparticles with Dual Functional Properties: Drug Delivery and Magnetic Resonance Imaging

PubMed Central

Jain, Tapan K.; Richey, John; Strand, Michelle; Leslie-Pelecky, Diandra L.; Flask, Chris; Labhasetwar, Vinod

2008-01-01

There is significant interest in recent years in developing MNPs having multifunctional characteristics with complimentary roles. In this study, we investigated the drug delivery and magnetic resonance imaging (MRI) properties of our novel oleic acid-coated iron-oxide and pluronic-stabilized magnetic nanoparticles (MNPs). The drug incorporation efficiency of doxorubicin and paclitaxel (alone or in combination) in MNPs was 74–95%; the drug release was sustained and the incorporated drugs had marginal effects on physical (size and zeta potential) or magnetization properties of the MNPs. The drugs in combination incorporated in MNPs demonstrated highly synergistic antiproliferative activity in breast cancer cells. The T2 relaxivity (r2) was higher for our MNPs than Feridex IV, whereas the T1 relaxivity (r1) was better for Feridex IV than for our MNPs, suggesting greater sensitivity of our MNPs than Feridex IV in T2 weighted imaging. The circulation half-life (t1/2), determined from the changes in the MRI signal intensity in carotid arteries in mice, was longer for our MNPs than Feridex IV (t1/2 = 31.2 vs 6.4 min). MNPs with combined characteristics of MRI and drug delivery could be of high clinical significance in the treatment of various disease conditions. PMID:18649936

Interobserver agreement on histopathological lesions in class III or IV lupus nephritis.

PubMed

Wilhelmus, Suzanne; Cook, H Terence; Noël, Laure-Hélène; Ferrario, Franco; Wolterbeek, Ron; Bruijn, Jan A; Bajema, Ingeborg M

2015-01-07

To treat lupus nephritis effectively, proper identification of the histologic class is essential. Although the classification system for lupus nephritis is nearly 40 years old, remarkably few studies have investigated interobserver agreement. Interobserver agreement among nephropathologists was studied, particularly with respect to the recognition of class III/IV lupus nephritis lesions, and possible causes of disagreement were determined. A link to a survey containing pictures of 30 glomeruli was provided to all 360 members of the Renal Pathology Society; 34 responses were received from 12 countries (a response rate of 9.4%). The nephropathologist was asked whether glomerular lesions were present that would categorize the biopsy as class III/IV. If so, additional parameters were scored. To determine the interobserver agreement among the participants, κ or intraclass correlation values were calculated. The intraclass correlation or κ-value was also calculated for two separate levels of experience (specifically, nephropathologists who were new to the field or moderately experienced [less experienced] and nephropathologists who were highly experienced). Intraclass correlation for the presence of a class III/IV lesion was 0.39 (poor). The κ/intraclass correlation values for the additional parameters were as follows: active, chronic, or both: 0.36; segmental versus global: 0.39; endocapillary proliferation: 0.46; influx of inflammatory cells: 0.32; swelling of endothelial cells: 0.46; extracapillary proliferation: 0.57; type of crescent: 0.46; and wire loops: 0.35. The highly experienced nephropathologists had significantly less interobserver variability compared with the less experienced nephropathologists (P=0.004). There is generally poor agreement in terms of recognizing class III/IV lesions. Because experience clearly increases interobserver agreement, this agreement may be improved by training nephropathologists. These results also underscore the importance of a central review by experienced nephropathologists in clinical trials. Copyright © 2015 by the American Society of Nephrology.

A 3-tier classification of cerebral arteriovenous malformations. Clinical article.

PubMed

Spetzler, Robert F; Ponce, Francisco A

2011-03-01

The authors propose a 3-tier classification for cerebral arteriovenous malformations (AVMs). The classification is based on the original 5-tier Spetzler-Martin grading system, and reflects the treatment paradigm for these lesions. The implications of this modification in the literature are explored. Class A combines Grades I and II AVMs, Class B are Grade III AVMs, and Class C combines Grades IV and V AVMs. Recommended management is surgery for Class A AVMs, multimodality treatment for Class B, and observation for Class C, with exceptions to the latter including recurrent hemorrhages and progressive neurological deficits. To evaluate whether combining grades is warranted from the perspective of surgical outcomes, the 3-tier system was applied to 1476 patients from 7 surgical series in which results were stratified according to Spetzler-Martin grades. Pairwise comparisons of individual Spetzler-Martin grades in the series analyzed showed the fewest significant differences (p < 0.05) in outcomes between Grades I and II AVMs and between Grades IV and V AVMs. In the pooled data analysis, significant differences in outcomes were found between all grades except IV and V (p = 0.38), and the lowest relative risks were found between Grades I and II (1.066) and between Grades IV and V (1.095). Using the pooled data, the predictive accuracies for surgical outcomes of the 5-tier and 3-tier systems were equivalent (receiver operating characteristic curve area 0.711 and 0.713, respectively). Combining Grades I and II AVMs and combining Grades IV and V AVMs is justified in part because the differences in surgical results between these respective pairs are small. The proposed 3-tier classification of AVMs offers simplification of the Spetzler-Martin system, provides a guide to treatment, and is predictive of outcome. The revised classification not only simplifies treatment recommendations; by placing patients into 3 as opposed to 5 groups, statistical power is markedly increased for series comparisons.

How Safe and Innovative Are First-in-Class Drugs Approved by Health Canada: A Cohort Study

PubMed Central

2016-01-01

Introduction: First-in-class drugs use a unique mechanism of action. This study assessed the therapeutic innovativeness and safety of these drugs approved by Health Canada from 1997–2012. Methods: A list of new drugs was compiled and a database from the Food and Drug Administration was used to determine first-in-class status. Post-market safety warnings and drugs withdrawn for safety reasons were identified from the MedEffect Canada website. Therapeutic innovation evaluations came from the Patented Medicine Prices Review Board (PMPRB) and Prescrire International. The proportion of first-in-class drugs that were innovative was compared to the proportion of non-first-in-class drugs that were innovative. Kaplan–Meier survival curves assessed safety. Results: In all, 462 drugs were approved by Health Canada during the period under study. Among these, 345 were evaluated by PMPRB and/or Prescrire, and first-in-class data were available for 292. Ninety-eight of the 292 were first-in-class and 16 were innovative compared to 9 of 194 drugs that were not-first-in-class. There was no difference in safety between the two groups. Discussion: Overall, the benefit-to-harm ratio of first-in-class drugs, as measured by post-market safety warnings/withdrawals, is better than those that were not-first-in-class. PMID:28032825

37 CFR 2.6 - Trademark fees.

Code of Federal Regulations, 2010 CFR

2010-07-01

... filing an application on paper, per class $375.00 (ii) For filing an application through TEAS, per class $325.00 (iii) For filing a TEAS Plus application under § 2.22, per class $275.00 (iv) Additional...

Pharmacokinetic properties and tolerability of single-dose terbutaline in patients with severe asthma treated in the pediatric intensive care unit

PubMed Central

Lebovitz, Daniel J; Smith, Paul G; O'Riordan, MaryAnn; Reed, Michael D

2004-01-01

Background: Asthmatic children requiring treatment in the pediatric intensive care unit (PICU) receive aggressive drug therapy that may include IV administration of β2-receptor agonists to prevent progression to life-threatening respiratory failure. The only pharmacologic agent in this class currently available for parenteral use in the United States is terbutaline. Study of IV dosing of terbutaline in the pediatric population has been limited. Objective: The aim of this study was to determine the pharmacokinetic (PK) properties and tolerability of single-dose terbutaline in pediatric patients across a broad age range who were admitted to the PICU and were receiving maximal conventional asthma drug therapy. Methods: This study was conducted at the PICU at Rainbow Babies and Children's Hospital (Cleveland, Ohio). Patients aged 6 months to 16 years with severe exacerbation of reactive airways disease and who were undergoing maximal conventional therapy and had an arterial catheter were enrolled. Patients were arbitrarily assigned to receive a single IV infusion of 1 of 3 doses of terbutaline (10, 20, or 30 μg/kg), infused over 5 minutes. Blood samples were obtained for the determination of plasma terbutaline concentrations just before terbutaline was administered (baseline), immediately on completion of the IV infusion, and at 10, 20, and 40 minutes and 1, 2, 4, 8, 16, 32, 48, and 72 hours after the 5-minute infusion. PK properties (elimination half-life [tl2], mean residence time [MRT], apparent steady-state volume of distribution [Vdss], and total body clearance [CI]) were determined and adverse effects were recorded. Results: The determination of terbutaline PK properties was possible in 50 of 56 enrolled patients (31 boys, 19 girls; mean [SD] age, 6.5 [4.5] years). The PK properties of terbutaline were linear over the dose range studied and, with the exception of the expected dose-dependent increases in peak terbutaline plasma concentration and area under the terbutaline plasma concentration-time curve, no statistically significant differences were observed in PK relative to dose. Therefore, we pooled the data for all subsequent analyses. Statistically significant correlations with patient age were observed with tl2 (r = 0.4, P < 0.006), MRT (r = 0.4, P < 0.002), and Vdss (r = 0.33, P < 0.02), but not C1 (r = −0.03, P = NS). Single-dose terbutaline administration was generally well tolerated. Conclusions: Single-dose IV terbutaline was well tolerated in this study. In maximally treated asthmatic patients in the PICU, terbutaline elimination may be more rapid than in nonacutely ill children. These PK data suggest that if the drug is to be administered intravenously, the continuous IV infusion method, including loading doses for any subsequent dose escalations, may be the most appropriate. The influence of age and safety of long-term, continuous terbutaline IV infusion requires further study. PMID:24936108

Psychiatric comorbidity and the persistence of drug use disorders in the United States

PubMed Central

Fenton, Miriam C.; Keyes, Katherine; Geier, Timothy; Greenstein, Eliana; Skodol, Andrew; Krueger, Bob; Grant, Bridget F.; Hasin, Deborah S.

2011-01-01

Context DSM-IV drug use disorders, a major public health problem, are highly comorbid with other psychiatric disorders, but little is known about the role of this comorbidity when studied prospectively in the general population. Aims Determine the role of comorbid psychopathology in the three-year persistence of drug use disorders. Design Secondary data analysis using Waves 1 (2001-2) and 2 (2004-5) of the National Epidemiologic Survey on Alcohol and Related Conditions. Participants Respondents with current DSM-IV drug use disorder at Wave 1 who participated in Wave 2 (N=613). Measurements AUDADIS-IV obtained DSM-IV Axis I and II diagnoses. Persistent drug use disorder was defined as meeting full criteria for any drug use disorder between Waves 1 and 2. Findings Drug use disorders persisted in 30.9% of respondents. No Axis I disorders predicted persistence. Antisocial (OR=2.75; 95% CI=1.27–5.99), borderline (OR=1.91; 95% CI=1.06–3.45) and schizotypal (OR=2.77; 95% CI=1.42–5.39) personality disorders were significant predictors of persistent drug use disorders, controlling for demographics, psychiatric comorbidity, family history, treatment and number of drug use disorders. Deceitfulness and lack of remorse were the strongest antisocial criteria predictors of drug use disorder persistence, identity disturbance and self-damaging impulsivity were the strongest borderline criteria predictors, and ideas of reference and social anxiety were the strongest schizotypal criteria predictors. Conclusions Antisocial, borderline and schizotypal personality disorders are specific predictors of drug use disorder persistence over a three-year period. PMID:21883607

Cloning and heterologous expression of a novel subgroup of class IV polyhydroxyalkanoate synthase genes from the genus Bacillus.

PubMed

Mizuno, Kouhei; Kihara, Takahiro; Tsuge, Takeharu; Lundgren, Benjamin R; Sarwar, Zaara; Pinto, Atahualpa; Nomura, Christopher T

2017-01-01

Many microorganisms harbor genes necessary to synthesize biodegradable plastics known as polyhydroxyalkanoates (PHAs). We surveyed a genomic database and discovered a new cluster of class IV PHA synthase genes (phaRC). These genes are different in sequence and operon structure from any previously reported PHA synthase. The newly discovered PhaRC synthase was demonstrated to produce PHAs in recombinant Escherichia coli.

Incipient class II mixed valency in a plutonium solid-state compound

NASA Astrophysics Data System (ADS)

Cary, Samantha K.; Galley, Shane S.; Marsh, Matthew L.; Hobart, David L.; Baumbach, Ryan E.; Cross, Justin N.; Stritzinger, Jared T.; Polinski, Matthew J.; Maron, Laurent; Albrecht-Schmitt, Thomas E.

2017-09-01

Electron transfer in mixed-valent transition-metal complexes, clusters and materials is ubiquitous in both natural and synthetic systems. The degree to which intervalence charge transfer (IVCT) occurs, dependent on the degree of delocalization, places these within class II or III of the Robin-Day system. In contrast to the d-block, compounds of f-block elements typically exhibit class I behaviour (no IVCT) because of localization of the valence electrons and poor spatial overlap between metal and ligand orbitals. Here, we report experimental and computational evidence for delocalization of 5f electrons in the mixed-valent PuIII/PuIV solid-state compound, Pu3(DPA)5(H2O)2 (DPA = 2,6-pyridinedicarboxylate). The properties of this compound are benchmarked by the pure PuIII and PuIV dipicolinate complexes, [PuIII(DPA)(H2O)4]Br and PuIV(DPA)2(H2O)3·3H2O, as well as by a second mixed-valent compound, PuIII[PuIV(DPA)3H0.5]2, that falls into class I instead. Metal-to-ligand charge transfer is involved in both the formation of Pu3(DPA)5(H2O)2 and in the IVCT.

Optical radiation hazards of laser welding processes. Part II: CO2 laser.

PubMed

Rockwell, R J; Moss, C E

1989-08-01

There has been an extensive growth within the last five years in the use of high-powered lasers in various metalworking processes. The two types of lasers used most frequently for laser welding/cutting processes are the Neodymium-yttrium-aluminum-garnet (Nd:YAG) and the carbon dioxide (CO2) systems. When such lasers are operated in an open beam configuration, they are designated as a Class IV laser system. Class IV lasers are high-powered lasers that may present an eye and skin hazard under most common exposure conditions, either directly or when the beam has been diffusely scattered. Significant control measures are required for unenclosed (open beam), Class IV laser systems since workers may be exposed to scattered or reflected beams during the operation, maintenance, and service of these lasers. In addition to ocular and/or skin exposure hazards, such lasers also may present a multitude of nonlaser beam occupational concerns. Radiant energy measurements are reported for both the scattered laser radiation and the plasma-related plume radiations released during typical high-powered CO2 laser-target interactions. In addition, the application of the nominal hazard zone (NHZ) and other control measures also are discussed with special emphasis on Class IV industrial CO2 laser systems.

Cocrystals of Hydrochlorothiazide: Solubility and Diffusion/Permeability Enhancements through Drug-Coformer Interactions.

PubMed

Sanphui, Palash; Devi, V Kusum; Clara, Deepa; Malviya, Nidhi; Ganguly, Somnath; Desiraju, Gautam R

2015-05-04

Hydrochlorothiazide (HCT) is a diuretic and a BCS class IV drug with low solubility and low permeability, exhibiting poor oral absorption. The present study attempts to improve the physicochemical properties of the drug using a crystal engineering approach with cocrystals. Such multicomponent crystals of HCT with nicotinic acid (NIC), nicotinamide (NCT), 4-aminobenzoic acid (PABA), succinamide (SAM), and resorcinol (RES) were prepared using liquid-assisted grinding, and their solubilities in pH 7.4 buffer were evaluated. Diffusion and membrane permeability were studied using a Franz diffusion cell. Except for the SAM and NIC cocrystals, all other binary systems exhibited improved solubility. All of the cocrystals showed improved diffusion/membrane permeability compared to that of HCT with the exception of the SAM cocrystal. When the solubility was high, as in the case of PABA, NCT, and RES cocrystals, the flux/permeability dropped slightly. This is in agreement with the expected interplay between solubility and permeability. Improved solubility/permeability is attributed to new drug-coformer interactions. Cocrystals of SAM, however, showed poor solubility and flux. This cocrystal contains a primary sulfonamide dimer synthon similar to that of HCT polymorphs, which may be a reason for its unusual behavior. Hirshfeld surface analysis was carried out in all cases to determine whether a correlation exists between cocrystal permeability and drug-coformer interactions.

Organization and variation analysis of 5S rDNA in different ploidy-level hybrids of red crucian carp × topmouth culter.

PubMed

He, Weiguo; Qin, Qinbo; Liu, Shaojun; Li, Tangluo; Wang, Jing; Xiao, Jun; Xie, Lihua; Zhang, Chun; Liu, Yun

2012-01-01

Through distant crossing, diploid, triploid and tetraploid hybrids of red crucian carp (Carassius auratus red var., RCC♀, Cyprininae, 2n = 100) × topmouth culter (Erythroculter ilishaeformis Bleeker, TC♂, Cultrinae, 2n = 48) were successfully produced. Diploid hybrids possessed 74 chromosomes with one set from RCC and one set from TC; triploid hybrids harbored 124 chromosomes with two sets from RCC and one set from TC; tetraploid hybrids had 148 chromosomes with two sets from RCC and two sets from TC. The 5S rDNA of the three different ploidy-level hybrids and their parents were sequenced and analyzed. There were three monomeric 5S rDNA classes (designated class I: 203 bp; class II: 340 bp; and class III: 477 bp) in RCC and two monomeric 5S rDNA classes (designated class IV: 188 bp, and class V: 286 bp) in TC. In the hybrid offspring, diploid hybrids inherited three 5S rDNA classes from their female parent (RCC) and only class IV from their male parent (TC). Triploid hybrids inherited class II and class III from their female parent (RCC) and class IV from their male parent (TC). Tetraploid hybrids gained class II and class III from their female parent (RCC), and generated a new 5S rDNA sequence (designated class I-N). The specific paternal 5S rDNA sequence of class V was not found in the hybrid offspring. Sequence analysis of 5S rDNA revealed the influence of hybridization and polyploidization on the organization and variation of 5S rDNA in fish. This is the first report on the coexistence in vertebrates of viable diploid, triploid and tetraploid hybrids produced by crossing parents with different chromosome numbers, and these new hybrids are novel specimens for studying the genomic variation in the first generation of interspecific hybrids, which has significance for evolution and fish genetics.

Latent class instrumental variables: a clinical and biostatistical perspective.

PubMed

Baker, Stuart G; Kramer, Barnett S; Lindeman, Karen S

2016-01-15

In some two-arm randomized trials, some participants receive the treatment assigned to the other arm as a result of technical problems, refusal of a treatment invitation, or a choice of treatment in an encouragement design. In some before-and-after studies, the availability of a new treatment changes from one time period to this next. Under assumptions that are often reasonable, the latent class instrumental variable (IV) method estimates the effect of treatment received in the aforementioned scenarios involving all-or-none compliance and all-or-none availability. Key aspects are four initial latent classes (sometimes called principal strata) based on treatment received if in each randomization group or time period, the exclusion restriction assumption (in which randomization group or time period is an instrumental variable), the monotonicity assumption (which drops an implausible latent class from the analysis), and the estimated effect of receiving treatment in one latent class (sometimes called efficacy, the local average treatment effect, or the complier average causal effect). Since its independent formulations in the biostatistics and econometrics literatures, the latent class IV method (which has no well-established name) has gained increasing popularity. We review the latent class IV method from a clinical and biostatistical perspective, focusing on underlying assumptions, methodological extensions, and applications in our fields of obstetrics and cancer research. Copyright © 2015 John Wiley & Sons, Ltd.

Resveratrol as a Pan-HDAC Inhibitor Alters the Acetylation Status of Jistone Proteins in Human-Derived Hepatoblastoma Cells

PubMed Central

Böcker, Alexander; Busch, Christian; Weiland, Timo; Noor, Seema; Leischner, Christian; Schleicher, Sabine; Mayer, Mascha; Weiss, Thomas S.; Bischoff, Stephan C.; Lauer, Ulrich M.; Bitzer, Michael

2013-01-01

The polyphenolic alcohol resveratrol has demonstrated promising activities for the prevention and treatment of cancer. Different modes of action have been described for resveratrol including the activation of sirtuins, which represent the class III histone deacetylases (HDACs). However, little is known about the activity of resveratrol on the classical HDACs of class I, II and IV, although these classes are involved in cancer development or progression and inhibitors of HDACs (HDACi) are currently under investigation as promising novel anticancer drugs. We could show by in silico docking studies that resveratrol has the chemical structure to inhibit the activity of different human HDAC enzymes. In vitro analyses of overall HDAC inhibition and a detailed HDAC profiling showed that resveratrol inhibited all eleven human HDACs of class I, II and IV in a dose-dependent manner. Transferring this molecular mechanism into cancer therapy strategies, resveratrol treatment was analyzed on solid tumor cell lines. Despite the fact that hepatocellular carcinoma (HCC) is known to be particularly resistant against conventional chemotherapeutics, treatment of HCC with established HDACi already has shown promising results. Testing of resveratrol on hepatoma cell lines HepG2, Hep3B and HuH7 revealed a dose-dependent antiproliferative effect on all cell lines. Interestingly, only for HepG2 cells a specific inhibition of HDACs and in turn a histone hyperacetylation caused by resveratrol was detected. Additional testing of human blood samples demonstrated a HDACi activity by resveratrol ex vivo. Concluding toxicity studies showed that primary human hepatocytes tolerated resveratrol, whereas in vivo chicken embryotoxicity assays demonstrated severe toxicity at high concentrations. Taken together, this novel pan-HDACi activity opens up a new perspective of resveratrol for cancer therapy alone or in combination with other chemotherapeutics. Moreover, resveratrol may serve as a lead structure for chemical optimization of bioavailability, pharmacology or HDAC inhibition. PMID:24023672

Impact of Multiple Pharmacy Use on Medication Adherence and Drug-drug Interactions in Older Adults with Medicare Part D

PubMed Central

Marcum, Zachary A.; Driessen, Julia; Thorpe, Carolyn T.; Gellad, Walid F.; Donohue, Julie M.

2014-01-01

Objective To assess the association between multiple pharmacy use and medication adherence and potential drug-drug interactions (DDIs) among older adults. Design, Setting, and Participants Cross-sectional propensity score-weighted analysis of 2009 claims data from a nationally representative sample of 926,956 Medicare Part D beneficiaries aged >65 continuously enrolled in fee-for-service Medicare and Part D that year, and filled >1 prescription at a community/retail or mail order pharmacy. Multiple pharmacy use was defined as concurrent (overlapping time periods) or sequential use (non-overlapping time periods) of >2 pharmacies in the year. Measurements Medication adherence was calculated using a proportion of days covered ≥0.80 for eight therapeutic categories (β-blockers, renin angiotensin system antagonists, calcium channel blockers, statins, sulfonylureas, biguanides [i.e., metformin], thiazolidinediones, and dipeptidyl peptidase-IV inhibitors). Potential DDIs arising from use of certain drugs across a broad set of classes were defined as the concurrent filling of two interacting drugs. Results Overall, 38.1% of the sample used multiple pharmacies. Those using multiple pharmacies (both concurrently and sequentially) consistently had higher adjusted odds of non-adherence (ranging from 1.10 to 1.31, p<0.001) across all chronic medication classes assessed after controlling for socio-demographic, health status and access to care factors, compared to single pharmacy users. The adjusted predicted probability of exposure to a DDI was also slightly higher for those using multiple pharmacies concurrently (3.6%) compared to single pharmacy users (3.2%, AOR 1.11, 95% CI 1.08–1.15) but lower in individuals using multiple pharmacies sequentially (2.8%, AOR 0.85, 95% CI 0.81–0.91). Conclusions Filling prescriptions at multiple pharmacies was associated with lower medication adherence across multiple chronic medications, and a small but statistically significant increase in DDIs among concurrent pharmacy users. PMID:24521363

HIV infection among intravenous drug users: epidemiology and risk reduction.

PubMed

Des Jarlais, D C; Friedman, S R

1987-07-01

Research on the epidemiology of HIV infection among IV drug users is still at a relatively early stage. Multilocation studies that would permit better geographic comparisons are greatly needed. Multi-method studies within single geographic areas are also needed to assess possible biases with respect to sample recruitment and data collection procedures. The continuation of the epidemic provides a changing historical context that complicates any comparisons. Despite these problems, there are some consistencies that can be seen across studies. Studies of HIV seroprevalence among IV drug users show wide variation among cities in the United States and Europe. The time that the virus was introduced into the IV drug using group within the city is one factor in explaining these differences; other cross-city factors have yet to be identified. Once HIV has been introduced into the IV drug use group within a particular geographic area, there is the possibility of rapid spread up to seroprevalence levels of 50% or greater. Thus, a currently low seroprevalence rate should not be seen as a stable situation. Frequency of injection and sharing of equipment with multiple other drug users (particularly at shooting galleries) have been frequently associated with HIV exposure. Being female, ethnicity (in the USA) and engaging in prostitution also may be associated with increased risk for HIV exposure, suggesting that prevention programs should include special consideration of sex and ethnic differences. Studies of AIDS risk reduction show that substantial proportions of IV drug users are changing their behavior to avoid exposure to HIV. This risk reduction is probably more advanced in New York, with its high seroprevalence and incidence of cases, but is also occurring in cities with lower seroprevalence and limited numbers of cases. The primary forms of risk reduction are increasing the use of sterile equipment, reducing the number of needle sharing partners, and reducing the frequency of injection. These behavior changes are very similar to the frequently identified behavioral risk factors associated with HIV exposure, suggesting that they should be effective in at least slowing the spread of HIV among IV drug users. No linkage of risk reduction to decreases in seroconversion has yet been shown, however, and greater risk reduction is clearly required. A variety of prevention strategies will probably be needed to reduce the spread of HIV among IV drug users. Prevention of initiation into drug injection is an undeniable long-term goal for the control of HIV infection, but there is very little research being conducted in this area.

Implementing smart infusion pumps with dose-error reduction software: real-world experiences.

PubMed

Heron, Claire

2017-04-27

Intravenous (IV) drug administration, especially with 'smart pumps', is complex and susceptible to errors. Although errors can occur at any stage of the IV medication process, most errors occur during reconstitution and administration. Dose-error reduction software (DERS) loaded on to infusion pumps incorporates a drug library with predefined upper and lower drug dose limits and infusion rates, which can reduce IV infusion errors. Although this is an important advance for patient safety at the point of care, uptake is still relatively low. This article discuses the challenges and benefits of implementing DERS in clinical practice as experienced by three UK trusts.

Cardiovascular and Diabetic Medications That Cause Bradykinin-Mediated Angioedema.

PubMed

Hudey, Stephanie N; Westermann-Clark, Emma; Lockey, Richard F

Medication-induced angioedema is a bradykinin-mediated process that results from increased production or decreased degradation of bradykinin. These reactions are documented for several cardiac medications including blockers of the renin-angiotensin-aldosterone system (RAAS). Other cardiovascular and diabetes medications further increase the risk of medication-induced angioedema, particularly with concomitant use of RAAS inhibitors. Dipeptidyl peptidase IV inhibitors are a class of oral diabetic agents that affect bradykinin and substance P degradation and therefore can lead to angioedema. Neprilysin inhibitors are a separate class of cardiac medications, which includes sacubitril, and can lead to drug-induced angioedema especially when used in combination with RAAS inhibitors. This article discusses the proposed mechanisms by which these medications cause angioedema and how medication-induced angioedema differs from mast cell-mediated angioedema. It also details how to recognize medication-induced angioedema and the treatment options available. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation.

PubMed

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-09-01

The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs.

Furosemide Loaded Silica-Lipid Hybrid Microparticles: Formulation Development, in vitro and ex vivo Evaluation

PubMed Central

Sambaraj, Swapna; Ammula, Divya; Nagabandi, Vijaykumar

2015-01-01

Purpose: The main objective of the current research work was to formulate and evaluate furosemide loaded silica lipid hybrid microparticles for improved oral delivery. A novel silica-lipid hybrid microparticulate system is used for enhancing the oral absorption of low solubility and low permeability of (BCS Class IV) drugs. Silica-lipid hybrid microparticles include the drug solubilising effect of dispersed lipids and stabilizing effect of hydrophilic silica particles to increase drug solubilisation, which leads to enhanced oral bioavailability. Methods: The slica lipid hybrid (SLH) microparticles were composed of poorly soluble drug (furosemide), dispersion of oil phase (Soya bean oil and miglyol) in lecithin (Phospholipoid 90H), non-ionic surfactant (Polysorbate 80) and adsorbent (Aerosol 380). Saturation solubility studies were performed in different oils and surfactants with increased concentration of drug revealed increased solubility of furosemide. Results: In vitro dissolution studies conducted under simulated gastric medium revealed 2-4 fold increase in dissolution efficiencies for SLH microparticles compared to that of pure drug (furosemide) and marketed formulation Lasix®. Ex vivo studies showed enhanced lipid digestibility, which improved drug permeability. Solid-state characterization of SLH microparticles by X-ray powder diffraction and Fourier transform infrared spectroscopic analysis confirmed non-crystalline nature and more compatibility of furosemide in silica-lipid hybrid microparticles. Conclusion: It can be concluded that the role of lipids and hydrophilic silica based carrier highlighted in enhancing solubility and permeability, and hence the oral bioavailability of poorly soluble drugs. PMID:26504763

Synthesis, spectral, DFT modeling, cytotoxicity and microbial studies of novel Zr(IV), Ce(IV) and U(VI) piroxicam complexes

NASA Astrophysics Data System (ADS)

El-Shwiniy, Walaa H.; Zordok, Wael A.

2018-06-01

The Zr(IV), Ce(IV) and U(VI) piroxicam anti-inflammatory drug complexes were prepared and characterized using elemental analyses, conductance, IR, UV-Vis, magnetic moment, IHNMR and thermal analysis. The ratio of metal: Pir is found to be 1:2 in all complexes estimated by using molar ratio method. The conductance data reveal that Zr(IV) and U(VI) chelates are non-electrolytes except Ce(IV) complex is electrolyte. Infrared spectroscopic confirm that the Pir behaves as a bidentate ligand co-ordinated to the metal ions via the oxygen and nitrogen atoms of ν(Cdbnd O)carbonyl and ν(Cdbnd N)pyridyl, respectively. The kinetic parameters of thermogravimetric and its differential, such as activation energy, entropy of activation, enthalpy of activation, and Gibbs free energy evaluated using Coats-Redfern and Horowitz-Metzger equations for Pir and complexes. The geometry of the piroxicam drug in the Free State differs significantly from that in the metal complex. In the time of metal ion-drug bond formation the drug switches-on from the closed structure (equilibrium geometry) to the open one. The antimicrobial tests were assessed towards some types of bacteria and fungi. The in vitro cell cytotoxicity of the complexes in comparison with Pir against colon carcinoma (HCT-116) cell line was measured. Optimized geometrical structure of piroxicam ligand by using DFT calculations.

Using computer-aided drug design and medicinal chemistry strategies in the fight against diabetes.

PubMed

Semighini, Evandro P; Resende, Jonathan A; de Andrade, Peterson; Morais, Pedro A B; Carvalho, Ivone; Taft, Carlton A; Silva, Carlos H T P

2011-04-01

The aim of this work is to present a simple, practical and efficient protocol for drug design, in particular Diabetes, which includes selection of the illness, good choice of a target as well as a bioactive ligand and then usage of various computer aided drug design and medicinal chemistry tools to design novel potential drug candidates in different diseases. We have selected the validated target dipeptidyl peptidase IV (DPP-IV), whose inhibition contributes to reduce glucose levels in type 2 diabetes patients. The most active inhibitor with complex X-ray structure reported was initially extracted from the BindingDB database. By using molecular modification strategies widely used in medicinal chemistry, besides current state-of-the-art tools in drug design (including flexible docking, virtual screening, molecular interaction fields, molecular dynamics, ADME and toxicity predictions), we have proposed 4 novel potential DPP-IV inhibitors with drug properties for Diabetes control, which have been supported and validated by all the computational tools used herewith.

Effect of morphine, methadone, hydromorphone or oxymorphone on the thermal threshold, following intravenous or buccal administration to cats.

PubMed

Pypendop, Bruno H; Shilo-Benjamini, Yael; Ilkiw, Jan E

2016-11-01

To determine the effects of morphine, methadone, hydromorphone or oxymorphone on the thermal threshold in cats, following buccal and intravenous (IV) administration. Randomized crossover study. Six healthy adult female ovariohysterectomized cats weighing 4.5 ± 0.4 kg. Morphine sulfate (0.2 mg kg -1 IV or 0.5 mg kg -1 buccal), methadone hydrochloride (0.3 mg kg -1 IV or 0.75 mg kg -1 buccal), hydromorphone hydrochloride (0.1 mg kg -1 IV or 0.25 mg kg -1 buccal) or oxymorphone hydrochloride (0.1 mg kg -1 IV or 0.25 mg kg -1 buccal) were administered. All cats were administered all treatments. Skin temperature and thermal threshold were measured in duplicate prior to drug administration, and at various times up to 8 hours after drug administration. The difference between thermal threshold and skin temperature (ΔT) was analyzed. Administration of methadone and hydromorphone IV resulted in significant increases in ΔT at 40 minutes after drug administration. Buccal administration of methadone resulted in significant increases in thermal threshold, although no significant difference from baseline measurement was detected at any time point. IV administration of morphine and oxymorphone, and buccal administration of morphine, hydromorphone and oxymorphone did not cause significant thermal antinociception. At the doses used in this study, IV administration of methadone and hydromorphone, and buccal administration of methadone resulted in transient thermal antinociception. The results of this study do not allow us to predict the usefulness of these drugs for providing analgesia in clinical patients. © 2016 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

40 CFR Appendix I to Part 1054 - Summary of Previous Emission Standards

Code of Federal Regulations, 2014 CFR

2014-07-01

... Engines (g/kW-hr) a Engine displacement class HC NOX CO Class III 295 5.36 805 Class IV 241 5.36 805 Class...—Phase 2 Emission Standards for Handheld Engines (g/kW-hr) a Engine displacement class HC+NOX CO Class...-hr) a Engine displacement class HC+NOX CO Class I 16.1 519 Class II 13.4 519 a Phase 1 standards are...

40 CFR Appendix I to Part 1054 - Summary of Previous Emission Standards

Code of Federal Regulations, 2012 CFR

2012-07-01

... Engines (g/kW-hr) a Engine displacement class HC NOX CO Class III 295 5.36 805 Class IV 241 5.36 805 Class...—Phase 2 Emission Standards for Handheld Engines (g/kW-hr) a Engine displacement class HC+NOX CO Class...-hr) a Engine displacement class HC+NOX CO Class I 16.1 519 Class II 13.4 519 a Phase 1 standards are...

40 CFR Appendix I to Part 1054 - Summary of Previous Emission Standards

Code of Federal Regulations, 2013 CFR

2013-07-01

... Engines (g/kW-hr) a Engine displacement class HC NOX CO Class III 295 5.36 805 Class IV 241 5.36 805 Class...—Phase 2 Emission Standards for Handheld Engines (g/kW-hr) a Engine displacement class HC+NOX CO Class...-hr) a Engine displacement class HC+NOX CO Class I 16.1 519 Class II 13.4 519 a Phase 1 standards are...

40 CFR Appendix I to Part 1054 - Summary of Previous Emission Standards

Code of Federal Regulations, 2010 CFR

2010-07-01

... Engines (g/kW-hr) a Engine displacement class HC NOX CO Class III 295 5.36 805 Class IV 241 5.36 805 Class...—Phase 2 Emission Standards for Handheld Engines (g/kW-hr) a Engine displacement class HC+NOX CO Class...-hr) a Engine displacement class HC+NOX CO Class I 16.1 519 Class II 13.4 519 a Phase 1 standards are...

40 CFR Appendix I to Part 1054 - Summary of Previous Emission Standards

Code of Federal Regulations, 2011 CFR

2011-07-01

... Engines (g/kW-hr) a Engine displacement class HC NOX CO Class III 295 5.36 805 Class IV 241 5.36 805 Class...—Phase 2 Emission Standards for Handheld Engines (g/kW-hr) a Engine displacement class HC+NOX CO Class...-hr) a Engine displacement class HC+NOX CO Class I 16.1 519 Class II 13.4 519 a Phase 1 standards are...

14 CFR 61.5 - Certificates and ratings issued under this part.

Code of Federal Regulations, 2013 CFR

2013-01-01

...-control aircraft. (2) Airplane class ratings— (i) Single-engine land. (ii) Multiengine land. (iii) Single-engine sea. (iv) Multiengine sea. (3) Rotorcraft class ratings— (i) Helicopter. (ii) Gyroplane. (4) Lighter-than-air class ratings— (i) Airship. (ii) Balloon. (5) Weight-shift-control aircraft class ratings...

14 CFR 61.5 - Certificates and ratings issued under this part.

Code of Federal Regulations, 2014 CFR

2014-01-01

...-control aircraft. (2) Airplane class ratings— (i) Single-engine land. (ii) Multiengine land. (iii) Single-engine sea. (iv) Multiengine sea. (3) Rotorcraft class ratings— (i) Helicopter. (ii) Gyroplane. (4) Lighter-than-air class ratings— (i) Airship. (ii) Balloon. (5) Weight-shift-control aircraft class ratings...

14 CFR 61.5 - Certificates and ratings issued under this part.

Code of Federal Regulations, 2012 CFR

2012-01-01

...-control aircraft. (2) Airplane class ratings— (i) Single-engine land. (ii) Multiengine land. (iii) Single-engine sea. (iv) Multiengine sea. (3) Rotorcraft class ratings— (i) Helicopter. (ii) Gyroplane. (4) Lighter-than-air class ratings— (i) Airship. (ii) Balloon. (5) Weight-shift-control aircraft class ratings...

Intravenous Carbamazepine for Adults With Seizures.

PubMed

Vickery, P Brittany; Tillery, Erika E; DeFalco, Alicia Potter

2018-03-01

To review the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions, and place in therapy of the intravenous (IV) formulation of carbamazepine (Carnexiv) for the treatment of seizures in adult patients. A comprehensive PubMed and EBSCOhost search (1945 to August 2017) was performed utilizing the keywords carbamazepine, Carnexiv, carbamazepine intravenous, IV carbamazepine, seizures, epilepsy, and seizure disorder. Additional data were obtained from literature review citations, manufacturer's product labeling, and Lundbeck website as well as Clinicaltrials.gov and governmental sources. All English-language trials evaluating IV carbamazepine were analyzed for this review. IV carbamazepine is FDA approved as temporary replacement therapy for treatment of adult seizures. Based on a phase I trial and pooled data from 2 open-label bioavailability studies comparing oral with IV dosing, there was no noted indication of loss of seizure control in patients switched to short-term replacement antiepileptic drug therapy with IV carbamazepine. The recommended dose of IV carbamazepine is 70% of the patient's oral dose, given every 6 hours via 30-minute infusions. The adverse effect profile of IV carbamazepine is similar to that of the oral formulation, with the exception of added infusion-site reactions. IV carbamazepine is a reasonable option for adults with generalized tonic-clonic or focal seizures, previously stabilized on oral carbamazepine, who are unable to tolerate oral medications for up to 7 days. Unknown acquisition cost and lack of availability in the United States limit its use currently.

In vivo multimodality imaging and cancer therapy by near-infrared light-triggered trans-platinum pro-drug-conjugated upconverison nanoparticles.

PubMed

Dai, Yunlu; Xiao, Haihua; Liu, Jianhua; Yuan, Qinghai; Ma, Ping'an; Yang, Dongmei; Li, Chunxia; Cheng, Ziyong; Hou, Zhiyao; Yang, Piaoping; Lin, Jun

2013-12-18

Controlling anticancer drug activity and release on demand is very significant in cancer therapy. The photoactivated platinum(IV) pro-drug is stable in the dark and can be activated by UV light. In this study, we develop a multifunctional drug delivery system combining upconversion luminescence/magnetic resonance/computer tomography trimodality imaging and NIR-activated platinum pro-drug delivery. We use the core-shell structured upconversion nanoparticles to convert the absorbed NIR light into UV to activate the trans-platinum(IV) pro-drug, trans,trans,trans-[Pt(N3)2(NH3)(py)(O2CCH2CH2COOH)2]. Compared with using the UV directly, the NIR has a higher tissue penetration depth and is less harmful to health. Meanwhile, the upconversion nanoparticles can effectively deliver the platinum(IV) pro-drugs into the cells by endocytosis. The mice treated with pro-drug-conjugated nanoparticles under near-infrared (NIR) irradiation demonstrated better inhibition of tumor growth than that under direct UV irradiation. This multifunctional nanocomposite could be used as multimodality bioimaging contrast agents and transducers by converting NIR light into UV for control of drug activity in practical cancer therapy.

Neuropilin-1-targeted gold nanoparticles enhance therapeutic efficacy of platinum(IV) drug for prostate cancer treatment.

PubMed

Kumar, Anil; Huo, Shuaidong; Zhang, Xu; Liu, Juan; Tan, Aaron; Li, Shengliang; Jin, Shubin; Xue, Xiangdong; Zhao, YuanYuan; Ji, Tianjiao; Han, Lu; Liu, Hong; Zhang, XiaoNing; Zhang, Jinchao; Zou, Guozhang; Wang, Tianyou; Tang, Suoqin; Liang, Xing-Jie

2014-05-27

Platinum-based anticancer drugs such as cisplatin, oxaliplatin, and carboplatin are some of the most potent chemotherapeutic agents but have limited applications due to severe dose-limiting side effects and a tendency for cancer cells to rapidly develop resistance. The therapeutic index can be improved through use of nanocarrier systems to target cancer cells efficiently. We developed a unique strategy to deliver a platinum(IV) drug to prostate cancer cells by constructing glutathione-stabilized (Au@GSH) gold nanoparticles. Glutathione (GSH) has well-known antioxidant properties, which lead to cancer regression. Here, we exploit the advantages of both the antioxidant properties and high surface-area-to-volume ratio of Au@GSH NPs to demonstrate their potential for delivery of a platinum(IV) drug by targeting the neuropilin-1 receptor (Nrp-1). A lethal dose of a platinum(IV) drug functionalized with the Nrp-1-targeting peptide (CRGDK) was delivered specifically to prostate cancer cells in vitro. Targeted peptide ensures specific binding to the Nrp-1 receptor, leading to enhanced cellular uptake level and cell toxicity. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when functionalized with the targeting peptide and drug. The uptake of drug-loaded nanocarriers is dependent on the interaction with Nrp-1 in cell lines expressing high (PC-3) and low (DU-145) levels of Nrp-1, as confirmed through inductively coupled plasma mass spectrometry and confocal microscopy. The nanocarriers have effective anticancer activity, through upregulation of nuclear factor kappa-B (NF-κB) protein (p50 and p65) expression and activation of NF-κB-DNA-binding activity. Our preliminary investigations with platinum(IV)-functionalized gold nanoparticles along with a targeting peptide hold significant promise for future cancer treatment.

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement.

PubMed

Krull, Scott M; Ma, Zhelun; Li, Meng; Davé, Rajesh N; Bilgili, Ecevit

2016-01-01

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 μm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

Hemodynamic-GUIDEd Management of Heart Failure

ClinicalTrials.gov

2018-03-29

Heart Failure; Heart Failure, Systolic; Heart Failure, Diastolic; Heart Failure NYHA Class II; Heart Failure NYHA Class III; Heart Failure NYHA Class IV; Heart Failure，Congestive; Heart Failure With Reduced Ejection Fraction; Heart Failure With Normal Ejection Fraction; Heart Failure; With Decompensation

Comprehensive summary--Predict-IV: A systems toxicology approach to improve pharmaceutical drug safety testing.

PubMed

Mueller, Stefan O; Dekant, Wolfgang; Jennings, Paul; Testai, Emanuela; Bois, Frederic

2015-12-25

This special issue of Toxicology in Vitro is dedicated to disseminating the results of the EU-funded collaborative project "Profiling the toxicity of new drugs: a non animal-based approach integrating toxicodynamics and biokinetics" (Predict-IV; Grant 202222). The project's overall aim was to develop strategies to improve the assessment of drug safety in the early stage of development and late discovery phase, by an intelligent combination of non animal-based test systems, cell biology, mechanistic toxicology and in silico modeling, in a rapid and cost effective manner. This overview introduces the scope and overall achievements of Predict-IV. Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemiluminescence of the reaction system Ce(IV)-non-steroidal anti-inflammatory drugs containing europium(III) ions and its application to the determination of naproxen in pharmaceutical preparations and urine.

PubMed

Kaczmarek, Małgorzata

2011-11-01

The chemiluminescence (CL) of oxidation of non-steroidal anti-inflammatory drugs (NSAIDs) by Ce(IV) ions, was recorded in the presence and absence europium(III) ions, in solution of pH ~ 4 of solution. Kinetic curves and CL emission spectra of the all studied systems were discussed. CL of measurable intensity was observed in the Ce(IV)-NP-Eu(III) reaction system only in acidic solutions. The CL spectrum rcegistered for this system shows emission bands, typical of Eu(III) ions, with maximum at λ ~ 600 nm. The chemiluminescent method, based on Eu(III) emission in reaction system of NP-Ce(IV)-Eu(III) in acid solution was therefore used for the determination of naproxen in mixture of non-steroidal anti-inflammatory drugs.

The Activity of Class I-IV Alcohol Dehydrogenase Isoenzymes and Aldehyde Dehydrogenase in Bladder Cancer Cells.

PubMed

Orywal, Karolina; Jelski, Wojciech; Werel, Tadeusz; Szmitkowski, Maciej

2018-01-02

The aim of this study was to determine the differences in the activity of Alcohol Dehydrogenase (ADH) isoenzymes and Aldehyde Dehydrogenase (ALDH) in normal and cancerous bladder cells. Class III, IV of ADH and total ADH activity were measured by the photometric method and class I, II ADH and ALDH activity by the fluorometric method. Significantly higher total activity of ADH was found in both, low-grade and high-grade bladder cancer, in comparison to healthy tissues. The increased activity of total ADH in bladder cancer cells may be the cause of metabolic disorders in cancer cells, which may intensify carcinogenesis.

New laser protective eyewear

NASA Astrophysics Data System (ADS)

McLear, Mark

1996-04-01

Laser technology has significantly impacted our everyday life. Lasers are now used to correct your vision, clear your arteries, and are used in the manufacturing of such diverse products as automobiles, cigarettes, and computers. Lasers are no longer a research tool looking for an application. They are now an integral part of manufacturing. In the case of Class IV lasers, this explosion in laser applications has exposed thousands of individuals to potential safety hazards including eye damage. Specific protective eyewear designed to attenuate the energy of the laser beam below the maximum permissible exposure is required for Class 3B and Class IV lasers according to laser safety standards.

21 CFR 866.5360 - Cohn fraction IV immuno-logical test system.

Code of Federal Regulations, 2010 CFR

2010-04-01

... SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Immunological Test Systems § 866.5360 Cohn fraction IV immuno-logical test system. (a) Identification. A Cohn fraction IV immunological... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cohn fraction IV immuno-logical test system. 866...

Physician prescribing behavior and its impact on patient-level outcomes.

PubMed

Joyce, Geoffrey F; Carrera, Mariana P; Goldman, Dana P; Sood, Neeraj

2011-12-01

Concerns over rising drug costs, pharmaceutical advertising, and potential conflicts of interest have focused attention on physician prescribing behavior. We examine how broadly physicians prescribe within the 10 most prevalent therapeutic classes, the factors affecting their choices, and the impact of their prescribing behavior on patient-level outcomes. Retrospective study from 2005 to 2007 examining prescribers with at least 5 initial prescriptions within a class from 2005 to 2007. Medical and pharmacy claims are linked to prescriber information from 146 different health plans, reflecting 1975 to 8923 unique providers per drug class. Primary outcomes are the number of distinct drugs in a class initially prescribed by a physician over 1- and 3-year periods, medication possession ratio, and out-of-pocket costs. In 8 of 10 therapeutic classes, the median physician prescribes at least 3 different drugs and fewer than 1 in 6 physicians prescribe only brand drugs. Physicians prescribing only 1 or 2 drugs in a class are more likely to prescribe the most advertised drug. Physicians who prescribe fewer drugs are less likely to see patients with other comorbid conditions and varied formulary designs. Prescribing fewer drugs is associated with lower rates of medication adherence and higher out-ofpocket costs for drugs, but the effects are small and inconsistent across classes. Physicians prescribe more broadly than commonly perceived. Though narrow prescribers are more likely to prescribe highly advertised drugs, few physicians prescribe these drugs exclusively. Narrow prescribing has modest effects on medication adherence and out-of-pocket costs in some classes.

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).

Analysis of Anthrax Immune Globulin Intravenous with Antimicrobial Treatment in Injection Drug Users, Scotland, 2009-2010.

PubMed

Cui, Xizhong; Nolen, Leisha D; Sun, Junfeng; Booth, Malcolm; Donaldson, Lindsay; Quinn, Conrad P; Boyer, Anne E; Hendricks, Katherine; Shadomy, Sean; Bothma, Pieter; Judd, Owen; McConnell, Paul; Bower, William A; Eichacker, Peter Q

2017-01-01

We studied anthrax immune globulin intravenous (AIG-IV) use from a 2009-2010 outbreak of Bacillus anthracis soft tissue infection in injection drug users in Scotland, UK, and we compared findings from 15 AIG-IV recipients with findings from 28 nonrecipients. Death rates did not differ significantly between recipients and nonrecipients (33% vs. 21%). However, whereas only 8 (27%) of 30 patients at low risk for death (admission sequential organ failure assessment score of 0-5) received AIG-IV, 7 (54%) of the 13 patients at high risk for death (sequential organ failure assessment score of 6-11) received treatment. AIG-IV recipients had surgery more often and, among survivors, had longer hospital stays than did nonrecipients. AIG-IV recipients were sicker than nonrecipients. This difference and the small number of higher risk patients confound assessment of AIG-IV effectiveness in this outbreak.

Diameter-dependent release of a cisplatin pro-drug from small and large functionalized carbon nanotubes

NASA Astrophysics Data System (ADS)

Muzi, Laura; Ménard-Moyon, Cécilia; Russier, Julie; Li, Jian; Chin, Chee Fei; Ang, Wee Han; Pastorin, Giorgia; Risuleo, Gianfranco; Bianco, Alberto

2015-03-01

The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and increased drug efflux once internalized. The use of functionalized carbon nanotubes (CNTs) as chemotherapeutic drug delivery systems is a promising strategy to overcome such limitations due to their ability to enhance cellular internalization of poorly permeable drugs and thus increase the drug bioavailability at the diseased site, compared to the free drug. Furthermore, the possibility to encapsulate agents in the nanotubes' inner cavity can protect the drug from early inactivation and their external functionalizable surface is useful for selective targeting. In this study, a hydrophobic platinum(iv) complex was encapsulated within the inner space of two different diameter functionalized multi-walled CNTs (Pt(iv)@CNTs). The behavior of the complexes, compared to the free drug, was investigated on both HeLa human cancer cells and RAW 264.7 murine macrophages. Both CNT samples efficiently induced cell death in HeLa cancer cells 72 hours after the end of exposure to CNTs. Although the larger diameter CNTs were more cytotoxic on HeLa cells compared to both the free drug and the smaller diameter nanotubes, the latter allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. In contrast, both Pt(iv)@CNT constructs were poorly cytotoxic on macrophages and induced negligible cell activation and no pro-inflammatory cytokine production. Both CNT samples were efficiently internalized by the two types of cells, as demonstrated by transmission electron microscopy observations and flow cytometry analysis. Finally, the platinum levels found in the cells after Pt(iv)@CNT exposure demonstrate that they can promote drug accumulation inside cells in comparison with treatment with the free complex. To conclude, our study shows that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug and its slow release inside tumor cells, by tuning the CNT diameter, without inducing a high inflammatory response.The use of platinum-based chemotherapeutic drugs in cancer therapy still suffers from severe disadvantages, such as lack of appropriate selectivity for tumor tissues and insurgence of multi-drug resistance. Moreover, drug efficacy can be attenuated by several mechanisms such as premature drug inactivation, reduced drug uptake inside cells and increased drug efflux once internalized. The use of functionalized carbon nanotubes (CNTs) as chemotherapeutic drug delivery systems is a promising strategy to overcome such limitations due to their ability to enhance cellular internalization of poorly permeable drugs and thus increase the drug bioavailability at the diseased site, compared to the free drug. Furthermore, the possibility to encapsulate agents in the nanotubes' inner cavity can protect the drug from early inactivation and their external functionalizable surface is useful for selective targeting. In this study, a hydrophobic platinum(iv) complex was encapsulated within the inner space of two different diameter functionalized multi-walled CNTs (Pt(iv)@CNTs). The behavior of the complexes, compared to the free drug, was investigated on both HeLa human cancer cells and RAW 264.7 murine macrophages. Both CNT samples efficiently induced cell death in HeLa cancer cells 72 hours after the end of exposure to CNTs. Although the larger diameter CNTs were more cytotoxic on HeLa cells compared to both the free drug and the smaller diameter nanotubes, the latter allowed a prolonged release of the encapsulated drug, thus increasing its anticancer efficacy. In contrast, both Pt(iv)@CNT constructs were poorly cytotoxic on macrophages and induced negligible cell activation and no pro-inflammatory cytokine production. Both CNT samples were efficiently internalized by the two types of cells, as demonstrated by transmission electron microscopy observations and flow cytometry analysis. Finally, the platinum levels found in the cells after Pt(iv)@CNT exposure demonstrate that they can promote drug accumulation inside cells in comparison with treatment with the free complex. To conclude, our study shows that CNTs are promising nanocarriers to improve the accumulation of a chemotherapeutic drug and its slow release inside tumor cells, by tuning the CNT diameter, without inducing a high inflammatory response. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr00220f

Independent Review of the Defense Logistics Agencys Roles and Missions

DTIC Science & Technology

2014-12-01

remaining wholesale consumables missions of tires, packaged petroleum, oils , and lubricants, and gases and cylinders were transferred from the...housekeeping supplies and equipment. Class III: Petroleum, oils , and lubricants. Class IV: Construction materials. Class V: Ammunition. Class VI...own appropriated funds that are deposited 9 The Construction and Equipment program within DLA Troop Support provides some Class VII non- weapons

Primary Angioplasty in Patients Older Than 75 Years. Profile of Patients and Procedures, Outcomes, and Predictors of Prognosis in the ESTROFA IM+75 Registry.

PubMed

de la Torre Hernández, José M; Brugaletta, Salvatore; Gómez Hospital, Joan A; Baz, José A; Pérez de Prado, Armando; López Palop, Ramón; Cid, Belén; García Camarero, Tamara; Diego, Alejandro; Gimeno de Carlos, Federico; Fernández Díaz, José A; Sanchis, Juan; Alfonso, Fernando; Blanco, Roberto; Botas, Javier; Navarro Cuartero, Javier; Moreu, José; Bosa, Francisco; Vegas Valle, José M; Elízaga, Jaime; Arrebola, Antonio L; Ruiz Arroyo, José R; Hernández-Hernández, Felipe; Salvatella, Neus; Monteagudo, Marta; Gómez Jaume, Alfredo; Carrillo, Xavier; Martín Reyes, Roberto; Lozano, Fernando; Rumoroso, José R; Andraka, Leire; Domínguez, Antonio J

2017-02-01

The proportion of elderly patients undergoing primary angioplasty is growing. The present study describes the clinical profile, procedural characteristics, outcomes, and predictors of outcome. A 31-center registry of consecutive patients older than 75 years treated with primary angioplasty. Clinical and procedural data were collected, and the patients underwent clinical follow-up. The study included 3576 patients (39.3% women, 48.5% with renal failure, 11.5% in Killip III or IV, and 29.8% with>6hours of chest pain). Multivessel disease was present in 55.4% and nonculprit lesions were additionally treated in 24.8%. Radial access was used in 56.4%, bivalirudin in 11.8%, thromboaspiration in 55.9%, and drug-eluting stents in 26.6%. The 1-month and 2-year incidences of cardiovascular death were 10.1% and 14.7%, respectively. The 2-year rates of definite or probable thrombosis, repeat revascularization, and BARC bleeding>2 were 3.1%, 2.3%, and 4.2%, respectively. Predictive factors were diabetes mellitus, renal failure, atrial fibrillation, delay to reperfusion>6hours, ejection fraction<45%, Killip class III-IV, radial access, bivalirudin, drug-eluting stents, final TIMI flow of III, and incomplete revascularization at discharge. Notable registry findings include frequently delayed presentation and a high prevalence of adverse factors such as renal failure and multivessel disease. Positive procedure-related predictors include shorter delay, use of radial access, bivalirudin, drug-eluting stents, and complete revascularization before discharge. Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Psychometric properties of DSM assessments of illicit drug abuse and dependence: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

PubMed

Lynskey, M T; Agrawal, A

2007-09-01

DSM-IV criteria for illicit drug abuse and dependence are largely based on criteria developed for alcohol use disorders and there is a lack of research evidence on the psychometric properties of these symptoms when applied to illicit drugs. This study utilizes data on abuse/dependence criteria for cannabis, cocaine, stimulants, sedatives, tranquilizers, opiates, hallucinogens and inhalants from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC, n=43 093). Analyses included factor analysis to explore the dimensionality of illicit drug abuse and dependence criteria, calculation of item difficulty and discrimination within an item response framework and a descriptive analysis of 'diagnostic orphans': individuals meeting criteria for 1-2 dependence symptoms but not abuse. Rates of psychiatric disorders were compared across groups. Results favor a uni-dimensional construct for abuse/dependence on each of the eight drug classes. Factor loadings, item difficulty and discrimination were remarkably consistent across drug categories. For each drug category, between 29% and 51% of all individuals meeting criteria for at least one symptom did not receive a formal diagnosis of either abuse or dependence and were therefore classified as 'orphans'. Mean rates of disorder in these individuals suggested that illicit drug use disorders may be more adequately described along a spectrum of severity. While there were remarkable similarities across categories of illicit drugs, consideration of item difficulty suggested that some alterations to DSM regarding the relevant severity of specific abuse and dependence criteria may be warranted.

Cost analysis of biologic drugs in rheumatoid arthritis first line treatment after methotrexate failure according to patients' body weight.

PubMed

Román Ivorra, José Andrés; Ivorra, José; Monte-Boquet, Emilio; Canal, Cristina; Oyagüez, Itziar; Gómez-Barrera, Manuel

2016-01-01

The objective was to assess the influence of patients' weight in the cost of rheumatoid arthritis treatment with biologic drugs used in first line after non-adequate response to methotrexate. Pharmaceutical and administration costs were calculated in two scenarios: non-optimization and optimization of intravenous (IV) vials. The retrospective analysis of 66 patients from a Spanish 1,000 beds-hospital Rheumatology Clinic Service was used to obtain posology and weight data. The study time horizon was two years. Costs were expressed in 2013 euros. For an average 69kg-weighted patient the lowest cost corresponded to abatacept subcutaneous (SC ABA) (€21,028.09) in the scenario without IV vials optimization and infliximab (IFX) (€20,779.29) with optimization. Considering patients' weight in the scenario without IV vials optimization infliximab (IFX) was the least expensive drug in patients ranged 45-49kg, IV ABA in 50-59kg and SC ABA in patients over 60kg. With IV vials optimization IFX was the least expensive drug in patients under 69kg and SC ABA over 70kg. Assuming comparable effectiveness of biological drugs, patient's weight is a variable to consider, potentials savings could reach €20,000 in two years. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

Usefulness of the brain natriuretic peptide to atrial natriuretic peptide ratio in determining the severity of mitral regurgitation.

PubMed

Shimamoto, Ken; Kusumoto, Miyako; Sakai, Rieko; Watanabe, Hirota; Ihara, Syunichi; Koike, Natsuka; Kawana, Masatoshi

2007-03-15

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels were characterized in subjects with mitral regurgitation (MR). Sixty-two cases of moderate or severe chronic MR were studied. The blood levels of neurohormonal factors were stratified by the known MR prognostic factors of New York Heart Association (NYHA) functional class, left ventricular end-diastolic diameters, left ventricular end-systolic diameter (LVDs), ejection fraction (EF), left atrial diameter and presence of atrial fibrillation (AF). ANP levels were higher in NYHA class II and lower in classes I and III/IV (P=0.0206). BNP levels were higher in NYHA class II than class I (P=0.0355). The BNP/ANP ratio was significantly higher in NYHA classes II and III/IV than in class I (P=0.0007). To differentiate between NYHA classes I/II and III/IV, a cut-off BNP/ANP ratio of 2.97 produced a sensitivity of 78% and specificity of 87%. Compared with subjects in sinus rhythm, patients with AF had an enlarged left atrium and lower ANP levels. The BNP/ANP ratio correlated significantly with left atrial diameter, LVDs and EF (r=0.429, P=0.0017; r=0.351, P=0.0117; and r=-0.349, P=0.0122; respectively), and was significantly higher among all the known operative indications for MR tested (LVDs 45 mm or more, EF 60% or less, NYHA class II or greater and AF; P=0.0073, P=0.003, P=0.0102 and P=0.0149, respectively). In chronic MR, levels of ANP and BNP, and the BNP/ANP ratio are potential indicators of disease severity.

Multidrug resistance in epilepsy and polymorphisms in the voltage-gated sodium channel genes SCN1A, SCN2A, and SCN3A: correlation among phenotype, genotype, and mRNA expression.

PubMed

Kwan, Patrick; Poon, Wai Sang; Ng, Ho-Keung; Kang, David E; Wong, Virginia; Ng, Ping Wing; Lui, Colin H T; Sin, Ngai Chuen; Wong, Ka S; Baum, Larry

2008-11-01

Many antiepileptic drugs (AEDs) prevent seizures by blocking voltage-gated brain sodium channels. However, treatment is ineffective in 30% of epilepsy patients, which might, at least in part, result from polymorphisms of the sodium channel genes. We investigated the association of AED responsiveness with genetic polymorphisms and correlated any association with mRNA expression of the neuronal sodium channels. We performed genotyping of tagging and candidate single nucleotide polymorphisms (SNPs) of SCN1A, 2A, and 3A in 471 Chinese epilepsy patients (272 drug responsive and 199 drug resistant). A total of 27 SNPs were selected based on the HapMap database. Genotype distributions in drug-responsive and drug-resistant patients were compared. SCN2A mRNA was quantified by real-time PCR in 24 brain and 57 blood samples. Its level was compared between patients with different genotypes of an SCN2A SNP found to be associated with drug responsiveness. SCN2A IVS7-32A>G (rs2304016) A alleles were associated with drug resistance (odds ratio = 2.1, 95% confidence interval: 1.2-3.7, P=0.007). Haplotypes containing the IVS7-32A>G allele A were also associated with drug resistance. IVS7-32A>G is located within the putative splicing branch site for splicing exons 7 and 9. PCR of reverse-transcribed RNA from blood or brain of patients with different IVS7-32A>G genotypes using primers in exons 7 and 9 showed no skipping of exon 8, and real-time PCR showed no difference in SCN2A mRNA levels among genotypes. Results of this study suggest an association between SCN2A IVS7-32A>G and AED responsiveness, without evidence of an effect on splicing or mRNA expression.

Redo surgery risk in patients with cardiac prosthetic valve dysfunction

PubMed Central

Maciejewski, Marek; Piestrzeniewicz, Katarzyna; Bielecka-Dąbrowa, Agata; Piechowiak, Monika; Jaszewski, Ryszard

2011-01-01

Introduction The aim of the study was to analyse the risk factors of early and late mortality in patients undergoing the first reoperation for prosthetic valve dysfunction. Material and methods A retrospective observational study was performed in 194 consecutive patients (M = 75, F = 119; mean age 53.2 ±11 years) with a mechanical prosthetic valve (n = 103 cases; 53%) or bioprosthesis (91; 47%). Univariate and multivariate Cox statistical analysis was performed to determine risk factors of early and late mortality. Results The overall early mortality was 18.6%: 31.4% in patients with symptoms of NYHA functional class III-IV and 3.4% in pts in NYHA class I-II. Multivariate analysis identified symptoms of NYHA class III-IV and endocarditis as independent predictors of early mortality. The overall late mortality (> 30 days) was 8.2% (0.62% year/patient). Multivariate analysis identified age at the time of reoperation as a strong independent predictor of late mortality. Conclusions Reoperation in patients with prosthetic valves, performed urgently, especially in patients with symptoms of NYHA class III-IV or in the case of endocarditis, bears a high mortality rate. Risk of planned reoperation, mostly in patients with symptoms of NYHA class I-II, does not differ from the risk of the first operation. PMID:22291767

Why we prefer levetiracetam over phenytoin for treatment of status epilepticus.

PubMed

Zaccara, G; Giorgi, F S; Amantini, A; Giannasi, G; Campostrini, R; Giovannelli, F; Paganini, M; Nazerian, P

2018-06-01

Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine-resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses

PubMed Central

Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

2015-01-01

The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1–CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. PMID:25694549

The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses.

PubMed

Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

2015-04-01

The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1-CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Utilisation of the isobole methodology to study dietary peptide-drug and peptide-peptide interactive effects on dipeptidyl peptidase IV (DPP-IV) inhibition.

PubMed

Nongonierma, Alice B; FitzGerald, Richard J

2015-01-01

Inhibition of dipeptidyl peptidase-IV (DPP-IV) is used as a means to regulate post-prandial serum glucose in type 2 diabetics. The effect of drug (Sitagliptin®)/peptide and binary peptide mixtures on DPP-IV inhibition was studied using an isobole approach. Five peptides (Ile-Pro-Ile-Gln-Tyr, Trp-Lys, Trp-Pro, Trp-Arg and Trp-Leu), having DPP-IV half maximum inhibitory concentration values (IC₅₀)<60 μM and reported to act through different inhibition mechanisms, were investigated. The dose response relationship of Sitagliptin : peptide (1:0, 0:1, 1:852, 1:426 and 1:1704 on a molar basis) and binary Ile-Pro-Ile-Gln-Tyr : peptide (1:0, 0:1, 1:1, 1:2 and 2:1 on a molar basis) mixtures for DPP-IV inhibition was characterised. Isobolographic analysis showed, in most instances, an additive effect on DPP-IV inhibition. However, a synergistic effect was observed with two Sitagliptin:Ile-Pro-Ile-Gln-Tyr (1:426 and 1:852) mixtures and an antagonistic effect was seen with one Sitagliptin : Trp-Pro (1:852) mixture, and three binary peptide mixtures (Ile-Pro-Ile-Gln-Tyr : Trp-Lys (1:1 and 2:1) and Ile-Pro-Ile-Gln-Tyr:Trp-Leu (1:2)). The results show that Sitagliptin and food protein-derived peptides can interact, thereby enhancing overall DPP-IV inhibition. Combination of Sitagliptin with food protein-derived peptides may help in reducing drug dosage and possible associated side-effects.

Intravenous parecoxib sodium as an analgesic alternative to morphine in acute trauma pain in the emergency department.

PubMed

Baharuddin, Kamarul Aryffin; Rahman, Nik Hisamuddin Na; Wahab, Shaik Farid Abdull; Halim, Nurkhairulnizam A; Ahmad, Rashidi

2014-01-03

Parecoxib sodium is the first parenteral COX-2 inhibitor used for pain management licensed for postoperative pain. However, no study has assessed the usage of parecoxib for acute traumatic pain in the emergency department (ED). The objective of this study was to investigate a potential alternative analgesic agent in the ED by determining the mean reduction of pain score between acute traumatic pain patients who were administered with intravenous (IV) parecoxib sodium versus IV morphine sulfate. The onset of perceptible analgesic effect and side effects were also evaluated. A randomized, double-blinded study comparing IV parecoxib 40 mg versus IV morphine at 0.10 mg/kg was conducted in adult patients presented with acute traumatic pain with numeric rating scale (NRS) of 6 or more within 6 hours of injury. Patients were randomized using a computer-generated randomization plan. Drug preparation and dispensing were performed by a pharmacist. Periodic assessment of blood pressure, pulse rate, oxygen saturation, and NRS were taken at 0, 5, 15, and 30 minute intervals after the administration of the study drug. The primary outcome was the reduction of NRS. Side effect and drug evaluation was conducted within 30 minutes of drug administration. There was no statistically significant difference in the reduction of mean NRS between patients in the IV parecoxib group or IV morphine group (P = 0.095). The mean NRS for patients treated with IV morphine were 7.1 at 0 minutes, 4.5 at 5 minutes, 3.1 at 15 minutes, and 2.0 at 30 minutes. Whereas mean NRS for patients who received IV parecoxib were 7.8 at 0 minutes, 5.7 at 5 minutes, 4.7 at 15 minutes, and 3.9 at 30 minutes. The onset of perceptible analgesic effects could be seen as early as 5 minutes. Dizziness was experienced in 42.9% of patients who received IV morphine compared to none in the parecoxib group. There was non-significant trend toward superiority of IV morphine over IV parecoxib. Looking at its effectiveness and the lack of opioid-related side-effects, the usage of IV parecoxib sodium may be extended further to a variety of cases in the ED.

Intravenous parecoxib sodium as an analgesic alternative to morphine in acute trauma pain in the emergency department

PubMed Central

2014-01-01

Background Parecoxib sodium is the first parenteral COX-2 inhibitor used for pain management licensed for postoperative pain. However, no study has assessed the usage of parecoxib for acute traumatic pain in the emergency department (ED). The objective of this study was to investigate a potential alternative analgesic agent in the ED by determining the mean reduction of pain score between acute traumatic pain patients who were administered with intravenous (IV) parecoxib sodium versus IV morphine sulfate. The onset of perceptible analgesic effect and side effects were also evaluated. Methods A randomized, double-blinded study comparing IV parecoxib 40 mg versus IV morphine at 0.10 mg/kg was conducted in adult patients presented with acute traumatic pain with numeric rating scale (NRS) of 6 or more within 6 hours of injury. Patients were randomized using a computer-generated randomization plan. Drug preparation and dispensing were performed by a pharmacist. Periodic assessment of blood pressure, pulse rate, oxygen saturation, and NRS were taken at 0, 5, 15, and 30 minute intervals after the administration of the study drug. The primary outcome was the reduction of NRS. Side effect and drug evaluation was conducted within 30 minutes of drug administration. Results There was no statistically significant difference in the reduction of mean NRS between patients in the IV parecoxib group or IV morphine group (P = 0.095). The mean NRS for patients treated with IV morphine were 7.1 at 0 minutes, 4.5 at 5 minutes, 3.1 at 15 minutes, and 2.0 at 30 minutes. Whereas mean NRS for patients who received IV parecoxib were 7.8 at 0 minutes, 5.7 at 5 minutes, 4.7 at 15 minutes, and 3.9 at 30 minutes. The onset of perceptible analgesic effects could be seen as early as 5 minutes. Dizziness was experienced in 42.9% of patients who received IV morphine compared to none in the parecoxib group. Conclusions There was non-significant trend toward superiority of IV morphine over IV parecoxib. Looking at its effectiveness and the lack of opioid-related side-effects, the usage of IV parecoxib sodium may be extended further to a variety of cases in the ED. PMID:24386899

Physicochemical characterisation and investigation of the bonding mechanisms of API-titanate nanotube composites as new drug carrier systems.

PubMed

Sipos, Barbara; Pintye-Hódi, Klára; Kónya, Zoltán; Kelemen, András; Regdon, Géza; Sovány, Tamás

2017-02-25

Titanate nanotube (TNT) has recently been explored as a new carrier material for active pharmaceutical ingredients (API). The aim of the present work was to reveal the physicochemical properties of API-TNT composites, focusing on the interactions between the TNTs and the incorporated APIs. Drugs belonging to different Biopharmaceutical Classification System (BCS) classes were loaded into TNTs: diltiazem hydrochloride (BCS I.), diclofenac sodium (BCS II.), atenolol (BCS III.) and hydrochlorothiazide (BCS IV.). Experimental results demonstrated that it is feasible for spiral cross-sectioned titanate nanotubes to carry drugs and maintain their bioactivity. The structural properties of the composites were characterized by a range of analytical techniques, including FT-IR, DSC, TG-MS, etc. The interactions between APIs and TNTs were identified as electrostatic attractions, mainly dominated by hydrogen bonds. Based on the results, it can be stated that the strength of the association depends on the hydrogen donor strength of the API. The drug release of incorporated APIs was evaluated from compressed tablets and compared to that of pure APIs. Differences noticed in the dissolution profiles due to incorporation showed a correlation with the strength of interactions between the APIs and the TNTs observed in the above analytical studies. Copyright © 2016 Elsevier B.V. All rights reserved.

Evidence That the [beta] Subunit of Chlamydia trachomatis Ribonucleotide Reductase Is Active with the Manganese Ion of Its Manganese(IV)/Iron(III) Cofactor in Site 1

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

Dassama, Laura M.K.; Boal, Amie K.; Krebs, Carsten

2014-10-02

The reaction of a class I ribonucleotide reductase (RNR) begins when a cofactor in the {beta} subunit oxidizes a cysteine residue {approx}35 {angstrom} away in the {alpha} subunit, generating a thiyl radical. In the class Ic enzyme from Chlamydia trachomatis (Ct), the cysteine oxidant is the Mn{sup IV} ion of a Mn{sup IV}/Fe{sup III} cluster, which assembles in a reaction between O{sub 2} and the Mn{sup II}/Fe{sup II} complex of {beta}. The heterodinuclear nature of the cofactor raises the question of which site, 1 or 2, contains the Mn{sup IV} ion. Because site 1 is closer to the conserved locationmore » of the cysteine-oxidizing tyrosyl radical of class Ia and Ib RNRs, we suggested that the Mn{sup IV} ion most likely resides in this site (i.e., {sup 1}Mn{sup IV}/{sup 2}Fe{sup III}), but a subsequent computational study favored its occupation of site 2 ({sup 1}Fe{sup III}/{sup 2}Mn{sup IV}). In this work, we have sought to resolve the location of the Mn{sup IV} ion in Ct RNR-{beta} by correlating X-ray crystallographic anomalous scattering intensities with catalytic activity for samples of the protein reconstituted in vitro by two different procedures. In samples containing primarily Mn{sup IV}/Fe{sup III} clusters, Mn preferentially occupies site 1, but some anomalous scattering from site 2 is observed, implying that both {sup 1}Mn{sup II}/{sup 2}Fe{sup II} and {sup 1}Fe{sup II}/{sup 2}Mn{sup II} complexes are competent to react with O{sub 2} to produce the corresponding oxidized states. However, with diminished Mn{sup II} loading in the reconstitution, there is no evidence for Mn occupancy of site 2, and the greater activity of these 'low-Mn' samples on a per-Mn basis implies that the {sup 1}Mn{sup IV}/{sup 2}Fe{sup III}-{beta} is at least the more active of the two oxidized forms and may be the only active form.« less

Pharmacokinetics and selected pharmacodynamics of trazodone following intravenous and oral administration to horses undergoing fitness training.

PubMed

Knych, Heather K; Mama, Khursheed R; Steffey, Eugene P; Stanley, Scott D; Kass, Philip H

2017-10-01

OBJECTIVE To measure concentrations of trazodone and its major metabolite in plasma and urine after administration to healthy horses and concurrently assess selected physiologic and behavioral effects of the drug. ANIMALS 11 Thoroughbred horses enrolled in a fitness training program. PROCEDURES In a pilot investigation, 4 horses received trazodone IV (n = 2) or orally (2) to select a dose for the full study; 1 horse received a vehicle control treatment IV. For the full study, trazodone was initially administered IV (1.5 mg/kg) to 6 horses and subsequently given orally (4 mg/kg), with a 5-week washout period between treatments. Blood and urine samples were collected prior to drug administration and at multiple time points up to 48 hours afterward. Samples were analyzed for trazodone and metabolite concentrations, and pharmacokinetic parameters were determined; plasma drug concentrations following IV administration best fit a 3-compartment model. Behavioral and physiologic effects were assessed. RESULTS After IV administration, total clearance of trazodone was 6.85 ± 2.80 mL/min/kg, volume of distribution at steady state was 1.06 ± 0.07 L/kg, and elimination half-life was 8.58 ± 1.88 hours. Terminal phase half-life was 7.11 ± 1.70 hours after oral administration. Horses had signs of aggression and excitation, tremors, and ataxia at the highest IV dose (2 mg/kg) in the pilot investigation. After IV drug administration in the full study (1.5 mg/kg), horses were ataxic and had tremors; sedation was evident after oral administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of trazodone to horses elicited a wide range of effects. Additional study is warranted before clinical use of trazodone in horses can be recommended.

Assessing the Impact of Drug Use on Hospital Costs

PubMed Central

Stuart, Bruce C; Doshi, Jalpa A; Terza, Joseph V

2009-01-01

Objective To assess whether outpatient prescription drug utilization produces offsets in the cost of hospitalization for Medicare beneficiaries. Data Sources/Study Setting The study analyzed a sample (N=3,101) of community-dwelling fee-for-service U.S. Medicare beneficiaries drawn from the 1999 and 2000 Medicare Current Beneficiary Surveys. Study Design Using a two-part model specification, we regressed any hospital admission (part 1: probit) and hospital spending by those with one or more admissions (part 2: nonlinear least squares regression) on drug use in a standard model with strong covariate controls and a residual inclusion instrumental variable (IV) model using an exogenous measure of drug coverage as the instrument. Principal Findings The covariate control model predicted that each additional prescription drug used (mean=30) raised hospital spending by $16 (p<.001). The residual inclusion IV model prediction was that each additional prescription fill reduced hospital spending by $104 (p<.001). Conclusions The findings indicate that drug use is associated with cost offsets in hospitalization among Medicare beneficiaries, once omitted variable bias is corrected using an IV technique appropriate for nonlinear applications. PMID:18783453

Utility of NBD-Cl for the spectrophotometric determination of some skeletal muscle relaxant and antihistaminic drugs

NASA Astrophysics Data System (ADS)

Saleh, Hanaa M.; EL-Henawee, Magda M.; Ragab, Gamal H.; El-Hay, Soad S. Abd

2007-08-01

A simple, accurate, precise and sensitive colorimetric method for the determination of some skeletal muscle relaxant drugs, namely orphenadrine citrate ( I), baclofen ( II), antihistaminic drugs as acrivastine ( III) and fexofenadine hydrochloride ( IV) is described. This method is based on the formation of charge transfer complex with 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) in non-aqueous medium. The orange color products were measured at 472, 465, 475 and 469 nm for drugs I, II, III and IV, respectively. The optimization of various experimental conditions was described. Beer's Law was obeyed in the range (2.5-17.5), (5-70), (2.5-25) and (10-50) μg/ml for drugs I, II, III and IV, respectively. The molar absorptivity ( ɛ), sandell sensitivity, detection (LOD) and quantitation limits (LOQ) are calculated. The procedure was favorably applied for determination of certain pharmaceutical dosage forms containing the studied drugs. The obtained results were compared with the official and reported methods. There were no significant differences between proposed, reported and the official methods.

Drug-target interaction prediction via class imbalance-aware ensemble learning.

PubMed

Ezzat, Ali; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

2016-12-22

Multiple computational methods for predicting drug-target interactions have been developed to facilitate the drug discovery process. These methods use available data on known drug-target interactions to train classifiers with the purpose of predicting new undiscovered interactions. However, a key challenge regarding this data that has not yet been addressed by these methods, namely class imbalance, is potentially degrading the prediction performance. Class imbalance can be divided into two sub-problems. Firstly, the number of known interacting drug-target pairs is much smaller than that of non-interacting drug-target pairs. This imbalance ratio between interacting and non-interacting drug-target pairs is referred to as the between-class imbalance. Between-class imbalance degrades prediction performance due to the bias in prediction results towards the majority class (i.e. the non-interacting pairs), leading to more prediction errors in the minority class (i.e. the interacting pairs). Secondly, there are multiple types of drug-target interactions in the data with some types having relatively fewer members (or are less represented) than others. This variation in representation of the different interaction types leads to another kind of imbalance referred to as the within-class imbalance. In within-class imbalance, prediction results are biased towards the better represented interaction types, leading to more prediction errors in the less represented interaction types. We propose an ensemble learning method that incorporates techniques to address the issues of between-class imbalance and within-class imbalance. Experiments show that the proposed method improves results over 4 state-of-the-art methods. In addition, we simulated cases for new drugs and targets to see how our method would perform in predicting their interactions. New drugs and targets are those for which no prior interactions are known. Our method displayed satisfactory prediction performance and was able to predict many of the interactions successfully. Our proposed method has improved the prediction performance over the existing work, thus proving the importance of addressing problems pertaining to class imbalance in the data.

PHYSICIAN PRESCRIBING BEHAVIOR AND ITS IMPACT ON PATIENT-LEVEL OUTCOMES

PubMed Central

Joyce, Geoffrey F.; Carrera, Mariana; Goldman, Dana P.; Sood, Neeraj

2013-01-01

OBJECTIVE Concerns over rising drug costs, pharmaceutical advertising and potential conflicts of interest have focused attention on physician prescribing behavior. We examine how broadly physicians prescribe within the ten most prevalent therapeutic classes, the factors affecting their choices, and its impact on patient-level outcomes. STUDY DESIGN Retrospective study from 2005 to 2007 examining prescribers with at least five initial prescriptions within a class from 2005–2007. Medical and pharmacy claims are linked to prescriber information from 146 different health plans, reflecting 1,975 to 8,923 unique providers per drug class. METHODS Primary outcomes are the number of distinct drugs in a class initially prescribed by a physician over 1- and 3-year periods, medication possession ratio, and out of pocket costs. RESULTS In 8 of 10 therapeutic classes, the median physician prescribes at least 3 different drugs and less than one in six physicians prescribes only brand drugs. Physicians prescribing only one or two drugs in a class are more likely to prescribe the most advertised drug. Physicians who prescribe fewer drugs are less likely to see patients with other comorbid conditions and varied formulary designs. Prescribing fewer drugs is associated with lower rates of medication adherence and higher out-of-pocket costs for drugs, but the effects are small and inconsistent across classes. CONCLUSIONS Physicians prescribe more broadly than commonly perceived. Though narrow prescribers are more likely to prescribe highly advertised drugs, few physicians prescribe these drugs exclusively. Narrow prescribing has modest effects on medication adherence and out of pocket costs in some classes. PMID:22216870

Histone deacetylase inhibitors: Potential in cancer therapy.

PubMed

Marks, P A; Xu, W-S

2009-07-01

The role of histone deacetylases (HDAC) and the potential of these enzymes as therapeutic targets for cancer, neurodegenerative diseases and a number of other disorders is an area of rapidly expanding investigation. There are 18 HDACs in humans. These enzymes are not redundant in function. Eleven of the HDACs are zinc dependent, classified on the basis of homology to yeast HDACs: Class I includes HDACs 1, 2, 3, and 8; Class IIA includes HDACs 4, 5, 7, and 9; Class IIB, HDACs 6 and 10; and Class IV, HDAC 11. Class III HDACs, sirtuins 1-7, have an absolute requirement for NAD(+), are not zinc dependent and generally not inhibited by compounds that inhibit zinc dependent deacetylases. In addition to histones, HDACs have many nonhistone protein substrates which have a role in regulation of gene expression, cell proliferation, cell migration, cell death, and angiogenesis. HDAC inhibitors (HDACi) have been discovered of different chemical structure. HDACi cause accumulation of acetylated forms of proteins which can alter their structure and function. HDACi can induce different phenotypes in various transformed cells, including growth arrest, apoptosis, reactive oxygen species facilitated cell death and mitotic cell death. Normal cells are relatively resistant to HDACi induced cell death. Several HDACi are in various stages of development, including clinical trials as monotherapy and in combination with other anti-cancer drugs and radiation. The first HDACi approved by the FDA for cancer therapy is suberoylanilide hydroxamic acid (SAHA, vorinostat, Zolinza), approved for treatment of cutaneous T-cell lymphoma. 2009 Wiley-Liss, Inc.

Women at Risk for Human Immunodeficiency Virus.

ERIC Educational Resources Information Center

Quadagno, David; And Others

This article reports results from a survey among women at risk for contracting Human Immunodeficiency Virus (HIV) as well as transmitting it in a vertical (to offspring) and horizontal (sexual partner or intravenous [IV] drug usage) mode. Little is known about the extent of HIV knowledge, sexual behaviors, and IV drug usage for women at risk for…

Clinical profile of patients with biopsy proven lupus nephritis at a tertiary care hospital from Northern Pakistan, 1995 to 2012.

PubMed

Ali, Akhtar; Mehmood, Anjum; Ali, Muhammad Usman

2017-01-01

TTo highlight the clinical spectrum of biopsy-proven lupus nephritis by analysing any variations in its histological subtypes across gender, varying age groups, serum creatinine levels and anti-double stranded deoxyribonucleic acid levels. This retrospective, observational study was conducted at the Lady Reading Hospital in collaboration with the Fauji Foundation Hospital, Peshawar, Pakistan, and comprised patient records of biopsy-proven lupus nephritis from 1995 to 2012. The cases were analysed according to clinical presentations and histological pattern of systemic lupus erythematosus nephritis. EpiData 3.1 and SPSS 17 were used for data analyses. Of the 2,000 renal biopsies performed, lupus nephritis was found in 74(3.7%) cases. Of them, 63(85.1%) were females and 11(14.9%) males. The mean age of the cases was 23.88±9.73 years (range: 10-55 years). Class IV lupus nephritis was seen in 38(51.4%) patients, followed by Class II in 15(20.3%), Class III in 10(13.5%), Class V and VI in 4(5.4%) each and Class I in 3(4.1%). Out of the combined Class III and IV cases, 25(52.08%) had serum creatinine levels of >1.2 mg/dL, whereas positive anti-double stranded deoxyribonucleic acid titers up to 50 IU/L were seen in all of the 48(100%) such patients. Overall, microscopic haematuria was found in 52(70.3%) cases, followed by arthralgia in 40(54.1%). Moreover, 32(50.8%) females and 6(54.5%) males had Type IV nephritis. Class VI lupus nephritis, in particular, were significantly more prominent in 31-40 years of age group when compared to other histological subtypes and age groups (p=0.0096, odds ratio: 23.25, 95% confidence interval: 2.15-251.21). Female predominance was observed in all histological sub-types of lupus nephritis. Class IV lupus was the most common histological pattern. Microscopic haematuria was the most common clinical presentation.

Formation of virtual isthmus: A new scenario of spiral wave death after a decrease in excitability

NASA Astrophysics Data System (ADS)

Erofeev, I. S.; Agladze, K. I.

2015-11-01

Termination of rotating (spiral) waves or reentry is crucial when fighting with the most dangerous cardiac tachyarrhythmia. To increase the efficiency of the antiarrhythmic drugs as well as finding new prospective ones it is decisive to know the mechanisms how they act and influence the reentry dynamics. The most popular view on the mode of action of the contemporary antiarrhythmic drugs is that they increase the core of the rotating wave (reentry) to that extent that it is not enough space in the real heart for the reentry to exist. Since the excitation in cardiac cells is essentially change of the membrane potential, it relies on the functioning of the membrane ion channels. Thus, membrane ion channels serve as primary targets for the substances, which may serve as antiarrhythmics. At least, the entire group of antiarrhythmics class I (modulating activity of sodium channels) and partially class IV (modulating activity of calcium channels) are believed to destabilize and terminate reentry by decreasing the excitability of cardiac tissue. We developed an experimental model employing cardiac tissue culture and photosensitizer (AzoTAB) to study the process of the rotating wave termination while decreasing the excitability of the tissue. A new scenario of spiral wave cessation was observed: an asymmetric growth of the rotating wave core and subsequent formation of a virtual isthmus, which eventually caused a conduction block and the termination of the reentry.

Simulation of dendritic growth reveals necessary and sufficient parameters to describe the shapes of dendritic trees

NASA Astrophysics Data System (ADS)

Trottier, Olivier; Ganguly, Sujoy; Bowne-Anderson, Hugo; Liang, Xin; Howard, Jonathon

For the last 120 years, the development of neuronal shapes has been of great interest to the scientific community. Over the last 30 years, significant work has been done on the molecular processes responsible for dendritic development. In our ongoing research, we use the class IV sensory neurons of the Drosophila melanogaster larva as a model system to understand the growth of dendritic arbors. Our main goal is to elucidate the mechanisms that the neuron uses to determine the shape of its dendritic tree. We have observed the development of the class IV neuron's dendritic tree in the larval stage and have concluded that morphogenesis is defined by 3 distinct processes: 1) branch growth, 2) branching and 3) branch retraction. As the first step towards understanding dendritic growth, we have implemented these three processes in a computational model. Our simulations are able to reproduce the branch length distribution, number of branches and fractal dimension of the class IV neurons for a small range of parameters.

A new class of relativistic stellar models

NASA Astrophysics Data System (ADS)

Haggag, Salah

1995-03-01

Einstein field equations for a static and spherically symmetric perfect fluid are considered. A formulation given by Patino and Rago is used to obtain a class of nine solutions, two of them are Tolman solutions I, IV and the remaining seven are new. The solutions are the correct ones corresponding to expressions derived by Patino and Rago which have been shown by Knutsen to be incorrect. Similar to Tolan solution IV each of the new solutions satisfies energy conditions inside a sphere in some range of two independent parameters. Besides, each solution could be matched to the exterior Schwarzschild solution at a boundary where the pressure vanishes and thus the solutions constitute a class of new physically reasonable stellar models.

Biopharmaceutical classification of drugs using intrinsic dissolution rate (IDR) and rat intestinal permeability.

PubMed

Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Azimi, Mandana; Valizadeh, Hadi

2009-09-01

The solubility and dissolution rate of active ingredients are of major importance in preformulation studies of pharmaceutical dosage forms. In the present study, passively absorbed drugs are classified based on their intrinsic dissolution rate (IDR) and their intestinal permeabilities. IDR was determined by measuring the dissolution of a non-disintegrating disk of drug, and effective intestinal permeability of tested drugs in rat jejunum was determined using single perfusion technique. The obtained intrinsic dissolution rate values were in the range of 0.035-56.8 mg/min/cm(2) for tested drugs. The minimum and maximum intestinal permeabilities in rat intestine were determined to be 1.6 x 10(-5) and 2 x 10(-4)cm/s, respectively. Four classes of drugs were defined: Category I: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR>1(mg/min/cm(2)), Category II: P(eff,rat)>5 x 10(-5) (cm/s) or P(eff,human)>4.7 x 10(-5) (cm/s), IDR<1(mg/min/cm(2)), Category III: P(eff,rat)<5 x 10(-5) (cm/s) or P(eff,human)<4.7 x 10(-5) (cm/s), IDR>1 (mg/min/cm(2)) and Category IV: P(eff,rat)<5 x 10(-5) (cm/s) or P(eff,human)<4.7 x 10(-5) (cm/s), IDR<1(mg/min/cm(2)). According to the results obtained and proposed classification of drugs, it is concluded that drugs could be categorized correctly based on their IDR and intestinal permeability values.

Mechanisms of termination and prevention of atrial fibrillation by drug therapy

PubMed Central

Workman, AJ; Smith, GL; Rankin, AC

2011-01-01

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na+ channel blockers, β-adrenoceptor antagonists, action potential prolonging drugs, and Ca2+ channel blockers; the “upstream therapies”, e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as “atrial-selective” multiple ion channel blockers, gap junction-enhancers, and intracellular Ca2+-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms. PMID:21334377

In vitro biphasic dissolution tests and their suitability for establishing in vitro-in vivo correlations: A historical review.

PubMed

Pestieau, Aude; Evrard, Brigitte

2017-05-01

For many decades, one of the most critical issues in the pharmaceutical industry has been the poor solubility of some drugs. Indeed, a prerequisite for drug absorption is the presence of dissolved drug at the absorption site and this can be challenging for compounds with low aqueous solubility such as BCS class II (low solubility, high permeability) and IV (low solubility, low permeability) compounds. If the development of oral delivery formulations of these compounds is frequently challenging to formulation scientists in the pharmaceutical industry, the in vitro evaluation of these new formulations is also a great challenge. One alternative approach to overcome the problems encountered with conventional dissolution methods is the use of biphasic dissolution systems. This review provides an overview of the origin and the evolution over time of the biphasic systems and the growing interest among scientists regarding their suitability for establishing in vitro-in vivo correlations. The evolution of these systems and their applications from the 1960s to the present day, such as in system variants and improvements, analysis of complex formulations, discriminatory power, bio-relevance, precipitation and supersaturation visualization, etc. will be discussed. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of a class IV hurricane on emergency department operations.

PubMed

Sheppa, C M; Stevens, J; Philbrick, J T; Canada, M

1993-09-01

The objective of this study was to determine the impact on emergency department (ED) operations of Hurricane Hugo, a class IV hurricane that struck Charleston, South Carolina, on September 21, 1989. The study design was a retrospective record-based descriptive study and mail survey of the ED of a 300-bed regional medical center directly in the path of the storm. During the 3 weeks after the storm, ED patient volume increased 19% over that of the 3 weeks before the storm. Increased visit volumes were evident for at least 3 months. Compared with a similar period of the previous year, there was an increase in the proportion of patients seen for lacerations of all types, puncture wounds, stings, and falls. Sixty-two percent of physician offices were still closed 7 days after the storm. The direct effects of a class IV hurricane on ED operations included major alterations in the volume and types of patient visits. Because of the evacuation of approximately 40% of the coastal population and storm damage hindering travel, the increase in visit volume was less in magnitude but of longer duration has been reported in class III hurricanes.

Predictors of Operative Mortality for Coronary Bypass Grafting in Patients with Ischemic Heart Disease

PubMed Central

Langou, Rene A.; Wiles, John C.; Peduzzi, Peter N.; Hammond, Graeme; Cohen, Lawrence S.

1978-01-01

Predictors for operative mortality (OM) were studied in 172 consecutive patients (pts) undergoing coronary artery grafts (CAG) for angina pectoris. Seventy eight pts had Class IV angina; of the 147 patients given propranolol, 41 were gradually withdrawn from propranolol and finally discontinued 24 hours before surgery, and 106 were abruptly withdrawn from propranolol 24 hours before CAG; 20 pts had left main coronary disease; 156 pts had cardiopulmonary bypass (CPB) time shorter than 20 minutes, and 16 pts had a CPB longer than 120 minutes. The operative mortality was 5.2% (9/172) for the entire group. Class IV angina (OM 7%), abrupt propranolol withdrawal (OM 6.6%), left main coronary artery disease (OM 25%), and CPB longer than 120 minutes (OM 50%), all significantly increased OM. These variables were interdependent, however, as many pts belonged to several predictor categories, combinations of predictors were examined, in order to more accurately predict the risk of individual pts. The combination of left main coronary artery disease and CPB longer than 120 minutes; and Class IV angina and CPB longer than 120 minutes were significantly associated with higher operative mortality. We conclude that Class IV angina, abrupt propranolol withdrawal, left main coronary artery disease and prolonged CPB are potent, interdependent predictors of OM in pts undergoing CAG. Consideration of these predictors, alone and in combination, allows effective prediction of OM for CAG in patients with stable angina pectoris. PMID:307873

Biomechanical 3-Dimensional Finite Element Analysis of Obturator Protheses Retained with Zygomatic and Dental Implants in Maxillary Defects

PubMed Central

Akay, Canan; Yaluğ, Suat

2015-01-01

Background The objective of this study was to investigate the stress distribution in the bone around zygomatic and dental implants for 3 different implant-retained obturator prostheses designs in a Aramany class IV maxillary defect using 3-dimensional finite element analysis (FEA). Material\\Methods A 3-dimensional finite element model of an Aramany class IV defect was created. Three different implant-retained obturator prostheses were modeled: model 1 with 1 zygomatic implant and 1 dental implant, model 2 with 1 zygomatic implant and 2 dental implants, and model 3 with 2 zygomatic implants. Locator attachments were used as a superstructure. A 150-N load was applied 3 different ways. Qualitative analysis was based on the scale of maximum principal stress; values obtained through quantitative analysis are expressed in MPa. Results In all loading conditions, model 3 (when compared models 1 and 2) showed the lowest maximum principal stress value. Model 3 is the most appropirate reconstruction in Aramany class IV maxillary defects. Two zygomatic implants can reduce the stresses in model 3. The distribution of stresses on prostheses were more rational with the help of zygoma implants, which can distribute the stresses on each part of the maxilla. Conclusions Aramany class IV obturator prosthesis placement of 2 zygomatic implants in each side of the maxilla is more advantageous than placement of dental implants. In the non-defective side, increasing the number of dental implants is not as suitable as zygomatic implants. PMID:25714086

Study design for the "effect of METOprolol in CARDioproteCtioN during an acute myocardial InfarCtion" (METOCARD-CNIC): a randomized, controlled parallel-group, observer-blinded clinical trial of early pre-reperfusion metoprolol administration in ST-segment elevation myocardial infarction.

PubMed

Ibanez, Borja; Fuster, Valentin; Macaya, Carlos; Sánchez-Brunete, Vicente; Pizarro, Gonzalo; López-Romero, Pedro; Mateos, Alonso; Jiménez-Borreguero, Jesús; Fernández-Ortiz, Antonio; Sanz, Ginés; Fernández-Friera, Leticia; Corral, Ervigio; Barreiro, Maria-Victoria; Ruiz-Mateos, Borja; Goicolea, Javier; Hernández-Antolín, Rosana; Acebal, Carlos; García-Rubira, Juan Carlos; Albarrán, Agustín; Zamorano, José Luis; Casado, Isabel; Valenciano, Juan; Fernández-Vázquez, Felipe; de la Torre, José María; Pérez de Prado, Armando; Iglesias-Vázquez, José Antonio; Martínez-Tenorio, Pedro; Iñiguez, Andrés

2012-10-01

Infarct size predicts post-infarction mortality. Oral β-blockade within 24 hours of a ST-segment elevation acute myocardial infarction (STEMI) is a class-IA indication, however early intravenous (IV) β-blockers initiation is not encouraged. In recent magnetic resonance imaging (MRI)-based experimental studies, the β(1)-blocker metoprolol has been shown to reduce infarct size only when administered before coronary reperfusion. To date, there is not a single trial comparing the pre- vs. post-reperfusion β-blocker initiation in STEMI. The METOCARD-CNIC trial is testing whether the early initiation of IV metoprolol before primary percutaneous coronary intervention (pPCI) could reduce infarct size and improve outcomes when compared to oral post-pPCI metoprolol initiation. The METOCARD-CNIC trial is a randomized parallel-group single-blind (to outcome evaluators) clinical effectiveness trial conducted in 5 Counties across Spain that will enroll 220 participants. Eligible are 18- to 80-year-old patients with anterior STEMI revascularized by pPCI ≤6 hours from symptom onset. Exclusion criteria are Killip-class ≥III, atrioventricular block or active treatment with β-blockers/bronchodilators. Primary end point is infarct size evaluated by MRI 5 to 7 days post-STEMI. Prespecified major secondary end points are salvage-index, left ventricular ejection fraction recovery (day 5-7 to 6 months), the composite of (death/malignant ventricular arrhythmias/reinfarction/admission due to heart failure), and myocardial perfusion. The METOCARD-CNIC trial is testing the hypothesis that the early initiation of IV metoprolol pre-reperfusion reduces infarct size in comparison to initiation of oral metoprolol post-reperfusion. Given the implications of infarct size reduction in STEMI, if positive, this trial might evidence that a refined use of an approved inexpensive drug can improve outcomes of patients with STEMI. Copyright © 2012 Mosby, Inc. All rights reserved.

Comedications alter drug-induced liver injury reporting frequency: Data mining in the WHO VigiBase™

PubMed Central

Suzuki, Ayako; Yuen, Nancy A.; Ilic, Katarina; Miller, Richard T.; Reese, Melinda J.; Brown, H. Roger; Ambroso, Jeffrey I.; Falls, J. Gregory; Hunt, Christine M.

2015-01-01

Polypharmacy is common, and may modify mechanisms of drug-induced liver injury. We examined the effect of these drug–drug interactions on liver safety reports of four drugs highly associated with hepatotoxicity. In the WHO VigiBase™, liver event reports were examined for acetaminophen, isoniazid, valproic acid, and amoxicillin/clavulanic acid. Then, we evaluated the liver event reporting frequency of these 4 drugs in the presence of co-reported medications. Each of the 4 primary drugs was reported as having more than 2000 liver events, and co-reported with more than 600 different medications. Overall, the effect of 2275 co-reported drugs (316 drug classes) on the reporting frequency was analyzed. Decreased liver event reporting frequency was associated with 245 drugs/122 drug classes, including anti-TNFα, opioids, and folic acid. Increased liver event reporting frequency was associated with 170 drugs/82 drug classes; in particular, halogenated hydrocarbons, carboxamides, and bile acid sequestrants. After adjusting for age, gender, and other co-reported drug classes, multiple co-reported drug classes were significantly associated with decreased/increased liver event reporting frequency in a drug-specific/unspecific manner. In conclusion, co-reported medications were associated with changes in the liver event reporting frequency of drugs commonly associated with hepatotoxicity, suggesting that comedications may modify drug hepatic safety. PMID:25988394

Mechanism of enhanced oral absorption of morin by phospholipid complex based self-nanoemulsifying drug delivery system.

PubMed

Zhang, Jinjie; Li, Jianbo; Ju, Yuan; Fu, Yao; Gong, Tao; Zhang, Zhirong

2015-02-02

Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.

Framing of Transitional Pedagogic Practices in the Sciences: Enabling Access

ERIC Educational Resources Information Center

Ellery, Karen

2017-01-01

Educational literature shows that students from working-class backgrounds are significantly less likely to persist to completion in higher education than middle-class students. This paper draws theoretically and analytically on Bernstein's ([1990. "Class, Codes and Control, Volume IV: The Structuring of Pedagogic Discourse." London:…

Economic and clinical aspects of intravenous versus oral busulfan in adult patients for conditioning prior to HSCT.

PubMed

Berger, Karin; Schopohl, Dorothee; Rieger, Christina; Ostermann, Helmut

2015-12-01

Busulfan (BU) used as cytoreductive conditioning prior to hematopoietic stem cell transplantation (HSCT) is available as intravenous (IV) and oral (O) preparation. IV-BU has clinical advantages associated with relevant incremental costs. The aim was to determine the economic impact of IV-BU versus O-BU in adult HSCT recipients from a German health care providers' perspective. A budget-impact model (BIM) including costs and risks for oral mucositis (OM), infection with OM, and hepatic sinusoidal obstruction syndrome (SOS) was developed. Model inputs are literature data comparing clinical effects of IV-BU versus O-BU and German cost data (conditioning therapy, treatment of OM, infections, SOS without/with multiorgan failure) from literature and tariff lists. Base case calculations resulted the following: total costs of adverse events were €86,434 with O-BU and €44,376 with IV-BU for ten patients each. Considering costs of adverse events and drugs, about €5840 for ten patients receiving IV-BU are saved. Sensitivity analyses were conducted in several ways. Cost savings range between €4910 and €12,640 per ten patients for all adverse events and €2070 or €1140 per ten patients considering SOS only. Drug treatment of SOS and treatment of multiorgan failure during severe SOS are major cost drivers. Worst case scenario calculations (assuming -25% risk of all adverse events for O-BU and +25% for IV-BU) yield up to €27,570 per ten patients with IV-BU. Considering costs of adverse events and drugs, IV-BU is the dominant alternative from a German providers' perspective. For more comprehensive economic evaluations, additional epidemiological data, evidence on clinical outcomes, patient-reported outcomes, and treatment patterns are needed.

A review of ethylphenidate in deaths in east and west Scotland.

PubMed

Parks, Claire; McKeown, Denise; Torrance, Hazel J

2015-12-01

Ethylphenidate is a psychostimulant and analogue of methylphenidate. Interestingly it is also produced as a metabolite from the co-ingestion of methylphenidate and alcohol (ethanol). In the UK, between April and June 2015, ethylphenidate and 6 other methylphenidate based novel psychoactive substances (NPS) were subjected to a temporary class drug order under the Misuse of Drugs Act 1971. Ethylphenidate is being abused by both novel and habitual drug users, more prominently in the East of Scotland. What is unknown in the literature is the contribution of ethylphenidate in deaths. A search was conducted for an 18 month period (July 2013 to December 2014) to identify cases where ethylphenidate was detected during post-mortem toxicological analysis. Nineteen cases were identified and these cases were examined with regards to case circumstances, pathology findings, toxicology results and adverse effects. The individuals ranged in age from 20 to 54 (median 37) and the majority were male (n=14) and from the East of Scotland (n=16), more specifically Edinburgh and surrounding area. Current or previous heroin abuse was a common theme in these cases (n=16) and injection was a common route of administration of "legal highs" or "burst". The concentration of ethylphenidate in the cases ranged from 0.008 mg/L to over 2 mg/L in post-mortem femoral blood (median 0.25 mg/L, average 0.39 mg/L). Other drugs commonly detected were benzodiazepines (n=15), followed by opiates (n=11, 4 of which were positive for 6-monoacetylmorphine) and then methadone (n=8). All 19 cases received a full post-mortem examination and there were 10 cases where drug toxicity was the sole or potentially contributory factor to the cause of death. Ethylphenidate was specifically mentioned in the cause of death for 5 cases, chronic intravenous (IV) drug use was named as part of the cause of death for 2 cases and in 6 cases there was evidence of complications and infections through IV drug use. As far as it is known to the authors, this is the first review of post-mortem cases involving the use of ethylphenidate in East and West Scotland. This study can be used as a guide for toxicologists and pathologists when interpreting cases which are positive for ethylphenidate. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Analysis of class II (hydrolytic) and class I (beta-lyase) apurinic/apyrimidinic endonucleases with a synthetic DNA substrate.

PubMed Central

Levin, J D; Demple, B

1990-01-01

We have developed simple and sensitive assays that distinguish the main classes of apurinic/apyrimidinic (AP) endonucleases: Class I enzymes that cleave on the 3' side of AP sites by beta-elimination, and Class II enzymes that cleave by hydrolysis on the 5' side. The distinction of the two types depends on the use of a synthetic DNA polymer that contains AP sites with 5'-[32P]phosphate residues. Using this approach, we now show directly that Escherichia coli endonuclease IV and human AP endonuclease are Class II enzymes, as inferred previously on the basis of indirect assays. The assay method does not exhibit significant interference by nonspecific nucleases or primary amines, which allows the ready determination of different AP endonuclease activities in crude cell extracts. In this way, we show that virtually all of the Class II AP endonuclease activity in E. coli can be accounted for by two enzymes: exonuclease III and endonuclease IV. In the yeast Saccharomyces cerevisiae, the Class II AP endonuclease activity is totally dependent on a single enzyme, the Apn1 protein, but there are probably multiple Class I enzymes. The versatility and ease of our approach should be useful for characterizing this important class of DNA repair enzymes in diverse systems. PMID:1698278

How the Change in IBS Criteria From Rome III to Rome IV Impacts on Clinical Characteristics and Key Pathophysiological Factors.

PubMed

Aziz, Imran; Törnblom, Hans; Palsson, Olafur S; Whitehead, William E; Simrén, Magnus

2018-06-08

The diagnostic criteria for irritable bowel syndrome (IBS) have recently been updated from Rome III to Rome IV. Whereas in Rome III a diagnosis of IBS entailed chronic abdominal pain or discomfort at least 3 days per month, in Rome IV the term discomfort has been removed and the frequency of abdominal pain increased to at least 1 day per week. We examined how this change in IBS criteria impacts on clinical characteristics and pathophysiological factors. A total of 542 Swedish subjects with Rome III IBS completed a baseline questionnaire enquiring for the number of abdominal pain days in the last 10 days; this was subsequently used as a surrogate marker to identify Rome IV IBS, in that (a) those with 0 or 1 day of pain were classed as Rome IV-negative, and (b) those with ≥2 days of pain were classed as Rome IV-positive. Comparisons were made between Rome IV-positive and -negative IBS groups for demographics, IBS subtype, gastrointestinal and psychological symptoms, somatisation, fatigue, disease-specific quality of life, rectal sensitivity, and oro-anal transit time. Overall, 85% of Rome III IBS patients fulfilled the Rome IV criteria for IBS, but 15% did not. Rome IV-positive subjects were significantly more likely to be female, have poorer quality of life, greater pain severity, bloating, somatisation, fatigue, and rectal sensitivity than Rome IV-negative subjects. There were no differences in severity of anxiety or depression, IBS subtypes, bowel habit dissatisfaction, or oro-anal transit time. Finally, increasing number of pain days correlated positively with symptoms and visceral hypersensitivity. Most Rome III-positive IBS patients seeking healthcare fulfil the Rome IV IBS criteria. They constitute a more severe group than those who lose their IBS diagnosis.

Post surgical pain management with poly(ortho esters).

PubMed

Barr, John; Woodburn, Kathryn W; Ng, Steven Y; Shen, Hui-Rong; Heller, Jorge

2002-10-16

Poly(ortho esters), POE, are synthetic bioerodible polymers that can be prepared as solid materials, or as viscous, injectable polymers. These materials have evolved through a number of families, and the latest member of this family, POE IV, is particularly well suited to drug delivery since latent acid is integrated into the polymer backbone, thereby, modulating surface erosion. POE IV predominantly undergoes surface erosion and is able to moderate drug release over periods from days to many months. One indication in which the POE IV polymer is currently being investigated is in sustained post-surgical pain management. The local anesthetic agent, mepivacaine, has been incorporated into a viscous, injectable POE IV and its potential to provide longer-acting anesthesia has been explored in non-clinical models.

Point-of-care detection and real-time monitoring of intravenously delivered drugs via tubing with an integrated SERS sensor

NASA Astrophysics Data System (ADS)

Wu, Hsin-Yu; Cunningham, Brian T.

2014-04-01

We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml-1) well below typical administered dosages (mg ml-1). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml-1) well below typical administered dosages (mg ml-1). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery. Electronic supplementary information (ESI) available: Fabrication of PNA substrates, fabrication details of the flow cell, details of FDTD simulation, characterization of the scattering volume, and detection of diltiazem diluted in DI water and PBS. See DOI: 10.1039/c4nr00027g

Fluoxetine Blocks Nav1.5 Channels via a Mechanism Similar to That of Class 1 Antiarrhythmics

PubMed Central

Poulin, Hugo; Bruhova, Iva; Timour, Quadiri; Theriault, Olivier; Beaulieu, Jean-Martin; Frassati, Dominique

2014-01-01

The voltage-gated Nav1.5 channel is essential for the propagation of action potentials in the heart. Malfunctions of this channel are known to cause hereditary diseases. It is a prime target for class 1 antiarrhythmic drugs and a number of antidepressants. Our study investigated the Nav1.5 blocking properties of fluoxetine, a selective serotonin reuptake inhibitor. Nav1.5 channels were expressed in HEK-293 cells, and Na+ currents were recorded using the patch-clamp technique. Dose-response curves of racemic fluoxetine (IC50 = 39 μM) and its optical isomers had a similar IC50 [40 and 47 μM for the (+) and (−) isomers, respectively]. Norfluoxetine, a fluoxetine metabolite, had a higher affinity than fluoxetine, with an IC50 of 29 μM. Fluoxetine inhibited currents in a frequency-dependent manner, shifted steady-state inactivation to more hyperpolarized potentials, and slowed the recovery of Nav1.5 from inactivation. Mutating a phenylalanine (F1760) and a tyrosine (Y1767) in the S6 segment of domain (D) IV (DIVS6) significantly reduced the affinity of fluoxetine and its frequency-dependent inhibition. We used a noninactivating Nav1.5 mutant to show that fluoxetine displays open-channel block behavior. The molecular model of fluoxetine in Nav1.5 was in agreement with mutational experiments in which F1760 and Y1767 were found to be the key residues in binding fluoxetine. We concluded that fluoxetine blocks Nav1.5 by binding to the class 1 antiarrhythmic site. The blocking of cardiac Na+ channels should be taken into consideration when prescribing fluoxetine alone or in association with other drugs that may be cardiotoxic or for patients with conduction disorders. PMID:25028482

Psychosocial stressors and the prognosis of major depression: a test of Axis IV

PubMed Central

Gilman, Stephen E.; Trinh, Nhi-Ha; Smoller, Jordan W.; Fava, Maurizio; Murphy, Jane M.; Breslau, Joshua

2013-01-01

Background Axis IV is for reporting “psychosocial and environmental problems that may affect the diagnosis, treatment, and prognosis of mental disorders.” No studies have examined the prognostic value of Axis IV in DSM-IV. Method We analyzed data from 2,497 participants in the National Epidemiologic Survey on Alcohol and Related Conditions with major depressive episode (MDE). We hypothesized that psychosocial stressors predict a poor prognosis of MDE. Secondarily, we hypothesized that psychosocial stressors predict a poor prognosis of anxiety and substance use disorders. Stressors were defined according to DSM-IV’s taxonomy, and empirically using latent class analysis. Results Primary support group problems, occupational problems, and childhood adversity increased the risks of depressive episodes and suicidal ideation by 20–30%. Associations of the empirically derived classes of stressors with depression were larger in magnitude. Economic stressors conferred a 1.5-fold increase in risk for a depressive episode (CI=1.2–1.9); financial and interpersonal instability conferred a 1.3-fold increased risk of recurrent depression (CI=1.1–1.6). These two classes of stressors also predicted the recurrence of anxiety and substance use disorders. Stressors were not related to suicidal ideation independent from depression severity. Conclusions Psychosocial and environmental problems are associated with the prognosis of MDE and other Axis I disorders. Though DSM-IV’s taxonomy of stressors stands to be improved, these results provide empirical support for the prognostic value of Axis IV. Future work is needed to determine the reliability of Axis IV assessments in clinical practice, and the usefulness of this information to improving the clinical course of mental disorders. PMID:22640506

Inhaled sildenafil nanocomposites: lung accumulation and pulmonary pharmacokinetics.

PubMed

Ghasemian, Elham; Vatanara, Alireza; Rouini, Mohammad Reza; Rouholamini Najafabadi, Abdolhossein; Gilani, Kambiz; Lavasani, Hoda; Mohajel, Nasir

2016-12-01

Administration of sildenafil citrate (SC) is considered as a strategy in the treatment of pulmonary hypertension. This study reports production of the inhalable microparticles containing SC-loaded poly(lactide-co-glycolic acid)-nanoparticles. SC-nanoparticles were prepared by the double emulsion solvent evaporation method. Next, free SC and SC-loaded nanoparticles were spray dried in the presence of appropriate excipients (lactose, maltose and trehalose). Physicochemical properties and aerodynamic behavior of prepared powders were evaluated. In addition, drug accumulation from selected formulations in the rat lung tissue was compared with oral and IV administration. Size and fine particle fraction of selected nanocomposites and free SC microparticles were 7 and 4.5 µm, and 60.2% and 68.2%, respectively. Following oral and IV administration, the drug was not detectable in the lung after 4 and 6 h, respectively, but in SC-loaded nanoparticles, the drug was detectable in the lung even after 12 h of inhalation. Respirable particles containing free SC provided high concentration at first that was detectable up to 6 after insufflation. In vivo study demonstrated that pulmonary administration of sildenafil and sildenafil nanoparticles produced longer half-life and higher concentration of the drug in the lung tissue as compared to oral and IV administration. So, these formulations could be more effective than oral and IV administration of this drug.

Plasma concentrations, behavioural and physiological effects following intravenous and intramuscular detomidine in horses.

PubMed

Mama, K R; Grimsrud, K; Snell, T; Stanley, S

2009-11-01

Detomidine hydrochloride is used to provide sedation, muscle relaxation and analgesia in horses, but a lack of information pertaining to plasma concentration has limited the ability to correlate drug concentration with effect. To build on previous information and assess detomidine for i.v. and i.m. use in horses by simultaneously assessing plasma drug concentrations, physiological parameters and behavioural characteristics. Systemic effects would be seen following i.m. and i.v. detomidine administration and these effects would be positively correlated with plasma drug concentrations. Behavioural (e.g. head position) and physiological (e.g. heart rate) responses were recorded at fixed time points from 4 min to 24 h after i.m. or i.v. detomidine (30 microg/kg bwt) administration to 8 horses. Route of administration was assigned using a balanced crossover design. Blood was sampled at predetermined time points from 0.5 min to 48 h post administration for subsequent detomidine concentration measurements using liquid chromatography-mass spectrometry. Data were summarised as mean +/- s.d. for subsequent analysis of variance for repeated measures. Plasma detomidine concentration peaked earlier (1.5 min vs. 1.5 h) and was significantly higher (105.4 +/- 71.6 ng/ml vs. 6.9 +/- 1.4 ng/ml) after i.v. vs. i.m. administration. Physiological and behavioural changes were of a greater magnitude and observed at earlier time points for i.v. vs. i.m. groups. For example, head position decreased from an average of 116 cm in both groups to a low value 35 +/- 23 cm from the ground 10 min following i.v. detomidine and to 64 +/- 24 cm 60 min after i.m. detomidine. Changes in heart rate followed a similar pattern; low value of 17 beats/min 10 min after i.v. administration and 29 beats/min 30 min after i.m. administration. Plasma drug concentration and measured effects were correlated positively and varied with route of administration following a single dose of detomidine. Results support a significant influence of route of administration on desirable and undesirable drug effects that influence case management.

Changes in the social class gradient of cirrhosis mortality in England and Wales across the 20th century.

PubMed

Crombie, Iain K; Precious, Elaine

2011-01-01

To explore the nature of the social class gradient of cirrhosis mortality in England and Wales across the 20th century. Data on male cirrhosis mortality by social class were obtained from the Registrar General's Decennial Supplements for the years 1921-1991. Data for 1941 were not collected because of the second World War. In 1921, cirrhosis mortality was substantially higher among the professional and managerial classes (I and II) than among the other social classes (III-V). This marked social class difference persisted until 1961 when the differences between the social classes were inconsistent. By 1991, the gradient had reversed and the lower social classes (IV and V) had the higher mortality. The excess mortality was greatest for social class V. The change in the mortality gradient is stark: in 1921social classes I and II had a cirrhosis mortality at least twice that of social classes IV and V, but by 1991 this ratio had reversed. The reversal in the social class gradient of cirrhosis mortality indicates a major change in risk factor distribution across social classes. Differential changes in alcohol consumption are a possible explanation for this change, although the 1991 social class gradient in cirrhosis is inconsistent with alcohol consumption data from national surveys. Further research is required to clarify the explanation for the observed gradient, so that appropriate preventive measures can be put into place.

40 CFR 144.26 - Inventory requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... “Inventory of Injection Wells,” OMB No. 158-R0170. (b) Additional contents. For EPA administered programs...) Class II enhanced recovery wells; (ii) Class IV wells; (iii) The following Class V wells: (A) Sand or... (40 CFR 146.5 (e)(11)) (C) Geothermal energy recovery wells [§ 146.5(e)(12)]; (D) Brine return flow...

Transition of Intravenous Treprostinil to Oral Therapy in a Patient with Functional Class IV Chronic Thromboembolic Pulmonary Hypertension.

PubMed

Thurber, Kristina M; Williams, Breann M; Bates, Ruth E; Frantz, Robert P

2017-08-01

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42-year-old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross-taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability. © 2017 Pharmacotherapy Publications, Inc.

New modulated design and synthesis of quercetin-Cu(II)/Zn(II)-Sn2(IV) scaffold as anticancer agents: in vitro DNA binding profile, DNA cleavage pathway and Topo-I activity.

PubMed

Tabassum, Sartaj; Zaki, Mehvash; Afzal, Mohd; Arjmand, Farukh

2013-07-21

New molecular topologies quercetin-Cu(II)-Sn2(IV) and Zn(II)-Sn2(IV)1 and 2 were designed and synthesized to act as potential cancer chemotherapeutic agents. Their interaction with CT DNA by UV-vis and fluorescence spectroscopy was evaluated revealing an electrostatic mode of binding. Quercetin complexes are capable of promoting DNA cleavage involving both single and double strand breaks. Complex 1 cleaved pBR322 DNA via an oxidative mechanism while 2 followed a hydrolytic pathway, accessible to the minor groove of the DNA double helix in accordance with molecular docking studies with the DNA duplex of sequence d(CGCGAATTCGCG)2 dodecamer demonstrating that the complex was stabilized by additional electrostatic and hydrogen bonding interactions with the DNA. ROS such as OH˙, H2O2 and O2˙(-) are the major metabolites responsible for chronic diseases such as cancer, respiratory disorders, HIV, and diabetes etc., therefore eliminating ROS by molecular scaffolds involving SOD enzymatic activity has emerged as a potential way to develop a novel class of drugs. Therefore, in vitro superoxide dismutase activity of redox active complex 1 was evaluated by using a xanthine/xanthine oxidase-NBT assay which showed an IC50 value of 2.26 μM. Moreover, the cytotoxicity of both the complexes were screened on a panel of human carcinoma cell lines (GI50 values <8.7 μM) which revealed that 1 has a better prospect of acting as a cancer chemotherapeutic agent, and to elucidate the mechanism of tumor inhibition, Topo-I enzymatic activity was carried out. Furthermore, molecular modeling studies were carried out to understand molecular features important for drug-enzyme interactions which offer new insights into the experimental model observations.

Point-of-care detection and real-time monitoring of intravenously delivered drugs via tubing with an integrated SERS sensor.

PubMed

Wu, Hsin-Yu; Cunningham, Brian T

2014-05-21

We demonstrate an approach for detection, identification, and kinetic monitoring of drugs flowing within tubing, through the use of a plasmonic nanodome array (PNA) surface. The PNA structures are fabricated using a low-cost nanoreplica molding process upon a flexible plastic substrate that is subsequently integrated with a flow cell that connects in series with ordinary intravenous (IV) drug delivery tubing. To investigate the potential clinical applications for point-of-care detection and real-time monitoring, we perform SERS detection of ten pharmaceutical compounds (hydrocodone, levorphanol, morphine, oxycodone, methadone, phenobarbital, dopamine, diltiazem, promethazine, and mitoxantrone). We demonstrate dose-dependent SERS signal magnitude, resulting in detection limits (ng ml(-1)) well below typical administered dosages (mg ml(-1)). Further, we show that the detected drugs are not permanently attached to the PNA surface, and thus our approach is capable of performing continuous monitoring of drug delivery as materials flow through IV tubing that is connected in series with the sensor. Finally, we demonstrate the potential co-detection of multiple drugs when they are mixed together, and show excellent reproducibility and stability of SERS measurements for periods extending at least five days. The capabilities reported here demonstrate the potential to use PNA SERS surfaces for enhancing the safety of IV drug delivery.

Pediatric procedural sedation with ketamine: time to discharge after intramuscular versus intravenous administration.

PubMed

Ramaswamy, Preeti; Babl, Franz E; Deasy, Conor; Sharwood, Lisa N

2009-02-01

Ketamine is an attractive agent for pediatric procedural sedation. There are limited data on time to discharge comparing intramuscular (IM) vs. intravenous (IV) ketamine. The authors set out to determine whether IM or IV ketamine leads to quicker discharge from the emergency department (ED) and how side effect profiles compare. All patients who had received ketamine IM or IV at a tertiary children's hospital ED during the 3-year study period (2004-2007) were identified. Prospective sedation registry data, retrospective medical records, and administrative data were reviewed for drug dosages, use of additional agents, time of drug administration to discharge, total ED time (triage to discharge), and adverse events. A subgroup analysis for patients requiring five or fewer sutures (short suture group) was performed. A total of 229 patients were enrolled (60% male) with median age of 2.8 years (IQR =1.8-4.3 years) and median weight of 15.7 kg (range = 8.7-74 kg). Ketamine was most frequently employed for laceration repair (80%) and foreign body removal (9%). Overall, 48% received ketamine IM and 52% received it IV. In the short-suture subgroup, 52% received ketamine IM, while 48% received it IV. Multivariate linear regression analysis determined time from drug administration to patient discharge as 21 minutes shorter for IV compared with IM administration, adjusted for age and number of additional doses (R(2) = -0.35; 95% CI = -0.5 to -0.19; p < 0.001). Total time in the ED (triage to discharge) comparing IV versus IM administration, adjusting for age and gender and number of additional doses, was not significantly different (p = 0.16). In the short-suture subgroup, time to discharge from administration was also shorter in the IV ketamine group (R(2) = -0.454; 95%CI = -0.66 to -0.25; p < 0.001) but similar for total time in ED (p = 0.16). Overall, adverse events occurred in 35% (95% CI = 27% to 45%) of the IM group and 20% (95% CI = 13% to 28%) of the IV group (p = 0.01). Only one patient required brief bag-mask ventilation. In this institution, time from drug injection to discharge was shorter in the IV compared to IM ketamine group, both overall and for the short-suture group. However, time from triage to discharge was similar.

Integrating technology to improve medication administration.

PubMed

Prusch, Amanda E; Suess, Tina M; Paoletti, Richard D; Olin, Stephen T; Watts, Starann D

2011-05-01

The development, implementation, and evaluation of an i.v. interoperability program to advance medication safety at the bedside are described. I.V. interoperability integrates intelligent infusion devices (IIDs), the bar-code-assisted medication administration system, and the electronic medication administration record system into a bar-code-driven workflow that populates provider-ordered, pharmacist-validated infusion parameters on IIDs. The purpose of this project was to improve medication safety through the integration of these technologies and decrease the potential for error during i.v. medication administration. Four key phases were essential to developing and implementing i.v. interoperability: (a) preparation, (b) i.v. interoperability pilot, (c) preliminary validation, and (d) expansion. The establishment of pharmacy involvement in i.v. interoperability resulted in two additional safety checks: pharmacist infusion rate oversight and nurse independent validation of the autoprogrammed rate. After instituting i.v. interoperability, monthly compliance to the telemetry drug library increased to a mean ± S.D. of 72.1% ± 2.1% from 56.5% ± 1.5%, and the medical-surgical nursing unit's drug library monthly compliance rate increased to 58.6% ± 2.9% from 34.1% ± 2.6% (p < 0.001 for both comparisons). The number of manual pump edits decreased with both telemetry and medical-surgical drug libraries, demonstrating a reduction from 56.9 ± 12.8 to 14.2 ± 3.9 and from 61.2 ± 15.4 to 14.7 ± 3.8, respectively (p < 0.001 for both comparisons). Through the integration and incorporation of pharmacist oversight for rate changes, the telemetry and medical-surgical patient care areas demonstrated a 32% reduction in reported monthly errors involving i.v. administration of heparin. By integrating two stand-alone technologies, i.v. interoperability was implemented to improve medication administration. Medication errors were reduced, nursing workflow was simplified, and pharmacists became involved in checking infusion rates of i.v. medications.

Intravenous Solutions for Exploration Missions

NASA Technical Reports Server (NTRS)

Miller, Fletcher J.; Niederhaus, Charles; Barlow, Karen; Griffin, DeVon

2007-01-01

This paper describes the intravenous (IV) fluids requirements being developed for medical care during NASA s future exploration class missions. Previous research on IV solution generation and mixing in space is summarized. The current exploration baseline mission profiles are introduced, potential medical conditions described and evaluated for fluidic needs, and operational issues assessed. We briefly introduce potential methods for generating IV fluids in microgravity. Conclusions on the recommended fluid volume requirements are presented.

ADHD latent class clusters: DSM-IV subtypes and comorbidity

PubMed Central

Elia, Josephine; Arcos-Burgos, Mauricio; Bolton, Kelly L.; Ambrosini, Paul J.; Berrettini, Wade; Muenke, Maximilian

2014-01-01

ADHD (Attention Deficit Hyperactivity Disorder) has a complex, heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6–18, participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. PMID:19900717

Biotin-tagged platinum(iv) complexes as targeted cytostatic agents against breast cancer cells.

PubMed

Muhammad, Nafees; Sadia, Nasreen; Zhu, Chengcheng; Luo, Cheng; Guo, Zijian; Wang, Xiaoyong

2017-09-05

A biotin-guided platinum IV complex is highly cytotoxic against breast cancer cells but hypotoxic against mammary epithelial cells. The mono-biotinylated Pt IV complex is superior to the di-biotinylated one and hence a promising drug candidate for the targeted therapy of breast cancer.

Programmable Infusion Pumps in ICUs: An Analysis of Corresponding Adverse Drug Events

PubMed Central

Bower, Anthony G.; Paddock, Susan M.; Hilborne, Lee H.; Wallace, Peggy; Rothschild, Jeffrey M.; Griffin, Anne; Fairbanks, Rollin J.; Carlson, Beverly; Panzer, Robert J.; Brook, Robert H.

2007-01-01

Background Patients in intensive care units (ICUs) frequently experience adverse drug events involving intravenous medications (IV-ADEs), which are often preventable. Objectives To determine how frequently preventable IV-ADEs in ICUs match the safety features of a programmable infusion pump with safety software (“smart pump”) and to suggest potential improvements in smart-pump design. Design Using retrospective medical-record review, we examined preventable IV-ADEs in ICUs before and after 2 hospitals replaced conventional pumps with smart pumps. The smart pumps alerted users when programmed to deliver duplicate infusions or continuous-infusion doses outside hospital-defined ranges. Participants 4,604 critically ill adults at 1 academic and 1 nonacademic hospital. Measurements Preventable IV-ADEs matching smart-pump features and errors involved in preventable IV-ADEs. Results Of 100 preventable IV-ADEs identified, 4 involved errors matching smart-pump features. Two occurred before and 2 after smart-pump implementation. Overall, 29% of preventable IV-ADEs involved overdoses; 37%, failures to monitor for potential problems; and 45%, failures to intervene when problems appeared. Error descriptions suggested that expanding smart pumps’ capabilities might enable them to prevent more IV-ADEs. Conclusion The smart pumps we evaluated are unlikely to reduce preventable IV-ADEs in ICUs because they address only 4% of them. Expanding smart-pump capabilities might prevent more IV-ADEs. PMID:18095043

Targeted pancreatic cancer therapy with the small molecule drug conjugate SW IV-134.

PubMed

Hashim, Yassar M; Spitzer, Dirk; Vangveravong, Suwanna; Hornick, Mary C; Garg, Gunjal; Hornick, John R; Goedegebuure, Peter; Mach, Robert H; Hawkins, William G

2014-07-01

Pancreatic adenocarcinoma is highly resistant to conventional therapeutics and has been shown to evade apoptosis by deregulation of the X-linked and cellular inhibitors of apoptosis proteins (XIAP and cIAP). Second mitochondria-derived activator of caspases (Smac) induces and amplifies cell death by reversing the anti-apoptotic activity of IAPs. Thus, Smac-derived peptide analogues (peptidomimetics) have been developed and shown to represent promising cancer therapeutics. Sigma-2 receptors are overexpressed in many proliferating tumor cells including pancreatic cancer. Selected ligands to this receptor are rapidly internalized by cancer cells. These characteristics have made the sigma-2 receptor an attractive target for drug delivery because selective delivery to cancer cells has the potential to increase therapeutic efficacy while minimizing toxicity to normal tissues. Here, we describe the initial characterization of SW IV-134, a chemically linked drug conjugate between the sigma-2 ligand SW43 and the Smac mimetic SW IV-52 as a novel treatment option for pancreatic adenocarcinoma. The tumor killing characteristics of our dual-domain therapeutic SW IV-134 was far greater than either component in isolation or in an equimolar mix and suggests enhanced cellular delivery when chemically linked to the sigma-2 ligand. One of the key findings was that SW IV-134 retained target selectivity of the Smac cargo with the involvement of the NF-κB/TNFα signaling pathway. Importantly, SW IV-134 slowed tumor growth and improved survival in murine models of pancreatic cancer. Our data support further study of this novel therapeutic and this drug delivery strategy because it may eventually benefit patients with pancreatic cancer. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

New metastable form of glibenclamide prepared by redispersion from ternary solid dispersions containing polyvinylpyrrolidone-K30 and sodium lauryl sulfate.

PubMed

Thongnopkoon, Thanu; Puttipipatkhachorn, Satit

2016-01-01

Modification of polymorphic forms of poorly water-soluble drugs is one way to achieve the desirable properties. In this study, glibenclamide (GBM) particles with different polymorphic forms, including a new metastable form, were obtained from redispersion of ternary solid dispersion systems. The ternary solid dispersion systems, consisting of GBM, polyvinylpyrrolidone-K30 (PVP-K30) and sodium lauryl sulfate (SLS), were prepared by solvent evaporation method and subsequently redispersed in deionized water. The precipitated drug particles were then collected at a given time period. The drug particles with different polymorphic forms could be achieved depending on the polymer/surfactant ratio. Amorphous drug nanoparticles could be obtained by using a high polymer/surfactant ratio, whereas two different crystalline forms were obtained from the systems containing low polymer/surfactant ratios. Interestingly, a new metastable form IV of GBM with improved dissolution behavior could be obtained from the system of GBM:PVP-K30:SLS with the weight ratio of 2:2:4. This new polymorphic form IV of GBM was confirmed by differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffractometry (PXRD) and solid state 13 C nuclear magnetic resonance (NMR) spectroscopy. The molecular arrangement of the new polymorphic form IV of GBM was proposed. The GBM particles with polymorphic form IV also showed an improved dissolution behavior. In addition, it was found that the formation of the new polymorphic form IV of GBM by this process was reproducible.

Preliminary study of the effects of xylazine or detomidine with or without butorphanol for standing sedation in dairy cattle.

PubMed

Lin, Hui Chu; Riddell, M Gatz

2003-01-01

The sedative effect induced by administering xylazine hydrochloride or detomidine hydrochloride with or without butorphanol tartrate to standing dairy cattle was compared in two groups of six adult, healthy Holstein cows. One group received xylazine (0.02 mg/kg i.v.) followed by xylazine (0.02 mg/kg) and butorphanol (0.05 mg/kg i.v.) 1 week later. Cows in Group B received detomidine (0.01 mg/kg i.v.) followed by detomidine (0.01 mg/kg i.v.) and butorphanol (0.05 mg/kg i.v.) 1 week later. Heart rate, respiratory rate, and arterial blood pressure were monitored and recorded before drugs were administered and every 10 minutes for 1 hour after drug administration. The degree of sedation was evaluated and graded. Cows in each treatment group had significant decreases in heart rate and respiratory rate after test drugs were given. Durations of sedation were 49.0 +/- 12.7 minutes (xylazine), 36.0 +/- 14.1 (xylazine with butorphanol), 47.0 +/- 8.1 minutes (detomidine), and 43.0 +/- 14.0 minutes (detomidine with butorphanol). Ptosis and salivation were observed in cows of all groups following drug administration. Slow horizontal nystagmus was observed from three cows following administration of detomidine and butorphanol. All cows remained standing while sedated. The degree of sedation seemed to be most profound in cows receiving detomidine and least profound in cows receiving xylazine.

Synthesis, Biological Evaluation, and Molecular Docking of (R)-2-((8-(3-aminopiperidin-1-yl)-3-methyl-7-(3-methylbut-2-en-1-yl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)benzonitrile as Dipeptidyl Peptidase IV Inhibitors.

PubMed

Ran, Yan; Pei, Heying; Shao, Mingfeng; Chen, Lijuan

2016-02-01

Type 2 diabetes (T2D) is classified as a major metabolic disorder, which has affected approximately 194 million people worldwide. DPP-IV inhibitors as a new therapy have shown several advantages over traditional antidiabetic drugs. Based on the similar binding modes of Alogliptin and Linagliptin, molecular operation was conducted via combining pharmacophore hybridization with structural optimization between the two market drugs and racemic compounds 40 and 43 were reported as DPP-IV inhibitors in our previous studies. But the majority of DPP-IV inhibitors have developed into a small molecule with certain conformation; in this study, we described the synthesis, biological evaluation, and molecular docking of corresponding enantiomers of compounds 40 and 43. The most potent inhibitor is (R)-40 (IC50  = 23.5 nm, F = 74.67%, T1/2  = 4 h), which exhibited moderate antihyperglycemic activity as compared to the standard antidiabetic drug Linagliptin in OGTT. In addition, compound (R)-40 effectively improved the pathological state of DIO mice. Molecular docking studies clarified the favorable binding affinity between compound (R)-40 and DPP-IV active site. Thus, compound (R)-40 would be entitled to further development as a drug candidate on the basis of the suitable pharmacokinetic (PK) and desirable pharmacodynamic (PD) profiles. © 2015 John Wiley & Sons A/S.

Impacts of generic competition and benefit management practices on spending for prescription drugs: evidence from Medicare's Part D benefit.

PubMed

Sheingold, Steven; Nguyen, Nguyen Xuan

2014-01-01

This study estimates the effects of generic competition, increased cost-sharing, and benefit practices on utilization and spending for prescription drugs. We examined changes in Medicare price and utilization from 2007 to 2009 of all drugs in 28 therapeutic classes. The classes accounted for 80% of Medicare Part D spending in 2009 and included the 6 protected classes and 6 classes with practically no generic competition. All variables were constructed to measure each drug relative to its class at a specific plan sponsor. We estimated that the shift toward generic utilization had cut in half the rate of increase in the price of a prescription during 2007-2009. Specifically, the results showed that (1) rapid generic penetration had significantly held down costs per prescription, (2) copayment and other benefit practices shifted utilization to generics and favored brands, and (3) price increases were generally greater in less competitive classes of drugs. In many ways, Part D was implemented at a fortuitous time; since 2006, there have been relatively few new blockbuster drugs introduced, and many existing high-volume drugs used by beneficiaries were in therapeutic classes with multiple brands and generic alternatives. Under these conditions, our paper showed that plan sponsors have been able to contain costs by encouraging use of generics or drugs offering greater value within therapeutic classes. It is less clear what will happen to future Part D costs if a number of new and effective drugs for beneficiaries enter the market with no real competitors.

The "index cutback technique": a three-dimensional guided layering approach in direct class IV composite restorations.

PubMed

Ammannato, Riccardo; Ferraris, Federico; Allegri, Mario

One of the main difficulties encountered with conventional class IV direct composite restorations is the layering management in terms of three-dimensionality and shape control. The major concern is the predictability of the esthetic outcome, which is closely linked to the clinician's skills. This article presents a predictable approach to treat class IV direct composite restorations. The technique allows for the shape and thickness of different composite layers to be guided through transparent indexes that have been carried out previously on a planned wax-up. The final goal is to achieve a good esthetic outcome in an easy and fast way through a copy-and-paste approach. The "index cutback technique" is a complementary variant of the "index technique" for class IV direct restorations. After the casts have been generated, the technician creates a full wax-up of the tooth to be restored. A transparent silicone key of the full wax-up provides the full enamel index that is then cut with a blade along the incisal edge to achieve two enamel indexes, one palatal and one buccal. Then, the required amount of wax is removed from the full wax-up through a cutback step. The aim of this step is to remove a suitable amount of wax to leave a predetermined space for the composite enamel layers, both on the palatal and buccal surfaces. A second transparent silicone key is built on the cutback wax-up to achieve the cutback dentin index, which is then used to press the composite dentin onto the prepared tooth.

Few Drugs Display Flip-Flop Pharmacokinetics and These Are Primarily Associated with Classes 3 and 4 of the BDDCS.

PubMed

Garrison, Kimberly L; Sahin, Selma; Benet, Leslie Z

2015-09-01

This study was conducted to determine the number of drugs exhibiting flip-flop pharmacokinetics following oral (p.o.) dosing from immediate-release dosage forms and if they exhibit a common characteristic that may be predicted based on BDDCS classification. The literature was searched for drugs displaying flip-flop kinetics (i.e., absorption half-life larger than elimination half-life) in mammals in PubMed, via internet search engines and reviewing drug pharmacokinetic data. Twenty two drugs were identified as displaying flip-flop kinetics in humans (13 drugs), rat (nine drugs), monkey (three drugs), horse (two drugs), and/or rabbit (two drugs). Nineteen of the 22 drugs exhibiting flip-flop kinetics were BDDCS Classes 3 and 4. One of the three exceptions, meclofenamic acid (Class 2), was identified in the horse; however, it would not exhibit flip-flop kinetics in humans where the p.o. dosing terminal half-life is 1.4 h. The second, carvedilol, can be explained based on solubility issues, but the third sapropterin dihydrochloride (nominally Class 1) requires further consideration. The few drugs displaying p.o. flip-flop kinetics in humans are predominantly BDDCS Classes 3 and 4. New molecular entities predicted to be BDDCS Classes 3 and 4 could be liable to exhibit flip-flop kinetics when the elimination half life is short and should be suspected to be substrates for intestinal transporters. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Patterns of HIV Risks and Related Factors among People Who Inject Drugs in Kermanshah, Iran: A Latent Class Analysis.

PubMed

Sharifi, Hamid; Mirzazadeh, Ali; Noroozi, Alireza; Marshall, Brandon D L; Farhoudian, Ali; Higgs, Peter; Vameghi, Meroe; Mohhamadi Shahboulaghi, Farahnaz; Qorbani, Mostafa; Massah, Omid; Armoon, Bahram; Noroozi, Mehdi

2017-01-01

The objective of this study was to explore patterns of drug use and sexual risk behaviors among people who inject drugs (PWID) in Iran. We surveyed 500 PWID in Kermanshah concerning demographic characteristics, sexual risk behaviors, and drug-related risk behaviors in the month prior to study. We used latent class analysis (LCA) to establish a baseline model of risk profiles and to identify the optimal number of latent classes, and we used ordinal regression to identify factors associated with class membership. Three classes of multiple HIV risk were identified. The probability of membership in the high-risk class was 0.33, compared to 0.26 and 0.40 for the low- and moderate-risk classes, respectively. Compared to members in the lowest-risk class (reference group), the highest-risk class members had higher odds of being homeless (OR = 4.5, CI: 1.44-8.22; p = 0.001) in the past 12 months. Members of the high-risk class had lower odds of regularly visiting a needle and syringe exchange program as compared to the lowest-risk class members (AOR = 0.42, CI: 0.2-0.81; p = 0.01). Findings show the sexual and drug-related HIV risk clusters among PWID in Iran, and emphasize the importance of developing targeted prevention and harm reduction programs for all domains of risk behaviors, both sexual and drug use related.

A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes.

PubMed

Chen, Lei; Lu, Jing; Zhang, Ning; Huang, Tao; Cai, Yu-Dong

2014-04-01

In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC-classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs.

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

PubMed Central

Johnstone, Timothy C.; Suntharalingam, Kogularamanan; Lippard, Stephen J.

2016-01-01

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer,, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing non-classical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore non-classical platinum(II) complexes with trans geometry and with a monofunctional coordination mode, polynuclear platinum(II) compounds, platinum(IV) prodrugs, dual-treat agents, and photoactivatable platinum(IV) complexes. Nanodelivery particles designed to deliver platinum(IV) complexes will also be discussed, including carbon nanotubes, carbon nanoparticles, gold nanoparticles, quantum dots, upconversion nanoparticles, and polymeric micelles. Additional nanoformulations including supramolecular self-assembled structures, proteins, peptides, metal-organic frameworks, and coordination polymers will then be described. Finally, the significant clinical progress made by nanoparticle formulations of platinum(II) agents will be reviewed. We anticipate that such a synthesis of disparate research efforts will not only help to generate new drug development ideas and strategies, but also reflect our optimism that the next generation of platinum cancer drugs is about to arrive. PMID:26865551

Patterns of Drug Use and Serum Sodium Concentrations in Older Hospitalized Patients: A Latent Class Analysis Approach.

PubMed

Woodman, Richard J; Wood, Karen M; Kunnel, Aline; Dedigama, Maneesha; Pegoli, Matthew A; Soiza, Roy L; Mangoni, Arduino A

2016-12-01

Several drugs may lower serum sodium concentrations (NaC) in older patients. However, distinguishing their individual effects is particularly difficult in this population because of the high prevalence of polypharmacy and disease states that are per se associated with hyponatremia. Our objective was to identify specific patterns of medication use in older hospitalized patients and determine whether these patterns were associated with serum NaC. We collected clinical and demographic data, pre-admission drugs, Drug Burden Index (DBI) score, and average NaC during hospitalization in a consecutive series of older medical patients (n = 101, mean ± standard deviation [SD] age 87 ± 6 years). We used latent class analysis (LCA) to identify specific patterns of drug use and multivariate regression to determine the associations between 14 separate drug classes, identified patterns of drug use, and NaC. LCA revealed three patterns: lower overall drug use (class 1), anticoagulant use and higher drug use (class 2), and antiplatelet use (class 3). Mean (±SD) DBI score in each class was 2.7 ± 1.3, 3.3 ± 1.6, and 2.4 ± 1.5, respectively (p = 0.04). Mean (± SD) NaC in classes 1, 2, and 3 were 140.6 ± 6.8, 138.7 ± 5.3, and 136.5 ± 4.7 mmol/l, respectively (p = 0.006). After adjustment for age, sex, Charlson Comorbidity Index score, estimated glomerular filtration rate (eGFR), DBI score, and digoxin use, mean NaC in class 2 and class 3 was significantly lower than in class 1 (-3.9 mmol/l; 95% confidence interval [CI] -7.1 to -0.8, p = 0.01 and -5.2 mmol/l; 95% CI -7.9 to -2.5, p < 0.001, respectively). Mean serum NaC was not significantly associated with any of the 14 individually assessed drug classes. In addition to latent class, increasing age and higher eGFR were also independently associated with lower serum NaC (p = 0.002 and p = 0.03, respectively). LCA enabled us to identify patterns of drug use associated with lower serum NaC in older inpatients. Our results suggest that older patients using antiplatelets or anticoagulants are especially at risk of lower serum NaC.

Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ.

PubMed

Yuan, Youyong; Kwok, Ryan T K; Tang, Ben Zhong; Liu, Bin

2014-02-12

Targeted drug delivery to tumor cells with minimized side effects and real-time in situ monitoring of drug efficacy is highly desirable for personalized medicine. In this work, we report the synthesis and biological evaluation of a chemotherapeutic Pt(IV) prodrug whose two axial positions are functionalized with a cyclic arginine-glycine-aspartic acid (cRGD) tripeptide for targeting integrin αvβ3 overexpressed cancer cells and an apoptosis sensor which is composed of tetraphenylsilole (TPS) fluorophore with aggregation-induced emission (AIE) characteristics and a caspase-3 enzyme specific Asp-Glu-Val-Asp (DEVD) peptide. The targeted Pt(IV) prodrug can selectively bind to αvβ3 integrin overexpressed cancer cells to facilitate cellular uptake. In addition, the Pt(IV) prodrug can be reduced to active Pt(II) drug in cells and release the apoptosis sensor TPS-DEVD simultaneously. The reduced Pt(II) drug can induce the cell apoptosis and activate caspase-3 enzyme to cleave the DEVD peptide sequence. Due to free rotation of the phenylene rings, TPS-DEVD is nonemissive in aqueous media. The specific cleavage of DEVD by caspase-3 generates the hydrophobic TPS residue, which tends to aggregate, resulting in restriction of intramolecular rotations of the phenyl rings and ultimately leading to fluorescence enhancement. Such noninvasive and real-time imaging of drug-induced apoptosis in situ can be used as an indicator for early evaluation of the therapeutic responses of a specific anticancer drug.

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts

PubMed Central

Schuetze, Katherine B.; Stratton, Matthew S.; Blakeslee, Weston W.; Wempe, Michael F.; Wagner, Florence F.; Holson, Edward B.; Kuo, Yin-Ming; Andrews, Andrew J.; Gilbert, Tonya M.; Hooker, Jacob M.

2017-01-01

Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II, and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiologic and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103 [N-(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide], was shown to block cardiac fibrosis, a process involving excess extracellular matrix deposition, which often results in heart dysfunction. Here, we compare the mechanisms of action of structurally distinct HDAC inhibitors in isolated primary cardiac fibroblasts, which are the major extracellular matrix–producing cells of the heart. TSA, MGCD0103, and the cyclic peptide class I HDAC inhibitor, apicidin, exhibited a common ability to enhance histone acetylation, and all potently blocked cardiac fibroblast cell cycle progression. In contrast, MGCD0103, but not TSA or apicidin, paradoxically increased expression of a subset of fibrosis-associated genes. Using the cellular thermal shift assay, we provide evidence that the divergent effects of HDAC inhibitors on cardiac fibroblast gene expression relate to differential engagement of HDAC1- and HDAC2-containing complexes. These findings illustrate the importance of employing multiple compounds when pharmacologically assessing HDAC function in a cellular context and during HDAC inhibitor drug development. PMID:28174211

Epilepsy surgery in a pediatric population: a retrospective study of 129 children from a tertiary care hospital in a developing country along with assessment of quality of life.

PubMed

Dagar, Amit; Chandra, P Sarat; Chaudhary, Kapil; Avnish, Chauhan; Bal, C S; Gaikwad, Shailesh; Garg, Ajay; Sarkar, Chitra; Srivastava, A; Padma, M V; Rekha, Diwedi; Gulati, Sheffali; Paul, Vinod; Prasad, K; Singh, M B; Tripathi, Manjari

2011-01-01

To assess the outcome of a pediatric population operated for drug-resistant epilepsy from a large tertiary care center in India. Retrospectively: quality of life (QOL); prospectively: preoperative assessment included interictal EEG, MRI (as per epilepsy protocol), video-EEG. Ictal SPECT (with subtraction) and PET were performed when required. QOL scores were assessed using the HASS or SSQ for seizure severity, Quality of Life in Childhood Epilepsy (QOLCE) for QOL, and Child Behavior Check List (CBCL) for behavior. 142 were operated from January 2000 to June 2011 by the senior author. 118 patients with at least 1 year of follow-up were included in the study. Mean age at surgery was 9.8 ± 4.3 years. In addition, 40 patients underwent QOL assessment prospectively both before and after surgery. Mean duration of epilepsy was 5.3 ± 3.3 years. A class I outcome (Engel's) was seen in 79.5% patients, class II in 8.6%, class III in 10.7%, and class IV in 1 patient. As per surgical procedures, class I outcome in patients who underwent temporal resection, hemispherotomy and extratemporal resection was 76, 87 and 72%, respectively. QOL scores correlated with duration of seizures, epileptic encephalopathy and outcome of surgery, but not with side of surgery, age and sex. This study, the largest reported from India, has demonstrated satisfactory results for epilepsy surgery in children. Copyright © 2011 S. Karger AG, Basel.

Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs.

PubMed

Gandhi, Shivani V; Rodriguez, William; Khan, Mansoor; Polli, James E

2014-06-01

It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

2D and 3D T2-weighted MR sequences for the assessment of neurovascular bundle changes after nerve-sparing radical retropubic prostatectomy with erectile function correlation.

PubMed

Panebianco, Valeria; Sciarra, Alessandro; Osimani, Marcello; Lisi, Danilo; Ciccariello, Mauro; Salciccia, Stefano; Gentile, Vincenzo; Di Silverio, Franco; Passariello, Roberto

2009-01-01

The aim of this study was to assess the capability of a 3D isotropic MRI T2-weighted sequence (3D T2 ISO) in the depiction of changes of neurovascular bundles (NVBs) after bilateral nerve-sparing radical retropubic prostatectomy (RRP). Furthermore, our aim was also to introduce a new MRI classification score of the NVB alteration patterns using the International Index Erectile Function Five-Item (IIEF-5) score as standard of reference. Fifty-three consecutive patients were postoperatively submitted to two MR examinations, including both 2D TSE T2-weighted (2D T2) and 3D T2 ISO sequences. Image findings were scored using a relative five-point classification and correlated with the postoperative IIEF-5 score. Radiologists attributed 13.2% of patients to class 0, 11.3% to class I, 34% to class II, 24.5% to class III, and 16.9% to class IV. With 3D T2 ISO images, the same radiologists determined 43.3% class 0, 32% class I, 11.4% class II, 7.5% class III, and 5.7% class IV. In all cases, the correlation and regression analysis between the 3D T2 ISO and IIEF-5 score resulted in higher coefficients values. The 3D sequence correlated most closely with patients' grading of erectile function.

Pharmacokinetic interaction between liquiritigenin (LQ) and DDB: increased glucuronidation of LQ in the liver possibly due to increased hepatic blood flow rate by DDB.

PubMed

Kang, Hee E; Chung, Hye J; Kim, Hyung S; Lee, Jee W; Lee, Myung G

2010-01-31

It has been reported that both liquiritigenin (LQ) and dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) have a hepatoprotective effect, and administration of both drugs together shows additive protective effect against acute liver injuries. Therefore, the pharmacokinetic interaction between LQ and DDB in rats was studied. LQ (20 and 50mg/kg for the i.v. and p.o. administration, respectively), DDB (10mg/kg for both i.v. and p.o. administration), and both drugs together were once administered intravenously or orally to rats. After the i.v. administration of both drugs together, the Cl(nr) and AUC of LQ were significantly faster (by 30.5%) and smaller (by 22.5%), respectively, than those of without DDB due to the faster hepatic blood flow rate by DDB. After the p.o. administration of both drugs together, the AUC of LQ was comparable to that of without DDB due to negligible effect of DDB on intestinal metabolism of LQ. The pharmacokinetic parameters of DDB after both i.v. and p.o. administration were not altered by LQ, indicating that LQ did not considerably affect the pharmacokinetics of DDB in rats. Copyright 2009 Elsevier B.V. All rights reserved.

Tumour-associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

PubMed Central

Miller, Miles A.; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer H.; Iwamoto, Yoshiko; Yang, Katherine S.; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid C.; Weissleder, Ralph

2015-01-01

Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behaviour. Model TNPs comprising a fluorescent platinum(IV) pro-drug and a clinically tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directing cellular uptake toward tumour-associated macrophages (TAMs). Simultaneous imaging of TNP vehicle, its drug payload and single-cell DNA damage response reveals that TAMs serve as a local drug depot that accumulates significant vehicle from which DNA-damaging Pt payload gradually releases to neighbouring tumour cells. Correspondingly, TAM depletion reduces intratumoral TNP accumulation and efficacy. Thus, nanotherapeutics co-opt TAMs for drug delivery, which has implications for TNP design and for selecting patients into trials. PMID:26503691

Renal tubular acidosis type IV in hyperkalaemic patients--a fairy tale or reality?

PubMed

Haas, Christian S; Pohlenz, Inga; Lindner, Ulrich; Muck, Philip M; Arand, Jovana; Suefke, Sven; Lehnert, Hendrik

2013-05-01

Hyperkalaemia is a common feature in hospitalized patients and often attributed to drugs antagonizing the renin-angiotensin-aldosterone system (RAAS) and/or acute kidney injury (AKI), despite significantly preserved glomerular filtration rate (GFR). The objective of this study was to determine the prevalence and role of renal tubular acidosis type IV (RTA IV) in the development of significant hyperkalaemia. A single-centre retrospective study. Patients admitted to a University Hospital over 12 months. Patients with a potassium value > 6·0 mm were identified. Clinical and laboratory data were revisited, and patients with a normal anion gap metabolic acidosis were evaluated for the existence of RTA IV. A total of 57 patients having significant hyperkalaemia (>6·0 mm) were identified. Twelve patients had end-stage renal disease, while 21 patients had solely AKI or progressive chronic renal failure. RTA IV was present in 24 patients (42%), of whom 71% had pre-existing renal insufficiency because of diabetic nephropathy or tubulointerstitial nephritis. All hyperkalaemic patients with urinary/serum electrolytes suggestive of RTA IV had evidence of AKI, but creatinine levels were significantly lower (P < 0·05), while the number of drugs antagonizing the RAAS was comparable. We demonstrated that RTA IV (i) is very common in patients with hyperkalaemia; (ii) should always be suspected in hyperkalaemic patients with only moderately impaired GFR; and (iii) may result in significant hyperkalaemia in the presence of both AKI and drugs antagonizing the RAAS. © 2012 Blackwell Publishing Ltd.

40 CFR 90.104 - Compliance with emission standards.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Volume Engine Families Engine class Two-stroke engines 1 HC+NOX CO Four-stroke engines HC+NOX CO Engines...). Class IV 1.1 1.1 1.5 1.1 Class V 1.1 1.1 1.5 1.1 1 Two-stroke technologies to which these assigned deterioration factors apply include conventional two-strokes, compression wave designs, and stratified...

40 CFR 90.104 - Compliance with emission standards.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Volume Engine Families Engine class Two-stroke engines 1 HC+NOX CO Four-stroke engines HC+NOX CO Engines...). Class IV 1.1 1.1 1.5 1.1 Class V 1.1 1.1 1.5 1.1 1 Two-stroke technologies to which these assigned deterioration factors apply include conventional two-strokes, compression wave designs, and stratified...

40 CFR 90.104 - Compliance with emission standards.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Volume Engine Families Engine class Two-stroke engines 1 HC+NOX CO Four-stroke engines HC+NOX CO Engines...). Class IV 1.1 1.1 1.5 1.1 Class V 1.1 1.1 1.5 1.1 1 Two-stroke technologies to which these assigned deterioration factors apply include conventional two-strokes, compression wave designs, and stratified...

40 CFR 90.104 - Compliance with emission standards.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Volume Engine Families Engine class Two-stroke engines 1 HC+NOX CO Four-stroke engines HC+NOX CO Engines...). Class IV 1.1 1.1 1.5 1.1 Class V 1.1 1.1 1.5 1.1 1 Two-stroke technologies to which these assigned deterioration factors apply include conventional two-strokes, compression wave designs, and stratified...

40 CFR 90.104 - Compliance with emission standards.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Volume Engine Families Engine class Two-stroke engines 1 HC+NOX CO Four-stroke engines HC+NOX CO Engines...). Class IV 1.1 1.1 1.5 1.1 Class V 1.1 1.1 1.5 1.1 1 Two-stroke technologies to which these assigned deterioration factors apply include conventional two-strokes, compression wave designs, and stratified...

76 FR 56833 - Self-Regulatory Organizations; BATS Y-Exchange, Inc.; Notice of Filing of Proposed Rule Change To...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-14

... respective voting rights and of Class A and Class B common stock, (iv) setting forth certain limitations on... Incorporation, shares of Non-Voting Common Stock possess the same rights, preferences, powers, privileges... B Common Stock. Except for voting rights and certain conversion features, as described below, Class...

76 FR 56840 - Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing of Proposed Rule Change To...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-14

... respective voting rights and of Class A and Class B common stock, (iv) setting forth certain limitations on... Incorporation, shares of Non-Voting Common Stock possess the same rights, preferences, powers, privileges...-Voting Class B Common Stock. Except for voting rights and certain conversion features, as described below...

77 FR 24978 - Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Leases, Utah.

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-26

... Proposed Class II Reinstatement of Terminated Oil and Gas Leases, Utah. AGENCY: Bureau of Land Management, Interior. ACTION: Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Leases, Utah. SUMMARY: In accordance with Title IV of the Federal Oil and Gas Royalty Management Act (Pub. L. 97-451...

76 FR 14686 - Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-17

... Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah AGENCY: Bureau of Land Management, Interior. ACTION: Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah. SUMMARY: In accordance with Title IV of the Federal Oil and Gas Royalty Management Act (Pub. L. 97-451...

Improvement of Oral Bioavailability of Lopinavir Without Co-administration of Ritonavir Using Microspheres of Thiolated Xyloglucan.

PubMed

Madgulkar, Ashwini R; Bhalekar, Mangesh R; Kadam, Ashwini A

2018-01-01

Lopinavir is a BCS Class IV drug exhibiting poor bioavailability due to P-gp efflux and limited permeation. The aim of this research was to formulate and characterize microspheres of lopinavir using thiolated xyloglucan (TH-MPs) as carrier to improve its oral bioavailability without co-administration of ritonavir. Thiomeric microspheres were prepared by ionotropic gelation between alginic acid and calcium ions. Interaction studies were performed using Fourier transform infrared spectroscopy (FT-IR). The thiomeric microspheres were characterized for its entrapment efficiency, T 80 , surface morphology, and mucoadhesion employing in vitro wash off test. The microspheres were optimized by 3 2 factorial design. The optimized thiomeric microsphere formulation revealed 93.12% entrapment efficiency, time for 80% drug release (T 80 ) of 358.1 min, and 88% mucoadhesion after 1 h. The permeation of lopinavir from microspheres was enhanced 3.15 times as determined by ex vivo study using everted chick intestine and increased relative bioavailability over 3.22-fold over combination of lopinavir and ritonavir as determined by in vivo study in rat model.

Patterns of Drug Use, Risky Behavior, and Health Status Among Persons Who Inject Drugs Living in San Diego, California: A Latent Class Analysis

PubMed Central

Roth, Alexis M.; Armenta, Richard A.; Wagner, Karla D.; Roesch, Scott C.; Bluthenthal, Ricky N.; Cuevas-Mota, Jazmine; Garfein, Richard S.

2015-01-01

Background Among persons who inject drugs (PWID), polydrug use (the practice of mixing multiple drugs/alcohol sequentially or simultaneously) increases risk for HIV transmission and unintentional overdose deaths. Research has shown local drug markets influence drug use practices. However, little is known about the impact of drug mixing in markets dominated by black tar heroin and methamphetamine, such as the western United States. Methods Data were collected through an ongoing longitudinal study examining drug use, risk behavior, and health status among PWID. Latent class analysis (LCA) was used to identify patterns of substance use (heroin, methamphetamine, prescription drugs, alcohol, and marijuana) via multiple administration routes (injecting, smoking, and swallowing). Logistic regression was used to identify behaviors and health indicators associated with drug use class. Results The sample included 511 mostly white (51.5%) males (73.8%), with mean age of 43.5 years. Two distinct classes of drug users predominated: methamphetamine by multiple routes (51%) and heroin by injection (49%). In multivariable logistic regression, class membership was associated with age, race, and housing status. PWID who were HIV-seropositive and reported prior sexually transmitted infections had increased odds of belonging to the methamphetamine class. Those who were HCV positive and reported previous opioid overdose had an increased odds of being in the primarily heroin injection class (all P-values < .05). Conclusion Risk behaviors and health outcomes differed between PWID who primarily inject heroin vs. those who use methamphetamine. The findings suggest that in a region where PWID mainly use black tar heroin or methamphetamine, interventions tailored to sub-populations of PWID could improve effectiveness. PMID:25313832

Biowaiver extension potential and IVIVC for BCS Class II drugs by formulation design: Case study for cyclosporine self-microemulsifying formulation.

PubMed

Yang, Su-Geun

2010-11-01

The objective of this work was to suggest the biowaiver potential of biopharmaceutical classification system (BCS) Class II drugs in self-microemulsifying drug delivery systems (SMEDDS) which are known to increase the solubility, dissolution and oral absorption of water-insoluble drugs. Cyclosporine was selected as a representative BCS Class II drug. New generic candidate of cyclosporine SMEDDS (test) was applied for the study with brand SMEDDS (reference I) and cyclosporine self-emulsifying drug delivery systems (SEDDS, reference II). Solubility and dissolution of cyclosporine from SMEDDS were critically enhanced, which were the similar behaviors with BCS class I drug. The test showed the identical dissolution rate and the equivalent bioavailability (0.34, 0.42 and 0.68 of p values for AUC₀(→)₂₄(h), C(max) and T(max), respectively) with the reference I. Based on the results, level A in vitro-in vivo correlation (IVIVC) was established from these two SMEDDS formulations. This study serves as a good example for speculating the biowaiver extension potential of BCS Class II drugs specifically in solubilizing formulation such as SMEDDS.

BDDCS Class Prediction for New Molecular Entities

PubMed Central

Broccatelli, Fabio; Cruciani, Gabriele; Benet, Leslie Z.; Oprea, Tudor I.

2012-01-01

The Biopharmaceutics Drug Disposition Classification System (BDDCS) was successfully employed for predicting drug-drug interactions (DDIs) with respect to drug metabolizing enzymes (DMEs), drug transporters and their interplay. The major assumption of BDDCS is that the extent of metabolism (EoM) predicts high versus low intestinal permeability rate, and vice versa, at least when uptake transporters or paracellular transport are not involved. We recently published a collection of over 900 marketed drugs classified for BDDCS. We suggest that a reliable model for predicting BDDCS class, integrated with in vitro assays, could anticipate disposition and potential DDIs of new molecular entities (NMEs). Here we describe a computational procedure for predicting BDDCS class from molecular structures. The model was trained on a set of 300 oral drugs, and validated on an external set of 379 oral drugs, using 17 descriptors calculated or derived from the VolSurf+ software. For each molecule, a probability of BDDCS class membership was given, based on predicted EoM, FDA solubility (FDAS) and their confidence scores. The accuracy in predicting FDAS was 78% in training and 77% in validation, while for EoM prediction the accuracy was 82% in training and 79% in external validation. The actual BDDCS class corresponded to the highest ranked calculated class for 55% of the validation molecules, and it was within the top two ranked more than 92% of the times. The unbalanced stratification of the dataset didn’t affect the prediction, which showed highest accuracy in predicting classes 2 and 3 with respect to the most populated class 1. For class 4 drugs a general lack of predictability was observed. A linear discriminant analysis (LDA) confirmed the degree of accuracy for the prediction of the different BDDCS classes is tied to the structure of the dataset. This model could routinely be used in early drug discovery to prioritize in vitro tests for NMEs (e.g., affinity to transporters, intestinal metabolism, intestinal absorption and plasma protein binding). We further applied the BDDCS prediction model on a large set of medicinal chemistry compounds (over 30,000 chemicals). Based on this application, we suggest that solubility, and not permeability, is the major difference between NMEs and drugs. We anticipate that the forecast of BDDCS categories in early drug discovery may lead to a significant R&D cost reduction. PMID:22224483

Synthesis, spectroscopic, structural and thermal characterizations of vanadyl(IV) adenine complex prospective as antidiabetic drug agent

NASA Astrophysics Data System (ADS)

El-Megharbel, Samy M.; Hamza, Reham Z.; Refat, Moamen S.

2015-01-01

The vanadyl(IV) adenine complex; [VO(Adn)2]ṡSO4; was synthesized and characterized. The molar conductivity of this complex was measured in DMSO solution that showed an electrolyte nature. Spectroscopic investigation of the green solid complex studied here indicate that the adenine acts as a bidentate ligand, coordinated to vanadyl(IV) ions through the nitrogen atoms N7 and nitrogen atom of amino group. Thus, from the results presented the vanadyl(IV) complex has square pyramid geometry. Further characterizations using thermal analyses and scanning electron techniques was useful. The aim of this paper was to introduce a new drug model for the diabetic complications by synthesized a novel mononuclear vanadyl(IV) adenine complex to mimic insulin action and reducing blood sugar level. The antidiabetic ability of this complex was investigated in STZ-induced diabetic mice. The results suggested that VO(IV)/adenine complex has antidiabetic activity, it improved the lipid profile, it improved liver and kidney functions, also it ameliorated insulin hormone and blood glucose levels. The vanadyl(IV) complex possesses an antioxidant activity and this was clear through studying SOD, CAT, MDA, GSH and methionine synthase. The current results support the therapeutic potentiality of vanadyl(IV)/adenine complex for the management and treatment of diabetes.

Repellent and Anti-quorum Sensing Activity of Six Aromatic Plants Occurring in Colombia.

PubMed

Cervantes-Ceballos, Leonor; Caballero-Gallardo, Karina; Olivero-Verbel, Jesus

2015-10-01

Essential oils (EOs) are widely used as biopesticides and to control bacterial infections. This study describes the ability of six EOs isolated from plants cultivated in Colombia to perform as repellents against Ulomoides dermestoides and as quorum sensing (QS) inhibitors. EOs from Aloysia triphylla, Cymbopogon nardus, Lippia origanoides, Hyptis suaveolens, Swinglea glutinosa and Eucalyptus globulus were repellents classified as Class IV, IV, IV, III, II, and II, respectively, whereas the commercial repellent IR3535 only reached Class II after 2 h exposure. All EOs presented small, but significant inhibitory properties against the QS system in Escherichia coli (pJBA132) at 25 μg/mL after 4 h exposure. These data suggest evaluated EOs from Colombia are sustainable, promising new sources of natural repellents and could be important as anti-quorum sensing molecules.

14 CFR 61.5 - Certificates and ratings issued under this part.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... (iii) Glider. (iv) Lighter-than-air. (v) Powered-lift. (vi) Powered parachute. (vii) Weight-shift...—Airplane. (ii) Instrument—Helicopter. (iii) Instrument—Powered-lift. (c) The following ratings are placed.... (iii) Glider. (iv) Powered-lift. (2) Airplane class ratings— (i) Single-engine. (ii) Multiengine. (3...

14 CFR 61.5 - Certificates and ratings issued under this part.

Code of Federal Regulations, 2011 CFR

2011-01-01

.... (iii) Glider. (iv) Lighter-than-air. (v) Powered-lift. (vi) Powered parachute. (vii) Weight-shift...—Airplane. (ii) Instrument—Helicopter. (iii) Instrument—Powered-lift. (c) The following ratings are placed.... (iii) Glider. (iv) Powered-lift. (2) Airplane class ratings— (i) Single-engine. (ii) Multiengine. (3...

Congruence of Self-Reported Medications With Pharmacy Prescription Records In Low-Income Older Adults

PubMed Central

Caskie, Grace I. L.; Willis, Sherry L.

2013-01-01

Purpose This study examined the congruence of self-reported medications with computerized pharmacy records. Design and Methods Pharmacy records and self-reported medications were obtained for 294 members of a state pharmaceutical assistance program who also participated in ACTIVE, a clinical trial on cognitive training in nondemented elderly persons. The average age of the sample participants was 74.5 years (range = 65–91); 87.8% were females. Results Congruence between self-report and pharmacy data was generally high. Self-reports omitted drug classes in the pharmacy records less often than the pharmacy records did not include self-reported drug classes. The percentage of individuals with perfect agreement between self-reports and pharmacy records varied from 49% for major drug classes to 81 % for specific cardiovascular and central nervous system drugs. Within a drug class, agreement tended to be higher for individuals without a prescription in that class. Poorer health was consistently related to poorer self-report of medications. Implications Self-reported medications are most likely to be congruent with pharmacy records for drugs prescribed for more serious conditions, for more specific classes of drugs, and for healthier individuals. PMID:15075414

Exploring new classification criteria for the earliest type stars: the 3400 Aregion

NASA Astrophysics Data System (ADS)

Morrell, Nidia I.; Walborn, Nolan R.; Arias, Julia I.

2002-02-01

We propose spectroscopic observations of a sample of standard O2-O4 stars in the wavelength region containing the N IV 3479-83-85 Aand O IV 3381-85-3412 Alines, in order to analyze the behavior of these spectral features as a function of the spectral type. We aim to define new classification criteria for the hottest stars, evaluating these N IV and O IV lines near 3400 Aas possible temperature and luminosity discriminators. The former spectral class O3 has just been split into three different classes: O2, O3 and O3.5 (Walborn et al. 2001). The paucity of classification criteria at these types in the traditional wavelength domain (4000 - 4700 Å), makes clear the need to explore other spectral ranges in order to define additional constraints on the determination of spectral types and luminosity classes. The wavelength range around 3400 Ahas been observed in many faint, crowded early O-type stars by HST/FOS, the corresponding data being available from the HST archive. This enhances our interest in observing this spectral range in the classification standards for the early O-type stars in order to make these existing HST observations even more useful, allowing the determination of accurate spectral types for unknown objects from them, once the behavior of the new criteria in the standards has been charted.

42 CFR 418.54 - Condition of participation: Initial and comprehensive assessment of the patient.

Code of Federal Regulations, 2010 CFR

2010-10-01

... potential drug interactions. (iv) Duplicate drug therapy. (v) Drug therapy currently associated with... family and other individuals focusing on the social, spiritual, and cultural factors that may impact...

Fragment Based Strategies for Discovery of Novel HIV-1 Reverse Transcriptase and Integrase Inhibitors.

PubMed

Latham, Catherine F; La, Jennifer; Tinetti, Ricky N; Chalmers, David K; Tachedjian, Gilda

2016-01-01

Human immunodeficiency virus (HIV) remains a global health problem. While combined antiretroviral therapy has been successful in controlling the virus in patients, HIV can develop resistance to drugs used for treatment, rendering available drugs less effective and limiting treatment options. Initiatives to find novel drugs for HIV treatment are ongoing, although traditional drug design approaches often focus on known binding sites for inhibition of established drug targets like reverse transcriptase and integrase. These approaches tend towards generating more inhibitors in the same drug classes already used in the clinic. Lack of diversity in antiretroviral drug classes can result in limited treatment options, as cross-resistance can emerge to a whole drug class in patients treated with only one drug from that class. A fresh approach in the search for new HIV-1 drugs is fragment-based drug discovery (FBDD), a validated strategy for drug discovery based on using smaller libraries of low molecular weight molecules (<300 Da) screened using primarily biophysical assays. FBDD is aimed at not only finding novel drug scaffolds, but also probing the target protein to find new, often allosteric, inhibitory binding sites. Several fragment-based strategies have been successful in identifying novel inhibitory sites or scaffolds for two proven drug targets for HIV-1, reverse transcriptase and integrase. While any FBDD-generated HIV-1 drugs have yet to enter the clinic, recent FBDD initiatives against these two well-characterised HIV-1 targets have reinvigorated antiretroviral drug discovery and the search for novel classes of HIV-1 drugs.

Assessment: transcranial Doppler ultrasonography: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

PubMed

Sloan, M A; Alexandrov, A V; Tegeler, C H; Spencer, M P; Caplan, L R; Feldmann, E; Wechsler, L R; Newell, D W; Gomez, C R; Babikian, V L; Lefkowitz, D; Goldman, R S; Armon, C; Hsu, C Y; Goodin, D S

2004-05-11

To review the use of transcranial Doppler ultrasonography (TCD) and transcranial color-coded sonography (TCCS) for diagnosis. The authors searched the literature for evidence of 1) if TCD provides useful information in specific clinical settings; 2) if using this information improves clinical decision making, as reflected by improved patient outcomes; and 3) if TCD is preferable to other diagnostic tests in these clinical situations. TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk (Type A, Class I) and the detection and monitoring of angiographic vasospasm after spontaneous subarachnoid hemorrhage (Type A, Class I to II). TCD and TCCS provide important information and may have value for detection of intracranial steno-occlusive disease (Type B, Class II to III), vasomotor reactivity testing (Type B, Class II to III), detection of cerebral circulatory arrest/brain death (Type A, Class II), monitoring carotid endarterectomy (Type B, Class II to III), monitoring cerebral thrombolysis (Type B, Class II to III), and monitoring coronary artery bypass graft operations (Type B to C, Class II to III). Contrast-enhanced TCD/TCCS can also provide useful information in right-to-left cardiac/extracardiac shunts (Type A, Class II), intracranial occlusive disease (Type B, Class II to IV), and hemorrhagic cerebrovascular disease (Type B, Class II to IV), although other techniques may be preferable in these settings.

Risk prediction with procalcitonin and clinical rules in community-acquired pneumonia

PubMed Central

Huang, David T.; Weissfeld, Lisa A.; Kellum, John A.; Yealy, Donald M.; Kong, Lan; Martino, Michael; Angus, Derek C.

2009-01-01

Objective The Pneumonia Severity Index (PSI) and CURB-65 predict outcomes in community acquired pneumonia (CAP), but have limitations. Procalcitonin, a biomarker of bacterial infection, may provide prognostic information in CAP. Our objective was to describe the pattern of procalcitonin in CAP, and determine if procalcitonin provides prognostic information beyond PSI and CURB-65. Methods We conducted a multi-center prospective cohort study in 28 community and teaching emergency departments. Patients presenting with a clinical and radiographic diagnosis of CAP were enrolled. We stratified procalcitonin levels a priori into four tiers – I: < 0.1; II: ≥ 0.1 to <0.25; III: ≥ 0.25 to < 0.5; and IV: ≥ 0.5 ng/ml. Primary outcome was 30d mortality. Results 1651 patients formed the study cohort. Procalcitonin levels were broadly spread across tiers: 32.8% (I), 21.6% (II), 10.2% (III), 35.4% (IV). Used alone, procalcitonin had modest test characteristics: specificity (35%), sensitivity (92%), positive likelihood ratio (LR) (1.41), and negative LR (0.22). Adding procalcitonin to PSI in all subjects minimally improved performance. Adding procalcitonin to low risk PSI subjects (Class I–III) provided no additional information. However, subjects in procalcitonin tier I had low 30d mortality regardless of clinical risk, including those in higher risk classes (1.5% vs. 1.6% for those in PSI Class I–III vs. Class IV/V). Among high risk PSI subjects (Class IV/V), one quarter (126/546) were in procalcitonin tier I, and the negative LR of procalcitonin tier I was 0.09. Procalcitonin tier I was also associated with lower burden of other adverse outcomes. Similar results were seen with CURB-65 stratification. Conclusions Selective use of procalcitonin as an adjunct to existing rules may offer additional prognostic information in high risk patients. PMID:18342993

Long-term benefit of early pre-reperfusion metoprolol administration in patients with acute myocardial infarction: results from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction).

PubMed

Pizarro, Gonzalo; Fernández-Friera, Leticia; Fuster, Valentin; Fernández-Jiménez, Rodrigo; García-Ruiz, José M; García-Álvarez, Ana; Mateos, Alonso; Barreiro, María V; Escalera, Noemí; Rodriguez, Maite D; de Miguel, Antonio; García-Lunar, Inés; Parra-Fuertes, Juan J; Sánchez-González, Javier; Pardillos, Luis; Nieto, Beatriz; Jiménez, Adriana; Abejón, Raquel; Bastante, Teresa; Martínez de Vega, Vicente; Cabrera, José A; López-Melgar, Beatriz; Guzman, Gabriela; García-Prieto, Jaime; Mirelis, Jesús G; Zamorano, José Luis; Albarrán, Agustín; Goicolea, Javier; Escaned, Javier; Pocock, Stuart; Iñiguez, Andrés; Fernández-Ortiz, Antonio; Sánchez-Brunete, Vicente; Macaya, Carlos; Ibanez, Borja

2014-06-10

The goal of this trial was to study the long-term effects of intravenous (IV) metoprolol administration before reperfusion on left ventricular (LV) function and clinical events. Early IV metoprolol during ST-segment elevation myocardial infarction (STEMI) has been shown to reduce infarct size when used in conjunction with primary percutaneous coronary intervention (pPCI). The METOCARD-CNIC (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) trial recruited 270 patients with Killip class ≤II anterior STEMI presenting early after symptom onset (<6 h) and randomized them to pre-reperfusion IV metoprolol or control group. Long-term magnetic resonance imaging (MRI) was performed on 202 patients (101 per group) 6 months after STEMI. Patients had a minimal 12-month clinical follow-up. Left ventricular ejection fraction (LVEF) at the 6 months MRI was higher after IV metoprolol (48.7 ± 9.9% vs. 45.0 ± 11.7% in control subjects; adjusted treatment effect 3.49%; 95% confidence interval [CI]: 0.44% to 6.55%; p = 0.025). The occurrence of severely depressed LVEF (≤35%) at 6 months was significantly lower in patients treated with IV metoprolol (11% vs. 27%, p = 0.006). The proportion of patients fulfilling Class I indications for an implantable cardioverter-defibrillator (ICD) was significantly lower in the IV metoprolol group (7% vs. 20%, p = 0.012). At a median follow-up of 2 years, occurrence of the pre-specified composite of death, heart failure admission, reinfarction, and malignant arrhythmias was 10.8% in the IV metoprolol group versus 18.3% in the control group, adjusted hazard ratio (HR): 0.55; 95% CI: 0.26 to 1.04; p = 0.065. Heart failure admission was significantly lower in the IV metoprolol group (HR: 0.32; 95% CI: 0.015 to 0.95; p = 0.046). In patients with anterior Killip class ≤II STEMI undergoing pPCI, early IV metoprolol before reperfusion resulted in higher long-term LVEF, reduced incidence of severe LV systolic dysfunction and ICD indications, and fewer heart failure admissions. (Effect of METOprolol in CARDioproteCtioN During an Acute Myocardial InfarCtion. The METOCARD-CNIC Trial; NCT01311700). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90)

PubMed Central

Seaber, E.; On, N.; Dixon*, R. M.; Gibbens, M.; Leavens, W. J.; Liptrot, J.; Chittick, G.; Posner, J.; Rolan†, P. E.; Peck, R. W.

1997-01-01

Aims Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine. Methods After an initial test i.v. infusion, bioavailabilty was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 μCi []> 14C]-zolmitriptan, to five men and one woman on a single occasion. Results Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and iv dosing. Mean±s.d. oral bioavailability was 0.49±0.24 (0.38±0.16 in men and 0.60±0.28 in women). After oral dosing, Cmax and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-life was significantly longer after oral dosing (mean 22%, 95% CI 6–35%). Mean±s.d. values for CL, Vz and t1/2,z after i.v. dosing (all subjects) were 8.7±1.7 ml min−1 kg−1, 122±32 l and 2.30±0.59 h respectively. Following administration of 25 mg [14C]-zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4±6.5% in urine and 27.1±6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1±6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [14C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N-desmethyl metabolite (183C91), the inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabilites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose. Conclusions The data suggest that zolmitriptan undergoes first-pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailabilty for an acute oral migraine treatment and there are no significant unidentified metabolites in man. PMID:9205817

Complex Drug Use Patterns and Associated HIV Transmission Risk Behaviors in an Internet Sample of U.S. Men Who Have Sex with Men

PubMed Central

Yu, Gary; Wall, Melanie M.; Chiasson, Mary Ann; Hirshfield, Sabina

2015-01-01

Although the relationship between drug use and HIV risk among men who have sex with men (MSM) is well described, relatively few studies have employed empirical methods to assess underlying classes of drug use that may better predict the risk of HIV or sexually transmitted infections (STIs) among MSM. The aim of this study was to determinewhether latent class analysis (LCA) would identify underlying drug classes reported prior to sex, as well as predict unprotected anal intercourse (UAI) in the last sexual encounter among MSM. From 2004 to 2005, an anonymous online survey was conducted among 8,717 sexually active MSM recruited from gay-affiliated U.S. websites. LCA clustered participants into six distinct drug use classes based on the specific types and number of drugs used: (1) low/no drug use, (2) recreational drug use, (3) poppers with prescription erectile dysfunction (ED) drug use, (4) poppers with both prescription and non-prescription ED drug use, (5) recreational, club, and ED drug use, and (6) high polydrug use. Compared with men in Class 1, men in the highest drug use class were 4.84 times more likely to report UAI in their last sexual encounter and 3.78 times more likely to report an STI in the past year (both ps<.001). Younger MSM aged 18–29 were significantly more likely to report an STI than men aged 50 and above (p<.001). There is a need to better understand the complex relationship between a diverse set of drugs used among MSM and how polydrug use impacts sexual negotiation over time. PMID:25104104

Bisphosphonate-related osteonecrosis of the jaw: historical, ethical, and legal issues associated with prescribing.

PubMed

Faiman, Beth; Pillai, Aiswarya Lekshmi Pillai Chandran; Benghiac, Ana Gabriela

2013-01-01

The long-term effects of many drugs are unknown. Established risks are communicated to patients who participate in clinical trials during the informed consent process. However, unknown and unanticipated side effects of medications may occur years after treatment. Patients with metastatic bone cancer experience an imbalance between tumor cells and the bone marrow microenvironment. Increased cytokine release, osteoclastic activity, and uncoupled osteoblastic activity lead to weakened bone structure and osteolytic lesions. The bisphosphonates are a class of drugs available in IV and oral formulations to treat and prevent bone loss and decrease the risk of skeletal-related events. Intravenous bisphosphonates such as zoledronic acid and pamidronate disodium are approved by the US Food and Drug Administration for the treatment of bone pain and hypercalcemia of malignancy and the prevention of painful bone fractures in patients with metastatic bone cancer. Oral bisphosphonates such as alendronate, risedronate, and etidronate are used to reduce the risk of skeletal fractures in patients with osteoporosis and in breast cancer. Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but painful complication of treatment characterized by infection, exposed bone, and poor wound healing. In this article, we discuss BRONJ and identify past, present, and future ethical and legal issues surrounding bisphosphonate administration.

Three new hydrochlorothiazide cocrystals: Structural analyses and solubility studies

NASA Astrophysics Data System (ADS)

Ranjan, Subham; Devarapalli, Ramesh; Kundu, Sudeshna; Vangala, Venu R.; Ghosh, Animesh; Reddy, C. Malla

2017-04-01

Hydrochlorothiazide (HCT) is a diuretic BCS class IV drug with poor aqueous solubility and low permeability leading to poor oral absorption. The present work explores the cocrystallization technique to enhance the aqueous solubility of HCT. Three new cocrystals of HCT with water soluble coformers phenazine (PHEN), 4-dimethylaminopyridine (DMAP) and picolinamide (PICA) were prepared successfully by solution crystallization method and characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), fourier transform -infraredspectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Structural characterization revealed that the cocrystals with PHEN, DMAP and PICA exists in P21/n, P21/c and P21/n space groups, respectively. The improved solubility of HCT-DMAP (4 fold) and HCT-PHEN (1.4 fold) cocrystals whereas decreased solubility of HCT-PICA (0.5 fold) as compared to the free drug were determined after 4 h in phosphate buffer, pH 7.4, at 25 °C by using shaking flask method. HCT-DMAP showed a significant increase in solubility than all previously reported cocrystals of HCT suggest the role of a coformer. The study demonstrates that the selection of coformer could have pronounced impact on the physicochemical properties of HCT and cocrystallization can be a promising approach to improve aqueous solubility of drugs.

Controllable continuous sub-tenon drug delivery of dexamethasone disodium phosphate to ocular posterior segment in rabbit.

PubMed

Huang, Xuetao; Liu, Shaogang; Yang, Yezhen; Duan, Yiqin; Lin, Ding

2017-11-01

Corticosteroids have been used for treatment of posterior segment eye diseases, but the delivery of drug to the posterior segments is still a problem to resolve. In our study, we explore the feasibility of Sub-tenon's Controllable Continuous Drug Delivery to ocular posterior segment. Controllable continuous sub-tenon drug delivery (CCSDD) system, intravenous injections (IV) and sub-conjunctival injections (SC) were used to deliver dexamethasone disodium phosphate (DEXP) in rabbits, the dexamethasone concentration was measured in the ocular posterior segment tissue by Shimadzu LC-MS 2010 system at different time points in 24 h after first dose injection. Levels of dexamethasone were significantly higher at 12, 24 h in CCSDD than two other approaches, and at 3, 6 h in CCSDD than IV in vitreous body (p < 0.01); at 6, 12, 24 h in CCSDD than two other approaches, and at 1, 3 h in CCSDD than IV in retinal/choroidal compound (p < 0.01); at 3, 6, 12, 24 h in CCSDD than two other approaches, and at 1 h in CCSDD than IV in sclera (p < 0.05). The AUC 0-24 in CCSDD group is higher than two other groups in all ocular posterior segment tissue. Our results demonstrated that dexamethasone concentration could be sustained moderately higher in the posterior segment by CCSDD than SC and IV, indicating that CCSDD might be a therapeutic alternative to treat a variety of intractable posterior segment diseases.

The economic impact of introducing serotonin-noradrenaline reuptake inhibitors into the Brazilian national drug formulary: cost-effectiveness and budget-impact analyses.

PubMed

Machado, Márcio; Iskedjian, Michael; Ruiz, Inés A; Einarson, Thomas R

2007-01-01

To determine the cost effectiveness, from the Brazilian Ministry of Health viewpoint, of three antidepressant classes for major depressive disorder (MDD), and the budget impact of introducing serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) into the current Brazilian national drug formulary, assuming a 6-month treatment duration. An existing decision-tree model was adapted to Brazil, based on local guidelines. Clinical data were obtained from published meta-analyses. Patients included adults aged > or =18 years with MDD, diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, third and fourth editions (DSM-III/IV), with moderate-to-severe disease (Hamilton Depression Rating Scale [HAMD] > or =15 or Montgomery-Asberg Depression Rating Scale [MADRS] > or =18), without co-morbidities or co-medications, receiving > or =6 weeks of treatment with SNRIs, selective serotonin reuptake inhibitors (SSRIs) and/or tricyclic antidepressants (TCAs). Clinical outcome was remission (HAMD < or =7 or MADRS < or =12). Direct costs (drugs, physician visits, hospitalisations) were included. Drug costs were obtained from the 2006 Brazilian National Drug Price List, and hospitalisation and physician costs from the 2006 Healthcare System database. Costs were valued in Brazilian Reais ($Brz), year 2006 values ($Brz1 = $US0.47). Univariate and Monte Carlo sensitivity analyses tested model robustness. Expected costs per patient treated were SNRIs $Brz4848; SSRIs $Brz5466; and TCAs $Brz5046, and overall success rates (primary plus secondary treatment across all decision tree branches) were SNRIs 78.1%; SSRIs 74.0%; and TCAs 76.4%. Average costs/success were SNRIs $Brz6209; SSRIs $Brz7385; and TCAs $Brz6602. SNRIs dominated in incremental cost-effectiveness analyses. Monte Carlo analysis confirmed drug classes' relative positions; however, there was considerable uncertainty. Introducing SNRIs into the formulary could generate average savings of 1% of the total budget, with a 52% probability of savings. SNRIs appear to be cost effective against SSRIs and TCAs when prescribed to patients with MDD in Brazil. However, their inclusion into the national drug list would generate minor savings compared with the current formulary of SSRIs and TCAs. Thus, we considered such inclusion as 'cost-neutral', since no major probability of savings or increased expenditures were observed.

18 CFR 1316.7 - Drug-free workplace.

Code of Federal Regulations, 2010 CFR

2010-04-01

... available drug counseling, rehabilitation, and employee assistance programs; and (iv) The penalties that may... prohibition; (2) Establish a drug-free awareness program to inform such employees about— (i) The dangers of... termination; or (ii) Require such employee to satisfactorily participate in a drug abuse assistance or...

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

PubMed

Bruun, Emmi; Virta, Lauri J; Kälviäinen, Reetta; Keränen, Tapani

2017-08-01

A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions. Copyright © 2017 Elsevier Inc. All rights reserved.

AIDSinfo Drug Database

MedlinePlus

... HIV/AIDS-related drugs for that condition. OK Filters Approval: What's this? FDA-Approved Investigational Class: What's ... Encephalitis Tuberculosis Varicella-Zoster Virus Diseases Update Loading... Filter by approval status, drug class, and condition Browse ...

Investigating the Capability of IRS-P6-LISS IV Satellite Image for Pistachio Forests Density Mapping (case Study: Northeast of Iran)

NASA Astrophysics Data System (ADS)

Hoseini, F.; Darvishsefat, A. A.; Zargham, N.

2012-07-01

In order to investigate the capability of satellite images for Pistachio forests density mapping, IRS-P6-LISS IV data were analyzed in an area of 500 ha in Iran. After geometric correction, suitable training areas were determined based on fieldwork. Suitable spectral transformations like NDVI, PVI and PCA were performed. A ground truth map included of 34 plots (each plot 1 ha) were prepared. Hard and soft supervised classifications were performed with 5 density classes (0-5%, 5-10%, 10-15%, 15-20% and > 20%). Because of low separability of classes, some classes were merged and classifications were repeated with 3 classes. Finally, the highest overall accuracy and kappa coefficient of 70% and 0.44, respectively, were obtained with three classes (0-5%, 5-20%, and > 20%) by fuzzy classifier. Considering the low kappa value obtained, it could be concluded that the result of the classification was not desirable. Therefore, this approach is not appropriate for operational mapping of these valuable Pistachio forests.

75 FR 27785 - Final Effect of Designation of a Class of Employees for Addition to the Special Exposure Cohort

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-18

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Final Effect of Designation of a Class of Employees for Addition to the Special Exposure Cohort AGENCY: National Institute for Occupational Safety and Health... concerning the final effect of the decision to designate a class of employees from Area IV of the Santa...

[Evaluation of a chronic fatigue in patients with moderate-to-severe chronic heart failure].

PubMed

Jasiukeviciene, Lina; Vasiliauskas, Donatas; Kavoliūniene, Ausra; Marcinkeviciene, Jolanta; Grybauskiene, Regina; Grizas, Vytautas; Tumyniene, Vida

2008-01-01

To evaluate the chronic fatigue and its relation to the function of hypothalamus-pituitary-adrenal axis in patients with New York Heart Association (NYHA) functional class III-IV chronic heart failure. A total of 170 patients with NYHA functional class III-IV chronic heart failure completed MFI-20L, DUFS, and DEFS questionnaires assessing chronic fatigue and underwent echocardiography. Blood cortisol concentration was assessed at 8:00 am and 3:00 pm, and plasma N-terminal brain natriuretic pro-peptide (NT-proBNP) concentration was measured at 8:00 am. Neurohumoral investigations were repeated before cardiopulmonary exercise test and after it. The results of all questionnaires showed that 100% of patients with NYHA functional class III-IV heart failure complained of chronic fatigue. The level of overall fatigue was 54.5+/-31.5 points; physical fatigue - 56.8+/-24.6 points. Blood cortisol concentration at 8:00 am was normal (410.1+/-175.1 mmol/L) in majority of patients. Decreased concentration was only in four patients (122.4+/-15.5 mmol/L); one of these patients underwent heart transplantation. In the afternoon, blood cortisol concentration was insufficiently decreased (355.6+/-160.3 mmol/L); reaction to a physical stress was attenuated (Delta 92.9 mmol/L). Plasma NT-proBNP concentration was 2188.9+/-1852.2 pg/L; reaction to a physical stress was diminished (Delta 490.3 pg/L). All patients with NYHA class III-IV heart failure complained of daily chronic fatigue. Insufficiently decreased blood cortisol concentration in the afternoon showed that in the presence of chronic fatigue in long-term cardiovascular organic disease, disorder of a hypothalamus-pituitary-adrenal axis is involved.

Co-delivery of platinum drug and siNotch1 with micelleplex for enhanced hepatocellular carcinoma therapy.

PubMed

Shen, Song; Sun, Chun-Yang; Du, Xiao-Jiao; Li, Hong-Jun; Liu, Yang; Xia, Jin-Xing; Zhu, Yan-Hua; Wang, Jun

2015-11-01

As part of HCC tumor cellularity, cancer stem cells (CSCs) are considered a major obstacle to eradicate hepatocellular carcinoma (HCC), which is the third most common cause of cancer-related death worldwide, and the accumulation of chemotherapeutic drug-resistant CSCs invariably accounts for poor prognosis and HCC relapse. In the present study, we explored the efficacy of co-delivery of platinum drug and siRNA targeting Notch1 to treat CSCs-harboring HCC. To overcome the challenging obstacles of platinum drug and siRNA in the systemic administration, we developed a micellar nanoparticle (MNP) to deliver platinum(IV) prodrug and siNotch1, hereafter referred to as (Pt(IV))MNP/siNotch1. We demonstrated that (Pt(IV))MNP/siNotch1 was able to efficiently deliver two drugs into both non-CSCs and CSCs of SMMC7721, a HCC cell line. We further found that siRNA-mediated inhibition of Notch1 suppression can increase the sensitivity of HCC cells to platinum drugs and decrease the percentage of HCC CSCs, and consequently resulting in enhanced proliferation inhibition and apoptosis induction in HCC cells in vitro. Moreover, our results indicated that the combined drug delivery system can remarkably augment drug enrichment in tumor tissues, substantially suppressing the tumor growth while avoiding the accumulation of CSCs in a synergistic manner in the SMMC7721 xenograft model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Norelgestromin/ethinyl estradiol intravenous infusion formulation optimization, stability and compatibility testing: A case study to overcome polysorbate 80 interference in chromatographic analysis.

PubMed

Abdallah, Inas A; Hammell, Dana C; Hassan, Hazem E; Stinchcomb, Audra L

2016-06-05

Norelgestromin/ethinyl estradiol is a progestin/estrogen combination hormonal contraceptive indicated for the prevention of pregnancy in women. The very poor solubility and wettability of these drugs, along with their high potency (adsorption issues), give rise to difficulties in designing intravenous (IV) formulations to assess absolute bioavailability of products containing both drugs. The purpose of this study was to develop an IV formulation, evaluate its stability under different conditions and evaluate its compatibility with IV sets for potential use in absolute bioavailability studies in humans. Also, a selective high-performance liquid chromatography (HPLC) method for quantification of ethinyl estradiol and norelgestromin in polysorbate 80 matrix was developed and validated. Norelgestromin/ethinyl estradiol IV solution was prepared using sterile water for injection with 2.5% ethanol and 2.5% polysorbate 80 as a cosolvent/surfactant system to obtain a final drug solution of 25μg ethinyl estradiol and 252μg norelgestromin from a concentrated stock drug solution. The stabilities of the concentrated stock and IV solutions were assessed after storing them in the refrigerator (3.7±0.6°C) and at room temperature (19.5±0.5°C), respectively. Additional studies were conducted to examine the stability of the IV solution using an Alarias(®) low sorbing IV administration set with and without an inline filter. The solution was allowed to drip at 1mL/min over a 60min period. Samples were obtained at the beginning, middle and end of the 60min duration. The chemical stability was evaluated for up to 10 days. Norelgestromin and ethinyl estradiol concentration, purity, and degradant levels were determined using the HPLC method. The norelgestromin/ethinyl estradiol IV formulation met the chemical stability criteria when tested on day 1 through day 9 (216h). Norelgestromin concentrations assayed in stock and IV solutions were in the range of 90.0-98.5% and 90.9-98.8% after 9 days, respectively. As for ethinyl estradiol, the assayed concentrations were in the range of 91.8-100.9% and 92.7-100.8% for the stock and IV solutions, respectively. The administration set was found to be compatible with both drugs; the assayed concentrations were in the range of 99.2-100.3% for norelgestromin and 96.3-102.7% for ethinyl estradiol, but the inline filter showed some adsorption of ethinyl estradiol; where the assayed concentrations were in the range of 98.1-99.8% for norelgestromin and 95.9-97.4% for ethinyl estradiol. The present study provided evidence supporting the suitability of an intravenous formulation for norelgestromin/ethinyl estradiol using ethanol/polysorbate 80 as a cosolvent/surfactant system. Both IV and concentrated stock solutions when stored at room temperature and refrigeration, respectively, were found to be chemically stable up to 9 days. These results indicated that this formulation is chemically stable and can be used over the time period tested. This IV formulation can be used to evaluate the absolute bioavailability of products containing norelgestromin and ethinyl estradiol provided that microbial testing of the IV formulation is performed. Copyright © 2016. Published by Elsevier B.V.

Selection of drug-resistant HIV-1 during the early phase of viral decay is uncommon in treatment-naïve patients initiated on a three- or four-drug antiretroviral regimen including lamivudine.

PubMed

Bergroth, Tobias; Ekici, Halime; Gisslén, Magnus; Loes, Sabine Kinloch-de; Goh, Li-Ean; Freedman, Andrew; Lampe, Fiona; Johnson, Margaret A; Sönnerborg, Anders

2009-01-01

Therapy failure due to drug resistance development is a common phenomenon in HIV-infected patients. However, when the drug pressure leads to the earliest selection of drug-resistant HIV-1 populations is still unclear. In this study, the extent to which selection of the HIV-1 reverse transcriptase M184I/V mutations occur during the initial phase of viral decay in treatment-naïve HIV-1 infected patients receiving antiretroviral therapy (ART) was examined. Plasma virus from three cohorts of treatment-naïve patients initiating quadruple (n = 43), triple (n = 14) or dual (n = 15) lamivudine-containing ART were analyzed for M184I/V during the first 6 months of therapy using direct sequencing and a sensitive selective real-time PCR method. Among quadruple ART patients, who all were treated at primary HIV-1 infection, only one patient developed M184V after 6 weeks of therapy, having had wild-type virus at baseline. No mutations were found in chronically infected patients on triple ART. In patients on dual therapy, M184I/V mutants were found frequently. Selection of M184I/V mutants was found to be rare during the initial phase of viral decay after initiation of ART in adherent patients given a three or four-drug combination, in contrast to those receiving a less potent regimen. The results suggest that triple and quadruple lamivudine + PI or PI/r containing ART given to treatment-naïve adherent patients is potent enough to prevent development of resistance during the first months of therapy.

[Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden].

PubMed

Dezileaux, Barbara; Martinez, Florie

2016-06-01

Comparisons outpatient drug prescriptions: France, Denmark, Norway, Sweden. Project compares quantitatively outpatient drug prescriptions in France, Denmark, Norway and Sweden. Data were obtained from national databases; the unit of measurement was defined daily dose per 1000 inhabitants. The five most prescribed drug classes were compared in each country in 2009, then benzodiazepines and antibiotics from 2006 to 2012. A literature review was focused on the context of prescriptions for each country. In 2009, the five most prescribed drug classes in the four countries represented seven classes in total. France was not the biggest prescriber of drugs, but from 2006 to 2012 benzodiazepines and antibiotics were prescribed much more in France than in the other countries. The evolution of prescriptions was different for each country, and very stable in France. In 2009, France was not the biggest drugs consumer of all classes, but was characterized by high prescriptions in some classes. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

PubMed

Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

2009-09-01

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Antimicrobial peptide inhibition of fungalysin proteases that target plant type 19 Family IV defense chitinases

USDA-ARS?s Scientific Manuscript database

Cereal crops and other plants produce secreted seed chitinases that reduce pathogenic infection, most likely by targeting the fungal chitinous cell wall. We have shown that corn (Zea mays) produces three GH family 19, plant class IV chitinases, that help in protecting the plant against Fusarium and ...

Elucidating rifampin's inducing and inhibiting effects on glyburide pharmacokinetics and blood glucose in healthy volunteers: unmasking the differential effects of enzyme induction and transporter inhibition for a drug and its primary metabolite.

PubMed

Zheng, H X; Huang, Y; Frassetto, L A; Benet, L Z

2009-01-01

The effects of single doses of intravenous (IV) ciprofloxacin and rifampin and of multiple doses of rifampin on glyburide exposure and blood glucose levels were investigated in nine healthy volunteers. A single IV dose of rifampin significantly increased the area under the concentration-time curve (AUC) of glyburide and its metabolite. Blood glucose levels were significantly lower than those observed after dosing with glyburide alone. Multiple doses of rifampin induced an increase in liver enzyme levels, leading to a marked decrease in glyburide exposure and blood glucose levels. When IV rifampin was administered after multiple doses of rifampin, the inhibition of hepatic uptake transporters masked the induction effect; however, the relative changes in AUC for glyburide and its hydroxyl metabolite were similar to those seen under noninduced conditions. The studies reported here demonstrate how measurements of the levels of both the parent drug and its primary metabolite are useful in unmasking simultaneous drug-drug induction and inhibition effects and in characterizing enzymatic vs. transporter mechanisms.

28 CFR 36.104 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... of 1970 (45 U.S.C. 431(e)). Current illegal use of drugs means illegal use of drugs that occurred recently enough to justify a reasonable belief that a person's drug use is current or that continuing use... (whether symptomatic or asymptomatic), tuberculosis, drug addiction, and alcoholism; (iv) The phrase...

28 CFR 36.104 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... of 1970 (45 U.S.C. 431(e)). Current illegal use of drugs means illegal use of drugs that occurred recently enough to justify a reasonable belief that a person's drug use is current or that continuing use... (whether symptomatic or asymptomatic), tuberculosis, drug addiction, and alcoholism; (iv) The phrase...

28 CFR 36.104 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... of 1970 (45 U.S.C. 431(e)). Current illegal use of drugs means illegal use of drugs that occurred recently enough to justify a reasonable belief that a person's drug use is current or that continuing use... (whether symptomatic or asymptomatic), tuberculosis, drug addiction, and alcoholism; (iv) The phrase...

28 CFR 36.104 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... of 1970 (45 U.S.C. 431(e)). Current illegal use of drugs means illegal use of drugs that occurred recently enough to justify a reasonable belief that a person's drug use is current or that continuing use... (whether symptomatic or asymptomatic), tuberculosis, drug addiction, and alcoholism; (iv) The phrase...

chs-4, a class IV chitin synthase gene from Neurospora crassa.

PubMed

Din, A B; Specht, C A; Robbins, P W; Yarden, O

1996-02-05

In Saccharomyces cerevisiae, most of the cellular chitin is produced by chitin synthase III, which requires the product encoded by the CSD2/CAL1/DIT101/KT12 gene. We have identified, isolated and structurally characterized as CSD2/CAL1/DIT101/KT12 homologue in the filamentous ascomycete Neurospora crassa and have used a "reverse genetics" approach to determine its role in vivo. The yeast gene was used as a heterologous probe for the isolation of a N. crassa gene(designated chs-4) encoding a polypeptide belonging to a class of chitin synthases which we have designated class IV. The predicted polypeptide encoded by this gene is highly similar to those of S. cerevisiae and Candida albicans. N. crassa strains in which chs-4 had been inactivated by the Repeat-Induced point mutation (RIP) process grew and developed in a normal manner under standard growth conditions. However, when grown in the presence of sorbose (a carbon source which induces morphological changes accompanied by elevated chitin content), chitin levels in the chs-4RIP strain were significantly lower than those observed in the wild type. We suggest that CHS4 may serve as an auxiliary enzyme in N. crassa and that, in contrast to yeasts, it is possible that filamentous fungi may have more than one class IV chitin synthase.

Identification of branched-chain amino acid aminotransferases active towards (R)-(+)-1-phenylethylamine among PLP fold type IV transaminases.

PubMed

Bezsudnova, Ekaterina Yu; Dibrova, Daria V; Nikolaeva, Alena Yu; Rakitina, Tatiana V; Popov, Vladimir O

2018-04-10

New class IV transaminases with activity towards L-Leu, which is typical of branched-chain amino acid aminotransferases (BCAT), and with activity towards (R)-(+)-1-phenylethylamine ((R)-PEA), which is typical of (R)-selective (R)-amine:pyruvate transaminases, were identified by bioinformatics analysis, obtained in recombinant form, and analyzed. The values of catalytic activities in the reaction with L-Leu and (R)-PEA are comparable to those measured for characteristic transaminases with the corresponding specificity. Earlier, (R)-selective class IV transaminases were found to be active, apart from (R)-PEA, only with some other (R)-primary amines and D-amino acids. Sequences encoding new transaminases with mixed type of activity were found by searching for changes in the conserved motifs of sequences of BCAT by different bioinformatics tools. Copyright © 2018 Elsevier B.V. All rights reserved.

Cost-effectiveness of oral ibandronate compared with intravenous (i.v.) zoledronic acid or i.v. generic pamidronate in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy.

PubMed

De Cock, E; Hutton, J; Canney, P; Body, J J; Barrett-Lee, P; Neary, M P; Lewis, G

2005-12-01

Ibandronate is the first third-generation bisphosphonate to have both oral and intravenous (i.v.) efficacy. An incremental cost-effectiveness model compared oral ibandronate with i.v. zoledronic acid and i.v. generic pamidronate in female breast cancer patients with metastatic bone disease, undergoing i.v. chemotherapy. A global economic model was adapted to the UK National Health Service (NHS), with primary outcomes of direct healthcare costs and quality-adjusted life years (QALYs). Efficacy, measured as relative risk reduction of skeletal-related events (SREs), was obtained from clinical trials. Resource use data for i.v. bisphosphonates and the cost of managing SREs were obtained from published studies. Hospital management and SRE treatment costs were taken from unit cost databases. Monthly drug acquisition costs were obtained from the British National Formulary. Utility scores were applied to time with/without an SRE to adjust survival for quality of life. Model design and inputs were validated through expert UK clinician review. Total cost, including drug acquisition, was pound 386 less per patient with oral ibandronate vs. i.v. zoledronic acid and pound 224 less vs. i.v. generic pamidronate. Oral ibandronate gained 0.019 and 0.02 QALYs vs. i.v. zoledronic acid and i.v. pamidronate, respectively, making it the economically dominant option. At a threshold of pound 30,000 per QALY, oral ibandronate was cost-effective vs. zoledronic acid in 85% of simulations and vs. pamidronate in 79%. Oral ibandronate is a cost-effective treatment for metastatic bone disease from breast cancer due to reduced SREs, bone pain, and cost savings from avoidance of resource use commonly associated with bisphosphonate infusions.

An integrated safety analysis of intravenous ibuprofen (Caldolor®) in adults

PubMed Central

Southworth, Stephen R; Woodward, Emily J; Peng, Alex; Rock, Amy D

2015-01-01

Intravenous (IV) nonsteroidal anti-inflammatory drugs such as IV ibuprofen are increasingly used as a component of multimodal pain management in the inpatient and outpatient settings. The safety of IV ibuprofen as assessed in ten sponsored clinical studies is presented in this analysis. Overall, 1,752 adult patients have been included in safety and efficacy trials over 11 years; 1,220 of these patients have received IV ibuprofen and 532 received either placebo or comparator medication. The incidence of adverse events (AEs), serious AEs, and changes in vital signs and clinically significant laboratory parameters have been summarized and compared to patients receiving placebo or active comparator drug. Overall, IV ibuprofen has been well tolerated by hospitalized and outpatient patients when administered both prior to surgery and postoperatively as well as for nonsurgical pain or fever. The overall incidence of AEs is lower in patients receiving IV ibuprofen as compared to those receiving placebo in this integrated analysis. Specific analysis of hematological and renal effects showed no increased risk for patients receiving IV ibuprofen. A subset analysis of elderly patients suggests that no dose adjustment is needed in this higher risk population. This integrated safety analysis demonstrates that IV ibuprofen can be safely administered prior to surgery and continued in the postoperative period as a component of multimodal pain management. PMID:26604816

Outcome of bipolar electrocoagulation with lesionectomy in the treatment of epilepsy involving eloquent areas.

PubMed

Zhai, Feng; Zhou, Jian; Li, Tianfu; Cui, Zhiqiang; Luan, Guoming

2015-01-01

We have demonstrated previously that bipolar electrocoagulation on functional cortex (BCFC) is a safe and effective approach for epilepsy involving eloquent areas. Here, we report the results of BCFC with lesionectomy for patients with epileptogenic foci partially overlapping eloquent areas. Forty patients who had been treated with lesionectomy with BCFC were retrospectively reviewed with regard to seizure outcome and neurological deficits. Ten similar patients who had received lesionectomy with multiple subpial transections (MST) were examined as a control group. In the lesionectomy group with BCFC, Engel class I was achieved in 18 (45%) patients, class II in 8 (20%) patients, class III in 8 (20%) patients and class IV in 6 (15%) patients. Five (12.5%) patients developed mild hemiparesis and 1 (2.5%) patient mild sensory dysphasia. In the lesionectomy group with MST, Engel class I was achieved in 3 (30%) patients, class II in 2 (20%) patients, class III in 3 (30%) patients and class IV in 2 (20%) patients. Two (20%) patients developed mild hemiparesis and 1 (10%) patient moderate hemiparesis. All these complications recovered within 1-12 months. Compared with MST, the outcome of BCFC with lesionectomy is similar. But since MST leads to mechanical injury, while BCFC causes thermal injury, the complications of BCFC seem less severe. © 2014 S. Karger AG, Basel.

Heterogonous expression and characterization of a plant class IV chitinase from the pitcher of the carnivorous plant Nepenthes alata.

PubMed

Ishisaki, Kana; Honda, Yuji; Taniguchi, Hajime; Hatano, Naoya; Hamada, Tatsuro

2012-03-01

A class IV chitinase belonging to the glycoside hydrolase 19 family from Nepenthes alata (NaCHIT1) was expressed in Escherichia coli. The enzyme exhibited weak activity toward polymeric substrates and significant activity toward (GlcNAc)(n) [β-1,4-linked oligosaccharide of GlcNAc with a polymerization degree of n (n = 4-6)]. The enzyme hydrolyzed the third and fourth glycosidic linkages from the non-reducing end of (GlcNAc)(6). The pH optimum of the enzymatic reaction was 5.5 at 37°C. The optimal temperature for activity was 60°C in 50 mM sodium acetate buffer (pH 5.5). The anomeric form of the products indicated that it was an inverting enzyme. The k(cat)/K(m) of the (GlcNAc)(n) hydrolysis increased with an increase in the degree of polymerization. Amino acid sequence alignment analysis between NaCHIT1 and a class IV chitinase from a Picea abies (Norway spruce) suggested that the deletion of four loops likely led the enzyme to optimize the (GlcNAc)(n) hydrolytic reaction rather than the hydrolysis of polymeric substrates.

Nanos-mediated repression of hid protects larval sensory neurons after a global switch in sensitivity to apoptotic signals

PubMed Central

Bhogal, Balpreet; Plaza-Jennings, Amara

2016-01-01

Dendritic arbor morphology is a key determinant of neuronal function. Once established, dendrite branching patterns must be maintained as the animal develops to ensure receptive field coverage. The translational repressors Nanos (Nos) and Pumilio (Pum) are required to maintain dendrite growth and branching of Drosophila larval class IV dendritic arborization (da) neurons, but their specific regulatory role remains unknown. We show that Nos-Pum-mediated repression of the pro-apoptotic gene head involution defective (hid) is required to maintain a balance of dendritic growth and retraction in class IV da neurons and that upregulation of hid results in decreased branching because of an increase in caspase activity. The temporal requirement for nos correlates with an ecdysone-triggered switch in sensitivity to apoptotic stimuli that occurs during the mid-L3 transition. We find that hid is required during pupariation for caspase-dependent pruning of class IV da neurons and that Nos and Pum delay pruning. Together, these results suggest that Nos and Pum provide a crucial neuroprotective regulatory layer to ensure that neurons behave appropriately in response to developmental cues. PMID:27256879

Nanos-mediated repression of hid protects larval sensory neurons after a global switch in sensitivity to apoptotic signals.

PubMed

Bhogal, Balpreet; Plaza-Jennings, Amara; Gavis, Elizabeth R

2016-06-15

Dendritic arbor morphology is a key determinant of neuronal function. Once established, dendrite branching patterns must be maintained as the animal develops to ensure receptive field coverage. The translational repressors Nanos (Nos) and Pumilio (Pum) are required to maintain dendrite growth and branching of Drosophila larval class IV dendritic arborization (da) neurons, but their specific regulatory role remains unknown. We show that Nos-Pum-mediated repression of the pro-apoptotic gene head involution defective (hid) is required to maintain a balance of dendritic growth and retraction in class IV da neurons and that upregulation of hid results in decreased branching because of an increase in caspase activity. The temporal requirement for nos correlates with an ecdysone-triggered switch in sensitivity to apoptotic stimuli that occurs during the mid-L3 transition. We find that hid is required during pupariation for caspase-dependent pruning of class IV da neurons and that Nos and Pum delay pruning. Together, these results suggest that Nos and Pum provide a crucial neuroprotective regulatory layer to ensure that neurons behave appropriately in response to developmental cues. © 2016. Published by The Company of Biologists Ltd.

In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class.

PubMed

Mani, Nagraj; Gross, Christian H; Parsons, Jonathan D; Hanzelka, Brian; Müh, Ute; Mullin, Steve; Liao, Yusheng; Grillot, Anne-Laure; Stamos, Dean; Charifson, Paul S; Grossman, Trudy H

2006-04-01

Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

PubMed Central

Mani, Nagraj; Gross, Christian H.; Parsons, Jonathan D.; Hanzelka, Brian; Müh, Ute; Mullin, Steve; Liao, Yusheng; Grillot, Anne-Laure; Stamos, Dean; Charifson, Paul S.; Grossman, Trudy H.

2006-01-01

Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities. PMID:16569833

20 CFR 638.511 - Drug use and abuse.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 20 Employees' Benefits 3 2012-04-01 2012-04-01 false Drug use and abuse. 638.511 Section 638.511... TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.511 Drug use and abuse. The Job... and education programs related to drug and alcohol use and abuse. ...

20 CFR 638.511 - Drug use and abuse.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 3 2010-04-01 2010-04-01 false Drug use and abuse. 638.511 Section 638.511... TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.511 Drug use and abuse. The Job... and education programs related to drug and alcohol use and abuse. ...

20 CFR 638.511 - Drug use and abuse.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 20 Employees' Benefits 3 2011-04-01 2011-04-01 false Drug use and abuse. 638.511 Section 638.511... TITLE IV-B OF THE JOB TRAINING PARTNERSHIP ACT Center Operations § 638.511 Drug use and abuse. The Job... and education programs related to drug and alcohol use and abuse. ...

Purely in silico BCS classification: science based quality standards for the world's drugs.

PubMed

Dahan, Arik; Wolk, Omri; Kim, Young Hoon; Ramachandran, Chandrasekharan; Crippen, Gordon M; Takagi, Toshihide; Bermejo, Marival; Amidon, Gordon L

2013-11-04

BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Amoxicillin Trihydrate.

PubMed

Thambavita, Dhanusha; Galappatthy, Priyadarshani; Mannapperuma, Uthpali; Jayakody, Lal; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Groot, Dirk W; Langguth, Peter; Mehta, Mehul; Parr, Alan; Polli, James E; Shah, Vinod P; Dressman, Jennifer

2017-10-01

Literature and experimental data relevant to waiver of in vivo bioequivalence (BE) testing for the approval of immediate-release solid oral dosage forms containing amoxicillin trihydrate are reviewed. Solubility and permeability characteristics according to the Biopharmaceutics Classification System (BCS), therapeutic uses, therapeutic index, excipient interactions, as well as dissolution and BE and bioavailability studies were taken into consideration. Solubility and permeability studies indicate that amoxicillin doses up to 875 mg belong to BCS class I, whereas 1000 mg belongs to BCS class II and doses of more than 1000 mg belong to BCS class IV. Considering all aspects, the biowaiver procedure can be recommended for solid oral products of amoxicillin trihydrate immediate-release preparations containing amoxicillin as the single active pharmaceutical ingredient at dose strengths of 875 mg or less, provided (a) only the excipients listed in this monograph are used, and only in their usual amounts, (b) the biowaiver study is performed according to the World Health Organization-, U.S. Food and Drug Administration-, or European Medicines Agency-recommended method using the innovator as the comparator, and (c) results comply with criteria for "very rapidly dissolving" or "similarly rapidly dissolving." Products containing other excipients and those containing more than 875 mg amoxicillin per unit should be subjected to an in vivo BE study. Copyright © 2017 American Pharmacists Association®. All rights reserved.

Drug Use among Seniors on Public Drug Programs in Canada, 2012.

PubMed

Proulx, Jeff; Hunt, Jordan

2015-01-01

Seniors take more drugs than younger Canadians because, on average, they have a higher number of chronic conditions. Although taking multiple medications may be necessary to manage these conditions, it is important to consider the benefits and risks of each medication and the therapeutic goals of the patient. This article provides an in-depth look at the number and types of drugs used by seniors using drug claims data from the CIHI's National Prescription Drug Utilization Information System Database, representing approximately 70% of seniors in Canada. In 2012, almost two-thirds (65.9%) of seniors on public drug programs had claims for five or more drug classes, while 27.2% had claims for 10 or more, and 8.6% had claims for 15 or more. The most commonly used drug class was statins, used by nearly half (46.6%) of seniors. Nearly two-thirds (60.9%) of seniors living in long-term care (LTC) facilities had claims for 10 or more drug classes. Proton pump inhibitors were the most commonly used drug class among seniors living in LTC facilities (used by 37.0% of seniors in LTC facilities), while statins ranked seventh (29.8%).

Fractures and mortality in relation to different osteoporosis treatments.

PubMed

Yun, Huifeng; Delzell, Elizabeth; Saag, Kenneth G; Kilgore, Meredith L; Morrisey, Michael A; Muntner, Paul; Matthews, Robert; Guo, Lingli; Wright, Nicole; Smith, Wilson; Colón-Emeric, Cathleen; O'Connor, Christopher M; Lyles, Kenneth W; Curtis, Jeffrey R

2015-01-01

Few studies have assessed the effectiveness of different drugs for osteoporosis (OP). We aimed to determine if fracture and mortality rates vary among patients initiating different OP medications. We used the Medicare 5% sample to identify new users of intravenous (IV) zoledronic acid (n=1.674), oral bisphosphonates (n=32.626), IV ibandronate (n=492), calcitonin (n=2.606), raloxifene (n=1.950), or parathyroid hormone (n=549). We included beneficiaries who were ≥65 years of age, were continuously enrolled in fee-for-service Medicare and initiated therapy during 2007-2009. Outcomes were hip fracture, clinical vertebral fracture, and all-cause mortality, identified using inpatient and physician diagnosis codes for fracture, procedure codes for fracture repair, and vital status information. Cox regression models compared users of each medication to users of IV zoledronic acid, adjusting for multiple confounders. During follow-up (median, 0.8-1.5 years depending on the drug), 787 subjects had hip fractures, 986 had clinical vertebral fractures, and 2.999 died. Positive associations included IV ibandronate with hip fracture (adjusted hazard ratio (HR), 2.37; 95% confidence interval (CI) 1.25-4.51), calcitonin with vertebral fracture (HR=1.59, 95%CI 1.04-2.43), and calcitonin with mortality (HR=1.31; 95%CI 1.02-1.68). Adjusted HRs for other drug-outcome comparisons were not statistically significant. IV ibandronate and calcitonin were associated with higher rates of some types of fracture when compared to IV zolendronic acid. The relatively high mortality associated with use of calcitonin may reflect the poorer health of users of this agent.

77 FR 37058 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-20

...] Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance... availability of the draft guidance entitled ``Class II Special Controls Guidance Document: Implanted Blood... blood access devices may comply with the requirement of special controls for class II devices. This...

In vitro quantitative ((1))H and ((19))F nuclear magnetic resonance spectroscopy and imaging studies of fluvastatin™ in Lescol® XL tablets in a USP-IV dissolution cell.

PubMed

Zhang, Qilei; Gladden, Lynn; Avalle, Paolo; Mantle, Michael

2011-12-20

Swellable polymeric matrices are key systems in the controlled drug release area. Currently, the vast majority of research is still focused on polymer swelling dynamics. This study represents the first quantitative multi-nuclear (((1))H and ((19))F) fast magnetic resonance imaging study of the complete dissolution process of a commercial (Lescol® XL) tablet, whose formulation is based on the hydroxypropyl methylcellulose (HPMC) polymer under in vitro conditions in a standard USP-IV (United States Pharmacopeia apparatus IV) flow-through cell that is incorporated into high field superconducting magnetic resonance spectrometer. Quantitative RARE ((1))H magnetic resonance imaging (MRI) and ((19))F nuclear magnetic resonance (NMR) spectroscopy and imaging methods have been used to give information on: (i) dissolution media uptake and hydrodynamics; (ii) active pharmaceutical ingredient (API) mobilisation and dissolution; (iii) matrix swelling and dissolution and (iv) media activity within the swelling matrix. In order to better reflect the in vivo conditions, the bio-relevant media Simulated Gastric Fluid (SGF) and Fasted State Simulated Intestinal Fluid (FaSSIF) were used. A newly developed quantitative ultra-fast MRI technique was applied and the results clearly show the transport dynamics of media penetration and hydrodynamics along with the polymer swelling processes. The drug dissolution and mobility inside the gel matrix was characterised, in parallel to the ((1))H measurements, by ((19))F NMR spectroscopy and MRI, and the drug release profile in the bulk solution was recorded offline by UV spectrometer. We found that NMR spectroscopy and 1D-MRI can be uniquely used to monitor the drug dissolution/mobilisation process within the gel layer, and the results from ((19))F NMR spectra indicate that in the gel layer, the physical mobility of the drug changes from "dissolved immobilised drug" to "dissolved mobilised drug". Copyright © 2011 Elsevier B.V. All rights reserved.

Alcohol, cannabis and other drugs and subsequent suicide ideation and attempt among young Mexicans.

PubMed

Borges, Guilherme; Benjet, Corina; Orozco, Ricardo; Medina-Mora, Maria-Elena; Menendez, David

2017-08-01

To report results from a follow-up study of alcohol, cannabis and other drugs on suicidal behavior. We estimated prospective associations of substance use as a risk factor for incident suicide ideation and attempt, from a follow-up conducted in 2013 (n = 1071) of the original Mexican Adolescent Mental Health Survey conducted in 2005. Cannabis use before age 15 (ideation risk ratio (RR) = 3.97; 95% confidence interval (CI) = 1.43-11.03; attempt RR = 5.23; 95% CI = 1.17-23.32), early onset of DSM-IV drug use disorder (DUD) among cannabis users (ideation RR = 3.30; 95% CI = 1.11-9.84; attempt RR = 4.14; 95% CI = 1.28-13.36), high frequency of cannabis use (RR for attempts = 4.60; 1.03-20.60) and recent DSM-IV-DUD among cannabis users (RR for attempts = 4.74; 1.09-20.57) increased the RR. For "other drug use", significant results were found among those with high frequency use of other drugs such that they had a higher RR of suicide attempt (5.04; 1.03-24.64). For alcohol, only those who initiated alcohol before age 15 had higher RRs of suicide attempt (1.79; 1.00-3.20). Those who used cannabis at an early age, early onset of DSM-IV-DUD, and those with heavy cannabis use and recent DSM-IV-DUD among cannabis users in the last 12-months had increased risk of suicide ideation and attempt. Drugs other than cannabis showed some of these associations, but to a lesser degree. Prevention of substance use and treatment of those already engaged in drug use, by decreasing suicide ideation and attempt, may help to prevent suicide in Mexico. Copyright © 2017 Elsevier Ltd. All rights reserved.

An evaluation of prescribing trends and patterns of claims within the Preferred Drugs Initiative in Ireland (2011-2016): an interrupted time-series study.

PubMed

McDowell, Ronald; Bennett, Kathleen; Moriarty, Frank; Clarke, Sarah; Barry, Michael; Fahey, Tom

2018-04-20

To examine the impact of the Preferred Drugs Initiative (PDI), an Irish health policy aimed at enhancing evidence-based cost-effective prescribing, on prescribing trends and the cost of prescription medicines across seven medication classes. Retrospective repeated cross-sectional study spanning the years 2011 - 2016. Health Service Executive Primary Care Reimbursement Service pharmacy claims data for General Medical Services (GMS) patients, approximately 40% of the Irish population. Adults aged ≥18 years between 2011 and 2016 are eligible for the GMS scheme. The percentage of PDI medications within each drug class per calendar quarter. Linear regression was used to model prescribing of the preferred drug within each medication group and to assess the impact of PDI guidelines and other relevant changes in prescribing practice. Savings in drug expenditure were estimated. Between 2011 and 2016, around a quarter (23.59%) of all medications were for single-agent drugs licensed in the seven drug classes. There was a small increase in the percentage of PDI drugs, increasing from 4.64% of all medications in 2011 to 4.76% in 2016 (P<0.001). The percentage of preferred drugs within each drug class was significantly higher immediately following publication of the guidelines for all classes except urology, with the largest increases noted for lansoprazole (1.21%, 95% CI: 0.84% to 1.57%, P<0.001) and venlafaxine (0.71%, 95% CI: 0.15% to 1.27%, P=0.02). Trends in prescribing of the preferred drugs between PDI guidelines and the end of 2016 varied between drug classes. Total cost savings between 2013 and 2016 were estimated to be €2.7 million. There has been a small increase in prescribing of PDI drugs in response to prescribing guidelines, with inconsistent changes observed across therapeutic classes. These findings are relevant where health services are seeking to develop more active prescribing interventions aimed at changing prescribing practice. © 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.

76 FR 43690 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-21

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2007-D-0149] (Formerly 2007D-0309) Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Electrocardiograph Electrodes; Availability AGENCY: Food and Drug...

Toward the establishment of standardized in vitro tests for lipid-based formulations, part 3: understanding supersaturation versus precipitation potential during the in vitro digestion of type I, II, IIIA, IIIB and IV lipid-based formulations.

PubMed

Williams, Hywel D; Sassene, Philip; Kleberg, Karen; Calderone, Marilyn; Igonin, Annabel; Jule, Eduardo; Vertommen, Jan; Blundell, Ross; Benameur, Hassan; Müllertz, Anette; Pouton, Colin W; Porter, Christopher J H

2013-12-01

Recent studies have shown that digestion of lipid-based formulations (LBFs) can stimulate both supersaturation and precipitation. The current study has evaluated the drug, formulation and dose-dependence of the supersaturation - precipitation balance for a range of LBFs. Type I, II, IIIA/B LBFs containing medium-chain (MC) or long-chain (LC) lipids, and lipid-free Type IV LBF incorporating different doses of fenofibrate or tolfenamic acid were digested in vitro in a simulated intestinal medium. The degree of supersaturation was assessed through comparison of drug concentrations in aqueous digestion phases (APDIGEST) during LBF digestion and the equilibrium drug solubility in the same phases. Increasing fenofibrate or tolfenamic acid drug loads (i.e., dose) had negligible effects on LC LBF performance during digestion, but promoted drug crystallization (confirmed by XRPD) from MC and Type IV LBF. Drug crystallization was only evident in instances when the calculated maximum supersaturation ratio (SR(M)) was >3. This threshold SR(M) value was remarkably consistent across all LBF and was also consistent with previous studies with danazol. The maximum supersaturation ratio (SR(M)) provides an indication of the supersaturation 'pressure' exerted by formulation digestion and is strongly predictive of the likelihood of drug precipitation in vitro. This may also prove effective in discriminating the in vivo performance of LBFs.

Prospective Effects of Adolescent Indicators of Behavioral Disinhibition on DSM-IV Alcohol, Tobacco, and Illicit Drug Dependence in Young Adulthood

PubMed Central

Palmer, Rohan H. C.; Knopik, Valerie S.; Rhee, Soo Hyun; Hopfer, Christian J.; Corley, Robin C.; Young, Susan E.; Stallings, Michael C.; Hewitt, John K.

2013-01-01

Objective To identify robust predictors of drug dependence. Methods This longitudinal study included 2361 male and female twins from an ongoing longitudinal study at the Center for Antisocial Drug Dependence (CADD) at the University of Colorado Boulder and Denver campuses. Twins were recruited for the CADD project while they were between the ages of 12 and 18. Participants in the current study were on average approximately 15 years of age during the first wave of assessment and approximately 20 years of age at the second wave of assessment. The average time between assessments was five years. A structured interview was administered at each assessment to determine patterns of substance use and Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; Fourth Edition) attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), and drug dependence symptoms. Cloninger’s Tridimensional Personality Questionnaire was also used to assess novelty seeking tendencies (NS). At the second wave of assessment, DSM-IV dependence symptoms were reassessed using the same interview. Path analyses were used to examine direct and indirect mechanisms linking psychopathology and drug outcomes. Results Adolescent substance use, CD, and NS predicted young adult substance dependence, whereas the predictive effects of ADHD were few and inconsistent. Furthermore, CD and NS effects were partially mediated by adolescent substance use. Conclusions Adolescent conduct problems, novelty seeking, and drug use are important indices of future drug problems. The strongest predictor was novelty seeking. PMID:23685327

Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts.

PubMed

Schuetze, Katherine B; Stratton, Matthew S; Blakeslee, Weston W; Wempe, Michael F; Wagner, Florence F; Holson, Edward B; Kuo, Yin-Ming; Andrews, Andrew J; Gilbert, Tonya M; Hooker, Jacob M; McKinsey, Timothy A

2017-04-01

Inhibitors of zinc-dependent histone deacetylases (HDACs) profoundly affect cellular function by altering gene expression via changes in nucleosomal histone tail acetylation. Historically, investigators have employed pan-HDAC inhibitors, such as the hydroxamate trichostatin A (TSA), which simultaneously targets members of each of the three zinc-dependent HDAC classes (classes I, II, and IV). More recently, class- and isoform-selective HDAC inhibitors have been developed, providing invaluable chemical biology probes for dissecting the roles of distinct HDACs in the control of various physiologic and pathophysiological processes. For example, the benzamide class I HDAC-selective inhibitor, MGCD0103 [ N -(2-aminophenyl)-4-[[(4-pyridin-3-ylpyrimidin-2-yl)amino]methyl] benzamide], was shown to block cardiac fibrosis, a process involving excess extracellular matrix deposition, which often results in heart dysfunction. Here, we compare the mechanisms of action of structurally distinct HDAC inhibitors in isolated primary cardiac fibroblasts, which are the major extracellular matrix-producing cells of the heart. TSA, MGCD0103, and the cyclic peptide class I HDAC inhibitor, apicidin, exhibited a common ability to enhance histone acetylation, and all potently blocked cardiac fibroblast cell cycle progression. In contrast, MGCD0103, but not TSA or apicidin, paradoxically increased expression of a subset of fibrosis-associated genes. Using the cellular thermal shift assay, we provide evidence that the divergent effects of HDAC inhibitors on cardiac fibroblast gene expression relate to differential engagement of HDAC1- and HDAC2-containing complexes. These findings illustrate the importance of employing multiple compounds when pharmacologically assessing HDAC function in a cellular context and during HDAC inhibitor drug development. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Pharmacokinetics and effects of alfaxalone after intravenous and intramuscular administration to cats.

PubMed

Rodrigo-Mocholí, D; Escudero, E; Belda, E; Laredo, F G; Hernandis, V; Marín, P

2018-07-01

To determine the pharmacokinetics, and anaesthetic and sedative effects of alfaxalone after I/V and I/M administration to cats. Six European shorthair cats, three males and three females, with a mean weight of 4.21 (SD 0.53) kg and aged 3.8 (SD 0.9) years were enrolled in this crossover, two-treatment, two-period study. Alfaxalone at a dose of 5 mg/kg was administered either I/V or I/M. Blood samples were collected between 2-480 minutes after drug administration and analysed for concentrations of alfaxalone by HPLC. The plasma concentration-time curves were analysed by non-compartmental analysis. Sedation scores were evaluated between 5-120 minutes after drug administration using a numerical rating scale (from 0-18). Intervals from drug administration to sit, sternal and lateral recumbency during the induction phase, and to head-lift, sternal recumbency and standing position during recovery were recorded. The mean half-life and mean residence time of alfaxalone were longer after I/M (1.28 (SD 0.21) and 2.09 (SD 0.36) hours, respectively) than after I/V (0.49 (SD 0.07) and 0.66 (SD 0.16) hours, respectively) administration (p<0.05). Bioavailability after I/M injection of alfaxalone was 94.7 (SD 19.8)%. The mean intervals to sternal and lateral recumbency were longer in the I/M (3.73 (SD 1.99) and 6.12 (SD 0.90) minutes, respectively) compared to I/V (0 minutes for all animals) treated cats (p<0.01). Sedation scores indicative of general anaesthesia (scores >15) were recorded from 5-15 minutes after I/V administration and deep sedation (scores 11-15) at 20 and 30 minutes. Deep sedation was observed from 10-45 minutes after I/M administration. One cat from each group showed hyperkinesia during recovery, and the remainder had an uneventful recovery. Alfaxalone administered I/V in cats provides rapid and smooth induction of anaesthesia. After I/M administration, a longer exposure to the drug and an extended half life were obtained compared to I/V administration. Therefore I/M administration of alfaxalone could be a reliable, suitable and easy route in cats, taking into account that alfaxalone has a slower onset of sedation than when given I/V and achieves deep sedation rather than general anaesthesia.

The plasma and cerebrospinal fluid pharmacokinetics of erlotinib and its active metabolite (OSI-420) after intravenous administration of erlotinib in non-human primates.

PubMed

Meany, Holly J; Fox, Elizabeth; McCully, Cynthia; Tucker, Chris; Balis, Frank M

2008-08-01

Erlotinib hydrochloride is a small molecule inhibitor of epidermal growth factor receptor (EGFR). EGFR is over-expressed in primary brain tumors and solid tumors that metastasize to the central nervous system. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics of erlotinib and its active metabolite OSI-420 after an intravenous (IV) dose in a non-human primate model. Erlotinib was administered as a 1 h IV infusion to four adult rhesus monkeys. Serial blood and CSF samples were drawn over 48 h and erlotinib and OSI-420 were quantified with an HPLC/tandem mass spectroscopic assay. Pharmacokinetic parameters were estimated using non-compartmental and compartmental methods. CSF penetration was calculated from the AUC(CSF):AUC(plasma). Erlotinib disappearance from plasma after a short IV infusion was biexponential with a mean terminal half-life of 5.2 h and a mean clearance of 128 ml/min per m(2). OSI-420 exposure (AUC) in plasma was 30% (range 12-59%) of erlotinib, and OSI-420 clearance was more than 5-fold higher than erlotinib. Erlotinib and OSI-420 were detectable in CSF. The CSF penetration (AUC(CSF):AUC(plasma)) of erlotinib and OSI-420 was <5% relative to total plasma concentration, but CSF drug exposure was approximately 30% of plasma free drug exposure, which was calculated from published plasma protein binding values. The IV administration of erlotinib was well tolerated. Erlotinib and its active metabolite OSI-420 are measurable in CSF after an IV dose. The drug exposure (AUC) in the CSF is limited relative to total plasma concentrations but is substantial relative the free drug exposure in plasma.

Obtaining i.v. fosfomycin through an expanded-access protocol.

PubMed

Frederick, Corey M; Burnette, Jennifer; Aragon, Laura; Gauthier, Timothy P

2016-08-15

One hospital's experience with procuring i.v. fosfomycin via an expanded-access protocol to treat a panresistant infection is described. In mid-2014, a patient at a tertiary care institution had an infection caused by a gram-negative pathogen expressing notable drug resistance. Once it was determined by the infectious diseases (ID) attending physician that i.v. fosfomycin was a possible treatment for this patient, the ID pharmacist began the process of drug procurement. The research and ID pharmacists completed an investigational new drug (IND) application, which required patient-specific details and contributions from the ID physician. After obtaining approval of the IND, an Internet search identified a product vendor in the United Kingdom, who was then contacted to begin the drug purchasing and acquisition processes. Authorization of the transaction required signatures from key senior hospital administrators, including the chief financial officer and the chief operating officer. Approximately 6 days after beginning the acquisition process, the research pharmacist arranged for the wholesaler to expedite product delivery. The ID pharmacist contacted the wholesaler's shipping company at the U.S. Customs Office, providing relevant contact information to ensure that any unexpected circumstances could be quickly addressed. The product arrived at the U.S. Customs Office 8 days after beginning the acquisition process and was held in the U.S. Customs Office for 2 days. The patient received the first dose of i.v. fosfomycin 13 days after starting the expanded-access protocol process. I.V. fosfomycin was successfully procured through an FDA expanded-access protocol by coordinating efforts among ID physicians, pharmacists, and hospital executives. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Printed-Circuit-Board Soldering Training for Group IV Personnel.

ERIC Educational Resources Information Center

Hooprich, E. A.; Matlock, E. W.

As part of a larger program to determine which Navy skills can be learned by lower aptitude personnel, and which methods and techniques would be most effective, an experimental course in printed circuit board soldering was given to 186 Group IV students in 13 classes. Two different training approaches--one stressing instructor guidance and the…

Importance of nondrug costs of intravenous antibiotic therapy.

PubMed

van Zanten, Arthur R H; Engelfriet, Peter M; van Dillen, Karin; van Veen, Miriam; Nuijten, Mark J C; Polderman, Kees H

2003-12-01

Costs are one of the factors determining physicians' choice of medication to treat patients in specific situations. However, usually only the drug acquisition costs are taken into account, whereas other factors such as the use of disposable materials, the drug preparation time and the staff workload are insufficiently taken into consideration. We therefore decided to assess true overall costs of intravenous (IV) antibiotic administration by performing an activity-based costing approach. A prospective survey on costs and workload by means of a time and motion analysis and activity-based costing was performed in a 605-bed secondary referral centre with 20 intensive care unit beds. The subjects were 50 consecutive patients admitted to our hospital with community-acquired pneumonia or intra-abdominal infections requiring treatment with IV antibiotics. A time and motion analysis of 103 routine acts of preparing and administering IV antibiotics was performed in the intensive care unit and in the Department of Internal Medicine. To measure the entire process an inventory and work flowchart were made using detailed questionnaires completed by members of the nursing staff, the medical staff and the pharmacy staff. In addition, questionnaires were distributed to management and secretarial staff to determine additional overhead costs. The average costs for different methods of IV antibiotic administration were then compared by timing all steps in the process. Four different methods of drug administration were used: administration by volumetric pump, administration by syringe pump, administration by 'unaided' infusion bag, and administration by direct IV injection. The average times required for each of these procedures, including preparation and administration of the drug, were 4:49 +/- 2:37, 4:56 +/- 2:03, 5:51 +/- 3:33 and 9:21 +/- 2:16 min (mean minutes:seconds +/- standard deviation), respectively. When the costs for expended staff time and materials (not including drug costs) were calculated this resulted in average costs of 5.65, 7.28, 5.36 and 3.83, respectively, for administration of each dose of antibiotics. These costs represent between 11% and 53% of the total daily costs of antibiotic therapy. Compared with the acquisition costs, these indirect costs ranged from 13% to 113%. Not included in this comparison is the time required for insertion of an IV catheter, which was found to be 10:15 +/- 6:31 min with an average calculated cost of 9.17. Total costs of IV antibiotic administration are formed not only by the costs of the drugs themselves, but also, to a substantial degree, by the time expended by medical and nursing staff, costs of disposable materials and overhead costs. Physicians making decisions regarding the use of specific medications in intensive care unit patients should take these factors into account. Use of IV antibiotics is associated with considerable workload and additional costs that can exceed the acquisition costs of the medications themselves.

Soft gelatin capsules (softgels).

PubMed

Gullapalli, Rampurna Prasad

2010-10-01

It is estimated that more than 40% of new chemical entities (NCEs) coming out of the current drug discovery process have poor biopharmaceutical properties, such as low aqueous solubility and/or permeability. These suboptimal properties pose significant challenges for the oral absorption of the compounds and for the development of orally bioavailable dosage forms. Development of soft gelatin capsule (softgel) dosage form is of growing interest for the oral delivery of poorly water soluble compounds (BCS class II or class IV). The softgel dosage form offers several advantages over other oral dosage forms, such as delivering a liquid matrix designed to solubilize and improve the oral bioavailability of a poorly soluble compound as a unit dose solid dosage form, delivering low and ultra-low doses of a compound, delivering a low melting compound, and minimizing potential generation of dust during manufacturing and thereby improving the safety of production personnel. However, due to the very dynamic nature of the softgel dosage form, its development and stability during its shelf-life are fraught with several challenges. The goal of the current review is to provide an in-depth discussion on the softgel dosage form to formulation scientists who are considering developing softgels for therapeutic compounds.

The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

PubMed Central

Prichard, B N

1978-01-01

All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III). PMID:26370

A latent class analysis of substance use and culture among gay, bisexual and other men who have sex with men.

PubMed

Card, Kiffer G; Armstrong, Heather L; Carter, Allison; Cui, Zishan; Wang, Lu; Zhu, Julia; Lachowsky, Nathan J; Moore, David M; Hogg, Robert S; Roth, Eric A

2018-03-28

Assessments of gay and bisexual men's substance use often obscures salient sociocultural and identity-related experiences related to how they use drugs. Latent class analysis was used to examine how patterns of substance use represent the social, economic and identity-related experiences of this population. Participants were sexually active gay and bisexual men (including other men who have sex with men), aged ≥ 16 years, living in Metro Vancouver (n = 774). LCA indicators included all substances used in the past six months self-reported by more than 30 men. Model selection was made with consideration to model parsimony, interpretability and optimisation of statistical criteria. Multinomial regression identified factors associated with class membership. A six-class solution was identified representing: 'assorted drug use' (4.5%); 'club drug use' (9.5%); 'street drug use' (12.1%); 'sex drug use' (11.4%); 'conventional drug use' (i.e. tobacco, alcohol, marijuana; 25.9%); and 'limited drug use' (36.7%). Factors associated with class membership included age, sexual orientation, annual income, occupation, income from drug sales, housing stability, group sex event participation, gay bars/clubs attendance, sensation seeking and escape motivation. These results highlight the need for programmes and policies that seek to lessen social disparities and account for social distinctions among this population.

Anesthetic drugs in status epilepticus: Risk or rescue?

PubMed Central

Marsch, Stephan; Fuhr, Peter; Kaplan, Peter W.; Rüegg, Stephan

2014-01-01

Objective: To evaluate the risks of continuously administered IV anesthetic drugs (IVADs) on the outcome of adult patients with status epilepticus (SE). Methods: All intensive care unit patients with SE from 2005 to 2011 at a tertiary academic medical care center were included. Relative risks were calculated for the primary outcome measures of seizure control, Glasgow Outcome Scale score at discharge, and death. Poisson regression models were used to control for possible confounders and to assess effect modification. Results: Of 171 patients, 37% were treated with IVADs. Mortality was 18%. Patients with anesthetic drugs had more infections during SE (43% vs 11%; p < 0.0001) and a 2.9-fold relative risk for death (2.88; 95% confidence interval 1.45–5.73), independent of possible confounders (i.e., duration and severity of SE, nonanesthetic third-line antiepileptic drugs, and critical medical conditions) and without significant effect modification by different grades of SE severity and etiologies. As IVADs were used after first- and second-line drugs failed, there was a correlation between treatment-refractory SE and the use of IVADs, leading to insignificant results regarding the risk of IVADs and outcome after additional adjustment for refractory SE. Conclusion: Our findings heighten awareness regarding adverse effects of IVADs. Randomized controlled trials are needed to further clarify the association of IVADs with outcome in patients with SE. Classification of evidence: This study provides Class III evidence that patients with SE receiving IVADs have a higher proportion of infection and an increased risk of death as compared to patients not receiving IVADs. PMID:24319039

24 CFR 982.307 - Tenant screening.

Code of Federal Regulations, 2011 CFR

2011-04-01

... family, including information about the tenancy history of family members, or about drug-trafficking by... to the peaceful enjoyment of their housing; (iv) Drug-related criminal activity or other criminal...

19 CFR Appendix to Part 146 - Guidelines for Determining Producibility and Relative Values for Oil Refinery Zones

Code of Federal Regulations, 2012 CFR

2012-04-01

... × .20). Likewise, the class IV crude oil could produce aviation gasoline in an amount up to 8,500 pounds... Class III PF Crude 35,000 24,500 31,850 14,000 31,150 10,150 Class III D Crude 20,000 14,000 18,200 8,000 17,800 5,800 Class III NPF Crude 20,000 14,000 18,200 8,000 17,800 5,800 Feedstock factors are...

19 CFR Appendix to Part 146 - Guidelines for Determining Producibility and Relative Values for Oil Refinery Zones

Code of Federal Regulations, 2014 CFR

2014-04-01

... × .20). Likewise, the class IV crude oil could produce aviation gasoline in an amount up to 8,500 pounds... Class III PF Crude 35,000 24,500 31,850 14,000 31,150 10,150 Class III D Crude 20,000 14,000 18,200 8,000 17,800 5,800 Class III NPF Crude 20,000 14,000 18,200 8,000 17,800 5,800 Feedstock factors are...

Genetic Validation of Aminoacyl-tRNA Synthetases as Drug Targets in Trypanosoma brucei

PubMed Central

Kalidas, Savitha; Cestari, Igor; Monnerat, Severine; Li, Qiong; Regmi, Sandesh; Hasle, Nicholas; Labaied, Mehdi; Parsons, Marilyn; Stuart, Kenneth

2014-01-01

Human African trypanosomiasis (HAT) is an important public health threat in sub-Saharan Africa. Current drugs are unsatisfactory, and new drugs are being sought. Few validated enzyme targets are available to support drug discovery efforts, so our goal was to obtain essentiality data on genes with proven utility as drug targets. Aminoacyl-tRNA synthetases (aaRSs) are known drug targets for bacterial and fungal pathogens and are required for protein synthesis. Here we survey the essentiality of eight Trypanosoma brucei aaRSs by RNA interference (RNAi) gene expression knockdown, covering an enzyme from each major aaRS class: valyl-tRNA synthetase (ValRS) (class Ia), tryptophanyl-tRNA synthetase (TrpRS-1) (class Ib), arginyl-tRNA synthetase (ArgRS) (class Ic), glutamyl-tRNA synthetase (GluRS) (class 1c), threonyl-tRNA synthetase (ThrRS) (class IIa), asparaginyl-tRNA synthetase (AsnRS) (class IIb), and phenylalanyl-tRNA synthetase (α and β) (PheRS) (class IIc). Knockdown of mRNA encoding these enzymes in T. brucei mammalian stage parasites showed that all were essential for parasite growth and survival in vitro. The reduced expression resulted in growth, morphological, cell cycle, and DNA content abnormalities. ThrRS was characterized in greater detail, showing that the purified recombinant enzyme displayed ThrRS activity and that the protein localized to both the cytosol and mitochondrion. Borrelidin, a known inhibitor of ThrRS, was an inhibitor of T. brucei ThrRS and showed antitrypanosomal activity. The data show that aaRSs are essential for T. brucei survival and are likely to be excellent targets for drug discovery efforts. PMID:24562907

Direct visualization of in vitro drug mobilization from Lescol XL tablets using two-dimensional (19)F and (1)H magnetic resonance imaging.

PubMed

Chen, Chen; Gladden, Lynn F; Mantle, Michael D

2014-02-03

This article reports the application of in vitro multinuclear ((19)F and (1)H) two-dimensional magnetic resonance imaging (MRI) to study both dissolution media ingress and drug egress from a commercial Lescol XL extended release tablet in a United States Pharmacopeia Type IV (USP-IV) dissolution cell under pharmacopoeial conditions. Noninvasive spatial maps of tablet swelling and dissolution, as well as the mobilization and distribution of the drug are quantified and visualized. Two-dimensional active pharmaceutical ingredient (API) mobilization and distribution maps were obtained via (19)F MRI. (19)F API maps were coregistered with (1)H T2-relaxation time maps enabling the simultaneous visualization of drug distribution and gel layer dynamics within the swollen tablet. The behavior of the MRI data is also discussed in terms of its relationship to the UV drug release behavior.

uSIMPK. An Excel for Windows-based simulation program for instruction of basic pharmacokinetics principles to pharmacy students.

PubMed

Brocks, Dion R

2015-07-01

Pharmacokinetics can be a challenging topic to teach due to the complex relationships inherent between physiological parameters, mathematical descriptors and equations, and their combined impact on shaping the blood fluid concentration vs. time curves of drugs. A computer program was developed within Microsoft Excel for Windows, designed to assist in the instruction of basic pharmacokinetics within an entry-to-practice pharmacy class environment. The program is composed of a series of spreadsheets (modules) linked by Visual Basic for Applications, intended to illustrate the relationships between pharmacokinetic and in some cases physiological parameters, doses and dose rates and the drug blood fluid concentration vs. time curves. Each module is accompanied by a simulation user's guide, prompting the user to change specific independent parameters and then observe the impact of the change(s) on the drug concentration vs. time curve and on other dependent parameters. "Slider" (or "scroll") bars can be selected to readily see the effects of repeated changes on the dependencies. Topics covered include one compartment single dose administration (iv bolus, oral, short infusion), intravenous infusion, repeated doses, renal and hepatic clearance, nonlinear elimination, two compartment model, plasma protein binding and the relationship between pharmacokinetics and drug effect. The program has been used in various forms in the classroom over a number of years, with positive ratings generally being received from students for its use in the classroom. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Active intestinal drug absorption and the solubility-permeability interplay.

PubMed

Porat, Daniel; Dahan, Arik

2018-02-15

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Physics considerations in targeted anticancer drug delivery by magnetoelectric nanoparticles

NASA Astrophysics Data System (ADS)

Stimphil, Emmanuel; Nagesetti, Abhignyan; Guduru, Rakesh; Stewart, Tiffanie; Rodzinski, Alexandra; Liang, Ping; Khizroev, Sakhrat

2017-06-01

In regard to cancer therapy, magnetoelectric nanoparticles (MENs) have proven to be in a class of its own when compared to any other nanoparticle type. Like conventional magnetic nanoparticles, they can be used for externally controlled drug delivery via application of a magnetic field gradient and image-guided delivery. However, unlike conventional nanoparticles, due to the presence of a non-zero magnetoelectric effect, MENs provide a unique mix of important properties to address key challenges in modern cancer therapy: (i) a targeting mechanism driven by a physical force rather than antibody matching, (ii) a high-specificity delivery to enhance the cellular uptake of therapeutic drugs across the cancer cell membranes only, while sparing normal cells, (iii) an externally controlled mechanism to release drugs on demand, and (iv) a capability for image guided precision medicine. These properties separate MEN-based targeted delivery from traditional biotechnology approaches and lay a foundation for the complementary approach of technobiology. The biotechnology approach stems from the underlying biology and exploits bioinformatics to find the right therapy. In contrast, the technobiology approach is geared towards using the physics of molecular-level interactions between cells and nanoparticles to treat cancer at the most fundamental level and thus can be extended to all the cancers. This paper gives an overview of the current state of the art and presents an ab initio model to describe the underlying mechanisms of cancer treatment with MENs from the perspective of basic physics.

Latent Classes of Polydrug Users as a Predictor of Crash Involvement and Alcohol Consumption.

PubMed

Scherer, Michael; Romano, Eduardo; Voas, Robert; Taylor, Eileen

2018-05-01

Polydrug users have been shown to be at higher risk for alcohol consumption and crash involvement. However, research has shown that polydrug groups differ in some important ways. It is currently unknown how polydrug-using groups differ in terms of crash involvement and alcohol consumption. The current study used latent class analysis to examine subgroups of polydrug users (n = 384) among a sample of drivers in Virginia Beach, Virginia (N = 10,512). A series of logistic regression analyses were conducted to determine the relationship between polydrug use categories and crash involvement and alcohol consumption. Four distinct subclasses of users were identified among polydrug-using drivers: Class 1 is the "marijuana-amphetamines class" and accounts for 21.6% of polydrug users. Class 2 is the "benzo-antidepressant class" and accounts for 39.0% of polydrug users. Class 3 is the "opioid-benzo class" and accounts for 32.7% of polydrug users. Finally, Class 4 is the "marijuana-cocaine class" and accounts for 6.7% of the study sample. Drivers in the opioid-benzo class were significantly more likely than those in any other class as well as non-drug users and single-drug users to be involved in a crash and were more likely than those in most other conditions to consume alcohol. No significant difference was found between marijuana-amphetamine users or benzo-antidepressant users and non-drug users on crash risk. Some polydrug users are indeed at greater risk for crash involvement and alcohol consumption; however, not all polydrug users are significantly worse than single-drug users and/or non-drug users, and the practice of lumping polydrug users together when predicting crash risk runs the risk of inaccurately attributing crash involvement to certain drivers.

BCI Competition IV – Data Set I: Learning Discriminative Patterns for Self-Paced EEG-Based Motor Imagery Detection

PubMed Central

Zhang, Haihong; Guan, Cuntai; Ang, Kai Keng; Wang, Chuanchu

2012-01-01

Detecting motor imagery activities versus non-control in brain signals is the basis of self-paced brain-computer interfaces (BCIs), but also poses a considerable challenge to signal processing due to the complex and non-stationary characteristics of motor imagery as well as non-control. This paper presents a self-paced BCI based on a robust learning mechanism that extracts and selects spatio-spectral features for differentiating multiple EEG classes. It also employs a non-linear regression and post-processing technique for predicting the time-series of class labels from the spatio-spectral features. The method was validated in the BCI Competition IV on Dataset I where it produced the lowest prediction error of class labels continuously. This report also presents and discusses analysis of the method using the competition data set. PMID:22347153

Self-organized perturbations enhance class IV behavior and 1/f power spectrum in elementary cellular automata.

PubMed

Nakajima, Kohei; Haruna, Taichi

2011-09-01

In this paper, we propose a new class of cellular automata based on the modification of its state space. It is introduced to model a computation which is exposed to an environment. We formalized the computation as extension and projection processes of its state space and resulting misidentifications of the state. This is motivated to embed the role of an environment into the system itself, which naturally induces self-organized internal perturbations rather than the usual external perturbations. Implementing this structure into the elementary cellular automata, we characterized its effect by means of input entropy and power spectral analysis. As a result, the cellular automata with this structure showed robust class IV behavior and a 1/f power spectrum in a wide range of rule space comparative to the notion of the edge of chaos. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

77 FR 14403 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0167] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document: Norovirus Serological Reagents; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice...

Studying Psychosocial Barriers to Drug Treatment Among Chinese Methamphetamine Users Using A 3-Step Latent Class Analysis.

PubMed

Wang, Jichuan; Kelly, Brian C; Liu, Tieqiao; Hao, Wei

2016-03-01

Given the growth in methamphetamine use in China during the 21st century, we assessed perceived psychosocial barriers to drug treatment among this population. Using a sample of 303 methamphetamine users recruited via Respondent Driven Sampling, we use Latent Class Analysis (LCA) to identify possible distinct latent groups among Chinese methamphetamine users on the basis of their perceptions of psychosocial barriers to drug treatment. After covariates were included to predict latent class membership, the 3-step modeling approach was applied. Our findings indicate that the Chinese methamphetamine using population was heterogeneous on perceptions of drug treatment barriers; four distinct latent classes (subpopulations) were identified--Unsupported Deniers, Deniers, Privacy Anxious, and Low Barriers--and individual characteristics shaped the probability of class membership. Efforts to link Chinese methamphetamine users to treatment may require a multi-faceted approach that attends to differing perceptions about impediments to drug treatment. Copyright © 2015. Published by Elsevier Inc.

24 CFR 983.255 - Tenant screening.

Code of Federal Regulations, 2011 CFR

2011-04-01

... family, including information about the tenancy history of family members or about drug trafficking and... peaceful enjoyment of their housing; (iv) Drug-related criminal activity or other criminal activity that is...

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2013 CFR

2013-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2012 CFR

2012-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2014 CFR

2014-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

24 CFR 983.255 - Tenant screening.

Code of Federal Regulations, 2010 CFR

2010-04-01

... family, including information about the tenancy history of family members or about drug trafficking and... peaceful enjoyment of their housing; (iv) Drug-related criminal activity or other criminal activity that is...

The CHEMDNER corpus of chemicals and drugs and its annotation principles.

PubMed

Krallinger, Martin; Rabal, Obdulia; Leitner, Florian; Vazquez, Miguel; Salgado, David; Lu, Zhiyong; Leaman, Robert; Lu, Yanan; Ji, Donghong; Lowe, Daniel M; Sayle, Roger A; Batista-Navarro, Riza Theresa; Rak, Rafal; Huber, Torsten; Rocktäschel, Tim; Matos, Sérgio; Campos, David; Tang, Buzhou; Xu, Hua; Munkhdalai, Tsendsuren; Ryu, Keun Ho; Ramanan, S V; Nathan, Senthil; Žitnik, Slavko; Bajec, Marko; Weber, Lutz; Irmer, Matthias; Akhondi, Saber A; Kors, Jan A; Xu, Shuo; An, Xin; Sikdar, Utpal Kumar; Ekbal, Asif; Yoshioka, Masaharu; Dieb, Thaer M; Choi, Miji; Verspoor, Karin; Khabsa, Madian; Giles, C Lee; Liu, Hongfang; Ravikumar, Komandur Elayavilli; Lamurias, Andre; Couto, Francisco M; Dai, Hong-Jie; Tsai, Richard Tzong-Han; Ata, Caglar; Can, Tolga; Usié, Anabel; Alves, Rui; Segura-Bedmar, Isabel; Martínez, Paloma; Oyarzabal, Julen; Valencia, Alfonso

2015-01-01

The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/.

The CHEMDNER corpus of chemicals and drugs and its annotation principles

PubMed Central

2015-01-01

The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/ PMID:25810773

Comparison of lornoxicam and low-dose tramadol for management of post-thyroidectomy pain.

PubMed

Yücel, Ali; Yazıcı, Alper; Müderris, Togay; Gül, Fatih

2016-10-01

The present study sought to compare the analgesic efficacy and adverse effects of intravenous (IV) lornoxicam and tramadol to investigate if lornoxicam is a reasonable alternative to a weak opioid for post-thyroidectomy pain. Fifty patients of American Society of Anesthesiologists class I or II, 18 to 65 years of age, and who underwent thyroidectomy were assigned to 2 groups in a randomized manner. Group L received 8 mg of lornoxicam IV and Group T received 1 mg/kg of tramadol IV at conclusion of the operation. Pain intensity of patients was recorded at 15 and 30 minutes, and at 1, 2, 3, 4, 6, 12, and 24 hours after the initial dose with Numerical Rating Scale (NRS) and Ramsey Sedation Scale. Electrocardiogram, heart rate, systolic/diastolic and average artery pressure and peripheral oxygen saturations were monitored continuously during this period. Patients completed satisfaction questionnaires at 24th hour. Both drugs produced acceptable analgesia; however, significantly fewer patients reported 1 or more adverse events with lornoxicam than with tramadol. Most commonly seen in Group T was nausea/vomiting. NRS scores at 15 minutes, 30 minutes, and 1 hour were lower in Group L than in Group T (p<0.05), but there was no significant difference between groups after postoperative first hour. First analgesic requirement time was significantly longer in Group L compared to Group T (p<0.001). No serious complications were seen in either group. Lornoxicam is a safe and effective analgesic that may be used with fewer complications than low-dose tramadol for treatment of moderate to severe postoperative pain.

Prophylactic Use of Intravenous Clonidine Compared to Tramadol in Prevention of Intraoperative Shivering under Regional Anesthesia

PubMed Central

Guha (Banerjee), Sarmila; Nath, Pallab Kumar; Halder, Rita; Bandyopadhyay, Ujjwal

2017-01-01

Objectives: This study aimed to evaluate the relative efficacy of prophylactic intravenous (IV) clonidine and tramadol for control of intraoperative shivering following spinal anesthesia. Materials and Methods: After institutional ethical clearance, 142 patients were chosen from either gender, aged 20–60 years, physical status American Society of Anesthesiology Class I and II scheduled for elective infraumbilical surgery under spinal anesthesia. Patients were randomized into two groups: Group C (n = 71) received injection clonidine 50 μg) IV in 100 ml normal saline (NS) over 10 min and Group T (n = 71) received injection tramadol 50 mg IV. In 100 ml NS over 10 min after spinal anesthesia. Results: Incidence of shivering was not significant when compared between the two groups (P > 0.05). The axillary temperatures fell significantly in Group C from the baseline and remained at a significantly lower level up to 60 min after rescue drug was administered in patients who shivered. There was a similar fall in axillary temperature in Group T in patients having shivering, but the difference was not significant. When compared between the two groups among patients who shivered, the difference in fall of temperature was not significant. Side effects such as hypotension, bradycardia, and sedation were significantly more common in clonidine group, whereas nausea was significantly more common patients of tramadol group. Conclusion: Prophylactic administration of both tramadol and clonidine is effective for controlling shivering under spinal anesthesia. However, tramadol is better because of higher response rate, less sedation, and lesser hemodynamic alterations. PMID:28663645

Provision of Atraumatic Restorative Treatment (ART) restorations to Chinese pre-school children--a 30-month evaluation.

PubMed

Lo, E C; Holmgren, C J

2001-01-01

The objectives of this study were: to provide restorations using the ART approach to pre-school children in Southern China in a kindergarten environment, using a high-strength glass-ionomer restorative material; to assess the acceptability of this approach and to evaluate on a longitudinal basis the restorations placed. A total of 170 ART restorations were placed in 95 children, aged 5.1 +/- 0.7 years, by seven final-year dental students using standard ART procedures and hand instruments. The restorations were evaluated every six months thereafter by two calibrated independent examiners using explorers and mouth-mirrors. 93% of the children reported that they did not feel pain during treatment and 86% were willing to receive ART restorations again. The cumulative 12- and 30-month survival rates of Class I restorations were 91% and 79%, respectively. The corresponding figures for Class V restorations were 79% and 70%, while those for Class II restorations were 75% and 51%. The failure rates of Class III and IV restorations were high with more than half of them scored as missing within the first year. The ART approach was shown to be acceptable to Chinese pre-school children for providing restorative dental care outside the traditional clinical setting. The success rates were high for Class I and V restorations in primary teeth, modest for Class II, and low for Class III and IV restorations.

Five-year trends in antiretroviral usage and drug costs in HIV-infected children in Thailand.

PubMed

Collins, Intira; Cairns, John; Le Coeur, Sophie; Pagdi, Karin; Ngampiyaskul, Chaiwat; Layangool, Prapaisri; Borkird, Thitiporn; Na-Rajsima, Sathaporn; Wanchaitanawong, Vanichaya; Jourdain, Gonzague; Lallemant, Marc

2013-09-01

As antiretroviral treatment (ART) programs mature, data on drug utilization and costs are needed to assess durability of treatments and inform program planning. Children initiating ART were followed up in an observational cohort in Thailand. Treatment histories from 1999 to 2009 were reviewed. Treatment changes were categorized as: drug substitution (within class), switch across drug class (non nucleoside reverse-transcriptase inhibitors (NNRTI) to/from protease inhibitor (PI)), and to salvage therapy (dual PI or PI and NNRTI). Antiretroviral drug costs were calculated in 6-month cycles (US$ 2009 prices). Predictors of high drug cost including characteristics at start of ART (baseline), initial regimen, treatment change, and duration on ART were assessed using mixed-effects regression models. Five hundred seven children initiated ART with a median 54 (interquartile range, 36-72) months of follow-up. Fifty-two percent had a drug substitution, 21% switched across class, and 2% to salvage therapy. When allowing for drug substitution, 78% remained on their initial regimen. Mean drug cost increased from $251 to $428 per child per year in the first and fifth year of therapy, respectively. PI-based and salvage regimens accounted for 16% and 2% of treatments prescribed and 33% and 5% of total costs, respectively. Predictors of high cost include baseline age ≥ 8 years, non nevirapine-based initial regimen, switch across drug class, and to salvage regimen (P < 0.005). At 5 years, 21% of children switched across drug class and 2% received salvage therapy. The mean drug cost increased by 70%. Access to affordable second- and third-line drugs is essential for the sustainability of treatment programs.

Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study.

PubMed

Kesselheim, Aaron S; Wang, Bo; Franklin, Jessica M; Darrow, Jonathan J

2015-09-23

To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades. Cohort study. FDA approved novel therapeutics between 1987 and 2014. Publicly available sources provided each drug's year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA's four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review. Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not. The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P<0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction). In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative. © Kesselheim et al 2015.

Consumption Patterns of Nightlife Attendees in Munich: A Latent-Class Analysis.

PubMed

Hannemann, Tessa-Virginia; Kraus, Ludwig; Piontek, Daniela

2017-09-19

The affinity for substance use among patrons of nightclubs has been well established. With novel psychoactive substances (NPS) quickly emerging on the European drug market, trends, and patterns of use are potentially changing. (1) The detection of subgroups of consumers in the electronic dance music scene of a major German metropolitan city, (2) describing the consumption patterns of these subgroups, (3) exploring the prevalence and type of NPS consumption in this population at nightlife events in Munich. A total of 1571 patrons answered questions regarding their own substance use and the emergence of NPS as well as their experience with these substances. A latent class analysis was employed to detect consumption patterns within the sample. A four class model was determined reflecting different consumption patterns: the conservative class (34.9%) whose substance was limited to cannabis; the traditional class (36.6%) which especially consumed traditional club drugs; the psychedelic class (17.5%) which, in addition to traditional club drugs also consumed psychedelic drugs; and an unselective class (10.9%) which displayed the greatest likelihood of consumption of all assessed drugs. "Smoking mixtures" and methylone were the new substances mentioned most often, the number of substances mentioned differed between latent classes. Specific strategies are needed to reduce harm in those displaying the riskiest substance use. Although NPS use is still a fringe phenomenon its prevalence is greater in this subpopulation than in the general population, especially among users in the high-risk unselective class.

Controlling postoperative use of i.v. acetaminophen at an academic medical center.

PubMed

Vincent, William R; Huiras, Paul; Empfield, Jennifer; Horbowicz, Kevin J; Lewis, Keith; McAneny, David; Twitchell, David

2018-04-15

Results of an interprofessional formulary initiative to decrease postoperative prescribing of i.v. acetaminophen are reported. After a medical center added i.v. acetaminophen to its formulary, increased prescribing of the i.v. formulation and a 3-fold price increase resulted in monthly spending of more than $40,000, prompting an organizationwide effort to curtail that cost while maintaining effective pain management. The surgery, anesthesia, and pharmacy departments applied the Institute for Healthcare Improvement's Model for Improvement to implement (1) pharmacist-led enforcement of prescribing restrictions, (2) retrospective evaluation of i.v. acetaminophen's impact on rates of opioid-related adverse effects, (3) restriction of prescribing of the drug to 1 postoperative dose on select patient care services, and (4) guideline-driven pain management according to an enhanced recovery after surgery (ERAS) protocol. Monitored metrics included the monthly i.v. acetaminophen prescribing rate, the proportion of i.v. acetaminophen orders requiring pharmacist intervention to enforce prescribing restrictions, and prescribing rates for select adjunctive analgesics. Within a year of project implementation, the mean monthly i.v. acetaminophen prescribing rate decreased by 83% from baseline to about 6 doses per 100 patient-days, with a decline in the monthly drug cost to about $4,000. Documented pharmacist interventions increased 2.7-fold, and use of oral acetaminophen, ketorolac, and gabapentin in ERAS areas increased by 18% overall. An interprofessional initiative at a large medical center reduced postoperative use of i.v. acetaminophen by more than 80% and yielded over $400,000 in annual cost savings. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Primary biliary cirrhosis degree assessment by acoustic radiation force impulse imaging and hepatic fibrosis indicators.

PubMed

Zhang, Hai-Chun; Hu, Rong-Fei; Zhu, Ting; Tong, Ling; Zhang, Qiu-Qin

2016-06-14

To evaluate the assessment of primary biliary cirrhosis degree by acoustic radiation force impulse imaging (ARFI) and hepatic fibrosis indicators. One hundred and twenty patients who developed liver cirrhosis secondary to primary biliary cirrhosis were selected as the observation group, with the degree of patient liver cirrhosis graded by Child-Pugh (CP) score. Sixty healthy individuals were selected as the control group. The four indicators of hepatic fibrosis were detected in all research objects, including hyaluronic acid (HA), laminin (LN), type III collagen (PC III), and type IV collagen (IV-C). The liver parenchyma hardness value (LS) was then measured by ARFI technique. LS and the four indicators of liver fibrosis (HA, LN, PC III, and IV-C) were observed in different grade CP scores. The diagnostic value of LS and the four indicators of liver fibrosis in determining liver cirrhosis degree with PBC, whether used alone or in combination, were analyzed by receiver operating characteristic (ROC) curve. LS and the four indicators of liver fibrosis within the three classes (A, B, and C) of CP scores in the observation group were higher than in the control group, with C class > B class > A class; the differences were statistically significant (P < 0.01). Although AUC values of LS within the three classes of CP scores were higher than in the four indicators of liver fibrosis, sensitivity and specificity were unstable. The ROC curves of LS combined with the four indicators of liver fibrosis revealed that: AUC and sensitivity in all indicators combined in the A class of CP score were higher than in LS alone, albeit with slightly decreased specificity; AUC and specificity in all indicators combined in the B class of CP score were higher than in LS alone, with unchanged sensitivity; AUC values (0.967), sensitivity (97.4%), and specificity (90%) of all indicators combined in the C class of CP score were higher than in LS alone (0.936, 92.1%, 83.3%). The diagnostic value of PBC cirrhosis degree in liver cirrhosis degree assessment by ARFI combined with the four indicators of serum liver fibrosis is of satisfactory effectiveness and has important clinical application value.

[Efficacy of intravenous phenobarbital treatment for status epilepticus].

PubMed

Muramoto, Emiko; Mizobuchi, Masahiro; Sumi, Yoshihiro; Sako, Kazuya; Nihira, Atsuko; Takeuchi, Akiko; Nakamura, Hirohiko

2013-08-01

Intravenous phenobarbital (IV-PB) therapy was launched in Japan in October 2008. We retrospectively investigated its efficacy and tolerability in patients with status epilepticus. Forty-three consecutive patients received IV-PB for status epilepticus between June 2009 and April 2011. Among them, 39 patients had underlying diseases, which included acute diseases in 19 patients and chronic conditions in 20 patients. Although 18 patients had been taking antiepileptic drugs (AEDs) before the occurrence of status epilepticus, the blood AED concentrations in 8 patients was below the therapeutic levels. Before the administration of IV-PB, 39 patients were treated with intravenous benzodiazepine, 17 patients were treated with intravenous phenytoin, and 15 patients with intravenous infusion of lidocaine. The initial doses of IV-PB ranged from 125 to 1,250 mg (1.9-20.0 mg/kg). Additional doses of IV-PB were required in 12 patients. Seizures were controlled in 35 patients (81%) after IV-PB administration. Cessation of status epilepticus was attained in 24 patients after the initial dose and in 11 patients after additional doses. There were no serious adverse effects, although respiratory suppression was observed in 3 patients and drug eruption was observed in 1 patient. IV-PB is relatively safe and effective for controlling status epilepticus. If the first dose is not effective, additional doses are required up to the recommended maximum dose.

Joint Tactical Information Distribution System (JTIDS). Class 3 Terminal Conceptual Study. Volume 4. Appendix A. Mission Profile Detail. Appendix B. Moments of the Decision Variable for preamble Detection

DTIC Science & Technology

1978-07-07

i on CM . ’ oil ■ «) rH H O W CO rH 0) H H <: o I »d • •o H i ! • M CO X -H | i iQ M 4> m u...referred to Electronic Systems Division, Hanscom AFB, MA. Document partially illegible. AFGL ltr 15 May 1981 A I ’ ESD-ra-7B-l6l, Vol. IV V,^^7 -J...BEPORE COMPLETING FORM ESD-TR-78-161, Vol. IV 2 COVT ACCESSION NO I RCCIFICNT’S CATALOG NUMBCn 4. TITLE (mid Submit) JTIDS Class

Risk factors associated with difficult venous access in adult ED patients.

PubMed

Fields, J Matthew; Piela, Nicole E; Au, Arthur K; Ku, Bon S

2014-10-01

The objective was to determine risk factors associated with difficult venous access (DVA) in the emergency department (ED). This was a prospective, observational study conducted in the ED of an urban tertiary care hospital. Adult patients undergoing intravenous (IV) placement were consecutively enrolled during periods of block enrollment. The primary outcome was DVA, defined as 3 or more IV attempts or use of a method of rescue vascular access to establish IV access. Univariate and multivariate analyses for factors predicting DVA were performed using logistic regression. A total of 743 patients were enrolled, of which 88 (11.8%) met the criteria for DVA. In the adjusted analysis, only 3 medical conditions were significantly associated with DVA: diabetes (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.1-2.8), sickle cell disease (OR 3.8, 95% CI 1.5-9.5), and history of IV drug abuse (OR 2.5, 95% CI 1.1-5.7). Notably, age, body mass index, and dialysis were not. Of patients who reported a history of requiring multiple IV attempts in the past for IV access, 14% met criteria for DVA on this visit (OR 7.7 95% CI 3-18). Of the patients who reported a history of IV insertion into the external jugular, ultrasound-guided IV placement, or a central venous catheter for IV access, 26% had DVA on this visit (OR 16.7, 95% CI 6.8-41). Nearly 1 of every 9 to 10 adults in an urban ED had DVA. Diabetes, IV drug abuse, and sickle cell disease were found to be significantly associated with DVA. Copyright © 2014 Elsevier Inc. All rights reserved.

Usefulness of high-dose intravenous human immunoglobulins treatment for refractory recurrent pericarditis.

PubMed

Moretti, Michele; Buiatti, Alessandra; Merlo, Marco; Massa, Laura; Fabris, Enrico; Pinamonti, Bruno; Sinagra, Gianfranco

2013-11-01

The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases. Copyright © 2013 Elsevier Inc. All rights reserved.

Eliciting the Intension of Drug Value Sets – Principles and Quality Assurance Applications

PubMed Central

Bahr, Nathan J.; Nelson, Scott D.; Winnenburg, Rainer; Bodenreider, Olivier

2018-01-01

Value sets (VSs) used in electronic clinical quality measures are lists of codes from standard terminologies (“extensional” VSs), whose purpose (“intension”) is not always explicitly stated. We elicited the intension for the 09/01/2014 release of extensional medication value sets by comparison to drug classes from the October 2014 release of RxClass. Value sets matched drug classes if they shared common ingredients, as evidenced by Jaccard similarity score. We elicited the intension of 80 extensional value sets. The average Jaccard similarity was 0.65 for single classes and 0.80 for combination classes, with 34% (27/80) of the value sets having high similarity scores. Manual review by a pharmacist indicated 51% (41/80) of the drug classes selected as the best mapping for a value set matched the intension reflected in that value set name. This approach has the potential for facilitating the development and maintenance of medication value sets. PMID:29295218

Application of Cerium (IV) as an Oxidimetric Agent for the Determination of Ethionamide in Pharmaceutical Formulations

PubMed Central

2016-01-01

Two simple methods are described for the determination of ethionamide (ETM) in bulk drug and tablets using cerium (IV) sulphate as the oxidimetric agent. In both methods, the sample solution is treated with a measured excess of cerium (IV) solution in H2SO4 medium, and after a fixed standing time, the residual oxidant is determined either by back titration with standard iron (II) solution to a ferroin end point in titrimetry or by reacting with o-dianisidine followed by measurement of the absorbance of the orange-red coloured product at 470 nm in spectrophotometry. In titrimetry, the reaction proceeded with a stoichiometry of 1 : 2 (ETM : Ce (IV)) and the amount of cerium (IV) consumed by ETM was related to the latter's amount, and the method was applicable over 1.0–8.0 mg of drug. In spectrophotometry, Beer's law was obeyed over the concentration range of 0.5–5.0 μg/mL ETM with a molar absorptivity value of 2.66 × 104 L/(mol·cm). The limits of detection (LOD) and quantification (LOQ) calculated according to ICH guidelines were 0.013 and 0.043 μg/mL, respectively. The proposed titrimetric and spectrophotometric methods were found to yield reliable results when applied to bulk drug and tablets analysis, and hence they can be applied in quality control laboratories. PMID:27818836

Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico.

PubMed

Meacham, Meredith C; Roesch, Scott C; Strathdee, Steffanie A; Lindsay, Suzanne; Gonzalez-Zuniga, Patricia; Gaines, Tommi L

2018-01-01

Patterns of polydrug use among people who inject drugs (PWID) may be differentially associated with overdose and unique human immunodeficiency virus (HIV) risk factors. Subgroups of PWID in Tijuana, Mexico, were identified based on substances used, route of administration, frequency of use and co-injection indicators. Participants were PWID residing in Tijuana age ≥18 years sampled from 2011 to 2012 who reported injecting an illicit substance in the past month (n = 735). Latent class analysis identified discrete classes of polydrug use characterised by 11 indicators of past 6 months substance use. Multinomial logistic regression examined class membership association with HIV risk behaviours, overdose and other covariates using an automated three-step procedure in mplus to account for classification error. Participants were classified into five subgroups. Two polydrug and polyroute classes were defined by use of multiple substances through several routes of administration and were primarily distinguished from each other by cocaine use (class 1: 5%) or no cocaine use (class 2: 29%). The other classes consisted primarily of injectors: cocaine, methamphetamine and heroin injection (class 3: 4%); methamphetamine and heroin injection (class 4: 10%); and heroin injection (class 5: 52%). Compared with the heroin-only injection class, memberships in the two polydrug and polyroute use classes were independently associated with both HIV injection and sexual risk behaviours. Substance use patterns among PWID in Tijuana are highly heterogeneous, and polydrug and polyroute users are a high-risk subgroup who may require more tailored prevention and treatment interventions. [Meacham MC, Roesch SC, Strathdee SA, Lindsay S, Gonzalez-Zuniga P, Gaines TL. Latent classes of polydrug and polyroute use and associations with human immunodeficiency virus risk behaviours and overdose among people who inject drugs in Tijuana, Baja California, Mexico. Drug Alcohol Rev 2018;37:128-136]. © 2017 Australasian Professional Society on Alcohol and other Drugs.

NIH study uncovers new mechanism of action for class of chemotherapy drugs

Cancer.gov

NIH researchers have discovered a significant new mechanism of action for a class of chemotherapy drugs known as poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. They have also identified differences in the toxic capabilities of three drugs in

Relationship between renal pathology and the size of circulating immune complexes in patients with systemic lupus erythematosus

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

Wener, M.H.; Mannik, M.; Schwartz, M.M.

1987-03-01

Sera from 35 patients with biopsy-proven diffuse proliferative (WHO class IV) or membranous (WHO class V) lupus nephritis were analyzed for the presence and size of circulating immune complexes. Elevations of the C1q solid-phase assay (C1qSP) for immune complexes were found in sera from all patients with diffuse proliferative nephritis, with a mean +/- 1 SEM of 166.8 +/- 42.0 micrograms/AHG-equivalents/ml serum, and in 71.4% of the patients with membranous nephritis (83.1 +/- 26.7, p = 0.06). Using the WHO criteria for subclasses of membranous lupus nephritis, we also designated renal biopsies as nonproliferative (WHO classes Va and Vb) ormore » proliferative (WHO classes IV and Vc). Employing the latter groupings, we observed significant differences between C1qSP results of patients with nonproliferative (30.3 +/- 8.8) and proliferative (172.8 +/- 36.8, p less than 0.001) lupus nephritis. These data suggest that the presence of C1q-binding material in serum is pathophysiologically related to proliferative glomerular lesions, and that levels of C1qSP binding reflect renal lesions in SLE patients. Sucrose density gradient ultracentrifugation was performed on each serum, and gradient fractions analyzed for C1qSP-binding and total IgG, using techniques to minimize losses of immune complexes. The predominant peak of C1qSP activity sedimented with the 6.6S monomeric IgG. The 6.6S C1q-binding IgG was increased only in 1 of 10 patients with membranous lupus nephritis without proliferative changes, and was elevated in 16 of 25 patients with proliferative lesions (WHO classes IV and Vc).« less

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems.

PubMed

Khurana, Rajneet Kaur; Gaspar, Balan Louis; Welsby, Gail; Katare, O P; Singh, Kamalinder K; Singh, Bhupinder

2018-06-01

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of < 60 nm and > 80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency.

Implications of HLA-allele associations for the study of type IV drug hypersensitivity reactions.

PubMed

Sullivan, A; Watkinson, J; Waddington, J; Park, B K; Naisbitt, D J

2018-03-01

Type IV drug hypersensitivity remains an important clinical problem and an obstacle to the development of new drugs. Several forms of drug hypersensitivity are associated with expression of specific HLA alleles. Furthermore, drug-specific T-lymphocytes have been isolated from patients with reactions. Despite this, controversy remains as to how drugs interact with immune receptors to stimulate a T-cell response. Areas covered: This article reviews the pathways of T-cell activation by drugs and how the ever increasing number of associations between expression of HLA alleles and susceptibility to hypersensitivity is impacting on our research effort to understanding this form of iatrogenic disease. Expert opinion: For a drug to activate a T-cell, a complex is formed between HLA molecules, an HLA binding peptide, the drug and the T-cell receptor. T-cell responses can involve drugs and stable or reactive metabolites bound covalently or non-covalently to any component of this complex. Recent research has linked the HLA associations to the disease through the characterization of drug-specific T-cell responses restricted to specific alleles. However, there is now a need to identify the additional genetic or environment factors that determine susceptibility and use our increased knowledge to develop predictive immunogenicity tests that offer benefit to Pharma developing new drugs.

Inflammatory mediators in chronic heart failure in North India.

PubMed

Fedacko, Jan; Singh, Ram B; Gupta, Aditya; Hristova, Krasimira; Toda, Eri; Kumar, Adarsh; Saxena, Manoj; Baby, Anjum; Singh, Ranjana; Toru, Takahashi; Wilson, Douglas W

2014-08-01

Recent evidence shows that pro-inflammatory cytokines may be important in the assessment of severity and prognosis in congestive heart failure (CHF). In the present study, we examine the association of cytokines with causes, grade and prognosis of CHF patients. Of 127 patients with CHF, 11 were excluded and the remaining 116 patients with different aetiologies of CHF, and 250 age- and sex-matched control subjects, were evaluated in this case study. Severity of disease based on the New York Heart Association (NYHA) standards, fell within functional classes II to IV. The diagnosis of HF was based on clinical manifestations as well as on echocardiographic heart enlargement. Cytokines were measured by chemiluminescence. Causes of death were assessed based on death certificates. Multivariate logistic regression analysis was used to determine the risk factors of heart failure. Echocardiographic ejection fraction was 39.1 +/- 8.2% (mean +/- SD) in the study group indicating class II-IV heart failure. Laboratory data showed increase in biomarkers of oxidative stress, among HF patients compared to healthy subjects. Pro-inflammatory cytokines; IL-6 and TNF-alpha were significantly higher among HF patients compared to healthy subjects. TNF-alpha and IL-6, showed significant increase among patients with CHF due to ischaemic heart disease and cardiomyopathy compared to levels among CHF patients with valvular heart disease and hypertensive heart diseases. The levels of the cytokines were significantly higher among patients with class III and IV heart failure and those who died, compared to patients with class II heart failure. Multivariate logistic regression analysis revealed that CAD, cardiomyopathy, and IL-6 were strongly associated--and low ejection fraction and TNF-alpha--weakly associated with HF. Of 116 patients, 20 (17.2%) died during a follow-up of two years, and the deaths were mainly among NYHA class III and IV patients in whom the cause of CHF was CAD (10.9%) and cardiomyopathy (6.9%) which had greater levels of cytokines. The findings indicated that pro-inflammatory cytokines may be important indicators of causes, severity of CHF and prognosis among these patients.

Aldosterone antagonists in heart failure.

PubMed

Miller, Susan E; Alvarez, René J

2013-01-01

Chronic, systolic heart failure is an increasing and costly health problem, and treatments based on pathophysiology have evolved that include the use of aldosterone antagonists. Advances in the understanding of neurohormonal responses to heart failure have led to better pharmacologic treatments. The steroid hormone aldosterone has been associated with detrimental effects on the cardiovascular system, such as ventricular remodeling and endothelial dysfunction. This article will review the literature and guidelines that support the use of aldosterone antagonists in the treatment of chronic, systolic heart failure. Aldosterone antagonists are life-saving drugs that have been shown to decrease mortality in patients with New York Heart Association class III to IV heart failure and in patients with heart failure after an acute myocardial infarction. Additional studies are being conducted to determine if the role of aldosterone antagonists can be expanded to patients with less severe forms of heart failure. Aldosterone antagonists are an important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of systolic heart failure. These drugs have been shown to decrease mortality and reduce hospital readmission rates. The major complication of aldosterone antagonists is hyperkalemia, which can be avoided with appropriate patient selection and diligent monitoring.

Scientific perspectives on extending the provision for waivers of in vivo bioavailability and bioequivalence studies for drug products containing high solubility-low permeability drugs (BCS-Class 3).

PubMed

Stavchansky, Salomon

2008-06-01

Recently, there has been increased interest in extending the provision for waivers of in vivo bioavailability and bioequivalence (BA-BE) studies that appeared in the guidance published by the Food and Drug Administration (FDA) (1) to pharmaceutical products containing Class 3 drugs (High solubility-Low Permeability). The extension of the Biopharmaceutics Classification System (BCS) to Class 3 drugs is meritorious because of its impact on public health policy considerations. The rate limiting step in the absorption of Class 3 drugs is the permeability through the intestinal membrane. This commentary will focus its attention on the scientific considerations which need to be examined to assess the risk and the benefit prior to granting a waiver of in vivo bioavailability and/or bioequivalence studies for Class 3 drugs. It will examine the forces affecting the interconnectivity of the neuronal, immunological and hormonal systems in the gastrointestinal tract that may affect its permeability and functionality. It will also challenge the assumption that in vitro dissolution and in vitro permeability studies in tissue cultures in the presence and absence of excipients are good predictors for in vivo dissolution and in vivo permeability which are at the heart of the BCS.

Study of Default Options in Advance Directives

ClinicalTrials.gov

2015-06-29

COPD; Severe or Very Severe Airflow Obstruction and/or Receiving or Eligible to Receive Long-term Oxygen Therapy; Idiopathic Pulmonary Fibrosis; Other Interstitial Lung Disease Without Curative Therapy; Congestive Heart Failure; NYHA Class IV or NYHA Class III Plus 1 Hospitalization in the Past Year; Malignancy; Any Stage 3B or 4 Solid Tumor

78 FR 56732 - Submission of Information Collection Extensions Under the Paperwork Reduction Act

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-13

... Control Number 3141-0006; and (iv) issuance to tribes of certificates of self- regulation for Class II... the Commission for a certificate of self-regulation for its Class II gaming operation(s). The... to issue the certificate of self- regulation. Once a certificate of self-regulation has been issued...

78 FR 40766 - Renewals of Information Collections Under the Paperwork Reduction Act

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-08

... Control Number 3141-0006; and (iv) issuance to tribes of certificates of self-regulation for Class II.... Estimated Total Non-hour Cost Burden: $14,846,686. Title: Issuance of Certificates of Self-Regulation to... Commission for a certificate of self-regulation for its Class II gaming operation(s). The Commission will...

40 CFR 146.10 - Plugging and abandoning Class I, II, III, IV, and V wells.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) WATER PROGRAMS (CONTINUED) UNDERGROUND INJECTION CONTROL PROGRAM: CRITERIA AND STANDARDS General... of drinking water. The Director may allow Class III wells to use other plugging materials if the... sources of drinking water. (2) Placement of the cement plugs shall be accomplished by one of the following...

40 CFR 147.751 - EPA-administered program.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Indiana § 147.751 EPA-administered program. (a) Contents. The UIC program for all classes of wells on Indian lands, and for Class I, III, IV, and V wells on non-Indian lands in the State of Indiana is administered by the EPA. The...

40 CFR 147.751 - EPA-administered program.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Indiana § 147.751 EPA-administered program. (a) Contents. The UIC program for all classes of wells on Indian lands, and for Class I, III, IV, and V wells on non-Indian lands in the State of Indiana is administered by the EPA. The...

40 CFR 147.101 - EPA-administered program.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) STATE, TRIBAL, AND EPA-ADMINISTERED UNDERGROUND INJECTION CONTROL PROGRAMS Alaska § 147.101 EPA-administered program. (a) Contents. The UIC program in the State of Alaska for Class I, III, IV, and V wells, and for all classes of wells on Indian lands, is administered by EPA. This program consists of the UIC...

Working Smarter, Not Harder (Part IV).

ERIC Educational Resources Information Center

LaBelle, Sandy

2003-01-01

Discusses ways of improving student attitudes and motivation, such as changing the focus of tests, making students responsible for their work, using a grid to show test results, instituting in-class breaks, using a personal grade book, discussing with students the effects of sleep deprivation, and using separate folders for papers of each class.…

[Pharmacological studies on ginger. V. Pharmacological comparison between (6)-shogaol and capsaicin].

PubMed

Suekawa, M; Sone, H; Sakakibara, I; Ikeya, Y; Aburada, M; Hosoya, E

1986-11-01

Pharmacological actions of (6)-shogaol and capsaicin were studied. Both (6)-shogaol (0.5 mg/kg, i.v.) and capsaicin (0.1 mg/kg, i.v.) caused a triad such as a rapid fall in blood pressure, bradycardia and aponea in rats. Both drugs-induced marked pressor responses in blood pressure, which occurred after the rapid fall, were markedly reduced by a spinal destruction. In pithed rats, both drugs-induced peripheral pressor responses were markedly reduced with the combined treatment of [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine (10 mg/kg, i.v.) and the section of sciatic nerves. In isolated guinea-pig trachea, (6)-shogaol (100 microM) and capsaicin (10 microM) induced contractile responses which were slightly inhibited by substance P antagonist (10 microM), but exhibited also a tachyphylaxis. Furthermore, although (6)-shogaol (3.6 microM) showed positive inotropic and chronotropic actions on isolated atria in rats, this effect of (6)-shogaol disappeared by repeated injections or pretreatment (100 mg/kg, s.c.) of (6)-shogaol. These results suggest that (6)-shogaol and capsaicin have similar actions, and that both drugs may cause a peripheral action by releasing an unknown active substance from nerve ends.

The social class gradient in health in Spain and the health status of the Spanish Roma.

PubMed

La Parra Casado, Daniel; Gil González, Diana; de la Torre Esteve, María

2016-10-01

To determine the social class gradient in health in general Spain population and the health status of the Spanish Roma. The National Health Survey of Spanish Roma 2006 (sample size = 993 people; average age: 33.6 years; 53.1% women) and the National Health Surveys for Spain 2003 (sample size: 21,650 people; average age: 45.5 years; 51.2% women) and 2006 (sample size: 29,478 people; average age: 46 years; 50.7% women) are compared. Several indicators were chosen: self-perceived health, activity limitation, chronic diseases, hearing and sight problems, caries, and obesity. Analysis was based on age-standardised rates and logistic regression models. According to most indicators, Roma's health is worse than that of social class IV-V (manual workers). Some indicators show a remarkable difference between Roma and social class IV-V: experiencing three or more health problems, sight problems, and caries, in both sexes, and hearing problems and obesity, in women. Roma people are placed on an extreme position on the social gradient in health, a situation of extreme health inequality.

pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.

PubMed

Varma, Manthena V; Gardner, Iain; Steyn, Stefanus J; Nkansah, Paul; Rotter, Charles J; Whitney-Pickett, Carrie; Zhang, Hui; Di, Li; Cram, Michael; Fenner, Katherine S; El-Kattan, Ayman F

2012-05-07

The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 μg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified pH-dependent permeability and solubility criteria that can be used to assign provisional biopharmaceutics class at early stage of the drug discovery process. Additionally, such a classification system will enable discovery scientists to assess the potential limiting factors to oral absorption, as well as help predict the drug disposition mechanisms and potential drug-drug interactions.

Pea Chaperones under Centrifugation

NASA Astrophysics Data System (ADS)

Talalaiev, Oleksandr

2008-06-01

Etiolated Pisum sativum seedlings were subjected to altered g-forces by centrifugation (3-14g). By using semiquantitative RT-PCR, we studied transcripts of pea genes coding for chaperones that are representatives of small heat shock proteins (sHsps) family. Four members from the different classes of sHsps: cytosolic Hsp17.7 and Hsp18.1 (class I and class II accordingly), chloroplast Hsp21 (class III) and endoplasmic reticulum Hsp22.7 (class IV) were investigated. We conclude that exposure to 3, 7, 10 and 14g for 1h did not affect the level of sHsp transcripts.

Drug-specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions.

PubMed

Bager, Palle; Hvas, Christian L; Dahlerup, Jens F

2017-05-01

Intravenous (IV) iron infusions have been associated with hypophosphataemia (HP) and hypersensitivity reactions (HSRs). No studies have compared the side effects of ferric carboxymaltose (FCM) with those of isomaltoside 1000 (ISM). This study aimed to describe the occurrence of HP and HSRs following the administration of either FCM or ISM. Data on 231 outpatients treated with IV iron infusions, between November 2011 and April 2014, were collected. During that period, the department made a switch from FCM to ISM and then back to FCM. Of the 231 patients, 39 received both FCM and ISM during the period. The prevalences of HP and HSRs were compared between the two drugs. We found more HP events when FCM was given (64 vs. 9; P < 0.01). In contrast, more patients had mild HSRs when ISM was given (2.5% vs. 10.7%; P < 0.01). A comparison of the two drugs in the subpopulation who received both drug types (n = 39) revealed a difference in phosphate decrease (P < 0.01), with the most marked decrease occurring with FCM. Nine patients who had HSRs were exposed to both drugs. No potential HSR crossover between the two drugs was found. We found a higher risk of HP with FCM administration when compared to ISM administration. Conversely, we found a higher risk of mild HSRs with ISM administration when compared to FCM administration. The impacts of the two types of side effects should be considered when choosing an IV iron drug. © 2016 The British Pharmacological Society.

Drug selection in French university hospitals: analysis of formularies for nine competitive pharmacological classes.

PubMed

Gallini, Adeline; Juillard-Condat, Blandine; Saux, Marie-Claude; Taboulet, Florence

2011-11-01

To give a panorama of the selectivity and agreement of French university hospitals' drug formularies (HDF) for nine competitive classes. All university hospitals were asked to send their HDF and selection criteria as of January 2009 for nine competitive pharmacological classes (proton pump inhibitors, serotonin antagonists, low molecular weight heparins, erythropoietins, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, statins, α-adrenoreceptor antagonists and selective serotonin re-uptake inhibitors). Selectivity of HDF was estimated by the percentage of drug entities selected by the hospital within the pharmacological class. Agreement between hospitals was assessed with modified kappa coefficients for multi-raters. Twenty-one out of the 29 hospitals agreed to participate. These hospitals selected between 34% and 63% of the drug entities available for the nine classes, which represented 18 to 35 agents. Regarding the nature of chosen drug entities, the overall level of agreement was 'fair' and varied with pharmacological classes. Selection criteria were sent by only 12 hospitals. The technical component was the most important element in all hospitals. The weight of the economic component varied between 20% and 40% in the tender's grade. Large variations were seen in the number and nature of drugs selected by university hospitals which can be attributable to two successive decision-making processes (evaluation by the Drug and Therapeutics Committee followed by the purchasing process). © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Sexual Initiation and Complex Recent Polydrug Use Patterns Among Male Sex Workers in Vietnam: A Preliminary Epidemiological Trajectory.

PubMed

Yu, Gary; Goldsamt, Lloyd A; Clatts, Michael C; Giang, Lê Minh

2016-05-01

Little is known about the age of onset of sexual and drug risk and their association with complex patterns of recent drug use among male sex workers (MSW) in a developing country, such as Vietnam. The aim of this study was to determine whether latent class analysis (LCA) would aid in the detection of current individual and polydrug use combinations to predict how different trajectories of sexual and drug initiation contribute to different patterns of current illicit drug use. Data were collected from a cross-sectional survey administered to young MSWs between 2010 and 2011 in Vietnam (N = 710). LCA clustered participants into recent drug use groups, incorporating both the specific types and overall count of different drugs used. Men reported drug use within a 1 month period from an 11-item drug use list. LCA identified three distinct drug use classes: (1) alcohol use, (2) alcohol and tobacco use, and (3) high polydrug use. The current drug use classes are associated with sex worker status, housing stability, income level, educational attainment, marital status, sexual identity, and sexual preferences. High levels of drug use are strongly associated with being a recent sex worker, not having recent stable housing, higher than median income, more than a high school education, less likely to be currently in school and more likely to have non-homosexual preferences and heterosexual partners. An event history analysis approach (time-event displays) examined the timing of the age of onset of drug and sexual risks. Early ages of drug and sexual initiation are seen for all three classes. High current drug users show earlier onset of these risks, which are significantly delayed for moderate and low current drug users. LCA incorporating an overall count of different drugs detected three distinct current drug use classes. The data illustrates that the complexity of drug factors that must be accounted for, both in advancing our epidemiological understanding of the complexity of drug use and the use of drug and sexual risk initiation data to predict current drug use subtypes among high-risk populations.

Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route.

PubMed

Mittal, Deepti; Md, Shadab; Hasan, Quamrul; Fazil, Mohammad; Ali, Asgar; Baboota, Sanjula; Ali, Javed

2016-01-01

The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1 ± 10.31, 0.380 ± 0.01 and 96.43 ± 4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25 ng/ml) and AUC (2086.60 ng h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG-NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27 ± 1.8 to 69.27 ± 2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson's disease therapy.

Antihypertensive drugs.

PubMed

Laurent, Stéphane

2017-10-01

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators. Copyright © 2017. Published by Elsevier Ltd.

2005 NDIA Combat Vehicles Conference. Volume 2- Thursday Presentations and Videos

DTIC Science & Technology

2005-09-22

Mounted Combat System MULE: (Countermine) MULE: (Transport) Class II Class III Class IV Armed Robotic Vehicle ARV RSTA ARV Assault FCS Recovery and...Vehicles – Infantry Carrier Vehicle (ICV) – Armed Robotic Vehicle - Assault (ARV (A)) – Recon & Surveillance Vehicle (RSV)  Training Ammo for AP & AB...Holtz and Mr. Dick Williams, Boeing Mr. Dean Vanderstelt, General Dynamics Land Systems ( GDLS ) Mr. Mike Zoltoski, TARDEC Mr. Peter DeMasi, Program

Vented spikes improve delivery from intravenous bags with no air headspace.

PubMed

Galush, William J; Horst, Travis A

2015-07-01

Flexible plastic bags are the container of choice for most intravenous (i.v.) infusions. Under certain circumstances, however, the air-liquid interface present in these i.v. bags can lead to physical instability of protein biopharmaceuticals, resulting in product aggregation. In principle, the air headspace present in the bags can be removed to increase drug stability, but experiments described here show that this can result in incomplete draining of solution from the bag using gravity delivery, or generation of negative pressure in the bag when an infusion pump is used. It is expected that these issues could lead to incomplete delivery of medication to patients or pump-related problems, respectively. However, here it is shown that contrary to the standard pharmacy practice of using nonvented spikes with i.v. bags, the use of vented spikes with i.v. bags that lack air headspace allows complete delivery of the dose solution without impacting the physical stability of a protein-based drug. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

[Good morning, Mr. Representative. Anything new to tell us about? Analysis of the pharmacological products introduced by the drugs industry into a health district].

PubMed

Baena Díez, J M; López Mompó, C; López Gosp, D; Martínez Martínez, J L; Ellacuría Torres, A; Fuentes Rodríguez, S

2003-12-01

To study whether the visits of technical health representatives (ITS) mean that new drugs are introduced. Design. Prospective, descriptive study. Urban health centre. The products presented by 137 ITS from 83 drug laboratories in weekly sessions for a year were studied. The products presented, the year they were first marketed, intrinsic value (IV), newness and use potential, cost per package and defined daily dose and material handed over were studied. 472 drug products were introduced. The most common ones belonged to the cardiovascular group (27.3%), digestion and metabolism (14.8%) and anti-infection drugs (13.3%). 65.5% had been on the market for <5 years. 84.3% had a high IV. Only 31 products (6.6%) were new (95% CI, 4.5-9.2). 71% of these supposed no or very slight therapeutic improvement, 25.8% a modest improvement and 3.2% a major improvement. Mean cost was 19.3 euros per package and 2 euros per DDD, with significant differences found (P<.006) on stratifying by date of marketing (more recently marketed products cost more). 61% of the products were presented with additional material (leaflets, monographs, journals), 21.6% with gifts of symbolic value, and 19.9% with samples of the product. There were significant differences (P<.03) between the new drugs and the normal prescriptions issued at the centre. In the new drugs, there were fewer products with high IV and cost per package and per DDD was higher. The products introduced by the reps do not include any important new drugs. They are presented with abundant back-up and are more expensive than those normally prescribed.

Wound botulism.

PubMed

Burningham, M D; Walter, F G; Mechem, C; Haber, J; Ekins, B R

1994-12-01

Wound botulism is a rare infectious and toxicologic complication of trauma and i.v. drug abuse. Only 39 cases have been reported in detail in the English literature. This case report describes a patient with wound botulism who presented to four medical facilities before receiving definitive diagnosis and treatment. Although his history and physical examination were consistent with wound botulism, diagnosis and therapy were delayed because this rare disease was not considered initially in the differential diagnosis. Wound botulism should be considered in trauma patients and i.v. drug abusers who present with cranial nerve palsies and descending paresis.

An improved approach to measuring drug innovation finds steady rates of first-in-class pharmaceuticals, 1987-2011.

PubMed

Lanthier, Michael; Miller, Kathleen L; Nardinelli, Clark; Woodcock, Janet

2013-08-01

For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs--first-in-class, advance-in-class, and addition-to-class--to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole.

Clinical features and histological patterns of lupus nephritis in a single center of South India.

PubMed

Devadass, Clement Wilfred; Mysorekar, Vijaya Viswanath; Eshwarappa, Mahesh; Mekala, Lakshminarayanan; Siddaiah, M Gireesh; Channabasappa, K Gurudev

2016-01-01

Renal involvement occurs in up to 60% of patients with systemic lupus erythematosus (SLE) and signifies a poor prognosis. The class of lupus nephritis (LN), determined on renal biopsy evaluation, guides the therapeutic management and has prognostic connotations. Our aim is to determine the clinicolaboratory features and histopathological patterns of LN at presentation in our local (South Indian) population. The study was conducted in a tertiary care hospital in South India between 2009 and 2014 on SLE patients with clinical evidence of LN. The renal biopsies were examined by light and immunofluorescence microscopy and were classified according to the International Society of Nephrology/Renal Pathology Society Classification of LN. A total of 46 patients were included, with age range of 12-60 years and a female to male ratio of 8.2:1. Arthritis, dermatological manifestations, and fever occurred, respectively, in 43.5%, 39.1%, and 30.4% of the cases. Class IV LN was present in 17 (37.1%), Class III LN in ten (21.7%), Class II LN in nine (19.5%), Class V LN in eight (17.4%), Class I LN in one (2.2%), and Class VI LN in one (2.2%) patients. Antinuclear antibody (ANA) and dsDNA positivity were present, respectively, in 82.6% and 65.2% of the patients. The most common pattern of LN was Class IV LN followed by Class III LN. Relatively higher proportions of ANA and anti-dsDNA positivity were present in proliferative LN, and there was a high frequency of arthritis at presentation in our LN patients.

Latent classes of emotional and behavioural problems in epidemiological and referred samples and their relations to DSM-IV diagnoses.

PubMed

Bianchi, Valentina; Brambilla, Paolo; Garzitto, Marco; Colombo, Paola; Fornasari, Livia; Bellina, Monica; Bonivento, Carolina; Tesei, Alessandra; Piccin, Sara; Conte, Stefania; Perna, Giampaolo; Frigerio, Alessandra; Castiglioni, Isabella; Fabbro, Franco; Molteni, Massimo; Nobile, Maria

2017-05-01

Researchers' interest have recently moved toward the identification of recurrent psychopathological profiles characterized by concurrent elevations on different behavioural and emotional traits. This new strategy turned to be useful in terms of diagnosis and outcome prediction. We used a person-centred statistical approach to examine whether different groups could be identified in a referred sample and in a general-population sample of children and adolescents, and we investigated their relation to DSM-IV diagnoses. A latent class analysis (LCA) was performed on the Child Behaviour Checklist (CBCL) syndrome scales of the referred sample (N = 1225), of the general-population sample (N = 3418), and of the total sample. Models estimating 1-class through 5-class solutions were compared and agreement in the classification of subjects was evaluated. Chi square analyses, a logistic regression, and a multinomial logistic regression analysis were used to investigate the relations between classes and diagnoses. In the two samples and in the total sample, the best-fitting models were 4-class solutions. The identified classes were Internalizing Problems (15.68%), Severe Dysregulated (7.82%), Attention/Hyperactivity (10.19%), and Low Problems (66.32%). Subsequent analyses indicated a significant relationship between diagnoses and classes as well as a main association between the severe dysregulated class and comorbidity. Our data suggested the presence of four different psychopathological profiles related to different outcomes in terms of psychopathological diagnoses. In particular, our results underline the presence of a profile characterized by severe emotional and behavioural dysregulation that is mostly associated with the presence of multiple diagnosis.

Microleakage in conservative cavities varying the preparation method and surface treatment

PubMed Central

ATOUI, Juliana Abdallah; CHINELATTI, Michelle Alexandra; PALMA-DIBB, Regina Guenka; CORONA, Silmara Aparecida Milori

2010-01-01

Objective To assess microleakage in conservative class V cavities prepared with aluminum-oxide air abrasion or turbine and restored with self-etching or etch-and-rinse adhesive systems. Material and Methods Forty premolars were randomly assigned to 4 groups (I and II: air abrasion; III and IV: turbine) and class V cavities were prepared on the buccal surfaces. Conditioning approaches were: groups I/III - 37% phosphoric acid; groups II/IV -self-priming etchant (Tyrian-SPe). Cavities were restored with One Step Plus/Filtek Z250. After finishing, specimens were thermocycled, immersed in 50% silver nitrate, and serially sectioned. Microleakage at the occlusal and cervical interfaces was measured in mm and calculated by a software. Data were subjected to ANOVA and Tukey’s test (α=0.05). Results Forty premolars were randomly assigned to 4 groups (I and II: air abrasion; III and IV: turbine) and class V cavities were prepared on the buccal surfaces. Conditioning approaches were: groups I/III - 37% phosphoric acid; groups II/IV -self-priming etchant (Tyrian-SPe). Cavities were restored with One Step Plus/Filtek Z250. After finishing, specimens were thermocycled, immersed in 50% silver nitrate, and serially sectioned. Microleakage at the occlusal and cervical interfaces was measured in mm and calculated by a software. Data were subjected to ANOVA and Tukey’s test (α=0.05). Conclusion Marginal seal of cavities prepared with aluminum-oxide air abrasion was different from that of conventionally prepared cavities, and the etch-and-rinse system promoted higher marginal seal at both enamel and dentin margins. PMID:20835580

A new, empirically established hypochondriasis diagnosis.

PubMed

Fink, Per; Ørnbøl, Eva; Toft, Tomas; Sparle, Kaj Christensen; Frostholm, Lisbeth; Olesen, Frede

2004-09-01

The narrow ICD-10 and DSM-IV definition of hypochondriasis makes it rarely used yet does not prevent extensive diagnosis overlap. This study identified a distinct hypochondriasis symptom cluster and defined diagnostic criteria. Consecutive patients (N=1,785) consulting primary care physicians for new illness were screened for somatization, anxiety, depression, and alcohol abuse. A stratified subgroup of 701 patients were interviewed with the Schedules for Clinical Assessment in Neuropsychiatry and questions addressing common hypochondriasis symptoms. Symptom patterns were analyzed by latent class analysis. Patients fell into three classes based on six symptoms: preoccupation with the idea of harboring an illness or with bodily function, rumination about illness, suggestibility, unrealistic fear of infection, fascination with medical information, and fear of prescribed medication. All symptoms, particularly rumination, were frequent in one of the classes. Classification allowed definition of new diagnostic criteria for hypochondriasis and division of the cases into "mild" and "severe." The weighted prevalence of severe cases was 9.5% versus 5.8% for DSM-IV hypochondriasis. Compared with DSM-IV hypochondriasis, this approach produced less overlap with other somatoform disorders, similar overlap with nonsomatoform psychiatric disorders, and similar assessments by primary care physicians. Severe cases of the new hypochondriasis lasted 2 or more years in 54.3% of the subjects and 1 month or less in 27.2%. These results suggest that rumination about illness plus at least one of five other symptoms form a distinct diagnostic entity performing better than the current DSM-IV hypochondriasis diagnosis. However, these criteria are preliminary, awaiting cross-validation in other subject groups.

Competitiveness in follow-on drug R&D: a race or imitation?

PubMed

DiMasi, Joseph A; Faden, Laura B

2011-01-01

The development of 'follow on' or 'me too' drugs - generally defined as a drug with a similar chemical structure or the same mechanism of action as a drug that is already marketed - has attracted contrasting views. Some have argued that follow-on drugs often provide useful alternative or enhanced therapeutic options for particular patients or patient subpopulations, as well as introducing price competition. Others, however, consider that the development of such drugs is duplicative and that the resources needed would be better directed elsewhere. Implicit in some of this criticism is the notion that the development of me-too drugs is undertaken after a first-in-class drug has made it to market and proved commercially successful. In this Perspective, using analysis of development and patent filing histories of entrants to new drug classes in the past five decades, we provide new evidence that the development of multiple new drugs in a given class is better characterized as a race, rather than the imitation of successful products.

Levofloxacin 750-mg for 5 days for the treatment of hospitalized Fine Risk Class III/IV community-acquired pneumonia patients.

PubMed

Shorr, Andrew F; Khashab, Mohammed M; Xiang, Jim X; Tennenberg, Alan M; Kahn, James B

2006-12-01

The efficacy and safety of 750-mg, 5-day levofloxacin was recently shown to be comparable to 500-mg, 10-day levofloxacin in a randomized, double-blind, multicentre clinical trial for mild-to-severe community-acquired pneumonia (CAP). This subgroup analysis attempted to compare the safety and efficacy of a short-course levofloxacin regimen with traditional levofloxacin dosing for PSI Class III/IV patients. This retrospective, subgroup analysis focused on Pneumonia Severity Index Class III and IV patients enrolled in the study. Measurements included clinical and microbiological success rates, adverse events, and symptom resolution by day 3 of therapy. Of the 528 patients in the ITT population, 219 (41.5%) were categorized as PSI Class III/IV and included in this analysis. Among the clinically evaluable patients, 90.8% (69/76) of patients treated with the 750-mg regimen achieved clinical success, compared with 85.5% (71/83) treated with 500-mg levofloxacin (95% CI,-15.9 to 5.4). Eradication rates in the microbiologically evaluable population were comparable for the 750- and 500-mg regimens (88.9% vs 87.5%, respectively; 95% CI,-18.3 to 15.6). Both regimens were well tolerated and had comparable safety profiles. A greater proportion of patients in the 750-mg treatment group experienced resolution of fever (48.4% vs 34.0%; P=.046) and purulent sputum (48.4% vs 27.5%; P=.007) by day 3 of therapy. The 750-mg, 5-day levofloxacin course achieved comparable clinical and microbiologic efficacy to the 500-mg, 10-day regimen. By day 3 of therapy, a greater proportion of patients in the 750-mg group had objective and subjective resolution of fever. Further research is needed to determine the economic significance of short-course levofloxacin therapy.

Evaluation of a technique for color correction in restoring anterior teeth.

PubMed

Rauber, Gabrielle Branco; Bernardon, Jussara Karina; Vieira, Luiz Clovis Cardoso; Baratieri, Luiz Narciso

2017-09-01

This study aimed to evaluate the ability of the proposed technique in producing restorations that exhibit mimesis with tooth structure and to define a restorative clinical protocol. For this study a typodont was used. The right upper central incisor with Class IV lesion was restored with the layering technique (reference tooth, RT). For the left upper central incisor with Class IV lesion, six teeth were restored monochromatically (test teeth, TT), using DA3.5 (n = 3) and DA4 (n = 3) composite resins-resulting in six unsatisfactory color restorations. TT were divided into six groups depending on the color of unsatisfactory restoration and preparation depth. First, a preparation was realized on the labial surface with 0.5 mm, 0.7 mm or 1.0 mm of depth. A second preparation was then performed to reproduce the dentinal mamelons. Next, adhesive procedures were performed and the teeth restored. Opaque halo, opalescent halo and vestibular enamel were then reproduced by the addition of different composite resins. The RT and TT were photographed side by side in typodont to obtain six photographic prints. The photographs of the groups were subjected to visual evaluation by 120 volunteers via a questionnaire. Data were analyzed by the prevalence of answers, and Chi-square test was used to investigate the association between variables at .05 significance. Furthermore, ΔE of groups was evaluated in comparison RT. The results demonstrated that the moderate intensity restorations (DA3.5) with depths of 0.5 mm and 0.7 mm had the highest prevalence of acceptance. For severe intensity restorations (DA4), the preparation depth of 1.0 mm obtained better acceptance. The technique was able to modify the final color of Class IV restorations, producing satisfactory color restorations. This technique can be used for color correction in cases of Class IV restorations, in situations where there is no time for immediate layered restoration, and as a restorative technique. © 2017 Wiley Periodicals, Inc.

Investigating heterogeneity in violent offending liability among injection drug users from a developmental perspective.

PubMed

Torok, Michelle; Darke, Shane; Shand, Fiona; Kaye, Sharlene

2016-09-01

Violence is a major burden of harm among injecting drug users (IDU), however, the liability to violent offending is not well understood. The current study aimed to better understand differences in the liability to violence by determining whether IDU could be disaggregated into distinct violent offending classes, and determining the correlates of class membership. A total of 300 IDU from Sydney, Australia were administered a structured interview examining the prevalence and severity of drug use and violent offending histories, as well as early life risk factors (maltreatment, childhood mental disorder, trait personality). IDU were disaggregated into four distinct latent classes, comprising a non-violent class (24%), an adolescent-onset persistent class (33%), an adult-onset transient class (24%) and an early-onset, chronic class (19%). Pairwise and group comparisons of classes on predispositional and substance use risks showed that the EARLY class had the poorest psychosocial risk profile, while the NON class had the most favourable. Multinomial logistic regression revealed that higher trait impulsivity and aggression scores, having a history of conduct disorder, frequent childhood abuse, and more problematic alcohol use, were independently associated with more temporally stable and severe violent offending. The model explained 67% of variance in class membership (χ(2)=207.7, df=51, p<0.001). IDU can be meaningfully disaggregated into distinct violent offending classes using developmental criteria. The age of onset of violence was indicative of class membership insomuch as that the extent of early life risk exposure was differentially associated with greater long-term liability to violence and drug use. Copyright © 2016 Elsevier Ltd. All rights reserved.

21 CFR 807.37 - Inspection of establishment registration and device listings.

Code of Federal Regulations, 2010 CFR

2010-04-01

... device listings. 807.37 Section 807.37 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH... Devices and Radiological Health (HFZ-308), Food and Drug Administration, Department of Health and Human...; (ii) All labels submitted; (iii) All labeling submitted; (iv) All advertisements submitted; (v) All...

21 CFR 312.110 - Import and export requirements.

Code of Federal Regulations, 2014 CFR

2014-04-01

... drug has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland..., and § 1.101 of this chapter; or (3) The drug is being exported to Australia, Canada, Israel, Japan... specifications; (iv) The drug is not in conflict with the importing country's laws; (v) The outer shipping...

21 CFR 312.110 - Import and export requirements.

Code of Federal Regulations, 2012 CFR

2012-04-01

... drug has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland..., and § 1.101 of this chapter; or (3) The drug is being exported to Australia, Canada, Israel, Japan... specifications; (iv) The drug is not in conflict with the importing country's laws; (v) The outer shipping...

21 CFR 312.110 - Import and export requirements.

Code of Federal Regulations, 2011 CFR

2011-04-01

... drug has valid marketing authorization in Australia, Canada, Israel, Japan, New Zealand, Switzerland..., and § 1.101 of this chapter; or (3) The drug is being exported to Australia, Canada, Israel, Japan... specifications; (iv) The drug is not in conflict with the importing country's laws; (v) The outer shipping...

The Unprincipled War: Looking at the War on Drugs

DTIC Science & Technology

1993-06-18

Unidad Movid de Patrullaje Rural iv CHAPTER I INTRODUCTION Drug war - reality or rhetoric? Drugs from Latin America kill an estimated 10,000...PiP), the Peruvian equivalent to the U.S. Federal Bureau of Investigation; the Unidad Movil de Patrullaje Rural (UMOPR), the agency charged exclusively

42 CFR 414.908 - Competitive acquisition program.

Code of Federal Regulations, 2012 CFR

2012-10-01

... emergency deliveries; (iv) Does not receive payment for the CAP drug; (v) Except where applicable State... Payment for Drugs and Biologicals Under Part B § 414.908 Competitive acquisition program. (a... subpart. (3) The physician participating in the CAP— (i) Elects to use an approved CAP vendor for the drug...

42 CFR 414.908 - Competitive acquisition program.

Code of Federal Regulations, 2013 CFR

2013-10-01

... emergency deliveries; (iv) Does not receive payment for the CAP drug; (v) Except where applicable State... Payment for Drugs and Biologicals Under Part B § 414.908 Competitive acquisition program. (a... subpart. (3) The physician participating in the CAP— (i) Elects to use an approved CAP vendor for the drug...

42 CFR 414.908 - Competitive acquisition program.

Code of Federal Regulations, 2014 CFR

2014-10-01

... emergency deliveries; (iv) Does not receive payment for the CAP drug; (v) Except where applicable State... Payment for Drugs and Biologicals Under Part B § 414.908 Competitive acquisition program. (a... subpart. (3) The physician participating in the CAP— (i) Elects to use an approved CAP vendor for the drug...

Assessment of AIDS Risk among Treatment Seeking Drug Abusers.

ERIC Educational Resources Information Center

Black, John L.; And Others

Intravenous (IV) drug abusers are at risk for contracting transmittable diseases such as acquired immunodeficiency syndrome (AIDS) and hepatitis B. This study was conducted to investigate the prevalence of risk behaviors for acquiring and transmitting AIDS and hepatitis B among treatment-seeking drug abusers (N=168). Subjects participated in a…

21 CFR 520.2345e - Tetracycline oral liquid.

Code of Federal Regulations, 2012 CFR

2012-04-01

...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2345e Tetracycline oral... animals which are raised for food production; Federal law restricts this drug to use by or on the order of a licensed veterinarian. (iv) National Academy of Sciences/National Research Council (NAS/NRC...

21 CFR 520.2345e - Tetracycline oral liquid.

Code of Federal Regulations, 2013 CFR

2013-04-01

...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2345e Tetracycline oral... animals which are raised for food production; Federal law restricts this drug to use by or on the order of a licensed veterinarian. (iv) National Academy of Sciences/National Research Council (NAS/NRC...

21 CFR 520.2345e - Tetracycline oral liquid.

Code of Federal Regulations, 2014 CFR

2014-04-01

...) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2345e Tetracycline oral... animals which are raised for food production; Federal law restricts this drug to use by or on the order of a licensed veterinarian. (iv) National Academy of Sciences/National Research Council (NAS/NRC...

Complement activation as a bioequivalence issue relevant to the development of generic liposomes and other nanoparticulate drugs

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

Szebeni, Janos, E-mail: jszebeni2@gmail.com; Storm, Gert

Liposomes are known to activate the complement (C) system, which can lead in vivo to a hypersensitivity syndrome called C activation-related pseudoallergy (CARPA). CARPA has been getting increasing attention as a safety risk of i.v. therapy with liposomes, whose testing is now recommended in bioequivalence evaluations of generic liposomal drug candidates. This review highlights the adverse consequences of C activation, the unique symptoms of CARPA triggered by essentially all i.v. administered liposomal drugs, and the various features of vesicles influencing this adverse immune effect. For the case of Doxil, we also address the mechanism of C activation and the opsonization vs.more » long circulation (stealth) paradox. In reviewing the methods of assessing C activation and CARPA, we delineate the most sensitive porcine model and an algorithm for stepwise evaluation of the CARPA risk of i.v. liposomes, which are proposed for standardization for preclinical toxicology evaluation of liposomal and other nanoparticulate drug candidates. - Highlights: • Outlining of difficulties in generic development of liposomal drugs. • New regulatory requirements to evaluate CARPA in preclinical studies. • Review of complement activation by liposomes and its adverse consequences (CARPA). • Assays of C activation in vitro and CARPA in vivo, with the porcine test in focus. • Decision tree how to handle the risk of CARPA assessed by a battery of tests.« less

Liquid Salt as Green Solvent: A Novel Eco-Friendly Technique to Enhance Solubility and Stability of Poorly Soluble Drugs

NASA Astrophysics Data System (ADS)

Patel, Anant A.

As a result of tremendous efforts in past few decades, various techniques have been developed in order to resolve solubility issues associated with class II and IV drugs, However, majority of these techniques offer benefits associated with certain drawbacks; majorly including low drug loading, physical instability on storage and excessive use of environmentally challenging organic solvents. Hence, current effort was to develop an eco-friendly technique using liquid salt as green solvent, which can offer improvement in dissolution while maintaining long term stability. The liquid salt formulations (LSF) of poorly soluble model drugs ibuprofen, gemfibrozil and indomethacin were developed using 1-Ethyl-3-methylimidazolium ethyl sulfate (EMIM ES) as a non-toxic and environmentally friendly alternate to organic solvents. Liquid medications containing clear solutions of drug, EMIM ES and polysorbate 20, were adsorbed onto porous carrier Neusilin US2 to form free flowing powder. The LSF demonstrated greater rate and extent of dissolution compared to crystalline drugs. The dissolution data revealed that more than 80% drug release from LSF within 20 mins compared to less than 18% release from pure drugs. As high as 70% w/w liquid loading was achieved while maintaining good flowability and compressibility. In addition, the LSF samples exposed to high temperature and high humidity i.e. 40°C/80% RH for 8 weeks, demonstrated excellent physical stability without any signs of precipitation or crystallization. As most desirable form of administration is tablet, the developed liquid salt formulations were transformed into tablets using design of experiment approach by Design Expert Software. The tablet formulation composition and critical parameter were optimized using Box-Behnken Design. This innovative liquid salt formulation technique offered improvement in dissolution rate and extent as well as contributed to excellent physical stability on storage. Moreover, this formulation approach served as eco-friendly compelling alternate to conventional techniques involving organic solvents.

Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets.

PubMed

Sadia, Muzna; Arafat, Basel; Ahmed, Waqar; Forbes, Robert T; Alhnan, Mohamed A

2018-01-10

Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient-specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms. In this study, we demonstrate for the first time the use of a novel design approach of caplets with perforated channels to accelerate drug release from 3D printed tablets. This strategy has been implemented using a caplet design with perforating channels of increasing width (0.2, 0.4, 0.6, 0.8 or 1.0mm) and variable length, and alignment (parallel or at right angle to tablet long axis). Hydrochlorothiazide (BCS class IV drug) was chosen as the model drug as enhanced dissolution rate is vital to guarantee oral bioavailability. The inclusion of channels exhibited an increase in the surface area/volume ratio, however, the release pattern was also influenced by the width and the length of the channel. A channel width was ≥0.6mm deemed critical to meet the USP criteria of immediate release products. Shorter multiple channels (8.6mm) were more efficient at accelerating drug release than longer channels (18.2mm) despite having comparable surface area/mass ratio. This behaviour may be linked to the reduced flow resistance within the channels and the faster fragmentation during dissolution of these tablets. In conclusion, the width and length of the channel should be carefully considered in addition to surface area/mass when optimizing drug release from 3D printed designs. The incorporation of short channels can be adopted in the designs of dosage forms, implants or stents to enhance the release rate of eluting drug from polymer-rich structures. Copyright © 2017 Elsevier B.V. All rights reserved.

Multiple factors govern the association between pharmacology and toxicity in a class of drugs: toward a unification of class effect terminology.

PubMed

Smith, Dennis A; Harrison, Anthony; Morgan, Paul

2011-04-18

The term class effect has gained in use to describe a side effect including toxicity common to a series of drugs. There is no definition of what constitutes a class effect, and it is not applied against a rigid set of criteria.Thus, the finding of toxicity in one of a series of drugs can raise the concern of a class effect, especially if one or more of the others shows findings even slightly related or at very much lower incidence. This is particularly problematic when the term is used loosely or speculatively on initial events that are themselves of low incidence and serious. This speculation exaggerates and distorts the scientific process in establishing the true benefit risk of the individual drugs and can lead to lengthy development times, or highly restrictive labeling, to the detriment of patient welfare. To provide better definition and application of the term, we suggest that the term class effect toxicity is only used when a clear mechanistic link has been established between a safety concern and drug class based on (I) where the primary pharmacology delivers a clear rationale for the observed findings and toxicities; and (II) where the secondary pharmacology is obligate to the class of the molecule and not subject to variation of structure, and the selectivity cannot be impacted significantly by variations in potency introduced by structural manipulation. With these categorizations, we believe class effect toxicity will be mainly confined to I with examples such as the tetracycline class of antibacterials which inhibit protein synthesis both as a mechanism of antibacterial activity and to produce hepatic injury by mitochondrial injury in the liver.

Assessing the longitudinal stability of latent classes of substance use among gay, bisexual, and other men who have sex with men.

PubMed

Card, Kiffer G; Armstrong, Heather L; Carter, Allison; Cui, Zishan; Wang, Lu; Zhu, Julia; Lachowsky, Nathan J; Moore, David M; Hogg, Robert S; Roth, Eric A

2018-05-22

Association between substance use and HIV-risk among gay and bisexual men (GBM) is well documented. However, their substance use patterns are diverse, and it is unknown whether self-reported use patterns are stable over time. Sexually-active GBM, aged >16 years, were recruited in Metro Vancouver using respondent-driven sampling and followed across 5 study visits at six-month intervals (n = 449). To identify distinct patterns of substance use and their longitudinal stability, Latent Transition Analysis (LTA) was conducted for drugs reported by at least 30 participants. Intraclass correlation coefficients (ICC) quantified the stability of class assignments. Six classes characterizing 'limited drug use' (i.e., low use of all drugs, except alcohol), 'conventional drug use' (i.e., use of alcohol, marijuana, and tobacco), 'club drug use' (i.e., use of alcohol, cocaine, and psychedelics), 'sex drug use' (i.e., use of alcohol, crystal meth, GHB, poppers, and erectile dysfunction drugs), 'street drug use' (i.e., use of alcohol and street opioids) and 'assorted drug use' (i.e., use of most drugs) were identified. Across five visits (2.5 years), 26.3% (n = 118/449) of GBM transitioned between classes. The prevalence of limited use trended upwards (Baseline:24.5%, Visit 5:28.3%, p < 0.0001) and assorted use trended downwards (13.4%-9.6%, p = 0.001). All classes had strong longitudinal stability (ICC > 0.97). The stability of latent substance use patterns highlight the utility of these measures in identifying patterns of substance use among people who use drugs - potentially allowing for better assessment of these groups and interventions related to their health. Copyright © 2018 Elsevier B.V. All rights reserved.

A comparative study of fluoxetine, moclobemide, and tianeptine in the treatment of posttraumatic stress disorder following an earthquake.

PubMed

Onder, E; Tural, U; Aker, T

2006-04-01

Although antidepressant drugs have been proven as an effective treatment for posttraumatic stress disorder (PTSD), there are few comparative studies of antidepressants that are acting on different neurotransmitters. The main aim of this study is to compare the efficacy of different class of antidepressant drugs on the PTSD. SUBJECTS/MATERIALS AND METHODS: In this open label study, the patients who met DSM-IV criteria for PTSD were randomly assigned to flexible doses of fluoxetine, moclobemide, or tianeptine. After the first assessment, consecutive assessments were performed at the end of weeks 2, 4, 8, and 12 using clinician administered PTSD scale (CAPS) and Clinical Global Impression of Severity (CGI-S). Changes in the total score of CAPS and sub-scale scores of symptom clusters (re-experience, avoidance, and hyperarousal) were the main output of efficacy. All statistics were based on intention-to-treat and last-observation-carried-forward (LOCF) principles. Thirty-eight patients were assigned to fluoxetine, 35 patients were assigned to moclobemide, and 30 patients were assigned to tianeptine group. Gender distributions and mean ages of the treatment groups were not significantly different. Drop-out rates due to an adverse events or unknown reasons were not significantly different among fluoxetine (18.4%), moclobemide (14.3%), and tianeptine (20.0%) groups. All three treatments has led to a significant improvement in PTSD severity assessed with CAPS total score (ANOVA P < 0.001). Similarly, total scores of re-experiencing, avoidance, and hyperarousal clusters that are subscales of CAPS were significantly reduced by all three treatments (with ANOVA all P values < 0.001). There was not significant difference in terms of treatment effect between three groups. Treatment groups showed very similar improvement on all ratings scales. The findings support that fluoxetine, moclobemide, and tianeptine are all effective in the treatment of PTSD. Different mechanisms of action for these antidepressant drugs might result in the same common neurochemical end point. However, further studies using different classes of antidepressant drugs are needed.

Equatorial Ligand Perturbations Influence the Reactivity of Manganese(IV)-Oxo Complexes.

PubMed

Massie, Allyssa A; Denler, Melissa C; Cardoso, Luísa Thiara; Walker, Ashlie N; Hossain, M Kamal; Day, Victor W; Nordlander, Ebbe; Jackson, Timothy A

2017-04-03

Manganese(IV)-oxo complexes are often invoked as intermediates in Mn-catalyzed C-H bond activation reactions. While many synthetic Mn IV -oxo species are mild oxidants, other members of this class can attack strong C-H bonds. The basis for these reactivity differences is not well understood. Here we describe a series of Mn IV -oxo complexes with N5 pentadentate ligands that modulate the equatorial ligand field of the Mn IV center, as assessed by electronic absorption, electron paramagnetic resonance, and Mn K-edge X-ray absorption methods. Kinetic experiments show dramatic rate variations in hydrogen-atom and oxygen-atom transfer reactions, with faster rates corresponding to weaker equatorial ligand fields. For these Mn IV -oxo complexes, the rate enhancements are correlated with both 1) the energy of a low-lying 4 E excited state, which has been postulated to be involved in a two-state reactivity model, and 2) the Mn III/IV reduction potentials. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Relationship of serum uric acid and Killip class on mortality after acute ST-segment elevation myocardial infarction and primary percutaneous coronary intervention.

PubMed

Liu, Cheng-Wei; Liao, Pen-Chih; Chen, Kuo-Chin; Chiu, Yu-Wei; Liu, Yuan-Hung; Ke, Shin-Rong; Wu, Yen-Wen

2017-01-01

There is conflicting information regarding the association between hyperuricemia and survival in STEMI patients. Our study examined the interaction between hyperuricemia and Killip class on mortality of STEMI patients. We analyzed 951 consecutive STEMI patients between February 2006 and September 2012. Hyperuricemia was defined as SUA of at least 7mg/dL in males and 6mg/dL in females. Killip class I patients were divided into hyperuricemia and normouricemia groups. The Killip class I hyperuricemia and normouricemia groups had similar baseline and procedural characteristics, but the hyperuricemia group had significantly greater BMI, serum creatinine, and SUA, and a lower TIMI risk score (2, IQR: 1-4 vs. 3, IQR: 2-4, p=0.019). The hyperuricemia group also had greater 30-day and 1-year mortality rates (2.9% vs. 0.3%, p=0.022; 6.5% vs. 1.1%, p=0.002, respectively). However, hyperuricemia was not associated with mortality of patients in Killip classes II-IV or in the overall study population. Hyperuricemia was associated with increased mortality in subgroups of patients who were at least 65years-old, male, had BMI of 25kg/m 2 or less, were in Killip class I, without diabetes, and who did not receive intra-aortic balloon pump support. Hyperuricemia interacted with Killip class I in increasing the risk for 1-year mortality (p for interaction=0.038). Hyperuricemia increased the 1-year mortality of STEMI patients in Killip class I, but not of patients in Killip classes II-IV. An interaction of hyperuricemia and Killip class significantly affects the mortality of STEMI patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

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

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBCmore » cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with sensitivity. • The sigma-2 receptor is a potential biomarker in TNBC for prognosis and therapy.« less

A cross-national examination of differences in classification of lifetime alcohol use disorder between DSM-IV and DSM-5: Findings from the World Mental Health Survey

PubMed Central

Slade, Tim; Chiu, Wai-Tat; Glantz, Meyer; Kessler, Ronald C.; Lago, Luise; Sampson, Nancy; Al-Hamzawi, Ali; Florescu, Silvia; Moskalewicz, Jacek; Murphy, Sam; Navarro-Mateu, Fernando; de Galvis, Yolanda Torres; Viana, Maria Carmen; Xavier, Miguel; Degenhardt, Louisa

2016-01-01

Aims To examine the diagnostic overlap in DSM-IV and DSM-5 alcohol use disorder (AUD) and determine the clinical correlates of changing diagnostic status across the two classification systems. Design DSM-IV and DSM-5 definitions of AUD were compared using cross-national community survey data. Setting Nine low-, middle- and high-income countries. Participants/Cases 31,367 respondents to surveys in the World Health Organization World Mental Health Survey Initiative. Measures Composite International Diagnostic Interview, version 3.0 was used to derive DSM-IV and DSM-5 lifetime diagnoses of AUD. Clinical characteristics, also assessed in the surveys, included lifetime DSM-IV anxiety, mood and drug use disorders, lifetime suicidal ideation, plan and attempt, general functional impairment and psychological distress. Findings Compared to DSM-IV AUD (12.3%, SE=0.3%), the DSM-5 definition yielded slightly lower prevalence estimates (10.8%, SE=0.2%). Almost one third (n=802) of all DSM-IV Abuse cases switched to sub-threshold according to DSM-5 and one quarter (n=467) of all DSM-IV diagnostic orphans switched to mild AUD according to DSM-5. New cases of DSM-5 AUD were largely similar to those who maintained their AUD across both classifications. Similarly, new DSM-5 non-cases were similar to those who were sub-threshold across both classifications. The exception to this was with regards to the prevalence of any lifetime drug use disorder. Conclusions In this large cross-national community sample, the prevalence of DSM-5 lifetime AUD was only slightly lower than the prevalence of DSM-IV lifetime AUD. Nonetheless there was considerable diagnostic switching, with a large number of people inconsistently identified across the two DSM classifications. PMID:27426631

Therapeutic cure against human tumor xenografts in nude mice by a microtubule stabilization agent, fludelone, via parenteral or oral route.

PubMed

Chou, Ting-Chao; Dong, Huajin; Zhang, Xiuguo; Tong, William P; Danishefsky, Samuel J

2005-10-15

Epothilones, 16-membered macrolides isolated from a myxobacterium in soil, exert their antitumor effect, like Taxol, by induction of microtubule polymerization and microtubule stabilization. They are effective against tumor cells that are resistant to Taxol or vinblastine. We recently designed, via molecular editing and total synthesis, a new class of epothilones represented by 26-trifluoro-(E)-9,10-dehydro-12,13-desoxy-epothilone B (Fludelone), which has emerged as a lead candidate for clinical development. Treatment of nude mice bearing MX-1 human mammary carcinoma xenografts (as large as 3.4% body weight) with Fludelone (6-hour i.v. infusion, 25 mg/kg, q3d x 5, q3d x 4) led to complete disappearance and de facto "cure" (i.e., remission without a relapse for over 15% of the average life span of 2 years). The toxicities induced by bolus i.v. injection could be avoided through prolonged i.v. infusion, which allowed for a 10-fold increase in maximal tolerated dose. Complete remission of MX-1 xenografts was achieved with only one third of this maximal tolerated dose. Parallel studies with Taxol and Fludelone [20 mg/kg, 6-hour i.v. infusion (q2d x 4) x3] against HCT-116 human colon carcinoma xenografts revealed that both drugs achieved tumor remission; however, all Taxol-treated mice relapsed in approximately 1.3 months, whereas the Fludelone-treated mice were cured without any relapse for over 7 months. Furthermore, tumor remission was achieved by Fludelone against SK-OV-3 (ovary), PC-3 (prostate), and the Taxol-resistant CCRF-CEM/Taxol (leukemia) xenograft tumors. Most remarkably, p.o. administration of Fludelone (30 mg/kg, q2d x 7, q2d x 9, q2d x 5) against MX-1 xenografts achieved a nonrelapsing cure for as long as 8.4 months. The above results indicate that Fludelone is a highly promising compound for cancer chemotherapeutics.

77 FR 67449 - Medicare Program; End-Stage Renal Disease Prospective Payment System, Quality Incentive Program...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-09

... Blended Payment a. Update to the Drug Add-on to the Composite Rate Portion of the ESRD Blended Payment Rate i. Estimating Growth in Expenditures for Drugs and Biologicals in CY 2013 ii. Estimating Per Patient Growth iii. Applying the Growth Update to the Drug Add-On Adjustment iv. Update to the Drug Add-On...

Evaluation of various dissolution media for predicting in vivo performance of class I and II drugs.

PubMed

Galia, E; Nicolaides, E; Hörter, D; Löbenberg, R; Reppas, C; Dressman, J B

1998-05-01

In this paper we seek to verify the differences in dissolution behavior between class I and class II drugs and to evaluate the suitability of two new physiologically based media, of Simulated Gastric Fluid (SGF) and of milk for their ability to forecast trends in the in vivo performance of class II compounds and their formulations. Dissolution behavior of two class I drugs, i.e. acetaminophen and metoprolol, and of three class II drugs, i.e. danazol, mefenamic acid and ketoconazole, was studied with USP Apparatus 2 in water, SGF, milk, Simulated Intestinal Fluid without pancreatin (SIFsp) and in two media simulating the small intestinal contents in the fed (FeSSIF) and fasted (FaSSIF) states, respectively. Class I powders dissolved rapidly in all media tested. Acetaminophen dissolution in milk was slow from one tablet formulation, in all other cases dissolution was more than 85% complete in 15 minutes. The dissolution rate of metoprolol was shown to be dependent on formulation and manufacturing method, and one of the three tablet formulations did not meet compendial specifications (80%/30 minutes). Dissolution behavior of class II drugs was greatly affected by choice of medium. Dissolution from a capsule formulation of danazol proved to be dependent on the concentration of solubilizing agents, with a the 30-fold increase in percentage dissolved within 90 minutes upon changing from aqueous media without surfactants to FaSSIF. Use of FeSSIF or milk as the dissolution medium resulted in an even greater increase in percentage dissolved, 100 and 180-fold respectively. Dissolution of the weak acid mefenamic acid from a capsule formulation is dependent on both pH and bile salt concentration, which leads to an offset between increased bile salt concentration and lower pH in the fed state compared to the fasted state medium. The weak base ketoconazole showed complete dissolution from a tablet formulation in Simulated Gastric Fluid without pepsin (SGFsp) within 30 minutes, 70% dissolution in 2 hours under fed state simulated upper jejunal conditions but only 6% dissolution in 2 hours under fasted state conditions. As predicted, dissolution of class II drugs proved to be in general much more dependent on the medium than class I drugs. With the array of compendial and physiological media available, it should be possible to design a suitable set of tests to predict the in vivo dissolution of both class I and II drugs from immediate release formulations.

Alcohol-Use Disorders and Nonmedical Use of Prescription Drugs Among U.S. College Students*

PubMed Central

McCABE, SEAN ESTEBAN; WEST, BRADY T.; WECHSLER, HENRY

2008-01-01

Objective The purpose of this study was to examine the association between Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), alcohol-use disorders (AUDs) and nonmedical use of prescription drugs (NMPD) among U.S. college students. A secondary aim of this study was to identify individual-level and college-level characteristics associated with the co-occurrence of AUDs and NMPD. Method Data were collected from self-administered mail surveys, sent to a random sample of approximately 14,000 college students from a nationally representative sample of 119 U.S. colleges and universities. Results Among U.S. college students, those with AUDs represented approximately 75% of nonmedical users of prescription drugs. Multivariate logistic regression analyses indicated that college students with past-year DSM-IV alcohol abuse only (adjusted odds ratio [AOR] = 4.46, 95% confidence interval [CI] = 3.59-5.55) and students with past-year DSM-IV alcohol dependence (AOR = 9.17, 95% CI = 7.05-11.93) had significantly increased odds of NMPD in the past year compared with students without AUDs. The co-occurrence of AUDs and NMPD was more likely among college students who were male, white, earned lower grade point averages, and attended co-ed colleges and institutions located in Southern or Northeastern U.S. regions. Conclusions The findings provide evidence that NMPD is more prevalent among those college students with AUDs, especially individuals with past-year DSM-IV alcohol dependence. The assessment and treatment of AUDs among college students should account for other forms of drug use such as NMPD. PMID:17568959

Instrumental variable methods in comparative safety and effectiveness research.

PubMed

Brookhart, M Alan; Rassen, Jeremy A; Schneeweiss, Sebastian

2010-06-01

Instrumental variable (IV) methods have been proposed as a potential approach to the common problem of uncontrolled confounding in comparative studies of medical interventions, but IV methods are unfamiliar to many researchers. The goal of this article is to provide a non-technical, practical introduction to IV methods for comparative safety and effectiveness research. We outline the principles and basic assumptions necessary for valid IV estimation, discuss how to interpret the results of an IV study, provide a review of instruments that have been used in comparative effectiveness research, and suggest some minimal reporting standards for an IV analysis. Finally, we offer our perspective of the role of IV estimation vis-à-vis more traditional approaches based on statistical modeling of the exposure or outcome. We anticipate that IV methods will be often underpowered for drug safety studies of very rare outcomes, but may be potentially useful in studies of intended effects where uncontrolled confounding may be substantial.

Structural Basis for Assembly of the MnIV/FeIII Cofactor in the Class Ic Ribonucleotide Reductase from Chlamydia trachomatis‡

PubMed Central

Dassama, Laura M.K.; Krebs, Carsten; Bollinger, J. Martin; Rosenzweig, Amy C.; Boal, Amie K.

2013-01-01

The class Ic ribonucleotide reductase (RNR) from Chlamydia trachomatis (Ct) employs a MnIV/FeIII cofactor in each monomer of its β2 subunit to initiate nucleotide reduction. The cofactor forms by reaction of MnII/FeII-β2 with O2. Previously, in vitro cofactor assembly from apo β2 and divalent metal ions produced a mixture of two forms, with Mn in site 1 (MnIV/FeIII) or site 2 (FeIII/MnIV), of which the more active MnIV/FeIII product predominates. Here we have addressed the basis for metal site-selectivity by solving X-ray crystal structures of apo, MnII, and MnII/FeII complexes of Ct β2. A structure obtained anaerobically with equimolar MnII, FeII, and apo protein reveals exclusive incorporation of MnII in site 1 and FeII in site 2, in contrast to the more modest site-selectivity achieved previously. Site-specificity is controlled thermodynamically by the apo protein structure, as only minor adjustments of ligands occur upon metal binding. Additional structures imply that, by itself, MnII binds in either site. Together the structures are consistent with a model for in vitro cofactor assembly in which FeII specificity for site 2 drives assembly of the appropriately configured heterobimetallic center, provided that FeII is substoichiometric. This model suggests that use of an MnIV/FeIII cofactor in vivo could be an adaptation to FeII limitation. A 1.8 Å resolution model of the MnII/FeII-β2 complex reveals additional structural determinants for activation of the cofactor, including a proposed site for side-on (η2) addition of O2 to FeII and a short (3.2 Å) MnII-FeII interionic distance, promoting formation of the MnIV/FeIV activation intermediate. PMID:23924396

Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study.

PubMed

Garcés, Mercedes; Villanueva, Vicente; Mauri, José Angel; Suller, Ana; García, Carolina; López González, Franscisco Javier; Rodríguez Osorio, Xiana; Fernández Pajarín, Gustavo; Piera, Anna; Guillamón, Edelmira; Santafé, Consuelo; Castillo, Ascensión; Giner, Pau; Torres, Nerea; Escalza, Inés; Del Villar, Ana; García de Casasola, Maria Carmen; Bonet, Macarena; Noé, Enrique; Olmedilla, Nuria

2014-07-01

Status epilepticus (SE) and acute repetitive seizures (ARSs) frequently result in emergency visits. Wide variations in response are seen with standard antiepileptic drugs (AEDs). Oral and intravenous (IV) formulations of lacosamide are approved as adjunctive therapy in the treatment of partial-onset seizures in adults and adolescents. The aim of the retrospective multicenter observational study (LACO-IV) was to analyze data from a large cohort of patients with SE or ARSs of varying severity and etiology, who received IV lacosamide in the emergency setting. Patient clinical data were entered into a database; lacosamide use and efficacy and tolerability variables were analyzed. In SE, IV lacosamide tended to be used mainly in nonconvulsive status epilepticus as second- or third-line treatment. The proportion of patients with no seizures when IV lacosamide was the last drug administered was 76.5% (70.9% SE and 83.7% ARSs). The rate of seizure cessation ≤ 24 h after IV lacosamide administration was 57.1% (49.1% SE and 67.4% ARSs). Of the factors analyzed, a shorter latency from seizure onset to IV lacosamide infusion influenced treatment response significantly. A nonsignificant tendency towards a higher response was seen with lacosamide dose >200mg versus ≤ 200 mg. Analysis of response according to mechanism of action showed no significant differences in response to IV lacosamide in patients receiving prior sodium channel blocker (SCB) or non-SCB AEDs in the overall or SE population; however, in ARSs, a tendency towards a higher response was observed in those receiving non-SCB AEDs. The frequency and nature of adverse events observed were in line with those reported in other studies (somnolence being the most frequent). In the absence of randomized prospective controlled studies of IV lacosamide, our observations suggest that IV lacosamide may be a potential alternative for treatment of SE/ARSs when seizures fail to improve with standard AEDs or when AEDs are contraindicated or not recommended. Copyright © 2014 Elsevier Inc. All rights reserved.

77 FR 16123 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-19

...; Class II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the... Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document... II Special Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic Devices for the...

25 CFR 547.12 - What are the minimum technical standards for downloading on a Class II gaming system?

Code of Federal Regulations, 2013 CFR

2013-04-01

... limited to software, files, data, and prize schedules. (2) Downloads must use secure methodologies that... date of the completion of the download; (iii) The Class II gaming system components to which software was downloaded; (iv) The version(s) of download package and any software downloaded. Logging of the...

25 CFR 547.12 - What are the minimum technical standards for downloading on a Class II gaming system?

Code of Federal Regulations, 2014 CFR

2014-04-01

... limited to software, files, data, and prize schedules. (2) Downloads must use secure methodologies that... date of the completion of the download; (iii) The Class II gaming system components to which software was downloaded; (iv) The version(s) of download package and any software downloaded. Logging of the...

Wisconsin Technical College System Board Equity Staff Development Workshops and Services--Phase IV. Final Report.

ERIC Educational Resources Information Center

Baldus, Lorayne

A staff development program on gender equity was conducted for personnel in Wisconsin's technical colleges using the train-the-trainer method. The training took two approaches: a class for college personnel and career challenge training for project directors of single parent and displaced homemaker grants. The inservice class resulted in increased…

76 FR 46838 - Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Leases, Utah

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-03

... Proposed Class II Reinstatement of Terminated Oil and Gas Leases, Utah AGENCY: Bureau of Land Management, Interior. ACTION: Notice. SUMMARY: In accordance with Title IV of the Federal Oil and Gas Royalty... petition for reinstatement of oil and gas leases UTU-85226 and UTU-85230 lands in Uintah County, Utah, and...

77 FR 76069 - Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-26

... Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah AGENCY: Bureau of Land Management, Interior. ACTION: Notice. SUMMARY: In accordance with Title IV of the Federal Oil and Gas Royalty Management Act, Quinex Energy Corporation timely filed a petition for reinstatement of oil and gas lease...

76 FR 66080 - Notice of Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-25

... Proposed Class II Reinstatement of Terminated Oil and Gas Lease, Utah AGENCY: Bureau of Land Management, Interior. ACTION: Notice. SUMMARY: In accordance with Title IV of the Federal Oil and Gas Royalty Management Act, Bro Energy LLC timely filed a petition for reinstatement of oil and gas lease UTU85562 lands...

The nociception genes painless and Piezo are required for the cellular immune response of Drosophila larvae to wasp parasitization.

PubMed

Tokusumi, Yumiko; Tokusumi, Tsuyoshi; Schulz, Robert A

2017-05-13

In vertebrates, interaction between the nervous system and immune system is important to protect a challenged host from stress inputs from external sources. In this study, we demonstrate that sensory neurons are involved in the cellular immune response elicited by wasp infestation of Drosophila larvae. Multidendritic class IV neurons sense contacts from external stimuli and induce avoidance behaviors for host defense. Our findings show that inactivation of these sensory neurons impairs the cellular response against wasp parasitization. We also demonstrate that the nociception genes encoding the mechanosensory receptors Painless and Piezo, both expressed in class IV neurons, are essential for the normal cellular immune response to parasite challenge. Copyright © 2017. Published by Elsevier Inc.

[Evaluation of view points in forest park based on landscape sensitivity].

PubMed

Zhou, Rui; Li, Yue-hui; Hu, Yuan-man; Liu, Miao

2008-11-01

Based on topographical characteristics, five factors including comparative slope, comparative distance, mutual visibility, vision probability, and striking degree were chosen to assess the landscape sensitivity of major view points in Houshi National Forest Park. Spatial analysis in GIS was used for exploring the theory and method of landscape sensitivity of view points. The results showed that in the Park, there were totally 23 view points, but none of them reached up to class I. Among the 23 points, 10 were of class II , accounting for 43.5% of the total, 8 were of class III, accounting for 34.8%, and 5 were of classes IV and V, accounting for 21.7%. Around the view points of class II, the landscape should be strictly protected to maintain their natural feature; around the view points of class III, human-made landscape points should be developed according to the natural landscape feature, and wide tourism roads and small-size buildings could be constructed but the style of the buildings should be harmonious with surrounding nature landscape; while around the view points of classes IV and V, large-size multifunctional items and roads could be built to perfect the natural landscape. Through the multi-perspective and quantitative evaluation of landscape sensitivity, this study enriched the theory of landscape visual assessment and landscape apperception, and provided scientific base and direction for the planning and management of forest parks and other tourism areas.

Lean methodology in i.v. medication processes in a children's hospital.

PubMed

L'Hommedieu, Timothy; Kappeler, Karl

2010-12-15

The impact of lean methodology in i.v. medication processes in a children's hospital was studied. Medication orders at a children's hospital were analyzed for 30 days to identify the specific times when most medications were changed or discontinued. Value-stream mapping was used to define the current state of preparation and identify non-value-added tasks in the i.v. medication preparation and dispensing processes. An optimization model was created using specific measurements to establish the optimal number of batches and batch preparation times of batches. Returned i.v. medications were collected for 7 days before and after implementation of the lean process to determine the impact of the lean process changes. Patient-days increased from 1,836 during the first collection period to 2,017 during the second, and the total number of i.v. doses dispensed increased from 8,054 to 9,907. Wasted i.v. doses decreased from 1,339 (16.6% of the total doses dispensed) to 853 (8.6%). With the new process, Nationwide Children's Hospital was projected to realize a weekly savings of $8,197 ($426,244 annually), resulting in a 2.6% reduction in annual drug expenditure. The annual savings is a conservative estimate, due to the 10% increase in patient-days after the lean collection period compared with baseline. The differences in wasted doses and their costs were significant (p < 0.05). Implementing lean concepts in the i.v. medication preparation process had a positive effect on efficiency and drug cost.

Platinum(iv) prodrug conjugated Pd@Au nanoplates for chemotherapy and photothermal therapy

NASA Astrophysics Data System (ADS)

Shi, Saige; Chen, Xiaolan; Wei, Jingping; Huang, Yizhuan; Weng, Jian; Zheng, Nanfeng

2016-03-01

Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(iv) prodrug loading. Once injected into biological tissue, the Pt(iv) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(ii) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(ii) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment.Owing to the excellent near infrared (NIR) light absorption and efficient passive targeting toward tumor tissue, two-dimensional (2D) core-shell PEGylated Pd@Au nanoplates have great potential in both photothermal therapy and drug delivery systems. In this work, we successfully conjugate Pd@Au nanoplates with a platinum(iv) prodrug c,c,t-[Pt(NH3)2Cl2(O2CCH2CH2CO2H)2] to obtain a nanocomposite (Pd@Au-PEG-Pt) for combined photothermal-chemotherapy. The prepared Pd@Au-PEG-Pt nanocomposite showed excellent stability in physiological solutions and efficient Pt(iv) prodrug loading. Once injected into biological tissue, the Pt(iv) prodrug was easily reduced by physiological reductants (e.g. ascorbic acid or glutathione) into its cytotoxic and hydrophilic Pt(ii) form and released from the original nanocomposite, and the NIR laser irradiation could accelerate the release of Pt(ii) species. More importantly, Pd@Au-PEG-Pt has high tumor accumulation (29%ID per g), which makes excellent therapeutic efficiency at relatively low power density possible. The in vivo results suggested that, compared with single therapy the combined thermo-chemotherapy treatment with Pd@Au-PEG-Pt resulted in complete destruction of the tumor tissue without recurrence, while chemotherapy using Pd@Au-PEG-Pt without irradiation or photothermal treatment using Pd@Au-PEG alone did not. Our work highlights the prospects of a feasible drug delivery strategy of the Pt prodrug by using 2D Pd@Au nanoplates as drug delivery carriers for multimode cancer treatment. Electronic supplementary information (ESI) available: Synthesis process of Pt(iv) prodrug, mass data and FT-IR spectra of the intermediate product and Pt(iv) prodrug, TEM images of Pd@Au and Au NPs, thermal gravimetric analysis of nanoparticles, dispersion stability of Pd@Au-PEG-Pt NSs in different solutions, chemical reduction of Pt(ii) in a water bath, viability of different cell lines incubated with different concentrations of materials, uptake of different drugs by HeLa cells, size distribution of nanoparticles, tissue distribution by measuring the Pt amounts and zeta potential information of prodrug function nanomaterials. See DOI: 10.1039/c5nr09120a

21 CFR 1308.14 - Schedule IV.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Schedule IV. 1308.14 Section 1308.14 Food and... isomers is possible: (1) Fenfluramine 1670 (e) Stimulants. Unless specifically excepted or unless listed... the following substances having a stimulant effect on the central nervous system, including its salts...

The relationship between the success rate of empirical antifungal therapy with intravenous itraconazole and clinical parameters, including plasma levels of itraconazole, in immunocompromised patients receiving itraconazole oral solution as prophylaxis: a multicenter, prospective, open-label, observational study in Korea.

PubMed

Kim, Jin Seok; Cheong, June-Won; Kim, Yeo-Kyeoung; Park, Jinny; Mun, Yeung-Chul; Kang, Hye Jin; Yi, Hyeon Gyu; Lee, Je-Hwan; Kim, Yang Soo; Ryoo, Hun-Mo; Kim, Sung-Hyun; Kim, Ho Young; Kim, Jin Young; Lee, Dong-Gun; Kim, Hoon-Gu; Kim, Hawk; Joo, Young-Don; Min, Yoo Hong

2014-01-01

To identify the role of therapeutic drug monitoring of itraconazole (ITZ) in the setting of empirical antifungal therapy with intravenous (IV) ITZ, we performed a multicenter, prospective study in patients with hematological malignancies who had received antifungal prophylaxis with ITZ oral solution (OS). We evaluated the plasma levels of ITZ and hydroxy (OH) ITZ both before initiation of IV ITZ and on days 5-7 of IV ITZ. A total of 181 patients showed an overall success rate of 68.0 %. Prolonged baseline neutropenia and accompanying cardiovascular comorbidity were significantly associated with poor outcomes of the empirical antifungal therapy (P = 0.005 and P = 0.001, respectively). A significantly higher trough plasma level of OH ITZ per body weight was found in the patients who achieved success with empirical antifungal therapy (P = 0.036). There were no significant correlations between plasma concentrations of ITZ/OH ITZ (baseline or trough levels) and toxicities. Seven patients had a discontinuation of ITZ therapy due to toxicity. This study demonstrated that IV ITZ as empirical antifungal therapy was effective and therapeutic drug monitoring was helpful to estimate the outcome of empirical antifungal therapy in patients receiving antifungal prophylaxis with ITZ OS. To predict the outcome of empirical antifungal therapy with IV ITZ, we should evaluate baseline clinical characteristics and also perform the therapeutic drug monitoring of both ITZ and OH ITZ.

Agreement between PRE2DUP register data modeling method and comprehensive drug use interview among older persons

PubMed Central

Taipale, Heidi; Tanskanen, Antti; Koponen, Marjaana; Tolppanen, Anna-Maija; Tiihonen, Jari; Hartikainen, Sirpa

2016-01-01

Background PRE2DUP is a modeling method that generates drug use periods (ie, when drug use started and ended) from drug purchases recorded in dispensing-based register data. It is based on the evaluation of personal drug purchasing patterns and considers hospital stays, possible stockpiling of drugs, and package information. Objective The objective of this study was to investigate person-level agreement between self-reported drug use in the interview and drug use modeled from dispensing data with PRE2DUP method for various drug classes used by older persons. Methods Self-reported drug use was assessed from the GeMS Study including a random sample of persons aged ≥75 years from the city of Kuopio, Finland, in 2006. Drug purchases recorded in the Prescription register data of these persons were modeled to determine drug use periods with PRE2DUP modeling method. Agreement between self-reported drug use on the interview date and drug use calculated from register-based data was compared in order to find the frequently used drugs and drug classes, which was evaluated by Cohen’s kappa. Kappa values 0.61–0.80 were considered to represent good and 0.81–1.00 as very good agreement. Results Among 569 participants with mean age of 82 years, the agreement between interview and register data was very good for 75% and very good or good for 93% of the studied drugs or drug classes. Good or very good agreement was observed for drugs that are typically used on regular bases, whereas “as needed” drugs represented poorer results. Conclusion PRE2DUP modeling method validly describes regular drug use among older persons. For most of drug classes investigated, PRE2DUP-modeled register data described drug use as well as interview-based data which are more time-consuming to collect. Further studies should be conducted by comparing it with other methods and in different drug user populations. PMID:27785101

Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

PubMed

de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

2018-07-01

Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

Prediction of future uniform milk prices in Florida federal milk marketing order 6 from milk futures markets.

PubMed

De Vries, A; Feleke, S

2008-12-01

This study assessed the accuracy of 3 methods that predict the uniform milk price in Federal Milk Marketing Order 6 (Florida). Predictions were made for 1 to 12 mo into the future. Data were from January 2003 to May 2007. The CURRENT method assumed that future uniform milk prices were equal to the last announced uniform milk price. The F+BASIS and F+UTIL methods were based on the milk futures markets because the futures prices reflect the market's expectation of the class III and class IV cash prices that are announced monthly by USDA. The F+BASIS method added an exponentially weighted moving average of the difference between the class III cash price and the historical uniform milk price (also known as basis) to the class III futures price. The F+UTIL method used the class III and class IV futures prices, the most recently announced butter price, and historical utilizations to predict the skim milk prices, butterfat prices, and utilizations in all 4 classes. Predictions of future utilizations were made with a Holt-Winters smoothing method. Federal Milk Marketing Order 6 had high class I utilization (85 +/- 4.8%). Mean and standard deviation of the class III and class IV cash prices were $13.39 +/- 2.40/cwt (1 cwt = 45.36 kg) and $12.06 +/- 1.80/cwt, respectively. The actual uniform price in Tampa, Florida, was $16.62 +/- 2.16/cwt. The basis was $3.23 +/- 1.23/cwt. The F+BASIS and F+UTIL predictions were generally too low during the period considered because the class III cash prices were greater than the corresponding class III futures prices. For the 1- to 6-mo-ahead predictions, the root of the mean squared prediction errors from the F+BASIS method were $1.12, $1.20, $1.55, $1.91, $2.16, and $2.34/cwt, respectively. The root of the mean squared prediction errors ranged from $2.50 to $2.73/cwt for predictions up to 12 mo ahead. Results from the F+UTIL method were similar. The accuracies of the F+BASIS and F+UTIL methods for all 12 fore-cast horizons were not significantly different. Application of the modified Mariano-Diebold tests showed that no method included all the information contained in the other methods. In conclusion, both F+BASIS and F+UTIL methods tended to more accurately predict the future uniform milk prices than the CURRENT method, but prediction errors could be substantial even a few months into the future. The majority of the prediction error was caused by the inefficiency of the futures markets to predict the class III cash prices.

Permanent work incapacity, mortality and survival without work incapacity among occupations and social classes: a cohort study of ageing men in Geneva.

PubMed

Gubéran, E; Usel, M

1998-12-01

The objective of this retrospective cohort study was to investigate the burden of disability and death in men, from middle age to age of retirement, among occupational groups and classes in Geneva. Men were included if they resided in the Canton of Geneva, were 45 years of age in 1970-1972, and were not receiving a disability pension at the start of the follow-up. The cohort of 5137 men was followed up for 20 years and linked to national registers of disability pension allowance and of causes of death. There was a steep upward trend in incidence of permanent work incapacity with lower social class for all causes as well as for the seven causes of disability studied. Compared with professional occupations (social class I), the relative risk (RR) of permanent work incapacity was 11.4 for partly skilled and unskilled occupations (class IV+V) (95% confidence interval [CI]: 5.2-28.0). The social class gradient in mortality was in the same direction as that in work incapacity although much less steep (RR class IV+V to class I = 1.6, 95% CI : 1.1-2.2). Survival without work incapacity at the time of the 65th birthday ranged from only 57% in construction workers and labourers to 89% in science and related professionals. Unemployment in Geneva was below 1.5% during almost all the study period. Medically-ascertained permanent work incapacity and survival without work incapacity have shown considerably greater socioeconomic differentials than the mortality differentials.

A theranostic prodrug delivery system based on Pt(IV) conjugated nano-graphene oxide with synergistic effect to enhance the therapeutic efficacy of Pt drug.

PubMed

Li, Jingwen; Lyv, Zhonglin; Li, Yanli; Liu, Huan; Wang, Jinkui; Zhan, Wenjun; Chen, Hong; Chen, Huabing; Li, Xinming

2015-05-01

Due to their high NIR-optical absorption and high specific surface area, graphene oxide and graphene oxide-based nanocomposites have great potential in both drug delivery and photothermal therapy. In the work reported herein we successfully integrate a Pt(IV) complex (c,c,t-[Pt(NH3)2Cl2(OH)2]), PEGylated nano-graphene oxide (PEG-NGO), and a cell apoptosis sensor into a single platform to generate a multifunctional nanocomposite (PEG-NGO-Pt) which shows potential for targeted drug delivery and combined photothermal-chemotherapy under near infrared laser irradiation (NIR), and real-time monitoring of its therapeutic efficacy. Non-invasive imaging using a fluorescent probe immobilized on the GO shows an enhanced therapeutic effect of PEG-NGO-Pt in cancer treatment via apoptosis and cell death. Due to the enhanced cytotoxicity of cisplatin and the highly specific tumor targeting of PEG-NGO-Pt at elevated temperatures, this nanocomposite displays a synergistic effect in improving the therapeutic efficacy of the Pt drug with complete destruction of tumors, no tumor recurrence and minimal systemic toxicity in comparison with chemotherapy or photothermal treatment alone, highlighting the advantageous effects of integrating Pt(IV) with GO for anticancer treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Ablation or Reduction of Intraoperative Tourniquet Pain with Preoperative Administration of IV Ketorolac Tromethamine

DTIC Science & Technology

1994-08-01

non - steroidal anti - inflammatory drug . Anticipated conclusions of...tromethamine is a nonsteroidal, anti - inflammatory drug (NSAID) that does not have CNS activity. It is a potent analgesic with less anti - inflammatory ...nonsteroidal, anti - inflammatory drug that inhibits prostaglandin production. Administration of ketorolac tromethamine prior to tourniquet inflation

9 CFR 301.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... contains a pesticide chemical which is unsafe within the meaning of section 408 of the Federal Food, Drug... of section 409 of the Federal Food, Drug, and Cosmetic Act; (iv) If it bears or contains any color additive which is unsafe within the meaning of section 706 of the Federal Food, Drug, and Cosmetic Act...

The effect of the European Clinical Trials Directive on published drug research in anaesthesia.

PubMed

Walker, E; Hankins, M C; White, S M

2009-09-01

The clinical indications for anaesthetic drugs are developed through peer-reviewed publication of clinical trials. We performed a bibliometric analysis of all human research papers reported in nine general anaesthesia journals over 6 years (n = 6489), to determine any effects of the 2004 European Clinical Trials Directive on reported drug research in anaesthesia originating from Europe and the United Kingdom. We found 89% studies involved patients and 11% volunteers. Of 3234 (50%) drug studies, 96% were phase IV (post-marketing) trials. Worldwide, the number of research papers fell by 3.6% (p < 0.004) in the 3 years following introduction of the European Clinical Trials Directive (5% Europe, 18% United Kingdom), and drug research papers fell by 12% (p < 0.001; 15% Europe, 29% United Kingdom). The introduction of the Clinical Trials Directive has therefore coincided with a decline in European drug research, particularly that originating from the United Kingdom. We suggest a number of measures researchers could take in response, and we propose a simplification of the application process for phase IV clinical trials, emphasising patient risk assessment.

Physical compatibility of plazomicin with select i.v. drugs during simulated Y-site administration.

PubMed

Asempa, Tomefa E; Avery, Lindsay M; Kidd, James M; Kuti, Joseph L; Nicolau, David P

2018-06-12

The results of a study to determine the physical compatibility of plazomicin sulfate solution during simulated Y-site administration with 92 i.v. drugs are reported. Plazomicin injection solution (500 mg/10 mL) was diluted in 0.9% sodium chloride or 5% dextrose for injection to a final volume of 50 mL (final plazomicin concentration, 24 mg/mL), consistent with a 15-mg/kg dose administered to an 80-kg patient (i.e., 1,200 mg). All other i.v. drugs were reconstituted according to manufacturers' recommendations and diluted with 0.9% sodium chloride or 5% dextrose for injection to the upper range of concentrations used clinically. Y-site conditions were simulated by mixing 5 mL of plazomicin solution with 5 mL of tested drug solutions in a 1:1 ratio. Solutions were assessed for visual (via color and Tyndall beam testing), turbidity (using a laboratory-grade turbidimeter), and pH changes over a 60-minute observation period. Incompatibility was defined a priori as precipitation, color change, a positive Tyndall test, or a turbidity change of ≥0.5 nephelometric turbidity units at any time during the 60-minute observation period. Plazomicin was physically compatible with 79 of the 92 drugs tested. Determinations of physical incompatibility with plazomicin were made for 13 drugs: albumin, amiodarone, amphotericin B deoxycholate, anidulafungin, calcium chloride, daptomycin, esomeprazole, heparin, levofloxacin, methylprednisolone, micafungin, phenytoin, and propofol, CONCLUSION: Plazomicin at a concentration of 24 mg/mL was physically compatible with 85% of the drugs tested, including 31 of 36 antimicrobial agents. Copyright © 2018 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Market entry, power, pharmacokinetics: what makes a successful drug innovation?

PubMed

Alt, Susanne; Helmstädter, Axel

2018-02-01

Depending on the timing of market entry, radical innovations can be distinguished from incremental innovations. Whereas a radical innovation typically is the first available derivative of a drug class, incremental innovations are launched later and show a certain benefit compared with the radical innovation. Here, we use historical market data relating to pharmacokinetic (PK), pharmacodynamic (PD), and other drug-related properties to investigate which derivatives within certain drug classes have been most successful on the market. Based on our investigations, we suggest naming the most successful drugs 'overtaking innovation', because they often exceed the market share of all the other derivatives. Seven drug classes showed that the overtaking innovation is never a radical innovation, but rather an early incremental innovation, with advantages in manageability and/or tolerance. Copyright © 2017 Elsevier Ltd. All rights reserved.

Estimation of Potential Savings Through Therapeutic Substitution.

PubMed

Johansen, Michael E; Richardson, Caroline

2016-06-01

Therapeutic substitution offers potential to decrease pharmaceutical expenditures and potentially improve the efficiency of the health care system. To estimate potential savings through therapeutic substitution in terms of both overall and out-of-pocket expenditures of branded drugs when a generic in the same class with the same indication was available. Repeated cross-sectional study using the 107 132 individuals included in the nationally representative Medical Expenditure Panel Survey (2010-2012) along with their reported prescribed medicine use. The Orange Book, company financial statements, US Food and Drug Administration records, and published research were used for adjunctive information. Estimated excess expenditure due to branded drug overuse when a lower-cost generic in the same class with the same indication was available. The study included 107 132 individuals between 2010 and 2012, of whom 62.1% (95% CI, 61.4%-62.8%) reported use of any prescribed medicine. A total of 31.5% (95% CI, 30.7%-32.2%) used a medication from an included drug class, whereas 16.6% (95% CI, 16.0%-17.1%) of the population used a branded drug from the included classes compared with 24.0% (95% CI, 23.4%-24.7%) who used a generic and 9.1% (95% CI, 8.7%-9.4%) who used both. In the included drug classes, the majority of the drugs were generics, with a total of 93.5 billion standardized doses compared with 47.4 billion standardized doses of branded drugs. Total expenditure of the branded drugs accounted for $147 (95% CI, $137-$156) billion compared with $62.7 (95% CI, $58.9-$66.5) billion for the generics. Between 2010 and 2012, an estimated $73.0 (95% CI, $67.6-$78.5) billion in total excess expenditure and $24.6 (95% CI, $22.6-$26.5) billion in out-of-pocket excess expenditure was attributable to branded drug overuse. The excess was present across numerous drug classes throughout many aspects of medicine and equates to 9.6% of total and 14.1% of out-of-pocket prescribed medicine expenses. The drug classes with the highest excess expenditure included statins ($10.9 [SE, $0.41] billion), atypical antipsychotics ($9.99 [SE, $1.03] billion), proton pump inhibitors ($6.12 [SE, $0.38] billion), selective serotonin reuptake inhibitors ($6.08 [SE, $0.49] billion), and angiotensin receptor blockers ($5.53 [SE, $0.35] billion). Although therapeutic substitution is controversial, it offers a potential mechanism to significantly decrease drug costs if it can be implemented in a way that does not negatively affect quality of care.

75 FR 59726 - Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-28

... method comparison section and the sample selection inclusion and exclusion criteria section. The... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0428] Draft Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

76 FR 48870 - Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-09

... selection inclusion and exclusion criteria section. The revisions define and differentiate the required... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2010-D-0428] Guidance for Industry and Food and Drug Administration Staff; Class II Special Controls Guidance Document...

Friendship networks of inner-city adults: a latent class analysis and multi-level regression of supporter types and the association of supporter latent class membership with supporter and recipient drug use.

PubMed

Bohnert, Amy S B; German, Danielle; Knowlton, Amy R; Latkin, Carl A

2010-03-01

Social support is a multi-dimensional construct that is important to drug use cessation. The present study identified types of supportive friends among the social network members in a community-based sample and examined the relationship of supporter-type classes with supporter, recipient, and supporter-recipient relationship characteristics. We hypothesized that the most supportive network members and their support recipients would be less likely to be current heroin/cocaine users. Participants (n=1453) were recruited from low-income neighborhoods with a high prevalence of drug use. Participants identified their friends via a network inventory, and all nominated friends were included in a latent class analysis and grouped based on their probability of providing seven types of support. These latent classes were included as the dependent variable in a multi-level regression of supporter drug use, recipient drug use, and other characteristics. The best-fitting latent class model identified five support patterns: friends who provided Little/No Support, Low/Moderate Support, High Support, Socialization Support, and Financial Support. In bivariate models, friends in the High, Low/Moderate, and Financial Support were less likely to use heroin or cocaine and had less conflict with and were more trusted by the support recipient than friends in the Low/No Support class. Individuals with supporters in those same support classes compared to the Low/No Support class were less likely to use heroin or cocaine, or to be homeless or female. Multivariable models suggested similar trends. Those with current heroin/cocaine use were less likely to provide or receive comprehensive support from friends. Published by Elsevier Ireland Ltd.

Drug‐specific hypophosphatemia and hypersensitivity reactions following different intravenous iron infusions

PubMed Central

Hvas, Christian L.; Dahlerup, Jens F.

2017-01-01

Aims Intravenous (IV) iron infusions have been associated with hypophosphataemia (HP) and hypersensitivity reactions (HSRs). No studies have compared the side effects of ferric carboxymaltose (FCM) with those of isomaltoside 1000 (ISM). This study aimed to describe the occurrence of HP and HSRs following the administration of either FCM or ISM. Methods Data on 231 outpatients treated with IV iron infusions, between November 2011 and April 2014, were collected. During that period, the department made a switch from FCM to ISM and then back to FCM. Of the 231 patients, 39 received both FCM and ISM during the period. The prevalences of HP and HSRs were compared between the two drugs. Results We found more HP events when FCM was given (64 vs. 9; P < 0.01). In contrast, more patients had mild HSRs when ISM was given (2.5% vs. 10.7%; P < 0.01). A comparison of the two drugs in the subpopulation who received both drug types (n = 39) revealed a difference in phosphate decrease (P < 0.01), with the most marked decrease occurring with FCM. Nine patients who had HSRs were exposed to both drugs. No potential HSR crossover between the two drugs was found. Conclusion We found a higher risk of HP with FCM administration when compared to ISM administration. Conversely, we found a higher risk of mild HSRs with ISM administration when compared to FCM administration. The impacts of the two types of side effects should be considered when choosing an IV iron drug. PMID:27859495

Effect of Simvastatin, Coenzyme Q10, Resveratrol, Acetylcysteine and Acetylcarnitine on Mitochondrial Respiration.

PubMed

Fišar, Z; Hroudová, J; Singh, N; Kopřivová, A; Macečková, D

2016-01-01

Some therapeutic and/or adverse effects of drugs may be related to their effects on mitochondrial function. The effects of simvastatin, resveratrol, coenzyme Q10, acetylcysteine, and acetylcarnitine on Complex I-, Complex II-, or Complex IV-linked respiratory rate were determined in isolated brain mitochondria. The protective effects of these biologically active compounds on the calcium-induced decrease of the respiratory rate were also studied. We observed a significant inhibitory effect of simvastatin on mitochondrial respiration (IC50 = 24.0 μM for Complex I-linked respiration, IC50 = 31.3 μM for Complex II-linked respiration, and IC50 = 42.9 μM for Complex IV-linked respiration); the inhibitory effect of resveratrol was found at very high concentrations (IC50 = 162 μM for Complex I-linked respiration, IC50 = 564 μM for Complex II-linked respiration, and IC50 = 1454 μM for Complex IV-linked respiration). Concentrations required for effective simvastatin- or resveratrol-induced inhibition of mitochondrial respiration were found much higher than concentrations achieved under standard dosing of these drugs. Acetylcysteine and acetylcarnitine did not affect the oxygen consumption rate of mitochondria. Coenzyme Q10 induced an increase of Complex I-linked respiration. The increase of free calcium ions induced partial inhibition of the Complex I+II-linked mitochondrial respiration, and all tested drugs counteracted this inhibition. None of the tested drugs showed mitochondrial toxicity (characterized by respiratory rate inhibition) at drug concentrations achieved at therapeutic drug intake. Resveratrol, simvastatin, and acetylcarnitine had the greatest neuroprotective potential (characterized by protective effects against calcium-induced reduction of the respiratory rate).

Assessment of feasibility and efficacy of Class IV laser therapy for postoperative pain relief in off-pump coronary artery bypass surgery patients: A pilot study

PubMed Central

Karlekar, Anil; Bharati, Saswata; Saxena, Ravindra; Mehta, Kanchan

2015-01-01

Background: Laser therapy, for its established analgesic properties with minimal side effects, has been used for the treatment of chronic pain. However, it has not been used for the treatment of acute postoperative pain. This pilot study was designed to assess the feasibility and efficacy of Class IV laser on postoperative pain relief following off-pump coronary artery bypass graft (OPCABG) surgery, as a component of multimodal analgesia (MMA) technique. Methods: This open observational prospective study comprised of 100 adult patients (84 male, 16 female) who underwent OPCABG through sternotomy. For postoperative analgesia, they were subjected to laser therapy subjected to laser therapy in addition to the standard institutional pain management protocol comprising of IV infusion/bolus of tramadol and paracetamol and fentanyl bolus as rescue analgesic. Pain intensity was measured by Verbal Rating Scale (VRS). The laser therapy was scheduled as once a day regime for three consecutive postoperative days (PODs) starting on POD 1, 30 min following tracheal extubation. The subsequent laser applications were also scheduled at the same time of the day as on day 1 if VRS was ≥5. 10 W Class IV laser was applied over 150 cm2 sternal wound area for 150 s. VRS was used to assess pain severity and was recorded for statistical analysis using Friedman Test. Results: The mean (standard deviation [SD]) VRS of all the 100 patients just before application of the first dose of laser was 7.31 (0.94) while on MMT; the same fell to 4.0 (1.279) and 3.40 (2.697) at 1 h and 24 h respectively following first dose of laser. The change of VRS over first 24 h among all the 100 patients was statistically significant (P = 0.000). Laser was re-applied in 40 patients whose VRS was ≥5 (mean [SD] – 6.38 [0.868]) at 24th h. After receiving the 2nd dose of laser the VRS scores fell significantly (P = 0.000) and became 0 at 54th h. No patients required 3rd dose of the laser. No patient required rescue analgesic while on laser therapy. Conclusion: Class IV laser can be an effective technique for postoperative analgesia following OPCABG surgery through sternotomy when included as a component of MMA technique. PMID:26139735

Self dispersing mixed micelles forming systems for enhanced dissolution and intestinal permeability of hydrochlorothiazide.

PubMed

Sultan, Amal A; El-Gizawy, Sanaa A; Osman, Mohamed A; El Maghraby, Gamal M

2017-01-01

Mixed micelles provide promising strategy for enhancing dissolution and permeability of drugs. However, their fluid nature limited the stability of the loaded drug and hindered the development of stable oral dosage form. Accordingly, the objective was to develop solid self dispersing mixed micelle forming systems (MMFS) for enhanced dissolution and intestinal permeability of hydrochlorothiazide. Pseudoternary phase diagrams were constructed using sodium cholate, lecithin with either poloxamer 407 or PEG 4000 to determine the composition of MMFS. Both polymer free and poloxamer or PEG containing MMFS were prepared as homogenous matrices or as solid self dispersing powder. The later was developed by adsorption of MMFS on avicel-aerosil mixture. Differential scanning calorimetry provided an evidence for existence of hydrochlorothiazide as molecular dispersion in the MMFS. Dispersing polymer free, PEG 4000 or poloxamer based MMFS in aqueous medium produced micelles having size values of 119, 52.6 and 28nm, respectively. The zeta potential values were -61.8, -59.5 and -19.5mV for the same systems, respectively. Preparation of solid self dispersing MMFS enhanced the dissolution rate of hydrochlorothiazide. The intestinal absorption of hydrochlorothiazide from its aqueous solution and polymer incorporating mixed micellar systems was monitored using in situ rabbit intestinal perfusion technique. The permeability results showed a clear trend for enhanced membrane transport of the drug after being incorporated into poloxamer containing mixed micellar system. The study thus introduced a versatile easily formulated solid self dispersing system with high potential for solving the dissolution and permeability problems of class IV drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Use of abnormal and health psychology as topics in a classroom format to reduce alcohol and other drug abuse among college students at risk.

PubMed

Miley, W M

2001-12-01

This study was done to assess whether classes containing topics derived from two college courses, Abnormal Psychology and Health Psychology, could be used in a class room format to reduce alcohol and other drug abuse among at-risk college students. Topics covered included stress and stress management, alcohol and other drug use and abuse, chronic illnesses and psychological disorders that develop from an unhealthy lifestyle, and factors that play a role in good health and well-being. Students were enrolled in a semester-long course for college credit as an alternative to punitive sanctions for on-campus alcohol violations and other drug violations. The Midwest Institute on Drug Use Survey and the CORE Alcohol and Drug Survey were administered on the first and last days of class. Analysis indicated a significant self-reported reduction in drug use and associated negative symptoms and behavioral effects. Women were more likely to report reductions in drug use than men.

Social class inequalities in the use of and access to health services in Catalonia, Spain: what is the influence of supplemental private health insurance?

PubMed

Borrell, C; Fernandez, E; Schiaffino, A; Benach, J; Rajmil, L; Villalbi, J R; Segura, A

2001-04-01

To analyse social class inequalities in the access to and utilization of health services in Catalonia (Spain), and the influence of having private health insurance supplementing the National Health System (NHS) coverage. 1994 Catalan Health Interview Survey, a cross-sectional survey conducted in 1994. Catalonia (Spain). The participants were a representative sample of people aged over 14 years from the non-institutionalized population of Catalonia (n = 12,245). Health services utilization, perceived health, having only NHS or NHS plus a private health insurance, and social class. Although one-quarter of the population of Catalonia had a supplemental private health insurance, percentages were very different according to social class, ranging from almost 50% for classes I and II to 16% for classes IV and V in both sexes. No inequalities by social class were observed for the utilization of non-preventive health care services (consultation with a health professional in the last 2 weeks and hospitalization in the last year) among persons with poor self-perceived health status, i.e. those in most need. However, social inequalities still remain in the use of health services provided only partially by the NHS, and when characteristics of last consultation are taken into account. Subjects who paid for a private service waited an average of 18.8 minutes less than those attending the NHS. Within the NHS, social classes IV and V waited longer (35.5 minutes) than social classes I and II (28.4 minutes). The NHS in Catalonia, Spain, has reduced inequalities in the use of health services. Social inequalities remain in the use of those health services provided only partially by the NHS.

Prolonged Hypocalcemic Effect by Pulmonary Delivery of Calcitonin Loaded Poly(Methyl Vinyl Ether Maleic Acid) Bioadhesive Nanoparticles

PubMed Central

Varshosaz, J.; Minaiyan, M.; Forghanian, M.

2014-01-01

The purpose of the present study was to design a pulmonary controlled release system of salmon calcitonin (sCT). Therefore, poly(methyl vinyl ether maleic acid) [P(MVEMA)] nanoparticles were prepared by ionic cross-linking method using Fe2+ and Zn2+ ions. Physicochemical properties of nanoparticles were studied in vitro. The stability of sCT in the optimized nanoparticles was studied by electrophoretic gel method. Plasma calcium levels until 48 h were determined in rats as pulmonary-free sCT solution or nanoparticles (25 μg·kg−1), iv solution of sCT (5 μg·kg−1), and pulmonary blank nanoparticles. The drug remained stable during fabrication and tests on nanoparticles. The optimized nanoparticles showed proper physicochemical properties. Normalized reduction of plasma calcium levels was at least 2.76 times higher in pulmonary sCT nanoparticles compared to free solution. The duration of hypocalcemic effect of pulmonary sCT nanoparticles was 24 h, while it was just 1 h for the iv solution. There was not any significant difference between normalized blood calcium levels reduction in pulmonary drug solution and iv injection. Pharmacological activity of nanoparticles after pulmonary delivery was 65% of the iv route. Pulmonary delivery of P(MVEMA) nanoparticles of sCT enhanced and prolonged the hypocalcemic effect of the drug significantly. PMID:24701588

Estrogen rapidly enhances incisional pain of ovariectomized rats primarily through the G protein-coupled estrogen receptor.

PubMed

An, Guanghui; Li, Wenhui; Yan, Tao; Li, Shitong

2014-06-11

It has become increasingly apparent that the pain threshold of females and males varies in an estrogen dependent manner. To investigate the modulation of pain by estrogen and the molecular mechanisms involved in this process. A total of 48 rats were ovariectomized (OVX). At 14 and 20 days after OVX, rats were divided into eight groups: groups 1-4 were administered drugs intravenously (IV); groups 5-8 were administered through intrathecal (IT) catheter. Hind paw incision was made in all animals to determine incisional pain. Paw withdraw threshold (PWT) was tested prior to and 24 h after incision. The test drugs were applied 24 h after the incision. Rats were either IV or IT administered with: 17-β-estradiol (E2), G protein-coupled estrogen receptor (GPER)-selective agonist (G1), GPER-selective antagonist (G15) and E2 (G15+E2), or solvent. Before and 30 min after IV drug administration and 20 min during the IT catheter administration, PWT was tested and recorded. 24 h after incisional surgery, the PWT of all rats significantly decreased. Both in the IV group and IT group: administration of E2 and G1 significantly decreased PWT. Neither administration of G15+E2 nor solvent significantly changed PWT. Estrogen causes rapid reduction in the mechanical pain threshold of OVX rats via GPER.

Neurons of human nucleus accumbens.

PubMed

Sazdanović, Maja; Sazdanović, Predrag; Zivanović-Macuzić, Ivana; Jakovljević, Vladimir; Jeremić, Dejan; Peljto, Amir; Tosevski, Jovo

2011-08-01

Nucleus accumbens is a part of the ventral striatum also known as a drug active brain region, especially related with drug addiction. The aim of the study was to investigate the Golgi morphology of the nucleus accumbens neurons. The study was performed on the frontal and sagittal sections of 15 human brains by the Golgi Kopsch method. We classified neurons in the human nucleus accumbens according to their morphology and size into four types: type I--fusiform neurons; type II--fusiform neurons with lateral dendrite, arising from a part of the cell body; type III--pyramidal-like neuron; type IV--multipolar neuron. The medium spiny neurons, which are mostly noted regarding to the drug addictive conditions of the brain, correspond to the type IV--multipolar neurons. Two regions of human nucleus accumbens could be clearly recognized on Nissl and Golgi preparations each containing different predominant neuronal types. Central part of nucleus accumbens, core region, has a low density of impregnated neurons with predominant type III, pyramidal-like neurons, with spines on secondary branches and rare type IV, multipolar neurons. Contrary to the core, peripheral region, shell of nucleus, has a high density of impregnated neurons predominantly contained of type I and type IV--multipolar neurons, which all are rich in spines on secondary and tertiary dendritic branches. Our results indicate great morphological variability of human nucleus accumbens neurons. This requires further investigations and clarifying clinical significance of this important brain region.

Impact of Sterile Compounding Batch Frequency on Pharmaceutical Waste.

PubMed

Abbasi, Ghalib; Gay, Evan

2017-01-01

Purpose: To measure the impact of increasing sterile compounding batch frequency on pharmaceutical waste as it relates to cost and quantity. Methods: Pharmaceutical IV waste at a tertiary care hospital was observed and recorded for 7 days. The batching frequency of compounded sterile products (CSPs) was then increased from twice daily to 4 times daily. After a washout period, pharmaceutical IV waste was then recorded for another 7 days. The quantity of units wasted and the cost were compared between both phases to determine the impact that batching frequency has on IV waste, specifically among high- and low-cost drugs. Results: Patient days increased from 2,459 during phase 1 to 2,617 during phase 2. The total number of CSPs wasted decreased from 3.6 to 2.7 doses per 100 patient days. Overall cost was reduced from $4,585.36 in phase 1 to $4,453.88 in phase 2. The value of wasted high-cost drugs per 100 patient days increased from $146 in phase 1 to $149 in phase 2 ( p > .05). The value of wasted low cost drugs per 100 patient days decreased from $41 in phase 1 to $21 in phase 2 ( p < .05). Conclusion: Lean batch IV methodology reduced overall waste quantity and cost. The highest impact of the intervention was observed among low-cost CSPs.

Severe Neck Pain with Fever: Is it Meningitis?

PubMed

McCormick, Angela

2012-12-01

A 58-year-old male patient presented to the emergency department with complaints of severe neck pain. He admitted to drug use but denied using intravenous (IV) drugs. On exam, he had a fever of 100.7°F, positive Kernig's sign, and normal neurologic exam. The patient was suspected to have bacterial meningitis and was started on IV antibiotics. The next day the patient developed decreased hand grip. Magnetic resonance imaging of the spine the next day showed a soft-tissue mass impinging on the spinal canal. The patient was subsequently taken to the operating room where the epidural abscess was drained.

Mapping General Anesthetic Sites in Heteromeric γ-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.

PubMed

Forman, Stuart A; Miller, Keith W

2016-11-01

IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, produce important actions by enhancing γ-aminobutyric acid type A (GABAA) receptor activation. In this article, we review scientific studies that have located and mapped IV anesthetic sites using photoaffinity labeling and substituted cysteine modification protection. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors, and drugs that display stereoselectivity also show remarkably selective interactions with distinct interfacial sites. These results suggest strategies for developing new drugs that selectively modulate distinct GABAA receptor subtypes.

76 FR 6685 - Draft Guidance for Industry and Food and Drug Administration Staff; Recommended Warning for...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-07

... CONTACT: Subhas Malghan, Center for Devices and Radiological Health, Food and Drug Administration, 10903... respiratory ailments, and development of irritant dermatitis or Type IV allergy when glove powder is used on...

Cost analysis of voriconazole versus liposomal amphotericin B for primary therapy of invasive aspergillosis among patients with haematological disorders in Germany and Spain.

PubMed

Ostermann, Helmut; Solano, Carlos; Jarque, Isidro; Garcia-Vidal, Carolina; Gao, Xin; Barrueta, Jon Andoni; De Salas-Cansado, Marina; Stephens, Jennifer; Xue, Mei; Weber, Bertram; Charbonneau, Claudie

2014-09-24

The current healthcare climate demands pharmacoeconomic evaluations for different treatment strategies incorporating drug acquisition costs, costs incurred for hospitalisation, drug administration and preparation, diagnostic and laboratory testing and drug-related adverse events (AEs). Here we evaluate the pharmacoeconomics of voriconazole versus liposomal amphotericin B as first-line therapies for invasive aspergillosis (IA) in patients with haematological malignancy and prolonged neutropenia or who were undergoing haematopoietic stem-cell transplantation in Germany or Spain. A decision analytic model based on a decision tree was constructed to estimate the potential treatment costs of voriconazole versus liposomal amphotericin B. Each model pathway was defined by the probability of an event occurring and the costs of clinical outcomes. Outcome probabilities and cost inputs were derived from the published literature, clinical trials, expert panels and local database costs. In the base case, patients who failed to respond to first-line therapy were assumed to experience a single switch between comparator drugs or the other drug was added as second-line treatment. Base-case evaluation included only drug-management costs and additional hospitalisation costs due to severe AEs associated with first- and second-line therapies. Sensitivity analyses were conducted to assess the robustness of the results. Cost estimates were inflated to 2011 euros (€). Based on clinical trial success rates of 52.8% (voriconazole) and 50.0% (liposomal amphotericin B), voriconazole had lower total treatment costs compared with liposomal amphotericin B in both Germany (€ 12,256 versus € 18,133; length of therapy [LOT] = 10-day intravenous [IV] + 5-day oral voriconazole and 15-day IV liposomal amphotericin B) and Spain (€ 8,032 versus € 10,516; LOT = 7-day IV + 8-day oral voriconazole and 15-day IV liposomal amphotericin B). Assuming the same efficacy (50.0%) in first-line therapy, voriconazole maintained a lower total treatment cost compared with liposomal amphotericin B. Cost savings were primarily due to the lower drug acquisition costs and shorter IV LOT associated with voriconazole. Sensitivity analyses showed that the results were sensitive to drug price, particularly the cost of liposomal amphotericin B. Voriconazole is likely to be cost-saving compared with liposomal amphotericin B when used as a first-line treatment for IA in Germany and Spain.

Cost analysis of voriconazole versus liposomal amphotericin B for primary therapy of invasive aspergillosis among patients with haematological disorders in Germany and Spain

PubMed Central

2014-01-01

Background The current healthcare climate demands pharmacoeconomic evaluations for different treatment strategies incorporating drug acquisition costs, costs incurred for hospitalisation, drug administration and preparation, diagnostic and laboratory testing and drug-related adverse events (AEs). Here we evaluate the pharmacoeconomics of voriconazole versus liposomal amphotericin B as first-line therapies for invasive aspergillosis (IA) in patients with haematological malignancy and prolonged neutropenia or who were undergoing haematopoietic stem-cell transplantation in Germany or Spain. Methods A decision analytic model based on a decision tree was constructed to estimate the potential treatment costs of voriconazole versus liposomal amphotericin B. Each model pathway was defined by the probability of an event occurring and the costs of clinical outcomes. Outcome probabilities and cost inputs were derived from the published literature, clinical trials, expert panels and local database costs. In the base case, patients who failed to respond to first-line therapy were assumed to experience a single switch between comparator drugs or the other drug was added as second-line treatment. Base-case evaluation included only drug-management costs and additional hospitalisation costs due to severe AEs associated with first- and second-line therapies. Sensitivity analyses were conducted to assess the robustness of the results. Cost estimates were inflated to 2011 euros (€). Results Based on clinical trial success rates of 52.8% (voriconazole) and 50.0% (liposomal amphotericin B), voriconazole had lower total treatment costs compared with liposomal amphotericin B in both Germany (€12,256 versus €18,133; length of therapy [LOT] = 10-day intravenous [IV] + 5-day oral voriconazole and 15-day IV liposomal amphotericin B) and Spain (€8,032 versus €10,516; LOT = 7-day IV + 8-day oral voriconazole and 15-day IV liposomal amphotericin B). Assuming the same efficacy (50.0%) in first-line therapy, voriconazole maintained a lower total treatment cost compared with liposomal amphotericin B. Cost savings were primarily due to the lower drug acquisition costs and shorter IV LOT associated with voriconazole. Sensitivity analyses showed that the results were sensitive to drug price, particularly the cost of liposomal amphotericin B. Conclusions Voriconazole is likely to be cost-saving compared with liposomal amphotericin B when used as a first-line treatment for IA in Germany and Spain. PMID:25253630

Preclinical pharmacology of midazolam.

PubMed

Pieri, L

1983-01-01

Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. Midazolam was slightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in 'encéphale isolé' rats. This depression was reversed by Ro 15-1788, a recently discovered selective benzodiazepine antagonist. Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. Midazolam had one-third the potency of diazepam in displacing 3H-flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. The animal data suggest the usefulness of midazolam as an oral sleep-inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water-soluble injection form.

Safety considerations in the pharmacological management of atrial fibrillation.

PubMed

Camm, A John

2008-07-21

The pharmacological management of atrial fibrillation (AF) requires careful consideration from a safety perspective. This article focuses primarily on maintenance therapy using antiarrhythmic drugs (AADs). The foremost safety issue for AADs is the propensity of class IA and III agents to cause torsade de pointes arrhythmias. Class IA drugs, particularly quinidine, can induce torsade de pointes at low or subtherapeutic doses, but higher doses are not necessarily associated with an increased incidence. 'Pure' class III drugs such as dofetilide induce torsade de pointes in a dose-related manner, but some class III agents with more complex actions such as amiodarone have a markedly lower potential to cause this arrhythmia. The risk of torsade de pointes precludes the use of class IA and 'pure' class III agents in patients with left ventricular hypertrophy and bradycardia. Class IC agents may cause sustained monomorphic ventricular tachycardias and are generally precluded in ischaemic and structural heart disease. Advanced heart failure patients may be treated with amiodarone or dofetilide, but most other AADs are unsuitable. The most important extracardiac toxicities occurring with AADs are those of amiodarone. Drug interactions are a significant safety issue in the management of AF, including pharmacokinetic interactions in which plasma levels of the AAD are raised - increasing the risk of proarrhythmia - and concomitant use of drugs that prolong the QT interval. Notwithstanding these considerations, most patients with AF can be considered for rhythm control, provided there is adequate pre-treatment assessment and protocols for initiation, dosing and monitoring are followed with care.

Associations between attention deficit hyperactivity disorder symptom domains and DSM-IV lifetime substance dependence.

PubMed

Ameringer, Katherine J; Leventhal, Adam M

2013-01-01

Most studies of attention deficit hyperactivity disorder (ADHD) in the substance dependence literature have assessed ADHD as a single, categorical entity. This approach limits characterization across the spectrum of ADHD symptomatology and may mask differences across the two core domains of ADHD symptoms-hyperactive-impulsive (HI) and inattention (IN). Further, it is unclear whether relations of HI and IN symptoms to substance dependence extend across drug classes and to the general population. This cross-sectional study investigated associations of lifetime ADHD HI and IN symptom levels to individual classes of lifetime substance dependence (alcohol, nicotine, depressants, opioids, stimulants, cannabis, hallucinogens, polysubstance) in a population-based sample of 34,653 American adults. HI and IN were associated with the majority of dependence diagnoses in a linear pattern, such that each additional symptom was associated with a proportional increase in odds of dependence. After adjusting for the overlap between symptom domains, both HI and IN uniquely associated with alcohol, nicotine, and polysubstance dependence, but only HI uniquely associated with dependence on illicit substances. These findings suggest that individuals in the general population with elevated levels of ADHD (particularly HI) symptoms are at risk for various forms of substance dependence and could benefit from preventive interventions. Copyright © American Academy of Addiction Psychiatry.

Associations between Attention Deficit Hyperactivity Disorder Symptom Domains and DSM-IV Lifetime Substance Dependence

PubMed Central

Ameringer, Katherine J.; Leventhal, Adam M.

2013-01-01

Background and Objectives Most studies of attention deficit hyperactivity disorder (ADHD) in the substance dependence literature have assessed ADHD as a single, categorical entity. This approach limits characterization across the spectrum of ADHD symptomatology and may mask differences across the two core domains of ADHD symptoms—hyperactive-impulsive (HI) and inattention (IN). Further, it is unclear whether relations of HI and IN symptoms to substance dependence extend across drug classes and to the general population. Methods This cross-sectional study investigated associations of lifetime ADHD HI and IN symptom levels to individual classes of lifetime substance dependence (alcohol, nicotine, depressants, opioids, stimulants, cannabis, hallucinogens, polysubstance) in a population-based sample of 34,653 American adults. Results HI and IN were associated with the majority of dependence diagnoses in a linear pattern, such that each additional symptom was associated with a proportional increase in odds of dependence. After adjusting for the overlap between symptom domains, both HI and IN uniquely associated with alcohol, nicotine, and polysubstance dependence, but only HI uniquely associated with dependence on illicit substances. Conclusions and Scientific Significance These findings suggest that individuals in the general population with elevated levels of ADHD (particularly HI) symptoms are at risk for various forms of substance dependence and could benefit from preventive interventions. PMID:23398223

High Prescription Drug Utilization and Associated Costs among Medicaid-eligible Children with Autism Spectrum Disorders Identified by a Population-based Surveillance Network

PubMed Central

Logan, Sarah L.; Nicholas, Joyce S.; Carpenter, Laura A.; King, Lydia B.; Garrett-Mayer, Elizabeth; Charles, Jane M.

2011-01-01

Purpose This study assessed medication use and associated costs among 8- and 15-yearold children with autism spectrum disorders (ASD) identified by the South Carolina Autism and Developmental Disabilities Monitoring (SCADDM) Network. Methods All Medicaid-eligible SCADDM-identified children with ASD from surveillance years 2006 and 2007 were included (n=263). Children were classified as ASD cases when documented behaviors consistent with the DSM-IV-TR criteria for autistic disorder, Asperger disorder, or pervasive developmental disorder- not otherwise specified (PDD-NOS) were present in health and education evaluation records. Medication and cost data were obtained by linking population-based and Medicaid data. Results All 263 SCADDM-identified children had Medicaid data available; 56% (n=147) had a prescription of any type, 40% (n=105) used psychotropic medication, and 20% (n=52) used multiple psychotropic classes over the study period. Common combinations were (1) attention deficit hyperactivity disorder (ADHD) medications and an antihypertensive, antidepressant or antipsychotic; and (2) antidepressants and an antipsychotic. Multiple psychotropic classes were more common among older children. Both the overall distribution of the number of prescription claims and medication costs varied significantly by age. Conclusions Results confirm that medication use in ASD, alone or in combination, is common, costly, and may increase with age. PMID:22153288

The three latent classes of adolescent delinquency and the risk factors for membership in each class.

PubMed

Hasking, Penelope Anne; Scheier, Lawrence M; Abdallah, Arbi Ben

2011-01-01

This study used latent class analysis to examine subpopulation membership based on self-reports of delinquent behaviors obtained from Australian youth. Three discrete identifiable classes were derived based on 51 indicators of physical violence, property damage, minor infractions, drug use, and social delinquency. One class of youth engaged in primarily rule breaking and norm violations including underage alcohol use, typical of this age period. A second class was more actively delinquent emphasizing drug use, trespassing, and various forms of disobedience. A third class of highly delinquent youth differed from their counterparts by endorsing drug use, thievery that involved stealing money, goods, and cars, property damage, gambling, precocious sexual experiences, involvement with pornographic materials, and fighting. Multinomial logistic regression predicting class membership indicated highly delinquent youth were more likely to be older males, use venting coping strategies, and be fun or novelty seeking compared with rule breakers. Findings are discussed in terms of refining current taxonomic arguments regarding the structure of delinquency and implications for prevention of early-stage antisocial behavior. © 2010 Wiley-Liss, Inc.

Relation between body mass index, physical inactivity and use of prescription drugs: the Doetinchem Cohort Study.

PubMed

Milder, I E J; Klungel, O H; Mantel-Teeuwisse, A K; Verschuren, W M M; Bemelmans, W J E

2010-06-01

Obesity and physical inactivity are associated with several diseases such as diabetes, cardiovascular diseases, musculoskeletal complaints, osteoporosis, certain types of cancer and depression. However, few data are available on the specific types of medication associated with obesity and physical inactivity. The aim of this study was to determine the independent association of body mass index (BMI) and physical inactivity with use of specific classes of prescription drugs, and the interaction between BMI and physical inactivity. The Doetinchem Cohort Study is a population-based longitudinal study. We analyzed cross-sectional data of 1703 men and 1841 women, examined between 1998 and 2002, for whom drug-dispending data were available from the PHARMO database. Drugs were coded according to the WHO Anatomical Therapeutic Chemical (ATC) classification system. Body weight was measured during the physical examination. Physical activity was assessed using an extensive questionnaire. Persons were defined as a user of a certain drug class if they filed at least one prescription in the year around (+/-6 months) the examination. Compared with normal weight persons (BMI 18.5-25 kg m(-2)), obese persons (BMI>30 kg m(-2)) had a higher use of prescription drugs of several drug classes, especially cardiovascular drugs (OR (95% CI): 3.83 (2.61-5.64) in men and 2.80 (2.03-3.86) in women) and diabetes drugs (OR (95% CI): 5.72 (2.32-14.14) in men and 3.92 (1.80-8.54) in women). In women, physical inactivity was also associated with higher use of certain drug classes, such as drugs for blood and blood-forming organs (OR (95% CI): 2.11 (1.22-3.65)) and musculoskeletal drugs (OR (95% CI): 2.07 (1.45-2.97)), whereas in men this was not the case. We found no interaction between BMI and physical inactivity with respect to use of prescription drugs. In both men and women, obesity was associated with a higher use of several types of prescription drugs, whereas physical inactivity was only associated with a higher use of certain drug classes in women.