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1

Application of population pharmacokinetics for preclinical safety and efficacy studies.  

PubMed

From the beginning of the 1980s, population PK has been primarily used in clinical development and only in the last decade has it been convincingly applied in a preclinical setting. Sparse sampling and covariate analyses are key features of preclinical popPK, useful for toxicology and efficacy studies in animals to assemble data obtained from different studies; for describing individual PK and PD; for building mechanistic models; and for performing interspecies scaling-up of disposition and efficacy. Application in disease models, mainly in behavioral and neurological models, allows the quantitative description of PK and PD without frequent blood sampling and recurrent physiological measurements, which are the critical and compromising perturbations of experimental systems. A preclinical population approach to PK and PD, by its versatility and possibility of simulating 'what if' scenarios, offers a unique and potent tool in the development of new drugs, in particular biologics. PMID:23937139

Porzio, Stefano

2013-08-01

2

Protective efficacy of Modified Vaccinia virus Ankara in preclinical studies.  

PubMed

Modified Vaccinia virus Ankara (MVA) is a tissue culture-derived, highly attenuated strain of vaccinia virus (VACV) exhibiting characteristic defective replication in cells from mammalian hosts. In the 1960s MVA was originally generated as a candidate virus for safer vaccination against smallpox. Now, MVA is widely used in experimental vaccine development targeting important infectious diseases and cancer. Versatile technologies for genetic engineering, large-scale production, and quality control facilitate R&D of recombinant and non-recombinant MVA vaccines matching today's requirements for new biomedical products. Such vaccines are attractive candidates for delivering antigens from pathogens against which no, or no effective vaccine is available, including emerging infections caused by highly pathogenic influenza viruses, chikungunya virus, West Nile virus or zoonotic orthopoxviruses. Other directions are seeking valuable vaccines against highly complex diseases such as AIDS, malaria, and tuberculosis. Here, we highlight examples of MVA candidate vaccines against infectious diseases, and review the efforts made to assess both the efficacy of vaccination and immune correlates of protection in preclinical studies. PMID:23523402

Volz, Asisa; Sutter, Gerd

2013-03-21

3

Granulocyte-colony stimulating factor for stroke treatment: mechanisms of action and efficacy in preclinical studies  

PubMed Central

G-CSF is widely employed for the treatment of chemotherapy-induced neutropenia. Recently, neuroprotective effects of G-CSF in animal stroke models were discovered including infarct size reduction and enhancement of functional recovery. The underlying mechanisms of action of G-CSF in ischemia appear to be a direct anti-apoptotic activity in neurons and a neurogenesis inducing capacity. Additional effects may be based on the stimulation of new blood-vessel formation, the stimulation of immunocompetence and -modulation as well as on bone marrow mobilization. In addition to a discussion of these mechanisms, we will review the available preclinical studies and analyze their impact on the overall efficacy of G-CSF in experimental stroke.

2009-01-01

4

AMT: preclinical pharmacology studies.  

PubMed

Auron-Misheil-Therapy (AMT) consisting of aqueous camomile extract supplemented with calcium, vitamins, the antihistamine chlorpheniramine and human insulin is under development as anti-cancer treatment. AMT was preclinically investigated in tumour cell lines and tumour xenografts to guide clinical phase I/II studies. AMT was tested against 56 human tumour cell lines, in a clonogenic assay in 98 patient-derived xenografts and in in vivo studies. AMT showed in vitro cytotoxic activity with highest susceptibility in cervical cancer, glioblastoma and colon cancers. In the clonogenic assay, anti- cancer activity of AMT was most active in cervical and uterine tumours, in colon cancer, glioblastoma, leukaemia, melanoma and pancreatic cancer. In vivo, AMT showed slight activity in tumour xenograft models of colon and mammary cancer. It also showed immune stimulatory effects by induction of IL-6- and TNF-alpha secretion in human PBMCs. The immune stimulatory potential of AMT, together with slight anti-tumour efficacy observed in the present study, indicates a role of AMT in tumour therapy. PMID:19360346

Niazi, Faiz; Drevs, Joachim; Diergarten, Klaus; Dorn, Annette; Maier, Armin; Fiebig, Heinz Herbert; Bruyns, Eddy; Scheele, Jürgen

2009-05-01

5

Preclinical Efficacy Testing in Middle-Aged Rats: Nicotinamide, a Novel Neuroprotectant, Demonstrates Diminished Preclinical Efficacy after Controlled Cortical Impact  

PubMed Central

Abstract Age is a consistent predictor of poor outcome following traumatic brain injury (TBI). Although the elderly population has one of the highest rates of TBI-related hospitalization and death, few preclinical studies have attempted to model and treat TBI in the aged population. Recent studies have indicated that nicotinamide (NAM), a soluble B-group vitamin, improved functional recovery in experimental models of TBI in young animals. The purpose of the present study was to examine the preclinical efficacy of NAM in middle-aged rats. Groups of middle-aged (14-month-old) rats were assigned to NAM (500?mg/kg or 50?mg/kg) or saline alone (1?mL/kg) treatment conditions, and received unilateral cortical contusion injuries (CCI) and injections at 1?h and 24?h following injury. The animals were tested on a variety of tasks to assess vestibulomotor (tapered beam) and cognitive performance (reference and working memory in the Morris water maze), and were evaluated for lesion size, blood–brain barrier compromise, astrocytic activation, and edema formation. In summary, the preclinical efficacy of NAM as a treatment following CCI in middle-aged rats differs from that previously documented in younger rats; while treatment with 50?mg/kg NAM appeared to have no effect, the 500-mg/kg dose worsened performance in middle-aged animals. Histological indicators demonstrated more nuanced group differences, indicating that NAM may positively impact some of the cellular cascades following injury, but were not substantial enough to improve functional recovery. These findings emphasize the need to examine potential treatments for TBI utilizing non-standard populations, and may explain why so many treatments have failed in clinical trials.

Swan, Alicia A.; Chandrashekar, Rupa; Beare, Jason

2011-01-01

6

Preclinical efficacy studies of a novel nanoparticle-based formulation of paclitaxel that out-performs Abraxane  

Microsoft Academic Search

Purpose  Poly-(?-l-glutamylglutamine)–paclitaxel (PGG–PTX) is a novel polymer-based formulation of paclitaxel (PTX) in which the PTX is linked\\u000a to the polymer via ester bonds. PGG–PTX is of interest because it spontaneously forms very small nanoparticles in plasma.\\u000a In mouse models, PGG–PTX increased tumor exposure to PTX by 7.7-fold relative to that produced by PTX formulated in Cremophor.\\u000a In this study, the efficacy

Zhongling Feng; Gang Zhao; Lei Yu; David Gough; Stephen B. Howell

2010-01-01

7

Preclinical studies of low back pain  

PubMed Central

Chronic low back pain is a major cause of disability and health care costs. Current treatments are inadequate for many patients. A number of preclinical models have been developed that attempt to mimic aspects of clinical conditions that contribute to low back pain. These involve application of nucleus pulposus material near the lumbar dorsal root ganglia (DRG), chronic compression of the DRG, or localized inflammation of the DRG. These models, which are primarily implemented in rats, have many common features including behavioral hypersensitivity of the hindpaw, enhanced excitability and spontaneous activity of sensory neurons, and locally elevated levels of inflammatory mediators including cytokines. Clinically, epidural injection of steroids (glucocorticoids) is commonly used when more conservative treatments fail, but clinical trials evaluating these treatments have yielded mixed results. There are relatively few preclinical studies of steroid effects in low back pain models. One preclinical study suggests that the mineralocorticoid receptor, also present in the DRG, may have pro-inflammatory effects that oppose the activation of the glucocorticoid receptor. Although the glucocorticoid receptor is the target of anti-inflammatory steroids, many clinically used steroids activate both receptors. This could be one explanation for the limited effects of epidural steroids in some patients. Additional preclinical research is needed to address other possible reasons for limited efficacy of steroids, such as central sensitization or presence of an ongoing inflammatory stimulus in some forms of low back pain.

2013-01-01

8

Preclinical Studies to Predict Efficacy of Vascular Changes Induced by Combretastatin A-4 Disodium Phosphate in Patients  

SciTech Connect

Purpose: To determine how combretastatin A-4 disodium phosphate (CA4DP) dose-dependent changes in radiation response of a C3H mouse mammary carcinoma relate to measurements of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and how those mouse DCE-MRI results compare with published clinical DCE-MRI data. Methods and Materials: C3H mammary carcinomas grown in female CDF{sub 1} mice were treated when at 200 mm{sup 3} in size. Groups of mice were given graded radiation doses, either alone or followed 30 min later by an intraperitoneal injection of CA4DP, administered at doses of 10-250 mg/kg. The radiation dose producing local tumor control in 50% of treated animals at 90 days (TCD{sub 50}) was calculated for each CA4DP dose. DCE-MRI was performed before and 3 h after CA4DP administration, and parameters describing vascularity and interstitial volume were estimated. Results: TCD{sub 50} showed a dose-dependent decrease reaching significance at 25 mg/kg. At greater doses of 50 and 100 mg/kg, the TCD{sub 50} increased slightly and was not significantly different from that of controls. TCD{sub 50} significantly decreased again at 250 mg/kg. The drug dose-response curves for all post-treatment vascular DCE-MRI parameters showed a shape similar to that of the TCD{sub 50} curve. A similar dose dependency was seen with previously published clinical data. Conclusion: Our preclinical DCE-MRI data could predict the CA4DP enhancement of the tumor radiation response and suggest the clinical CA4DP doses necessary to improve the radiation response in patients.

Nielsen, Thomas [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark)], E-mail: thomas@oncology.dk; Murata, Rumi [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark); Maxwell, Ross J. [University of Newcastle Upon Tyne, Northern Institute for Cancer Research, Newcastle Upon Tyne (United Kingdom); Stodkilde-Jorgensen, Hans [MR Research Centre, Aarhus University Hospital, Aarhus (Denmark); Ostergaard, Leif [Department of Neuroradiology, Aarhus University Hospital, Aarhus (Denmark); Horsman, Michael R. [Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark)

2008-03-01

9

Efficacy of Pimobendan in the Prevention of Congestive Heart Failure or Sudden Death in Doberman Pinschers with Preclinical Dilated Cardiomyopathy (The PROTECT Study)  

PubMed Central

Background The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. Hypothesis That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Animals Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. Methods The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. Results The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). Conclusion and Clinical Importance The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.

Summerfield, NJ; Boswood, A; O'Grady, MR; Gordon, SG; Dukes-McEwan, J; Oyama, MA; Smith, S; Patteson, M; French, AT; Culshaw, GJ; Braz-Ruivo, L; Estrada, A; O'Sullivan, ML; Loureiro, J; Willis, R; Watson, P

2012-01-01

10

Mixed chimerism: Preclinical studies and clinical applications  

Microsoft Academic Search

Traditional approaches to allogeneic stem cell transplantation have relied on the use of toxic high-dose conditioning therapy to achieve allogeneic engraftment and control of underlying disease. Preclinical observations have shown that, for engraftment purposes, conditioning regimens can be reduced in intensity, resulting in reduced treatment toxicities. In preclinical canine studies, the use of potent pre- and postgrafting immunosuppression allowed for

Peter A McSweeney; Rainer Storb

1999-01-01

11

Combination therapy for hepatocellular carcinoma: Additive preclinical efficacy of the HDAC inhibitor panobinostat with sorafenib  

PubMed Central

Background & Aims Hepatocellular carcinoma (HCC) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy. Histone deacetylases (HDAC) are commonly dysregulated in cancer and therefore represent promising targets for therapies, however their role in HCC pathogenesis is still unknown. We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan-HDAC inhibitor panobinostat alone and in combination with sorafenib in preclinical models of liver cancer. Methods Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs, while the effects of panobinostat and sorafenib were evaluated in 3 liver cancer cell lines and a murine xenograft model. Results Aberrant HDAC expression was identified and validated in 91 and 243 HCCs, respectively. Upregulation of HDAC3 and 5 mRNAs were significantly correlated with DNA copy number gains. Inhibiting HDACs with panobinostat led to strong anti-tumoral effects in vitro and vivo, enhanced by the addition of sorafenib. Cell viability and proliferation declined, while apoptosis and autophagy increased. Panobinostat increased Histone H3 and HSP90 acetylation, downregulated BIRC5 (survivin) and upregulated CDH1. Combination therapy with panobinostat and sorafenib significantly decreased vessel density, and most significantly decreased tumor volume and increased survival in HCC xenografts. Conclusions Aberrant expression of several HDACs and copy number gains of HDAC3 and HDAC5 occur in HCC. Treatment with panobinostat combined with sorafenib demonstrated the highest preclinical efficacy in HCC models, providing the rationale for clinical studies with this novel combination.

Lachenmayer, Anja; Toffanin, Sara; Cabellos, Laia; Alsinet, Clara; Hoshida, Yujin; Villanueva, Augusto; Minguez, Beatriz; Tsai, Hung-Wen; Ward, Stephen C.; Thung, Swan; Friedman, Scott L.; Llovet, Josep M.

2012-01-01

12

Developing combination drugs in preclinical studies.  

PubMed

Although combination drugs have been available for many years, it is only recently that preclinical guidelines have been released by the Food and Drugs Administration (FDA) and EMEA and as yet they are not part of the ICH process. In addition, the World Health Organisation and FDA have issued guidelines for combination drugs developed specifically to treat HIV infections. Depending on the type of combination (marketed drug/marketed drug; marketed drug/NME and NME/NME), the scope and complexity of studies can vary greatly. In all cases, however, a key issue is the potential for pharmacokinetic and/or toxicologic interaction between the components. For a marketed drug/marketed drug combination, a detailed review of the preclinical data available may suffice; particularly when the components have a history of co-administration at about the same dose and ratio as that of the proposed combination. For a marketed drug/NME combination, in addition to a review of the data for the marketed drug, a full ICH programme of studies will be required for the NME, and a study of up to 90 days duration (in one species) for the combination. With an NME/NME combination, each component will require a full ICH battery of studies and a combination study in one species. In all cases, additional studies may be needed to address data gaps. Given the many novel and complex issues that arise when developing combination drugs, we recommend that, whenever possible, the preclinical study strategy is discussed with the regulatory authorities. PMID:20972744

Lodola, Alberto

2011-01-01

13

Preclinical Studies of Novel Targeted Therapies  

PubMed Central

Summary The bone marrow (BM) milieu confers drug resistance in multiple myeloma (MM) cells to conventional therapies. Therefore novel biologically-based therapies are needed. Preclinical studies have identified and validated molecular targeted therapeutics in MM. In particular, recognition of the biologic significance of the BM microenvironment both in MM pathogenesis and as a potential target for novel therapeutics has already derived several promising approaches. Thalidomide, lenalidomide (Revlimid®) and bortezomib (Velcade®) are directed not only at MM cells, but also BM milieu, and have rapidly from the bench to the bedside and FDA approval to treat MM.

Hideshima, Teru; Anderson, Kenneth C.

2008-01-01

14

Drug-eluting stents in preclinical studies: updated consensus recommendations for preclinical evaluation.  

PubMed

Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time. PMID:20031669

Schwartz, Robert S; Edelman, Elazer; Virmani, Renu; Carter, Andrew; Granada, Juan F; Kaluza, Greg L; Chronos, Nicolas A F; Robinson, Keith A; Waksman, Ron; Weinberger, Judah; Wilson, Gregory J; Wilensky, Robert L

2008-10-01

15

Drug-Eluting Stents in Preclinical Studies Updated Consensus Recommendations for Preclinical Evaluation  

PubMed Central

Coronary drug-eluting stents are commonplace in clinical practice with acceptable safety and efficacy. Preclinical evaluation of novel drug-eluting stent technologies has great importance for understanding safety and possibly efficacy of these technologies, and well-defined preclinical testing methods clearly benefit multiple communities within the developmental, testing, and clinical evaluation chain. An earlier consensus publication enjoyed widespread adoption but is in need of updating. This publication is an update, presenting an integrated view for testing drug-eluting technologies in preclinical models, including novel devices such as bioabsorbable coatings, totally bioabsorbable stents, bifurcation stents, and stent-free balloon-based drug delivery. This consensus document was produced by preclinical and translational scientists and investigators engaged in interventional technology community. The United States Food and Drug Administration (USFDA) recently issued a Draft Guidance for Industry Document for Drug-Eluting Stents. This expert consensus document is consistent with the Food and Drug Administration guidance. The dynamic nature of this field mandates future modifications and additions that will be added over time.

Schwartz, Robert S.; Edelman, Elazer; Virmani, Renu; Carter, Andrew; Granada, Juan F.; Kaluza, Greg L.; Chronos, Nicolas A.F.; Robinson, Keith A.; Waksman, Ron; Weinberger, Judah; Wilson, Gregory J.; Wilensky, Robert L.

2010-01-01

16

Enhanced efficacy of single-dose versus multi-dose azithromycin regimens in preclinical infection models  

Microsoft Academic Search

Objectives: As a result of the prolonged half-life and unique pharmacokinetic and pharmacodynamic (PK-PD) characteristics of azithromycin, shorter dosing regimens are being evaluated for the treatment of community-acquired infections. To provide further support for a shorter dosing regimen, the efficacy of azithromycin was determined in preclinical infection models comparing single- versus multi-dose regimens. Methods: The efficacy of single versus multi-dose

D. Girard; S. M. Finegan; M. W. Dunne; M. E. Lame

2005-01-01

17

A Summary of Preclinical Topical Microbicide Rectal Safety and Efficacy Evaluations in a Pigtailed Macaque Model  

PubMed Central

Background There is widespread recognition of the potential promise of vaginal microbicides as a tool to combat global HIV/AIDS and STI epidemics, and candidate product development has maintained a rapid pace in recent years; however, rectal microbicide development has received less attention. As it is likely that commercial products developed for vaginal use will also be used rectally, there is a clear need to assess the safety and efficacy of candidate microbicide products specifically in the rectal compartment. Methods We have developed a standardized protocol for preclinical rectal safety and (chlamydial) efficacy assessment of topical microbicide candidates in a non-human primate model. We evaluated a total of twelve test compounds for rectal safety (via rectal pH, microflora, and rectal lavage) and one compound for efficacy against rectal chlamydial infection. Results In this paper, we describe our methods in detail and summarize our results, particularly noting the ability of our model to distinguish products with deleterious effects on the rectal environment. We also outline the specific criteria used to recommend products move into preclinical rectal efficacy trials or be recommended for reformulation to the product developer. In sum, we observed significant adverse effects in two products. The single product that underwent efficacy evaluation was not observed to be protective against rectal chlamydial infection. Conclusions A preclinical safety and efficacy model is critical to promoting rectal microbicide development, which will ultimately offer a significant opportunity for intervention in the global HIV/AIDS epidemic.

Patton, Dorothy L.; Sweeney, Yvonne T. Cosgrove; Paul, Kathleen J.

2009-01-01

18

Isolation, physicochemical characterization and preclinical efficacy evaluation of soluble scleroglucan.  

PubMed

Herein we describe the isolation, physicochemical characterization and preclinical evaluation of a water-soluble biologic response modifier extracted from Sclerotium glucanicum. Alkaline extraction of insoluble S. glucanicum exopolymers produced a soluble scleroglucan composed of a triple-helical beta-1,3-linked glucopyranose backbone with single beta-1,6-linked glucopyranosyl branches every third subunit. Scleroglucan has a weight average molecular mass of 1.56 x 10(6) Da, a weight average root mean square distance from the center of gravity of the molecule to its farthest elements of 51.8 nm, a polydispersity (weight-average molecular mass/number average molecular mass) of 1.83 and intrinsic viscosity of 3.081 dl/g. Scleroglucan (250 mg/kg, intravenously) stimulated in vivo murine macrophage phagocytic activity (66%, P less than .001) and increased in vitro macrophage tumor cytotoxicity against syngeneic tumor targets by 124% (P less than .05). Scleroglucan enhanced (P less than .001) murine bone marrow proliferation in a biphasic manner by up to 328%. Scleroglucan therapy increased survival of mice challenged with syngeneic lymphoma, melanoma or adenocarcinoma. AKR/J mice bearing syngeneic lymphoma (1 x 10(3) cells, intraperitoneally) demonstrated increased (P less than .001) long-term survival (100% vs. 0%, greater than 64 days). C57Bl/6J mice bearing syngeneic melanoma B16 (5 x 10(5) cells, subcutaneously) demonstrated increased long-term survival (64% vs. 0%, P less than .05). C57Bl/6J mice bearing syngeneic adenocarcinoma BW10232 (1 x 10(5) cells, subcutaneously) demonstrated increased (P less than .05) median survival time. In addition, scleroglucan prophylaxis increased resistance of mice to challenge with Staphylococcus aureus, Candida albicans and mouse hepatitis virus A-59. Scleroglucan did not induce toxicity or hepatomegaly. We conclude that: 1) a branched, water-soluble beta-1,3-linked scleroglucan biologic response modifier can be extracted from S. glucanicum; 2) scleroglucan will stimulate immunity, modify experimental neoplastic disease and increase resistance to microbial challenge; and 3) scleroglucan shows promise as an immunopotentiating drug. PMID:1902259

Pretus, H A; Ensley, H E; McNamee, R B; Jones, E L; Browder, I W; Williams, D L

1991-04-01

19

Practical Anticipation of Human Efficacious Doses and Pharmacokinetics Using In Vitro and Preclinical In Vivo Data  

PubMed Central

Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and “developable” dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the “anticipation” of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for “AHD” demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus™. Methods to enhance prediction confidence such as in vitro–in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via “reverse pharmacology strategies” that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus™ in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments.

Lakshminarayana, Suresh B.; Hu, Wenyu; He, Handan

2009-01-01

20

Practical anticipation of human efficacious doses and pharmacokinetics using in vitro and preclinical in vivo data.  

PubMed

Accurate predictions of human pharmacokinetic and pharmacodynamic (PK/PD) profiles are critical in early drug development, as safe, efficacious, and "developable" dosing regimens of promising compounds have to be identified. While advantages of successful integration of preclinical PK/PD data in the "anticipation" of human doses (AHD) have been recognized, pharmaceutical scientists have faced difficulties with practical implementation, especially for PK/PD profile projections of compounds with challenging absorption, distribution, metabolism, excretion and formulation properties. In this article, practical projection approaches for formulation-dependent human PK/PD parameters and profiles of Biopharmaceutics Classification System classes I-IV drugs based on preclinical data are described. Case examples for "AHD" demonstrate the utility of preclinical and clinical PK/PD modeling for formulation risk identification, lead candidate differentiation, and prediction of clinical outcome. The application of allometric scaling methods and physiologically based pharmacokinetic approaches for clearance or volume of distribution projections is described using GastroPlus. Methods to enhance prediction confidence such as in vitro-in vivo extrapolations in clearance predictions using in vitro microsomal data are discussed. Examples for integration of clinical PK/PD and formulation data from frontrunner compounds via "reverse pharmacology strategies" that minimize uncertainty with PK/PD predictions are included. The use of integrated softwares such as GastroPlus in combination with established PK projection methods allow the projection of formulation-dependent preclinical and human PK/PD profiles required for compound differentiation and development risk assessments. PMID:19707878

Heimbach, Tycho; Lakshminarayana, Suresh B; Hu, Wenyu; He, Handan

2009-08-26

21

Assessing the preclinical efficacy of antivenoms: from the lethality neutralization assay to antivenomics.  

PubMed

The assessment of the capacity of antivenoms to neutralize the lethal activity of snake venoms is the gold standard in the preclinical analysis of antivenom efficacy, and is routinely performed by manufacturers and quality control laboratories. However, the complexity of snake venom composition and toxicological profile demands that, for many venoms, such as those of viperid snakes and some elapids, the neutralization of lethality be complemented with the analysis of the neutralization of other relevant toxic activities, such as hemorrhagic, myotoxic, necrotizing, procoagulant and defibrinogenating effects. This expanded protocol for preclinical testing of antivenoms should be used when a new antivenom is developed or when an existing antivenom is introduced in a new geographical setting for the neutralization of either homologous or heterologous venoms. In recent years, the assessment of the immunological reactivity of antivenoms has been enriched by the use of proteomic tools, with a methodology named 'antivenomics'. This allows the identification of venom components to which antivenoms have, or lack, antibodies, and thus complements the data gathered in neutralization tests, paving the way for a knowledge-based improvement of antivenom design and efficacy. International projects involving participants of manufacturing, quality control and academic research groups should be promoted in order to gain a deeper understanding on the preclinical neutralizing spectrum of antivenoms. PMID:23201503

Gutiérrez, José María; Solano, Gabriela; Pla, Davinia; Herrera, María; Segura, Álvaro; Villalta, Mauren; Vargas, Mariángela; Sanz, Libia; Lomonte, Bruno; Calvete, Juan J; León, Guillermo

2012-11-29

22

Intravital microscopy as a tool to study drug delivery in preclinical studies  

PubMed Central

The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies.

Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto

2010-01-01

23

Intravital microscopy as a tool to study drug delivery in preclinical studies.  

PubMed

The technical developments in the field of non-linear microscopy have made intravital microscopy one of the most successful techniques for studying physiological and pathological processes in live animals. Intravital microscopy has been utilized to address many biological questions in basic research and is now a fundamental tool for preclinical studies, with an enormous potential for clinical applications. The ability to dynamically image cellular and subcellular structures combined with the possibility to perform longitudinal studies have empowered investigators to use this discipline to study the mechanisms of action of therapeutic agents and assess the efficacy on their targets in vivo. The goal of this review is to provide a general overview of the recent advances in intravital microscopy and to discuss some of its applications in preclinical studies. PMID:20933026

Amornphimoltham, Panomwat; Masedunskas, Andrius; Weigert, Roberto

2010-10-07

24

Translation of stem cell research: points to consider in designing preclinical animal studies.  

PubMed

Stem cell-based therapies hold tremendous promise for the treatment of serious diseases and injuries. Although hematopoietic stem cell transplantation is routinely used as part of the treatment regime for some malignancies and genetic diseases, most stem cell-based therapeutic products are investigational and still require preclinical and clinical studies to support their many novel therapeutic uses. Because of the multiple sources of stem cells, the plethora of potential applications, and the novel mechanism of action of stem cell-based therapies, there is no single set of universal guidance documents that can be used to inform the preclinical development path for these therapeutics. Specific technical issues relating to the transplantation of human cells in animals, new delivery procedures, and laborious methods to characterize transplanted cells can present further challenges in the design and execution of preclinical animal studies for stem cell-based therapeutic products. In this article, we outline important parameters to guide the design of preclinical studies for stem cell-based therapeutics. In addition, we review the types of preclinical studies that should be considered depending on the nature and specific use of the intended stem cell therapeutic product. Finally, we describe important considerations in the design and execution of specific studies to monitor the efficacy, toxicity, biodistribution, and tumorigenicity of stem cell-based therapeutics. PMID:23197814

Frey-Vasconcells, Joyce; Whittlesey, Kevin J; Baum, Elona; Feigal, Ellen G

2012-02-06

25

Towards environmental construct validity in animal models of CNS disorders: optimizing translation of preclinical studies.  

PubMed

There is an enormous demand for new therapeutic interventions for a range of major disorders. The majority of clinical trials in recent years have been unsuccessful despite highly promising preclinical data. Therefore, an urgent issue confronting both the academic and commercial medical research sectors is how to optimize translation of preclinical studies. The vast majority of preclinical studies are currently performed using laboratory mice and rats. We will discuss the various opportunities for optimization of animal models of CNS disorders. One limitation of current approaches is that most studies are conducted on sedentary, unstimulated animals with unlimited access to food in the home cage, thus leading to metabolic and physiological compromise. Environmental enrichment, which enhances sensory stimulation, cognitive activity and physical exercise, has been demonstrated to induce dramatic effects on brain and behavior in both wild-type and genetically modified rodent models, relative to standard-housed littermate controls. Environmental enrichment also exerts beneficial effects outside the CNS, such as a reduction in excess body fat. We propose that therapeutic interventions which are found to show promise in standard-housed preclinical models should be subsequently tested under conditions of greater environmental enrichment to identify therapeutics which continue to show efficacy in housing contexts of superior 'environmental construct validity'. Other possible approaches to optimize the quality, validity and reporting of preclinical studies in animal models are also discussed. PMID:23574171

Burrows, Emma L; Hannan, Anthony J

2013-08-01

26

Evaluating the Suitability of Using Rat Models for Preclinical Efficacy and Side Effects with Inhaled Corticosteroids Nanosuspension Formulations  

NASA Astrophysics Data System (ADS)

Inhaled corticosteroids (ICS) are often prescribed as first-line therapy for patients with asthma Despite their efficacy and improved safety profile compared with oral corticosteroids, the potential for systemic side effects continues to cause concern. In order to reduce the potential for systemic side effects, the pharmaceutical industry has begun efforts to generate new drugs with pulmonary-targeted topical efficacy. One of the major challenges of this approach is to differentiate both efficacy and side effects (pulmonary vs. systemic) in a preclinical animal model. In this study, fluticasone and ciclesonide were used as tool compounds to explore the possibility of demonstrating both efficacy and side effects in a rat model using pulmonary delivery via intratracheal (IT) instillation with nanosuspension formulations. The inhibition of neutrophil infiltration into bronchoalveolar lavage fluid (BALF) and cytokine (TNF?) production were utilized to assess pulmonary efficacy, while adrenal and thymus involution as well as plasma corticosterone suppression was measured to assess systemic side effects. Based on neutrophil infiltration and cytokine production data, the ED50s for ciclesonide and fluticasone were calculated to be 0.1 and 0.03 mg, respectively. At the ED50, the average adrenal involution was 7.6 ± 5.3% for ciclesonide versus 16.6 ± 5.1% for fluticasone, while the average thymus involution was 41.0 ± 4.3% for ciclesonide versus 59.5 ± 5.8% for fluticasone. However, the differentiation became less significant when the dose was pushed to the EDmax (0.3 mg for ciclesonide, 0.1 mg for fluticasone). Overall, the efficacy and side effect profiles of the two compounds exhibited differentiation at low to mid doses (0.03-0.1 mg ciclesonide, 0.01-0.03 mg fluticasone), while this differentiation diminished at the maximum efficacious dose (0.3 mg ciclesonide, 0.1 mg fluticasone), likely due to overdosing in this model. We conclude that the rat LPS model using IT administration of nanosuspensions of ICS is a useful tool to demonstrate pulmonary-targeted efficacy and to differentiate the side effects. However, it is only suitable at sub-maximum efficacious levels.

Chiang, Po-Chang; Hu, Yiding; Blom, Jason D.; Thompson, David C.

2010-06-01

27

A New Three-Dimensional Ultrasound Microimaging Technology for Preclinical Studies Using a Transgenic Prostate Cancer Mouse Model  

Microsoft Academic Search

Prostate cancer is the most common cancer in adult men in North America. Preclinical studies of prostate cancer employ genetically engineered mouse models, because prostate cancer does not occur naturally in rodents. Widespread application of these models has been limited because autopsy was the only reliable method to evaluate treatment efficacy in longitudinal studies. This article reports the first use

Lauren A. Wirtzfeld; Guojun Wu; Michael Bygrave; Yasuto Yamasaki; Hideki Sakai; Madeleine Moussa; Jonathan I. Izawa; Donal B. Downey; Norman M. Greenberg; Aaron Fenster; Jim W. Xuan; James C. Lacefield

2005-01-01

28

Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors  

PubMed Central

Purpose Accumulating evidence supports the existence of breast cancer stem cells (BCSCs), which are characterized by their capacity to self-renew and divide indefinitely, and resistance to conventional therapies. The Notch pathway is important for stem cell renewal, and is a potential target for BCSC-directed therapy. Experimental Design Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in advanced breast cancer patients, designed to determine the maximally tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results Treatment with GSI reduced BCSCs in MC1 and BMC-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically meaningful doses of both drugs were possible, with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24?, ALDH+, and MSFE were observed in tumors of patients undergoing serial biopsies. Conclusions These preclinical data demonstrate that pharmacological inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial demonstrates feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer.

Schott, Anne F.; Landis, Melissa D.; Dontu, Gabriela; Griffith, Kent A.; Layman, Rachel M.; Krop, Ian; Paskett, Lacey A; Wong, Helen; Dobrolecki, Lacey E.; Froehlich, Amber M.; Paranilam, Jaya; Hayes, Daniel F.; Wicha, Max S.; Chang, Jenny C.

2013-01-01

29

Multimodal biomarker investigation on efficacy and mechanism of action for the mammalian target of rapamycin inhibitor, temsirolimus, in a preclinical mammary carcinoma OncoMouse model: a translational medicine study in support for early clinical development.  

PubMed

The mammalian target of rapamycin (mTOR) has proven to be a valid therapeutic target in a number of human cancers, and it is a candidate for clinical trials in human breast cancer. We report on a biomarker-based translational medicine approach to assess the efficacy and mechanism of action for the mTOR inhibitor temsirolimus (CCI-779) in a mammary carcinoma OncoMouse model [polyomavirus middle T antigen (PyMT)]. The mTOR signaling pathway biomarkers were assessed using a reverse-phase protein array. Pharmacokinetics studies were conducted in both the tumor and plasma compartments. Pharmacodynamic biomarkers for compound-target engagement of tumor phospho-S6 proteins were assayed by Western blot. Temsirolimus (intravenously once a week for 2 weeks) was administered in both early and advanced stages of tumors. Biomarkers for temsirolimus effects on tumor progression were assessed by three-dimensional ultrasound imaging in combination with immunohistochemistry to assess vascular density (Texas red-dextran and CD31 immunostaining) and macrophage burden (F4/80 antigen). Tumor growth was significantly arrested in temsirolimus (25 ± 14% from 8 to 10 weeks, p < 0.05, and 26 ± 17% from 11 to 13 weeks, p < 0.01), compared with 493 ± 160 and 376 ± 50% increases, respectively, in vehicle-treated groups. Temsirolimus reduced tumor vascular density, 36 to 48 and 58 to 60%, p < 0.05, by the Texas red-dextran method or CD31-positive vessel count, respectively. Temsirolimus reduced tumor macrophage burden by 46% at 13 weeks (p < 0.05). Temsirolimus inhibited (p < 0.05) the phosphoproteins S6 pS235/236 and S6 pS240/244 up to 81 and 87%, respectively. We conclude that the multimodal biomarkers of temsirolimus efficacy and mechanism of action (phosphoproteins) strongly suggest that it might translate to therapeutic efficacy in human tumors that bear congruency to features present in the mammary carcinoma of PyMT tumors. PMID:21835932

Wang, Xinkang; Zhan, Yutian; Zhao, Lei; Alvarez, John; Chaudhary, Inder; Zhou, Bin-Bing; Abraham, Robert T; Feuerstein, Giora Z

2011-08-11

30

[Preclinical study of anxiolytic activity and safety of Racium phytomedicine].  

PubMed

Results of a preclinical study of the anxiolytic activity and safety of original Racium phytomedicine are presented. The preparation possessed high anxiolytic activity, exhibits a wide range of therapeutic effects, produces no lethality in male and female rats and mice upon single intragastric and intraperitoneal introduction in doses up to 5 g/kg (VI class of toxicity according to OECD), induces no pathologic effects upon prolonged (120 days) administration in these rodents, and has no local irritant and/or allergen action. PMID:23012991

Kravchenko, E V; Nasek, V M; Ponteleeva, I V; Mazhar, M V; Sholomitskaia, E Iu; Zhukova, I A; San'ko, E V; Veselukha, O V; Nekhai, A S; Shafranovskaia, E V; Zhebrakova, I V

2012-01-01

31

ChimeriVax-West Nile Virus Live-Attenuated Vaccine: Preclinical Evaluation of Safety, Immunogenicity, and Efficacy  

PubMed Central

The availability of ChimeriVax vaccine technology for delivery of flavivirus protective antigens at the time West Nile (WN) virus was first detected in North America in 1999 contributed to the rapid development of the vaccine candidate against WN virus described here. ChimeriVax-Japanese encephalitis (JE), the first live- attenuated vaccine developed with this technology has successfully undergone phase I and II clinical trials. The ChimeriVax technology utilizes yellow fever virus (YF) 17D vaccine strain capsid and nonstructural genes to deliver the envelope gene of other flaviviruses as live-attenuated chimeric viruses. Amino acid sequence homology between the envelope protein (E) of JE and WN viruses facilitated targeting attenuating mutation sites to develop the WN vaccine. Here we discuss preclinical studies with the ChimeriVax-WN virus in mice and macaques. ChimeriVax-WN virus vaccine is less neurovirulent than the commercial YF 17D vaccine in mice and nonhuman primates. Attenuation of the virus is determined by the chimeric nature of the construct containing attenuating mutations in the YF 17D virus backbone and three point mutations introduced to alter residues 107, 316, and 440 in the WN virus E protein gene. The safety, immunogenicity, and efficacy of the ChimeriVax-WN02 vaccine in the macaque model indicate the vaccine candidate is expected to be safe and immunogenic for humans.

Arroyo, Juan; Miller, Chuck; Catalan, John; Myers, Gwendolyn A.; Ratterree, Marion S.; Trent, Dennis W.; Monath, Thomas P.

2004-01-01

32

Timings for Efficacy Studies  

Center for Biologics Evaluation and Research (CBER)

... HPV-009, A double blind, controlled, randomized, phase III study of the efficacy of an HPV16/18 VLP vaccine in the prevention of advanced cervical ... More results from www.fda.gov/biologicsbloodvaccines/vaccines/approvedproducts

33

Performance of Novel Kidney Biomarkers in Preclinical Toxicity Studies  

PubMed Central

The kidney is one of the main targets of drug toxicity, but early detection of renal damage is often difficult. As part of the InnoMed PredTox project, a collaborative effort aimed at assessing the value of combining omics technologies with conventional toxicology methods for improved preclinical safety assessment, we evaluated the performance of a panel of novel kidney biomarkers in preclinical toxicity studies. Rats were treated with a reference nephrotoxin or one of several proprietary compounds that were dropped from drug development in part due to renal toxicity. Animals were dosed at two dose levels for 1, 3, and 14 days. Putative kidney markers, including kidney injury molecule-1 (Kim-1), lipocalin-2 (Lcn2), clusterin, and tissue inhibitor of metalloproteinases-1, were analyzed in kidney and urine using quantitative real-time PCR, ELISA, and immunohistochemistry. Changes in gene/protein expression generally correlated well with renal histopathological alterations and were frequently detected at earlier time points or at lower doses than the traditional clinical parameters blood urea nitrogen and serum creatinine. Urinary Kim-1 and clusterin reflected changes in gene/protein expression and histopathological alterations in the target organ in the absence of functional changes. This confirms clusterin and Kim-1 as early and sensitive, noninvasive markers of renal injury. Although Lcn2 did not appear to be specific for kidney toxicity, its rapid response to inflammation and tissue damage in general may suggest its utility in routine toxicity testing.

Hoffmann, Dana; Adler, Melanie; Vaidya, Vishal S.; Rached, Eva; Mulrane, Laoighse; Gallagher, William M.; Callanan, John J.; Gautier, Jean C.; Matheis, Katja; Staedtler, Frank; Dieterle, Frank; Brandenburg, Arnd; Sposny, Alexandra; Hewitt, Philip; Ellinger-Ziegelbauer, Heidrun; Bonventre, Joseph V.; Dekant, Wolfgang; Mally, Angela

2010-01-01

34

Performance of novel kidney biomarkers in preclinical toxicity studies.  

PubMed

The kidney is one of the main targets of drug toxicity, but early detection of renal damage is often difficult. As part of the InnoMed PredTox project, a collaborative effort aimed at assessing the value of combining omics technologies with conventional toxicology methods for improved preclinical safety assessment, we evaluated the performance of a panel of novel kidney biomarkers in preclinical toxicity studies. Rats were treated with a reference nephrotoxin or one of several proprietary compounds that were dropped from drug development in part due to renal toxicity. Animals were dosed at two dose levels for 1, 3, and 14 days. Putative kidney markers, including kidney injury molecule-1 (Kim-1), lipocalin-2 (Lcn2), clusterin, and tissue inhibitor of metalloproteinases-1, were analyzed in kidney and urine using quantitative real-time PCR, ELISA, and immunohistochemistry. Changes in gene/protein expression generally correlated well with renal histopathological alterations and were frequently detected at earlier time points or at lower doses than the traditional clinical parameters blood urea nitrogen and serum creatinine. Urinary Kim-1 and clusterin reflected changes in gene/protein expression and histopathological alterations in the target organ in the absence of functional changes. This confirms clusterin and Kim-1 as early and sensitive, noninvasive markers of renal injury. Although Lcn2 did not appear to be specific for kidney toxicity, its rapid response to inflammation and tissue damage in general may suggest its utility in routine toxicity testing. PMID:20118187

Hoffmann, Dana; Adler, Melanie; Vaidya, Vishal S; Rached, Eva; Mulrane, Laoighse; Gallagher, William M; Callanan, John J; Gautier, Jean C; Matheis, Katja; Staedtler, Frank; Dieterle, Frank; Brandenburg, Arnd; Sposny, Alexandra; Hewitt, Philip; Ellinger-Ziegelbauer, Heidrun; Bonventre, Joseph V; Dekant, Wolfgang; Mally, Angela

2010-01-29

35

Preclinical evaluation of anticancer efficacy and pharmacological properties of FBA-TPQ, a novel synthetic makaluvamine analog.  

PubMed

We have recently designed and synthesized a novel iminoquinone anticancer agent, 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ) and initiated its preclinical development. Herein we investigated its efficacy, safety, and pharmacokinetics in in vitro and in vivo models of human pancreatic cancer. Our results demonstrated that FBA-TPQ inhibited pancreatic cancer cell growth, induced apoptosis, and caused cell cycle arrest in vitro. It inhibited the growth of xenograft tumors with minimal host toxicity. To facilitate future preclinical and clinical development of the agent, we also developed and validated a Rapid Resolution Liquid Chromatography (RRLC) method for quantitative analysis of FBA-TPQ in plasma and tissue samples. The method was found to be precise, accurate, and specific. Using this method, we carried out in vitro and in vivo evaluations of the pharmacological properties of FBA-TPQ, including stability in plasma, plasma protein binding, metabolism by S9 enzymes, plasma pharmacokinetics, and tissue distribution. Our results indicate that FBA-TPQ is a potential therapeutic agent for pancreatic cancer, providing a basis for future preclinical and clinical development. PMID:22822362

Zhang, Xiangrong; Xu, Hongxia; Zhang, Xu; Voruganti, Sukesh; Murugesan, Srinivasan; Nadkarni, Dwayaja H; Velu, Sadanandan E; Wang, Ming-Hai; Wang, Wei; Zhang, Ruiwen

2012-05-23

36

Resveratrol: A review of preclinical studies for human cancer prevention  

SciTech Connect

The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations.

Athar, Mohammad; Back, Jung Ho; Tang Xiuwei [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Kwang Ho [Department of Dermatology, Hallym University College of Medicine (Korea, Republic of); Kopelovich, Levy [Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892 (United States); Bickers, David R. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States); Kim, Arianna L. [Department of Dermatology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street VC15-204, New York, NY 10032 (United States)], E-mail: ak309@columbia.edu

2007-11-01

37

Preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vector for the treatment of Wiskott-Aldrich syndrome.  

PubMed

Gene therapy with ex vivo-transduced hematopoietic stem/progenitor cells may represent a valid therapeutic option for monogenic immunohematological disorders such as Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency associated with thrombocytopenia. We evaluated the preclinical safety and efficacy of human CD34(+) cells transduced with lentiviral vectors (LV) encoding WAS protein (WASp). We first set up and validated a transduction protocol for CD34(+) cells derived from bone marrow (BM) or mobilized peripheral blood (MPB) using a clinical grade, highly purified LV. Robust transduction of progenitor cells was obtained in normal donors and WAS patients' cells, without evidence of toxicity. To study biodistribution of human cells and exclude vector release in vivo, LV-transduced CD34(+) cells were transplanted in immunodeficient mice, showing a normal engraftment and differentiation ability towards transduced lymphoid and myeloid cells in hematopoietic tissues. Vector mobilization to host cells and transmission to germline cells of the LV were excluded by different molecular assays. Analysis of vector integrations showed polyclonal integration patterns in vitro and in human engrafted cells in vivo. In summary, this work establishes the preclinical safety and efficacy of human CD34(+) cells gene therapy for the treatment of WAS. PMID:22371846

Scaramuzza, Samantha; Biasco, Luca; Ripamonti, Anna; Castiello, Maria C; Loperfido, Mariana; Draghici, Elena; Hernandez, Raisa J; Benedicenti, Fabrizio; Radrizzani, Marina; Salomoni, Monica; Ranzani, Marco; Bartholomae, Cynthia C; Vicenzi, Elisa; Finocchi, Andrea; Bredius, Robbert; Bosticardo, Marita; Schmidt, Manfred; von Kalle, Christof; Montini, Eugenio; Biffi, Alessandra; Roncarolo, Maria G; Naldini, Luigi; Villa, Anna; Aiuti, Alessandro

2012-02-28

38

The Primate Preclinical Test Center for Immune Suppression Study.  

National Technical Information Service (NTIS)

During the period January 27, 1969 to January 31, 1970, 101 (70*) different antilymphocyte sera (ALS) were received from various transplant centers and collaborators throughout the United States at the 'Primate Preclinical Test Center for Immune Suppressi...

C. C. Darrow G. S. LaFontaine

1970-01-01

39

Characterization of Dysferlin Deficient SJL\\/J Mice to Assess Preclinical Drug Efficacy: Fasudil Exacerbates Muscle Disease Phenotype  

Microsoft Academic Search

The dysferlin deficient SJL\\/J mouse strain is commonly used to study dysferlin deficient myopathies. Therefore, we systematically evaluated behavior in relatively young (9–25 weeks) SJL\\/J mice and compared them to C57BL6 mice to determine which functional end points may be the most effective to use for preclinical studies in the SJL\\/J strain. SJL\\/J mice had reduced body weight, lower open

Sree Rayavarapu; Jack H. Van der meulen; Heather Gordish-Dressman; Eric P. Hoffman; Kanneboyina Nagaraju; Susan M. Knoblach

2010-01-01

40

Preclinical studies with platelet-activating factor antagonists in models of septic shock.  

PubMed

Since the isolation and elucidation of the structure of platelet-activating factor (PAF) in the late 1970's, several preclinical studies have suggested that PAF is a key mediator of septic shock induced in animals by either endotoxin or by Gram-negative bacteria. A number of PAF antagonists have been sythesized that protect animals from the lethal effects of endotoxin. Some of these antagonists are in early stages of clinical development. The most advanced cadidate is BN 52021, a ginkgolide, that is in Phase II/III clinical trials in patients with septic shock. Preliminary results with BN 52021 indicate that it is efficacious and significantly reduces mortality associated with Gram-negative sepsis. Pivotal trials with BN 52021 aer ongoing. The present review summarizes the biological effects of PAF and the effect of PAF antagonists in animal models of septic shock. The interrelationship of PAF and tumor necrosis factor (another key mediator of septic shock) is also discussed. PMID:18611559

Dejoy, S Q; Oronsky, A L; Wick, M M; Kerwar, S S

1993-01-01

41

Novel technology to prepare oral formulations for preclinical safety studies.  

PubMed

A novel method to prepare oral formulations, normally suspended dosage form, for preclinical safety studies in animals has been developed using a rotation/revolution mixer. Small hard balls made of zirconia were added to the mixing process to evaluate effectiveness in making a high quality suspension. The driving with balls loaded in the cylindrical container (vessel) of the mixer was quite efficient in dispersing and milling the particles of the active pharmaceutical ingredient (API) in an aqueous medium. The API powder and a small amount of oral aqueous medium (vehicle) were successfully mixed by the spinning motion of the balls in the vessel as though the paste-like suspension was kneaded with a mortar and pestle. It was found that the milled suspension with the mean size of 10-20microm could be prepared, in addition finer milling of less than 10microm could be achieved by selecting the material of vessel. Optimum driving conditions including mixing time, size and quantity of balls, and the standard operational procedure was established using compounds varying in physicochemical properties. The particle size and quantitative analysis by HPLC showed that the resultant suspension was well-milled and highly homogeneous with the nearly intended concentration of API. The proposed method established by this experiment could be applied to the actual safety studies in the real preparation scale of oral suspension. PMID:17942253

Niwa, Toshiyuki; Hashimoto, Naofumi

2007-08-24

42

A formulation-enabled preclinical efficacy assessment of a farnesoid X receptor agonist, GW4064, in hamsters and cynomolgus monkeys.  

PubMed

The farnesoid X receptor (FXR) belongs to one of the human nuclear receptor superfamilies that regulate gene transcription. FXR is widely expressed in liver, gall bladder, intestine, kidney, and adrenal glands. It serves as a key controller of bile acid homeostasis through its regulation of bile acid synthesis, conjugation, secretion, and absorption. FXR is also known to play a role in lipid regulation, triglyceride synthesis, and lipoprotein metabolism and clearance. We used a commercially available FXR agonist, GW4064, as a model compound to assess preclinical efficacy in two species (hamster and cynomolgus monkey). The crystalline GW4064, however, was found to have limited solubility, which resulted in poor oral bioavailability. This made it difficult to assess in vivo efficacy at the exposure levels desired. The physiochemical properties of GW4064 were assessed and both salt and self-emulsifying drug delivery system (SEDDS) formulation were developed and tested. The SEDDS formulation was found to greatly improve the oral bioavailability of GW4064, and permitted the evaluation of FXR agonist target efficacy. PMID:21660973

Chiang, Po-Chang; Thompson, David C; Ghosh, Sarbani; Heitmeier, Monique R

2011-06-09

43

Preclinical toxicity studies with two thymopoietin-like peptides.  

PubMed

Differentiation of T-lymphocytes is regulated by thymopoietin, a 49 amino acid polypeptide chain. The site of immunological activity is in the 32-36 (Arg-Lys-Asp-Val-Tyr) fragment. This pentapeptide can be reduced to a tetrapeptide (RGH-0206: Arg-Lys-Asp-Val) and further to a tripeptide (RGH-0205: Arg-Lys-Asp) which still retains immunological activity. To prepare Phase I and II clinical trials preclinical toxicity studies were duly performed. Mice, rats and dogs tolerated a single 1000 mg/kg dose i.v. without any symptom. In a 14-day i.v. test on Lati:Han:WISTAR rats daily doses of 10,25, 62.5, 150, 400 and 1000 mg/kg of either test compound were tolerated without symptom or damage. In a 28-day i.v. toxicity test on Wobe:BEAGLE dogs given daily doses of 6, 20 and 60 mg/kg of either test compound, no adverse reaction occurred. The low toxicity of both RGH-0205 and RGH-0206 are probably attributable to their short half-life, as half-life of the pentapeptide fraction is less than 30 sec in humans. It was concluded that the planned clinical dose of 1 mg/kg i.v. was safe for both peptides for short-term administration. PMID:3868381

Iván, E; Bodrogligeti, I; Juhász-Nagy, A; Német, L; Cholnoky, E

1985-01-01

44

Quetiapine: preclinical studies, pharmacokinetics, drug interactions, and dosing.  

PubMed

Quetiapine is a novel dibenzothiazepine atypical antipsychotic. Quetiapine shows affinity for various neurotransmitter receptors including serotonin, dopamine, histamine, and adrenergic receptors and has binding characteristics at the dopamine-2 receptor similar to those of clozapine. In animal models, the drug has a preclinical profile suggestive of antipsychotic activity with a reduced tendency to cause extrapyramidal symptoms (EPS) and sustained prolactin elevation. For example, quetiapine alters neurotensin neurotransmission and c-fos expression in limbic but not motor brain regions. The drug also demonstrates clozapine-like activity in a range of behavioral and biochemical tests and may possess neuroprotective properties. In humans, quetiapine exhibits linear pharmacokinetics with a mean terminal half-life of 7 hours. The primary route of elimination of quetiapine is through hepatic metabolism. Although not affected by smoking, alterations in quetiapine disposition due to age or hepatic impairment are manageable by appropriate dosage reduction. The optimal dosing range for quetiapine is 150 to 750 mg/day, and recent results suggest that once-daily dosing may be suitable for some patients. Finally, imaging studies with positron emission tomography confirm significant differences between quetiapine and typical antipsychotics that may be indicative of their differences in mechanism of action and propensity for producing EPS. PMID:12562141

Nemeroff, Charles B; Kinkead, Becky; Goldstein, Jeffrey

2002-01-01

45

Preclinical studies identify novel targeted pharmacological strategies for treatment of human malignant pleural mesothelioma  

PubMed Central

The incidence of human malignant pleural mesothelioma (hMPM) is still increasing worldwide. hMPM prognosis is poor even if the median survival time has been slightly improved after the introduction of the up-to-date chemotherapy. Nevertheless, large phase II/III trials support the combination of platinum derivatives and pemetrexed or raltitrexed, as preferred first-line schedule. Better understanding of the molecular machinery of hMPM will lead to the design and synthesis of novel compounds targeted against pathways identified as crucial for hMPM cell proliferation and spreading. Among them, several receptors tyrosine kinase show altered activity in subsets of hMPM. This observation suggests that these kinases might represent novel therapeutic targets in this chemotherapy-resistant disease. Over these foundations, several promising studies are ongoing at preclinical level and novel molecules are currently under evaluation as well. Yet, established tumour cell lines, used for decades to investigate the efficacy of anticancer agents, although still the main source of drug efficacy studies, after long-term cultures tend to biologically diverge from the original tumour, limiting the predictive potential of in vivo efficacy. Cancer stem cells (CSCs), a subpopulation of malignant cells capable of self-renewal and multilineage differentiation, are believed to play an essential role in cancer initiation, growth, metastasization and relapse, being responsible of chemo- and radiotherapy refractoriness. According to the current carcinogenesis theory, CSCs represent the tumour-initiating cell (TIC) fraction, the only clonogenic subpopulation able to originate a tumour mass. Consequently, the recently described isolation of TICs from hMPM, the proposed main pharmacological target for novel antitumoural drugs, may contribute to better dissect the biology and multidrug resistance pathways controlling hMPM growth.

Favoni, Roberto E; Daga, Antonio; Malatesta, Paolo; Florio, Tullio

2012-01-01

46

Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions  

PubMed Central

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

King, Alastair J.; Arnone, Marc R.; Bleam, Maureen R.; Moss, Katherine G.; Yang, Jingsong; Fedorowicz, Kelly E.; Smitheman, Kimberly N.; Erhardt, Joseph A.; Hughes-Earle, Angela; Kane-Carson, Laurie S.; Sinnamon, Robert H.; Qi, Hongwei; Rheault, Tara R.; Uehling, David E.; Laquerre, Sylvie G.

2013-01-01

47

Standardization of the Filovirus Plaque Assay for Use in Preclinical Studies  

PubMed Central

The filovirus plaque assay serves as the assay of choice to measure infectious virus in a cell culture, blood, or homogenized tissue sample. It has been in use for more than 30 years and is the generally accepted assay used to titrate virus in samples from animals treated with a potential antiviral therapeutic or vaccine. As these animal studies are required for the development of vaccines and therapeutics under the FDA Animal Rule, it is essential to have a standardized assay to compare their efficacies against the various filoviruses. Here, we present an evaluation of the conditions under which the filovirus plaque assay performs best for the Ebola virus Kikwit variant and the Angola variant of Marburg virus. The indicator cell type and source, inoculum volumes, length of incubation and general features of filovirus biology as visualized in the assay are addressed in terms of the impact on the sample viral titer calculations. These optimization studies have resulted in a plaque assay protocol which can be used for preclinical studies, and as a standardized protocol for use across institutions, to aid in data comparison. This protocol will be validated for use in GLP studies supporting advanced development of filovirus therapeutics and vaccines.

Shurtleff, Amy C.; Biggins, Julia E.; Keeney, Ashley E.; Zumbrun, Elizabeth E.; Bloomfield, Holly A.; Kuehne, Ana; Audet, Jennifer L.; Alfson, Kendra J.; Griffiths, Anthony; Olinger, Gene G.; Bavari, Sina

2012-01-01

48

Natural substances and Alzheimer's disease: from preclinical studies to evidence based medicine.  

PubMed

Over the last 10 years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either a free radical scavenging activity or the inhibition of pro-inflammatory pathways or the potentiation of the cell stress response. However, although these are interesting premises, clinical studies were not able to demonstrate significant beneficial effects of curcumin, Ginkgo biloba and acetyl-l-carnitine in improving cognitive functions in Alzheimer's disease patients. The aim of this review is to summarize the main pharmacologic features of curcumin, Ginkgo biloba and carnitines as well as to underlie the main outcomes reached by clinical studies designed to demonstrate the efficacy of these natural substances in Alzheimer's disease patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease. PMID:21939756

Mancuso, Cesare; Siciliano, Raffaella; Barone, Eugenio; Preziosi, Paolo

2011-09-14

49

Pharmacokinetics, Trypanosoma brucei gambiense Efficacy, and Time of Drug Action of DB829, a Preclinical Candidate for Treatment of Second-Stage Human African Trypanosomiasis.  

PubMed

Human African trypanosomiasis (HAT, also called sleeping sickness), a neglected tropical disease endemic to sub-Saharan Africa, is caused by the parasites Trypanosoma brucei gambiense and T. brucei rhodesiense. Current drugs against this disease have significant limitations, including toxicity, increasing resistance, and/or a complicated parenteral treatment regimen. DB829 is a novel aza-diamidine that demonstrated excellent efficacy in mice infected with T. b. rhodesiense or T. b. brucei parasites. The current study examined the pharmacokinetics, in vitro and in vivo activity against T. b. gambiense, and time of drug action of DB829 in comparison to pentamidine. DB829 showed outstanding in vivo efficacy in mice infected with parasites of T. b. gambiense strains, despite having higher in vitro 50% inhibitory concentrations (IC50s) than against T. b. rhodesiense strain STIB900. A single dose of DB829 administered intraperitoneally (5 mg/kg of body weight) cured all mice infected with different T. b. gambiense strains. No cross-resistance was observed between DB829 and pentamidine in T. b. gambiense strains isolated from melarsoprol-refractory patients. Compared to pentamidine, DB829 showed a greater systemic exposure when administered intraperitoneally, partially contributing to its improved efficacy. Isothermal microcalorimetry and in vivo time-to-kill studies revealed that DB829 is a slower-acting trypanocidal compound than pentamidine. A single dose of DB829 (20 mg/kg) administered intraperitoneally clears parasites from mouse blood within 2 to 5 days. In summary, DB829 is a promising preclinical candidate for the treatment of first- and second-stage HAT caused by both Trypanosoma brucei subspecies. PMID:23959303

Wenzler, Tanja; Yang, Sihyung; Braissant, Olivier; Boykin, David W; Brun, Reto; Wang, Michael Zhuo

2013-08-19

50

Pre-Clinical Assays Predict Pan-African Echis Viper Efficacy for a Species-Specific Antivenom  

PubMed Central

Background Snakebite is a significant cause of death and disability in subsistent farming populations of sub-Saharan Africa. Antivenom is the most effective treatment of envenoming and is manufactured from IgG of venom-immunised horses/sheep but, because of complex fiscal reasons, there is a paucity of antivenom in sub-Saharan Africa. To address the plight of thousands of snakebite victims in savannah Nigeria, the EchiTAb Study Group organised the production, testing and delivery of antivenoms designed to treat envenoming by the most medically-important snakes in the region. The Echis saw-scaled vipers have a wide African distribution and medical importance. In an effort to maximise the clinical utility of scarce antivenom resources in Africa, we aimed to ascertain, at the pre-clinical level, to what extent the E. ocellatus-specific EchiTAbG antivenom, which was designed specifically for Nigeria, neutralised the lethal activity of venom from two other African species, E. pyramidum leakeyi and E. coloratus. Methodology/Principal Findings Despite apparently quite distinctive venom protein profiles, we observed extensive cross-species similarity in the immuno-reactivity profiles of Echis species-specific antisera. Using WHO standard pre-clinical in vivo tests, we determined that the monospecific EchiTAbG antivenom was as effective at neutralising the venom-induced lethal effects of E. pyramidum leakeyi and E. coloratus as it was against E. ocellatus venom. Under the restricted conditions of this assay, the antivenom was ineffective against the lethal effects of venom from the non-African Echis species, E. carinatus sochureki. Conclusions/Significance Using WHO-recommended pre-clinical tests we have demonstrated that the new anti-E. ocellatus monospecific antivenom EchiTAbG, developed in response to the considerable snakebite-induced mortality and morbidity in Nigeria, neutralised the lethal effects of venoms from Echis species representing each taxonomic group of this genus in Africa. This suggests that this monospecific antivenom has potential to treat envenoming by most, perhaps all, African Echis species.

Casewell, Nicholas R.; Cook, Darren A. N.; Wagstaff, Simon C.; Nasidi, Abdulsalami; Durfa, Nandul; Wuster, Wolfgang; Harrison, Robert A.

2010-01-01

51

Anticancer activity of tolfenamic acid in medulloblastoma: a preclinical study.  

PubMed

Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 ?g/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 ?g/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ~40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin. PMID:23686785

Eslin, Don; Lee, Chris; Sankpal, Umesh T; Maliakal, Pius; Sutphin, Robert M; Abraham, Liz; Basha, Riyaz

2013-05-18

52

Natural substances and Alzheimer's disease: From preclinical studies to evidence based medicine  

Microsoft Academic Search

Over the last 10years, the potential therapeutic effects of nutraceuticals to prevent or delay Alzheimer's disease were proposed. Among dietary antioxidants curcumin, Ginkgo biloba and carnitines were extensively studied for their neuroprotective effects. The rationale for this alternative therapeutic approach was based on several preclinical studies which suggested the neuroprotective effects for curcumin, Ginkgo biloba and acetyl-l-carnitine due to either

Cesare Mancuso; Raffaella Siciliano; Eugenio Barone; Paolo Preziosi

53

Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study.  

PubMed

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-03-19

54

Investigating the Efficacy of Practical Skill Teaching: A Pilot-Study Comparing Three Educational Methods  

ERIC Educational Resources Information Center

|Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a…

Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

2013-01-01

55

Efficacy and pharmacokinetic\\/pharmacodynamic evaluation of the Aurora kinase A inhibitor MLN8237 against preclinical models of pediatric cancer  

Microsoft Academic Search

Purpose  To gain a greater understanding of the potential of the Aurora kinase A inhibitor MLN8237 in the treatment of pediatric malignancies.\\u000a \\u000a \\u000a \\u000a Methods  The activity of MLN8237 was evaluated against 28 neuroblastoma and Ewing sarcoma cell lines, and its in vivo efficacy was\\u000a studied over a range of doses against 12 pediatric tumor xenograft models. Pharmacokinetic, pharmacodynamic, and genomic studies\\u000a were undertaken.

Hernan Carol; Ingrid Boehm; C. Patrick Reynolds; Min H. Kang; John M. Maris; Christopher L. Morton; Richard Gorlick; E. Anders Kolb; Stephen T. Keir; Jianrong Wu; Amy E. Wozniak; Yu Yang; Mark Manfredi; Jeffrey Ecsedy; Jianmin Wang; Geoffrey Neale; Peter J. Houghton; Malcolm A. Smith; Richard B. Lock

56

Preclinical Toxicology Studies for New Drugs and Vaccines.  

National Technical Information Service (NTIS)

During the reporting period, Two Week Oral Toxicity Studies of WR2425 11 and WR2694 10 in Rats, In Vitro Mutagenicity Tests of WR2425 11 and WR2694 10, Four Week Oral Toxicity Studies of WR2425 11 and WR2694 10 in Dogs, Thirteen Week Oral Toxicity Studies...

B. S. Levine

1994-01-01

57

Spinal Cord Tolerance in the Age of Spinal Radiosurgery: Lessons from Pre-clinical Studies  

PubMed Central

Clinical implementation of spinal radiosurgery has increased rapidly in recent years but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970’s. The influences of field length, dose rate, inhomogeneous dose distributions and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in pre-clinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small and large animal models. Extensive investigation of inhomogeneous dose distributions in the rat has demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Pre-clinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data is sparse, but results from guinea pig, rat and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.

Medin, Paul M.; Boike, Thomas P.

2010-01-01

58

Toxicogenomics in drug discovery: from preclinical studies to clinical trials  

Microsoft Academic Search

Gene expression analysis applied to toxicology studies, also referred to as toxicogenomics, is rapidly being embraced by the pharmaceutical industry as a useful tool to identify safer drugs in a quicker, more cost-effective manner. Studies have already demonstrated the benefits of applying gene expression profiling towards drug safety evaluation, both for identifying mechanisms underlying toxicity, as well as for providing

Yi Yang; Eric A. G. Blomme; Jeffrey F. Waring

2004-01-01

59

Iron Deprivations Treatment of Breast Cancer: Pre-Clinical Studies.  

National Technical Information Service (NTIS)

Progress has been made in the study of iron deprivation as a potential treatment modality for breast cancer. Enhanced macrophage activation with an augmented acute phase response has been implicated as a source of potential treatment related toxicity. Def...

J. D. Kemp

1997-01-01

60

From Bench to Bedside: Lessons Learned in Translating Preclinical Studies in Cancer Drug Development  

PubMed Central

The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited.

2013-01-01

61

From bench to bedside: lessons learned in translating preclinical studies in cancer drug development.  

PubMed

The development of targeted agents in oncology has rapidly expanded over the past 2 decades and has led to clinically significant improvements in the treatment of numerous cancers. Unfortunately, not all success at the bench in preclinical experiments has translated to success at the bedside. As preclinical studies shift toward defining proof of mechanism, patient selection, and rational drug combinations, it is critical to understand the lessons learned from prior translational studies to gain an understanding of prior drug development successes and failures. By learning from prior drug development, future translational studies will provide more clinically relevant data, and the underlying hope is that the clinical success rate will improve and the treatment of patients with ineffective targeted therapy will be limited. PMID:24052618

Lieu, Christopher H; Tan, Aik-Choon; Leong, Stephen; Diamond, Jennifer R; Eckhardt, S Gail

2013-09-19

62

Racer efficacy study  

Technology Transfer Automated Retrieval System (TEKTRAN)

Racer (ammonium nonanoate) is a non-selective contact herbicide that controls several weed species. Racer has been labeled by EPA in the past year for weed control in food crops and is close to receiving approval for use by organic producers. The objective of this study was to verify results from ...

63

Therapeutic Applications of Incretin Mimetics for Metabolic Diseases: Preclinical Studies  

Technology Transfer Automated Retrieval System (TEKTRAN)

Exenatide (exendin-4) is an incretin mimetic peptide that shares several glucoregulatory actions with the endogenous incretin GLP-1. In addition to its actions on glucose control, exenatide produces effects to reduce food intake and body weight in all species studied. GLP-1 and exenatide have also b...

64

Preclinical Studies on the Anti-Migraine Drug, Sumatriptan  

Microsoft Academic Search

Sumatriptan is believed to constrict selectively the cranial vessels that are distended and inflamed during migraine. The action is mediated by activation of a 5-HT1 receptor subtype which has been shown in animals to be localized in cranial vessels. Further studies to elaborate sumatriptan’s precise clinical mode of action have focused on the human meningeal circulation and should lead to

P. P. A. Humphrey; W. Feniuk; A. S. Marriott; R. J. N. Tanner; M. R. Jackson; M. L. Tucker

1991-01-01

65

Robotic-assisted skull base surgery: preclinical study.  

PubMed

Abstract Objective and Study Design: To assess the feasibility of robotic-assisted skull base surgery, a preclincal cadaver study was conducted. Materials and Methods: The feasibility study was subdivided into three phases: Phase 1 (surgical corridor) entailed a review of the surgical access, Phase 2 (instrument configuration) entailed arrangements of the robotic instrument (da Vinci(®) Surgical System; Intuitive Surgical, Sunnyvale, CA) in relation to the surgical corridor and applied to a skull model, and Phase 3 was robotic-assisted skull base cadaver dissection. Results: Regarding the surgical corridor, the infratemporal area was accessed through a maxillary window, whereas the anterior skull base region was accessed through a combined single maxillary window and nasal corridor. Regarding instrument configuration, the camera was positioned above the two instrument arms, with both instrument arms angled at 30° to the camera axis with a flexed distal tip for the infratemporal skull base. For the anterior skull base, one of the robotic arms was inserted through the unilateral maxillary window, whereas the three-dimensional camera and the second arm were inserted through the nasal corridor. Regarding the robotic-assisted skull base cadaver dissection, we define the robotic set-up time in this study as the time required to move the robot into position, obtain adequate operative exposure, and place the robotic arms prior to the start of robotic dissection. The robotic set-up time for the anterior skull base dissection averaged 95 minutes, and that for pituitary resection was 61 minutes. The robotic set-up time for infratemporal dissection averaged 23 minutes. Operative time was 63.5 minutes. Robotic and endoscopic techniques can be combined during surgery. Conclusions: Robotic-assisted skull base surgery is feasible. The da Vinci instrument needs to be redesigned to be smaller and preferably with distal articulating tips, prior to clinical application of robotics to skull base surgery. PMID:24001158

Blanco, Ray Gervacio F; Boahene, Kofi

2013-09-01

66

Wireless Video Capsule Enteroscopy in Preclinical Studies: Methodical Design of Its Applicability in Experimental Pigs  

Microsoft Academic Search

The aim of this project was to develop a methodology to introduce wireless video capsule endoscopy in preclinical research.\\u000a Five mature female pigs (Sus scrofa domestica) were selected for the study. Capsule endoscopes (the EndoCapsule system; Olympus) were introduced into the duodenum endoscopically\\u000a in each of the animals. The life span of batteries (i.e., total time of endoscopy recording) was

Marcela Kopá?ová; Ilja Tachecí; Jaroslav Kv?tina; Jan Bureš; Martin Kuneš; Stanislav Špelda; V?ra Ty?ová; Zbyn?k Svoboda; Stanislav Rejchrt

2010-01-01

67

Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies  

Microsoft Academic Search

Preclinical models have examined the pharmacologic and pharmacodynamic activities of an anti-vascular endothelial growth factor (VEGF) humanized, monoclonal antibody, bevacizumab, and\\/or its murine equivalent A4.6.1. These studies found that single-agent therapy with bevacizumab\\/ A4.6.1 resulted in tumor growth inhibition of 20 different human tumor cell lines (13 tumor types) implanted into nude mice irrespective of the route of administration or

Hans-Peter Gerber; Napoleone Ferrara

2005-01-01

68

Interleukin-2 in bone marrow transplantation: preclinical studies.  

PubMed

Interleukin-2 (IL-2) promotes the generation and proliferation of killer cells in the peripheral blood and bone marrow (BM) both in vitro and in vivo. When employed in a syngeneic bone marrow transplantation (BMT) setting and followed by IL-2 therapy, murine BM cells activated with IL-2 in vitro (ABM) demonstrate potent graft-versus-leukemia (GVL) and anticytomegalovirus effects. ABM cells retain the capacity to reconstitute the hemopoietic system both in normal and leukemic mice. This therapy does not cause graft-versus-host disease (GVHD). Human ABM cells carry out purging of leukemia without loss of progenitor cell activity in vitro. The purging ability of ABM can be augmented by interleukin-1, interferon, and tumor necrosis factor. IL-2 therapy stimulates the veto suppressor cell activity of T cell-depleted BM, and has reduced GVHD and permitted engraftment of mismatched allogeneic BM in murine models. Future studies should determine the optimum treatment schedules with IL-2 for improving the GVL effect in autologous BMT, and for abolishing GVHD in allogeneic BMT settings. PMID:1326364

Charak, B S; Choudhary, G D; Tefft, M; Mazumder, A

1992-08-01

69

Pre-clinical Models for Oral and Periodontal Reconstructive Therapies  

PubMed Central

The development of new medical formulations (NMF) for reconstructive therapies has considerably improved the available treatment options for individuals requiring periodontal repair or oral implant rehabilitation. Progress in tissue engineering and regenerative medicine modalities strongly depends on validated pre-clinical research. Pre-clinical testing has contributed to the recent approval of NMF such as GEM 21S® and INFUSE® bone grafts for periodontal and oral regenerative therapies. However, the selection of a suitable pre-clinical model for evaluation of the safety and efficacy of a NMF remains a challenge. This review is designed to serve as a primer to choose the appropriate pre-clinical models for the evaluation of NMF in situations requiring periodontal or oral reconstruction. Here, we summarize commonly used pre-clinical models and provide examples of screening and functional studies of NMF that can be translated into clinical use.

Pellegrini, G.; Seol, Y.J.; Gruber, R.; Giannobile, W.V.

2009-01-01

70

Factors influencing the approaches to studying of preclinical and clinical students and postgraduate trainees  

PubMed Central

Background Students can be classified into three categories depending on their approaches to studying; namely, deep approach (DA), strategic approach (SA) and surface apathetic or superficial approach (SAA). The aim of this study was to identify factors affecting the approaches to studying among Sri Lankan medical undergraduates and post graduate trainees and to analyze the change in the pattern of study skills with time and experience. Method Pre-clinical and clinical students of the Faculty of Medicine, University of Colombo and postgraduate trainees in Surgery at the National Hospital of Sri Lanka were invited to complete the Approaches and Study Skills Inventory for Students (ASSIST) questionnaire. Results A total of 187 pre clinical (M: F = 96:91), 124 clinical (M: F = 61:63) and 53 post graduate trainees (M: F = 50:3) participated in the study. Approaches of male and female students were similar. SA was significantly affected by age among the preclinical students (p = 0.01), but not in other groups. Among pre-clinical students, males preferred a teacher who supported understanding (p = 0.04) but females preferred a passive transmission of information (p < 0.001). This, too, was not visible among other groups. A linear regression performed on group (batch), gender, island rank at GCE Advance Level (AL) examination, self appraisal score and the preference scores of type of teacher only managed to explain 35% or less of variance observed for each approach in individual groups. Conclusion Different factors affect the approach to studying in different groups but these explain only a small fraction of the variance observed.

2011-01-01

71

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies  

PubMed Central

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable.

2011-01-01

72

Accelerating drug discovery for Alzheimer's disease: best practices for preclinical animal studies.  

PubMed

Animal models have contributed significantly to our understanding of the underlying biological mechanisms of Alzheimer's disease (AD). As a result, over 300 interventions have been investigated and reported to mitigate pathological phenotypes or improve behavior in AD animal models or both. To date, however, very few of these findings have resulted in target validation in humans or successful translation to disease-modifying therapies. Challenges in translating preclinical studies to clinical trials include the inability of animal models to recapitulate the human disease, variations in breeding and colony maintenance, lack of standards in design, conduct and analysis of animal trials, and publication bias due to under-reporting of negative results in the scientific literature. The quality of animal model research on novel therapeutics can be improved by bringing the rigor of human clinical trials to animal studies. Research communities in several disease areas have developed recommendations for the conduct and reporting of preclinical studies in order to increase their validity, reproducibility, and predictive value. To address these issues in the AD community, the Alzheimer's Drug Discovery Foundation partnered with Charles River Discovery Services (Morrisville, NC, USA) and Cerebricon Ltd. (Kuopio, Finland) to convene an expert advisory panel of academic, industry, and government scientists to make recommendations on best practices for animal studies testing investigational AD therapies. The panel produced recommendations regarding the measurement, analysis, and reporting of relevant AD targets, th choice of animal model, quality control measures for breeding and colony maintenance, and preclinical animal study design. Major considerations to incorporate into preclinical study design include a priori hypotheses, pharmacokinetics-pharmacodynamics studies prior to proof-of-concept testing, biomarker measurements, sample size determination, and power analysis. The panel also recommended distinguishing between pilot 'exploratory' animal studies and more extensive 'therapeutic' studies to guide interpretation. Finally, the panel proposed infrastructure and resource development, such as the establishment of a public data repository in which both positive animal studies and negative ones could be reported. By promoting best practices, these recommendations can improve the methodological quality and predictive value of AD animal studies and make the translation to human clinical trials more efficient and reliable. PMID:21943025

Shineman, Diana W; Basi, Guriqbal S; Bizon, Jennifer L; Colton, Carol A; Greenberg, Barry D; Hollister, Beth A; Lincecum, John; Leblanc, Gabrielle G; Lee, Linda Bobbi H; Luo, Feng; Morgan, Dave; Morse, Iva; Refolo, Lorenzo M; Riddell, David R; Scearce-Levie, Kimberly; Sweeney, Patrick; Yrjänheikki, Juha; Fillit, Howard M

2011-09-28

73

Education Predicts Incidence of Preclinical Mobility Disability in Initially High-Functioning Older Women. The Women's Health and Aging Study II  

PubMed Central

Background. To examine the impact of educational attainment on the incidence of preclinical mobility disability (PCD). Methods. The Women's Health and Aging II Study is a prospective observational cohort study of 436 initially high-functioning community-dwelling women aged 70–79 years at baseline in Baltimore, Maryland. We measured the association of highest attained education level with preclinical mobility disability (PCD) over an 11-year period. PCD is defined as self-reported modification in any of four tasks without reporting difficulty in those tasks. The tasks were walking ½ mile, climbing up steps, doing heavy housework, and getting in/out of bed or chair. Results. Participants with less than 9 years of education were more likely to acquire incident PCD (hazard ratio: 3.1, 95% confidence interval = 1.2–7.7) than their counterparts with more education after adjusting for income, marital status, number of diseases, and high self-efficacy. Conclusions. Lower education level is an independent predictor of incident preclinical mobility disability. This association has important implications for primary and secondary prevention and can be easily assessed in clinical encounters.

Gregory, Patricia C.; Xue, Qian-Li; Tian, Jing; Thorpe, Roland J.; Fried, Linda P.

2011-01-01

74

Efficacy of recombinant anthrax vaccine against Bacillus anthracis aerosol spore challenge: preclinical evaluation in rabbits and Rhesus monkeys.  

PubMed

This report describes the immunogenicity and protective efficacy of Escherichia coli-expressed recombinant protective antigen (rPA) in New Zealand White rabbits and Rhesus Macaques against an aerosol challenge with Bacillus anthracis spores (IVRI strain, tox+cap+). A dose-ranging study was performed in which it became evident that the level of anti-PA IgG and toxin-neutralizing antibody titer was directly proportional to the dose of rPA administered. However, the onset time of primary and secondary immune response was not dependent on the dosage. Revaccination of primed animals with the same threshold dose yielded a robust and rapid secondary response. Quantitative differences in peak titers were obtained for both the animal models, in addition to qualitative differences in the immune kinetics. In spite of a weak priming response, the secondary response in rabbits peaked earlier than that in macaques once the booster dose was administered. However, evaluation of the post-challenge quantitative anti-rPA ELISA titer measurements indicated higher titers for non-human primates as compared to the lagomorphs. Importantly, 100% protection was seen for the dosage groups that received > or = 25 microg rPA, following a challenge against a target dose of 1000 LD(50) of aerosolized spores of Bacillus anthracis. PMID:19296443

Chawla, Anil; Midha, Shuchi; Bhatnagar, Rakesh

2009-03-01

75

Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies.  

PubMed

Research in the area of herbal psychopharmacology has revealed a variety of promising medicines that may provide benefit in the treatment of general anxiety and specific anxiety disorders. However, a comprehensive review of plant-based anxiolytics has been absent to date. This article (part 1) reviews herbal medicines for which only preclinical investigations for anxiolytic activity have been performed. In part 2, we review herbal medicines for which there have been clinical investigations for anxiolytic activity. An open-ended, language-restricted (English) search of MEDLINE (PubMed), CINAHL, Scopus and the Cochrane Library databases was conducted (up to 28 October 2012) using specific search criteria to identify herbal medicines that have been investigated for anxiolytic activity. This search of the literature revealed 1,525 papers, from which 53 herbal medicines were included in the full review (having at least one study using the whole plant extract). Of these plants, 21 had human clinical trial evidence (reviewed in part 2), with another 32 having solely preclinical studies (reviewed here in part 1). Preclinical evidence of anxiolytic activity (without human clinical trials) was found for Albizia julibrissin, Sonchus oleraceus, Uncaria rhynchophylla, Stachys lavandulifolia, Cecropia glazioui, Magnolia spp., Eschscholzia californica, Erythrina spp., Annona spp., Rubus brasiliensis, Apocynum venetum, Nauclea latifolia, Equisetum arvense, Tilia spp., Securidaca longepedunculata, Achillea millefolium, Leea indica, Juncus effusus, Coriandrum sativum, Eurycoma longifolia, Turnera diffusa, Euphorbia hirta, Justicia spp., Crocus sativus, Aloysia polystachya, Albies pindrow, Casimiroa edulis, Davilla rugosa, Gastrodia elata, Sphaerathus indicus, Zizyphus jujuba and Panax ginseng. Common mechanisms of action for the majority of botanicals reviewed primarily involve GABA, either via direct receptor binding or ionic channel or cell membrane modulation; GABA transaminase or glutamic acid decarboxylase inhibition; a range of monoaminergic effects; and potential cannabinoid receptor modulation. Future research should focus on conducting human clinical trials on the plants reviewed with promising anxiolytic activity. PMID:23436255

Sarris, Jerome; McIntyre, Erica; Camfield, David A

2013-03-01

76

Transforming growth factors-? are not good biomarkers of chemopreventive efficacy in a preclinical breast cancer model system  

PubMed Central

Using a carcinogen-initiated rat model of mammary tumorigenesis, we tested the hypothesis that transforming growth factor (TGF)-?s are useful biomarkers of chemopreventive efficacy in the breast. The chemopreventive agents tested were tamoxifen and the retinoids 9-cis-retinoic acid (9cRA) and N-(4-hydroxyphenyl)retinamide (4-HPR), because both antiestrogens and retinoids have previously been shown to upregulate TGF-?s in vitro. Despite demonstrable chemopreventive efficacy in this model, none of these agents, alone or in combination, had any significant impact on the expression of TGF-?s in the mammary ductal epithelium or periductal stroma as determined by immunohistochemistry. These data suggest that TGF-?s are not likely to be useful biomarkers of chemopreventive efficacy in a clinical setting.

Zujewski, JoAnne; Vaughn-Cooke, Anika; Flanders, Kathleen C; Eckhaus, Michael A; Lubet, Ronald A; Wakefield, Lalage M

2001-01-01

77

Look back in anger - what clinical studies tell us about preclinical work.  

PubMed

Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies. PMID:23861075

Hartung, Thomas

2013-01-01

78

Food for Thought Look Back in Anger - What Clinical Studies Tell Us About Preclinical Work  

PubMed Central

Summary Misled by animal studies and basic research? Whenever we take a closer look at the outcome of clinical trials in a field such as, most recently, stroke or septic shock, we see how limited the value of our preclinical models was. For all indications, 95% of drugs that enter clinical trials do not make it to the market, despite all promise of the (animal) models used to develop them. Drug development has started already to decrease its reliance on animal models: In Europe, for example, despite increasing R&D expenditure, animal use by pharmaceutical companies dropped by more than 25% from 2005 to 2008. In vitro studies are likewise limited: questionable cell authenticity, over-passaging, mycoplasma infections, and lack of differentiation as well as non-homeostatic and non-physiologic culture conditions endanger the relevance of these models. The standards of statistics and reporting often are poor, further impairing reliability. Alarming studies from industry show miserable reproducibility of landmark studies. This paper discusses factors contributing to the lack of reproducibility and relevance of pre-clinical research. The conclusion: Publish less but of better quality and do not rely on the face value of animal studies.

Hartung, Thomas

2013-01-01

79

Comparative Plasma Exposure and Lung Distribution of Two Human Use Commercial Azithromycin Formulations Assessed in Murine Model: A Preclinical Study  

PubMed Central

Azithromycin (AZM) therapeutic failure and relapses of patients treated with generic formulations have been observed in clinical practice. The main goal of this research was to compare in a preclinical study the serum exposure and lung tissue concentration of two commercial formulations AZM-based in murine model. The current study involved 264 healthy Balb-C. Mice were divided into two groups (n = 44): animals of Group A (reference formulation -R-) were orally treated with AZM suspension at 10?mg/kg of b.w. Experimental animals of Group B (generic formulation -G-) received identical treatment than Group A with a generic formulation AZM-based. The study was repeated twice as Phase II and III. Serum and lung tissue samples were taken 24?h post treatment. Validated microbiological assay was used to determine the serum pharmacokinetic and lung distribution of AZM. After the pharmacokinetic analysis was observed, a similar serum exposure for both formulations of AZM assayed. In contrast, statistical differences (P < 0.001) were obtained after comparing the concentrations of both formulations in lung tissue, being the values obtained for AUC and Cmax (AZM-R-) +1586 and 122%, respectively, than those obtained for AZM-G- in lung. These differences may indicate large differences on the distribution process of both formulations, which may explain the lack of efficacy/therapeutic failure observed on clinical practice.

Rivulgo, Virginia; Sparo, Monica; Ceci, Monica; Fumuso, Elida; Confalonieri, Alejandra; Sanchez Bruni, Sergio F.

2013-01-01

80

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents  

PubMed Central

In the current paradigm of anticancer drug development, candidate compounds are evaluated by testing their in vitro potency against molecular targets relevant to carcinogenesis, their effect on cultured cancer cells, and their ability to inhibit cancer growth in animal models. We discuss the key assumptions inherent in these approaches. In recent years, great emphasis has been placed on selecting for development compounds with nanomolar in vitro potency, expecting that they will be efficacious and safer based on the assumption that they can be used at lower doses (“the nanomolar rule”). However, this rule ignores critical parameters affecting efficacy and toxicity such as physiochemical and absorption, distribution, metabolism and excretion properties, off-target effects, and multitargeting activities. Thus, uncritical application of the nanomolar rule may reject efficacious compounds or select ineffective or toxic compounds. We present examples of efficacious chemotherapeutic (alkylating agents, hormonal agents, antimetabolites, thalidomide, and valproic acid) and chemopreventive (aspirin and sulindac) agents having millimolar potency and compounds with nanomolar potency (cyclooxygenase-2 inhibitors) that, nevertheless, failed or proved to be unsafe. The effect of candidate drugs on animal models of cancer is a better predictor of human drug efficacy; particularly useful are tumor xenografts. Given the cost of failure at clinical stages, it is imperative to keep in mind the limitations of the nanomolar rule and use relevant in vivo models early in drug discovery to prioritize candidates. Although in vivo models will continue having a major role in cancer drug development, more robust approaches that combine high predictive ability with simplicity and low cost should be developed.

Wong, C. C.; Cheng, Ka-Wing

2012-01-01

81

Platinum formulations as anticancer drugs clinical and pre-clinical studies.  

PubMed

This review summarizes clinical and pre-clinical results on platinum anti-cancer drug formulations. A concise summary of the use of oxidation state to modulate cancer pharmacology is given for Pt(IV) complexes, distinct from the clinically used Pt(II) drugs. The chemistry of platinum drug formulation combines aspects of kinetics of active moiety release from nominally weak-binding ligands (bond cleavage from platinum-carboxylate and platinum-phosphate) in polymers and nanoparticles with pharmacological considerations of plasma distribution and cellular accumulation. The action of any molecular entity as a drug is influenced by its ADME profile--absorption, distribution, metabolism and excretion. The purpose of drug formulation is to alter any or all of these parameters with the ultimate goal of improving the efficacy and reducing side effects with the possibility to target drugs directly to the tumor site. The diverse array of approaches includes liposomes, polymers (not limited to peptides, dendrimers, biodegradable polymers, polysaccharides, and metallic nanoparticles). Functionalization of the surfaces of nanoparticles with antibodies or cellular surface recognition motifs may further target specific cancers. PMID:22039867

P Farrell, Nicholas

2011-01-01

82

Advanced Pre-Clinical Research Approaches and Models to Studying Pediatric Anesthetic Neurotoxicity  

PubMed Central

Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non-human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticated research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey model (in vivo), when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course, and developmental stage at time of exposure (in vivo studies), serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre-clinical data to the human condition.

Wang, Cheng

2012-01-01

83

Inhibition of Aurora-B kinase activity confers antitumor efficacy in preclinical mouse models of early and advanced gastrointestinal neoplasia.  

PubMed

The Aurora family of kinases, play a fundamental role in cell division and are overexpressed in several cancers including colon. The activity of barasertib-hQPA, a selective inhibitor of Aurora-B kinase (ABK) was investigated in a range of preclinical models of gastrointestinal cancer. Treatment with barasertib-hQPA produced anti-proliferative and cytotoxic effects across a panel of human colorectal cancer (CRC) cell lines in vitro. Prodrug, barasertib [48-h subcutaneous (s.c.) infusion; 150 mg/kg/day] inhibited the growth of SW620, Colo205, HCT116 human colorectal tumor xenografts in nude mice significantly (Student's t-test, P<0.05, n=10-12 per group). Flow cytometric analysis of single cells from disaggregated barasertib-treated SW620 tumors revealed a decrease in phosphorylated histone H3 (phH3) and an increase in tumor cells with ?4N DNA content P<0.05). The activity of barasertib was then examined in ApcMin/+ mice, a spontaneous model of early intestinal neoplasia. Macroscopic evaluation of the small intestine revealed that barasertib treatment [25 mg/kg intra-peritoneal (i.p.) Q1Dx4 each week for 3 weeks] of 8-week old ApcMin/+ mice produced a 39% reduction in macroadenoma number (P=0.02) and a 43% reduction in overall adenoma burden (P=0.02) compared with vehicle-treated controls. Quantification of microscopic adenomas revealed a >64% reduction in the number of adenomas spanning more than one villus. Histological analysis of these adenomas revealed a number of distinct changes in barasertib-treated ApcMin/+ mice, including a 94% reduction in the proportion of phospho-histone H3-positive cells (P<0.001) and a 53% reduction in the number of cells per adenoma (P=0.001). These results provide a scientific rationale for investigating ABK inhibitors as a treatment for intestinal cancer. PMID:22858681

Alferez, Denis G; Goodlad, Robert A; Odedra, Rajesh; Sini, Patrizia; Crafter, Claire; Ryan, Anderson J; Wedge, Stephen R; Wright, Nicholas A; Anderson, Elizabeth; Wilkinson, Robert W

2012-07-31

84

Wireless video capsule enteroscopy in preclinical studies: methodical design of its applicability in experimental pigs.  

PubMed

The aim of this project was to develop a methodology to introduce wireless video capsule endoscopy in preclinical research. Five mature female pigs (Sus scrofa domestica) were selected for the study. Capsule endoscopes (the EndoCapsule system; Olympus) were introduced into the duodenum endoscopically in each of the animals. The life span of batteries (i.e., total time of endoscopy recording) was 487-540 min (median 492 min). The capsule endoscope reached the cecum during enteroscopy once (after 7 h 57 min), in the remaining cases, endoscopy recordings terminated in the distal or terminal ileum. All capsule enteroscopies found a normal pattern of the small intestine. The intestinal lumen is narrower, transverse folds are sparse or even absent, villi are wider but less prominent in pigs compared to humans. Capsule endoscopy in experimental pigs will be helpful for future trials on injury of different drugs and xenobiotics to the small bowel. PMID:19294508

Kopácová, Marcela; Tachecí, Ilja; Kvetina, Jaroslav; Bures, Jan; Kunes, Martin; Spelda, Stanislav; Tycová, Vera; Svoboda, Zbynek; Rejchrt, Stanislav

2009-03-18

85

Assessment of candidate biomarkers of drug-induced hepatobiliary injury in preclinical toxicity studies.  

PubMed

This study was designed to assess the value of a set of potential markers for improved detection of liver injury in preclinical toxicity studies. Male Wistar rats were treated with drug candidates (BAY16, EMD335823, BI-3) that previously failed during development, in part due to hepatotoxicity, at two dose levels for 1, 3 and 14 days. Concentrations of lipocalin-2/NGAL and clusterin, which are frequently overexpressed and released from damaged tissues, and thiostatin, recently identified within PredTox as being elevated in urine in response to liver injury, were determined in rat urine and serum by ELISA. This was supplemented by confirmatory qRT-PCR and immunohistochemical analyses in the target organ. Serum paraoxonase-1 activity (PON1), which has been suggested as a marker of hepatotoxicity, was determined using a fluorometric assay. Clusterin and PON1 were not consistently altered in response to liver injury. In contrast, thiostatin and NGAL were increased in serum and urine of treated animals in a time- and dose-dependent manner. These changes correlated well with mRNA expression in the target organ and generally reflected the onset and degree of drug-induced liver injury. Receiver-operating characteristics (ROC) analyses supported serum thiostatin, but not NGAL, as a better indicator of drug-induced hepatobiliary injury than conventional clinical chemistry parameters, i.e. ALP, ALT and AST. Although thiostatin, an acute phase protein expressed in a range of tissues, may not be specific for liver injury, our results indicate that thiostatin may serve as a sensitive, minimally-invasive diagnostic marker of inflammation and tissue damage in preclinical safety assessment. PMID:20362651

Adler, M; Hoffmann, D; Ellinger-Ziegelbauer, H; Hewitt, P; Matheis, K; Mulrane, L; Gallagher, W M; Callanan, J J; Suter, L; Fountoulakis, M M; Dekant, W; Mally, A

2010-04-01

86

Integration of preclinical and clinical knowledge to predict intravenous PK in human: Bilastine case study.  

PubMed

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes. PMID:23619917

Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

2013-04-26

87

The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is a debilitating neurodegenerative disorder associated with severe motor impairments caused by the loss of dopaminergic innervation of the striatum. Previous studies have demonstrated that positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGlu?), including N-phenyl-7-(hydroxyimino) cyclopropa[b]chromen-1a-carboxamide, can produce antiparkinsonian-like effects in preclinical models of PD. However, these early mGlu? PAMsexhibited unsuitable physiochemical properties for systemic dosing, requiring intracerebroventricular administration and limiting their broader utility as in vivo tools to further understand the role of mGlu? in the modulation of basal ganglia function relevant to PD. In the present study, we describe the pharmacologic characterization of a systemically active mGlu? PAM, N-(3-chlorophenyl)picolinamide (VU0364770), in several rodent PD models. VU0364770 showed efficacy alone or when administered in combination with L-DOPA or an adenosine 2A (A2A) receptor antagonist currently in clinical development (preladenant). When administered alone, VU0364770 exhibited efficacy in reversing haloperidol-induced catalepsy, forelimb asymmetry-induced by unilateral 6-hydroxydopamine (6-OHDA) lesions of the median forebrain bundle, and attentional deficits induced by bilateral 6-OHDA nigrostriatal lesions in rats. In addition, VU0364770 enhanced the efficacy of preladenant to reverse haloperidol-induced catalepsy when given in combination. The effects of VU0364770 to reverse forelimb asymmetry were also potentiated when the compound was coadministered with an inactive dose of L-DOPA, suggesting that mGlu? PAMs may provide L-DOPA-sparing activity. The present findings provide exciting support for the potential role of selective mGlu? PAMs as a novel approach for the symptomatic treatment of PD and a possible augmentation strategy with either L-DOPA or A2A antagonists. PMID:22088953

Jones, Carrie K; Bubser, Michael; Thompson, Analisa D; Dickerson, Jonathan W; Turle-Lorenzo, Nathalie; Amalric, Marianne; Blobaum, Anna L; Bridges, Thomas M; Morrison, Ryan D; Jadhav, Satyawan; Engers, Darren W; Italiano, Kimberly; Bode, Jacob; Daniels, J Scott; Lindsley, Craig W; Hopkins, Corey R; Conn, P Jeffrey; Niswender, Colleen M

2011-11-16

88

EFFECTS OF A BICARBONATE-ALKALINE MINERAL WATER ON GASTRIC FUNCTIONS AND FUNCTIONAL DYSPEPSIA: A PRECLINICAL AND CLINICAL STUDY  

Microsoft Academic Search

The present study was performed in order to evaluate: (1) the influence of a bicarbonate-alkaline mineral water (Uliveto®) on digestive symptoms in patients with functional dyspepsia; (2) the effects of Uliveto® on preclinical models of gastric functions. Selected patients complained of dyspeptic symptoms in the absence of digestive lesions or Helicobacter pylori infection within the previous 3 months. They were

MICHELE BERTONI; FILIPPO OLIVERI; MARTA MANGHETTI; ELENA BOCCOLINI; MARIA GRAZIA BELLOMINI; CORRADO BLANDIZZI; FERRUCCIO BONINO; MARIO DEL TACCA

2002-01-01

89

Exercise as a potential treatment for drug abuse: evidence from preclinical studies.  

PubMed

Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations. PMID:22347866

Smith, Mark A; Lynch, Wendy J

2012-01-12

90

Exercise as a Potential Treatment for Drug Abuse: Evidence from Preclinical Studies  

PubMed Central

Epidemiological studies reveal that individuals who engage in regular aerobic exercise are less likely to use and abuse illicit drugs. Until recently, very few studies had examined the causal influences that mediate this relationship, and it was not clear whether exercise was effective at reducing substance use and abuse. In the past few years, several preclinical studies have revealed that exercise reduces drug self-administration in laboratory animals. These studies have revealed that exercise produces protective effects in procedures designed to model different transitional phases that occur during the development of, and recover from, a substance use disorder (e.g., acquisition, maintenance, escalation, and relapse/reinstatement of drug use). Moreover, recent studies have revealed several behavioral and neurobiological consequences of exercise that may be responsible for its protective effects in these assays. Collectively, these studies have provided convincing evidence to support the development of exercise-based interventions to reduce compulsive patterns of drug intake in clinical and at-risk populations.

Smith, Mark A.; Lynch, Wendy J.

2012-01-01

91

Preclinical stroke research - advantages and disadvantages of the most common rodent models of focal ischaemia  

PubMed Central

This review describes the most commonly used rodent models and outcome measures in preclinical stroke research and discusses their strengths and limitations. Most models involve permanent or transient middle cerebral artery occlusion with therapeutic agents tested for their ability to reduce stroke-induced infarcts and improve neurological deficits. Many drugs have demonstrated preclinical efficacy but, other than thrombolytics, which restore blood flow, none have demonstrated efficacy in clinical trials. This failure to translate efficacy from bench to bedside is discussed alongside achievable steps to improve the ability of preclinical research to predict clinical efficacy: (i) Improvements in study quality and reporting. Study design must include randomization, blinding and predefined inclusion/exclusion criteria, and journal editors have the power to ensure statements on these and mortality data are included in preclinical publications. (ii) Negative and neutral studies must be published to enable preclinical meta-analyses and systematic reviews to more accurately predict drug efficacy in man. (iii) Preclinical groups should work within networks and agree on standardized procedures for assessing final infarct and functional outcome. This will improve research quality, timeliness and translational capacity. (iv) Greater uptake and improvements in non-invasive diagnostic imaging to detect and study potentially salvageable penumbral tissue, the target for acute neuroprotection. Drug effects on penumbra lifespan studied serially, followed by assessment of behavioural outcome and infarct within in the same animal group, will increase the power to detect drug efficacy preclinically. Similar progress in detecting drug efficacy clinically will follow from patient recruitment into acute stroke trials based on evidence of remaining penumbra. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4

Macrae, IM

2011-01-01

92

Effects of a bicarbonate-alkaline mineral water on gastric functions and functional dyspepsia: a preclinical and clinical study.  

PubMed

The present study was performed in order to evaluate: (1) the influence of a bicarbonate-alkaline mineral water (Uliveto) on digestive symptoms in patients with functional dyspepsia; (2) the effects of Uliveto on preclinical models of gastric functions. Selected patients complained of dyspeptic symptoms in the absence of digestive lesions or Helicobacter pylori infection within the previous 3 months. They were treated with Uliveto water (1.5 l day(-1)) for 30 days. Frequency and severity of symptoms were assessed at baseline and day 30 by a score system. Preclinical experiments were carried out on rats, allowed to drink Uliveto or oligomineral water for 30 days. Animals then underwent pylorus ligation to evaluate gastric secretion of acid, pepsinogen, and mucus. In separate experiments, gastric emptying was assessed. Crenotherapy was associated with a relief of epigastric pain, retrosternal pyrosis, postprandial fullness and gastric distention. At preclinical level, Uliveto water increased acid and pepsinogen secretions as well as gastric emptying, without changes in bound mucus. The enhancing actions of Uliveto on gastric secretions and emptying were prevented by L-365,260, an antagonist of gastrin/CCK-2 receptors. These findings indicate that a regular intake of Uliveto favors an improvement of dyspeptic symptoms. The preclinical study suggests that the clinical actions of Uliveto water depend mainly on its ability to enhance gastric motor and secretory functions. PMID:12457626

Bertoni, Michele; Olivieri, Filippo; manghetti, Marta; Boccolini, Elena; Bellomini, Maria Grazia; Blandizzi, Corrado; Bonino, Ferruccio; Del Tacca, Mario

2002-12-01

93

Preclinical Studies with Umbilical Cord Mesenchymal Stromal Cells in Different Animal Models for Muscular Dystrophy  

PubMed Central

Umbilical cord mesenchymal stromal cells (MSC) have been widely investigated for cell-based therapy studies as an alternative source to bone marrow transplantation. Umbilical cord tissue is a rich source of MSCs with potential to derivate at least muscle, cartilage, fat, and bone cells in vitro. The possibility to replace the defective muscle cells using cell therapy is a promising approach for the treatment of progressive muscular dystrophies (PMDs), independently of the specific gene mutation. Therefore, preclinical studies in different models of muscular dystrophies are of utmost importance. The main objective of the present study is to evaluate if umbilical cord MSCs have the potential to reach and differentiate into muscle cells in vivo in two animal models of PMDs. In order to address this question we injected (1) human umbilical cord tissue (hUCT) MSCs into the caudal vein of SJL mice; (2) hUCT and canine umbilical cord vein (cUCV) MSCs intra-arterially in GRMD dogs. Our results here reported support the safety of the procedure and indicate that the injected cells could engraft in the host muscle in both animal models but could not differentiate into muscle cells. These observations may provide important information aiming future therapy for muscular dystrophies.

Zucconi, Eder; Vieira, Natassia Moreira; Bueno, Carlos Roberto; Secco, Mariane; Jazedje, Tatiana; Costa Valadares, Marcos; Fussae Suzuki, Miriam; Bartolini, Paolo; Vainzof, Mariz; Zatz, Mayana

2011-01-01

94

Some Preclinical Studies on the Development of a Purified Gonococcal Pilus Vaccine for Gonorrhea.  

National Technical Information Service (NTIS)

Purified gonococcal pilus vaccines of two serological specificities were prepared, tested and evaluated in chimpanzees for safety, antigenicity, efficacy, cross-antigenicity and cross-efficacy. They proved to be safe and antigenic but not efficacious agai...

C. C. Brinton

1980-01-01

95

Preclinical Pharmacology, Efficacy and Safety of Varenicline in Smoking Cessation and Clinical Utility in High Risk Patients.  

PubMed

Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain ?(4)?(2) nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel ?(4)?(2) nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing post-marketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, and depression, psychosis, as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles or heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline. PMID:21278851

Xi, Zheng-Xiong

2010-04-01

96

Preclinical pharmacology, efficacy, and safety of varenicline in smoking cessation and clinical utility in high risk patients  

PubMed Central

Smoking is still the most prominent cause of preventable premature death in the United States and an increasing cause of morbidity and mortality throughout the world. Although the current treatments such as nicotine replacement therapy (NRT) and bupropion are effective, long-term abstinence rates are low. Mechanism studies suggest that the pleasurable effects of smoking are mediated predominantly by nicotine, which activates the brain reward system by activation of brain ?4?2 nicotinic acetylcholine receptors (nAChRs). Varenicline is a novel ?4?2 nAChR partial agonist and has been found to be even more effective than NRT or bupropion in attenuating smoking satisfaction and in relieving craving and withdrawal symptoms after abstinence. Thus, varenicline has been recently approved to be a first-line medication for smoking cessation in the United States and European countries. Varenicline is generally well tolerated in healthy adult smokers, with the most commonly reported adverse effects being nausea, insomnia, and headache. However, growing postmarketing data has linked varenicline to an increase in neuropsychiatric symptoms such as seizures, suicidal attempts, depression, and psychosis as well as serious injuries potentially relating to unconsciousness, dizziness, visual disturbances, or movement disorders. Therefore, new safety warnings are issued to certain high risk populations, such as patients with mental illness and operators of commercial vehicles and heavy machinery. In particular, pilots, air traffic controllers, truck and bus drivers have been banned from taking varenicline.

Xi, Zheng-Xiong

2010-01-01

97

Integration of efficacy, pharmacokinetic and safety assessment of interleukin-1 receptor antagonist in a preclinical model of arthritis.  

PubMed

Pharmacokinetic properties and safety profile of a drug are likely influenced by the disease state of a patient. In this study, we investigated the influence of arthritic processes on pharmacokinetics and immunotoxicity of interleukin-1 receptor antagonist (Anakinra) in the rat adjuvant arthritis model. Anakinra dose-dependently suppressed joint inflammation and degradation as demonstrated by reduced clinical arthritis score, paw thickness, synovial infiltration and bone degradation. In addition, plasma levels of chemokines MCP-1 and GRO/KC were reduced. Pharmacokinetic behaviour of Anakinra was influenced by disease state of the rats as judged from a decrease in C(max) and an increase of the MRT as the disease progressed at a dose of 24 and 72 mg Anakinra/kg body weight. The pharmacokinetic parameters increased dose-dependently, but non-proportionally with increasing dose. Low level anti-Anakinra antibody formation was observed at prolonged exposure to the biologic. Safety parameters, including haematology, splenic lymphocyte subset analysis, ex vivo stimulation of spleen cells and histopathology of immune system organs were affected by the disease itself to such extent that no additional effects of Anakinra could be observed. In conclusion, we demonstrated that pharmacokinetic behaviour of Anakinra was influenced by the arthritis background of the rats resulting in decreased internal exposure. PMID:21300126

Zuurmond, Anne-Marie; Koudijs, Angela; van El, Benno; Doornbos, Robert P; van Manen-Vernooij, Babs C T; Bastiaans, Jacqueline H M W; Penninks, André H; van Bilsen, Jolanda H M; Cnubben, Nicole H P; Degroot, Jeroen

2011-02-12

98

IGF ACTIVATION IN A MOLECULAR SUBCLASS OF HEPATOCELLULAR CARCINOMA AND PRE-CLINICAL EFFICACY OF IGF-1R BLOCKAGE  

PubMed Central

Background/Aims IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway Methods An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC Results Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 –resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R 25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivoA12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis Conclusions Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.

Tovar, Victoria; Alsinet, Clara; Villanueva, Augusto; Hoshida, Yujin; Chiang, Derek Y.; Sole, Manel; Thung, Swan; Moyano, Susana; Toffanin, Sara; Minguez, Beatriz; Cabellos, Laia; Peix, Judit; Schwartz, Myron; Mazzaferro, Vincenzo; Bruix, Jordi; Llovet, Josep M.

2013-01-01

99

Facilitating Multimodal Preclinical Imaging Studies in Mice by Using an Immobilization Bed  

PubMed Central

We have designed an immobilization bed that accommodates mice of all ages and sizes, to improve image registration for multimodal scans and for longitudinal preclinical imaging studies. Stationary pegs were placed such that they effectively immobilized mice and reduced set-up time. 22Na fiducial markers were placed into the pegs at unique depths to provide 3D references to facilitate image registration. Multiple users registered positron emission tomographic (PET) and CT data obtained with and without the bed to examine the effect of the bed on registration accuracy and interuser variability. The image registrations performed by different users were evaluated for their similarity by using the Entropy Correlation Coefficient as a metric. The immobilization bed significantly reduced variations in body movement and interuser variability. Average differences in quantification of tumor PET signal among users when registering images without versus with the fiduciary-marker bed fell from 9.1% to 0.8% for maximal percentage injected dose per gram (%ID/g), from 15.6% to 2.3% for mean %ID/g, and from 9.4% to 0.7% for the 90th percentile of the maximum %ID/g. The bed improves animal immobilization, greatly reduces interuser variability, and supports registration of image data acquired from different imaging sessions.

Nelson, Geoffrey S; Perez, Jessica; Colomer, Marta V; Ali, Rehan; Graves, Edward

2011-01-01

100

Preclinical animal study and clinical trail of modified extraoral craniofacial implants.  

PubMed

We report on our experience using a new endosseous implant designed to provide sufficient retention to various types of facial prostheses. In a preclinical animal experiment implants (N=12, 4 x 3.5 mm) were placed in the frontal calvarial region of nine adult pigs. The animals were sacrificed at 2, 4 and 8 weeks to evaluate the implant incorporation microradiographically. The clinical outcome and patient satisfaction of implant-retained prostheses were evaluated in a group of 10 patients with facial defects by using clinical assessment and standardized questionnaires for patients and relatives. In the prospective clinical study 33 identical modified implants for extraoral anchorage were placed for the fixation of various prostheses in the midfacial (eye, nose) and ear regions in the course of a clinical trial and observed over a follow-up period of 34 months. The bone-implant contact in the animal experiment reached 31% (+/-2) at 2 weeks, 39% (+/-1) after 4 weeks and 51% (+/-5) at 8 weeks. In the clinical trial, no implants were lost and all implants remained osseointegrated as confirmed clinically and radiographically, providing a stable prosthetic restoration. The analysis of the questionnaire indicates an improvement of the quality of life of patients with respect to aesthetic and psychological well-being. The results demonstrate that extraoral implants not only achieve sufficient osseointegration but also show good clinical handling and easy fixation possibilities for prosthetic anchorage. PMID:17392045

Petrovic, L; Schlegel, K A; Wiltfang, J; Neukam, F W; Rupprecht, S

2007-01-31

101

PRECLINICAL AND CLINICAL STUDIES ON THE INDUCTION OF RENAL ALLOGRAFT TOLERANCE THROUGH TRANSIENT MIXED CHIMERISM  

PubMed Central

Purpose of review This review updates the current status of research for induction of tolerance through a mixed chimerism approach in nonhuman primates and humans. Recent findings Allograft tolerance has been successfully achieved with a nonmyeloablative conditioning regimen and donor bone marrow transplantation in HLA-matched and mismatched kidney transplantation. In HLA-matched kidney transplantation, persistent mixed chimerism and renal allograft tolerance has been achieved in some patients. In HLA-mismatched combinations, induction of persistent mixed chimerism has not been achieved using a nonmyeloablative preparative regimen. Nevertheless, the transient mixed chimerism that has been achieved has resulted in long-term renal allograft tolerance in the majority of patients. Recent preclinical studies have demonstrated that the presence of heterologous memory T cell responses observed in primates, but not in rodents, may be a major barrier for induction of durable chimerism and tolerance in primates. Strategies to overcome such memory T cell responses may therefore be of great value in the development of reliable protocols for clinical tolerance induction. Summary Induction of tolerance in clinical kidney transplantation has been achieved via mixed chimerism approaches. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs and to organs from deceased donors will all be among the next steps in bringing tolerance to a wider range of clinical applications.

Kawai, Tatsuo; Cosimi, A. Benedict; Sachs, David H.

2011-01-01

102

Preclinical evaluation of Rh2 in PC3 human xenograft model for prostate cancer in vivo: formulation, pharmacokinetics, biodistribution and efficacy  

Microsoft Academic Search

Purpose  This study assesses the pharmacokinetics, biodistribution and efficacy of ginsenoside Rh2 as a single agent administered in\\u000a a novel oral dosage formulation.\\u000a \\u000a \\u000a \\u000a Methods  A novel oral dosage formulation of Rh2 has been described. Rh2 levels in blood and tissues following administration to nu\\/nu\\u000a nude mice were determined by high performance liquid chromatography tandem mass spectroscopy. Efficacy was determined in an\\u000a established

Alain G. Musende; Andy Eberding; Catherine Wood; Hans Adomat; Ladan Fazli; Antonio Hurtado-Coll; William Jia; Marcel B. Bally; Emma Tomlinson Guns

2009-01-01

103

Application of micro-ct assessment of 3-d bone microstructure in preclinical and clinical studies  

Microsoft Academic Search

As the mechanical competence of trabecular bone is a function of its apparent density and 3-D distribution, assessment of\\u000a 3-D trabecular structural characteristics may improve our ability to understand the pathophysiology of osteoporosis, to test\\u000a the efficacy of pharmaceutical intervention, and to estimate bone biomechanical properties. We have studied ovariectomy-induced\\u000a osteopenia in rats and its treatment with agents such as

Yebin Jiang; Jenny Zhao; Er-Yuan Liao; Ru-Chun Dai; Xian-Ping Wu; Harry K. Genant

2005-01-01

104

A Preclinical Study of the Effects of Seabuckthorn (Hippophae rhamnoides L.) Leaf Extract on Cutaneous Wound Healing in Albino Rats  

Microsoft Academic Search

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on

Asheesh Gupta; Ratan Kumar; Karan Pal; Pratul K. Banerjee; Ramesh C. Sawhney

2005-01-01

105

Pharmacokinetics of chemotherapeutic agents in pregnancy: a preclinical and clinical study  

Microsoft Academic Search

OBJECTIVE: To determine the impact of physiologic changes of pregnancy on pharmacokinetics of chemotherapeutic agents. DESIGN: A preclinical and a clinical case-control trial. SETTING: Institute of Primate Research Nairobi and collaborating hospitals in Belgium, the Netherlands and Czech Republic. POPULATION: Pregnant and nonpregnant women and baboons receiving chemotherapy. METHODS: Chemotherapy pharmacokinetics was compared between the pregnant and nonpregnant state. Standard-dosed

K. van Calsteren; R. Verbesselt; N. Ottevanger; M. Halaska; L. Heyns; R. de Bree; E. de Bruijn; D. Chai; M. Delforge; L. Noens; V. Renard; E. Witteveen; L. Rob; J. de Hoon; F. Amant

2010-01-01

106

Developing a Measurement Tool for Assessing Physiotherapy Students' Self-Efficacy: A Pilot Study  

ERIC Educational Resources Information Center

|The aim of this research was to determine if self-efficacy can be correlated with prior academic achievement and whether self-efficacy can be an outcome measure of education. A self-efficacy instrument was developed and administered to physiotherapy students following completion of their pre-clinical theory experience. The questionnaire results…

Jones, Anne; Sheppard, Lorraine

2012-01-01

107

Timing of Decompressive Surgery of Spinal Cord after Traumatic Spinal Cord Injury: An Evidence-Based Examination of Pre-Clinical and Clinical Studies  

PubMed Central

Abstract While the recommendations for spine surgery in specific cases of acute traumatic spinal cord injury (SCI) are well recognized, there is considerable uncertainty regarding the role of the timing of surgical decompression of the spinal cord in the management of patients with SCI. Given this, we sought to critically review the literature regarding the pre-clinical and clinical evidence on the potential impact of timing of surgical decompression of the spinal cord on outcomes after traumatic SCI. The primary literature search was performed using MEDLINE, CINAHL, EMBASE, and Cochrane databases. A secondary search strategy incorporated articles referenced in prior meta-analyses and systematic and nonsystematic review articles. Two reviewers independently assessed every study with regard to eligibility, level of evidence, and study quality. Of 198 abstracts of pre-clinical studies, 19 experimental studies using animal SCI models fulfilled our inclusion and exclusion criteria. Despite some discrepancies in the results of those pre-clinical studies, there is evidence for a biological rationale to support early decompression of the spinal cord. Of 153 abstracts of clinical studies, 22 fulfilled the inclusion and exclusion criteria. While the vast majority of the clinical studies were level-4 evidence, there were two studies of level-2b evidence. The quality assessment scores varied from 7 to 25 with a mean value of 12.41. While 2 of 22 clinical studies assessed feasibility and safety, 20 clinical studies examined efficacy of early surgical intervention to stabilize and align the spine and to decompress the spinal cord; the most common definitions of early operation used 24 and 72?h after SCI as timelines. A number of studies indicated that patients who undergo early surgical decompression can have similar outcomes to patients who received a delayed decompressive operation. However, there is evidence to suggest that early surgical intervention is safe and feasible and that it can improve clinical and neurological outcomes and reduce health care costs. Based on the current clinical evidence using a Delphi process, an expert panel recommended that early surgical intervention should be considered in all patients from 8 to 24?h following acute traumatic SCI.

Furlan, Julio C.; Noonan, Vanessa; Cadotte, David W.

2011-01-01

108

Tissue Damage in the Canine Normal Esophagus by Photoactivation with Talaporfin Sodium (Laserphyrin): A Preclinical Study  

PubMed Central

Background Treatment failure at the primary site after chemoradiotherapy is a major problem in achieving a complete response. Photodynamic therapy (PDT) with porfimer sodium (Photofrin®) has some problems such as the requirement for shielding from light for several weeks and a high incidence of skin phototoxicity. PDT with talaporfin sodium (Laserphyrin) is less toxic and is expected to have a better effect compared with Photofrin PDT. However, Laserphyrin PDT is not approved for use in the esophagus. In this preclinical study, we investigated tissue damage of the canine normal esophagus caused by photoactivation with Laserphyrin. Methodology/Principal Findings Diode laser irradiation was performed at 60 min after administration. An area 5 cm oral to the esophagogastric junction was irradiated at 25 J/cm2, 50 J/cm2, and 100 J/cm2 using a three-step escalation. The irradiated areas were evaluated endoscopically on postirradiation days 1 and 7, and were subjected to histological examination after autopsy. The areas injured by photoactivation were 52 mm2, 498 mm2, and 831 mm2 after irradiation at 25 J/cm2, 50 J/cm2, and 100 J/cm2, respectively. Tissue injury was observed in the muscle layer or even deeper at any irradiation level and became more severe as the irradiation dose increased. At 100 J/cm2 both inflammatory changes and necrosis were seen histologically in extra-adventitial tissue. Conclusions/Significance To minimize injury of the normal esophagus by photoactivation with Laserphyrin, diode laser irradiation at 25 J/cm2 appears to be safe. For human application, it would be desirable to investigate the optimal laser dose starting from this level.

Horimatsu, Takahiro; Muto, Manabu; Yoda, Yusuke; Yano, Tomonori; Ezoe, Yasumasa; Miyamoto, Shinichi; Chiba, Tsutomu

2012-01-01

109

Efficient production of recombinant IL-21 proteins for pre-clinical studies by a two-step dilution refolding method.  

PubMed

Produced by CD4(+) helper T cells and natural killer T (NKT) cells, interleukin-21 (IL-21) performs broad regulatory functions on B cells, CD4(+) T cells, CD8(+) T cells, NK cells and NKT cells. Targeting IL-21 to enhance the immune system has attracted great interests in the development of vaccination, anti-infection and anti-tumor therapies. Administration of IL-21 in pre-clinical models is however limited by relatively high expense of the recombinant IL-21 protein. Here, we report a rapid and cost-effective method to produce IL-21 using Escherichia coli (E. coli) by introducing a novel two-step dilution strategy for refolding. The method has been validated to produce milligrams of human IL-21, human IL-21/IL-4 chimera and mouse IL-21 with high bioactivities and low endotoxin, mostly suitable for in vitro and in vivo pre-clinical studies. PMID:23474188

Chen, Zhian; Cui, Yanfang; Leong, Yew Ann; Beddoe, Travis; Yu, Di

2013-03-06

110

Preclinical Toxicology and Biodistribution Studies of Recombinant Adeno-Associated Virus 1 Human Acid ?-Glucosidase.  

PubMed

Abstract A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid ?-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/?g genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/?g gDNA. Vector DNA was present in blood at 24?hr postinjection at up to 1.0×10(6) vg/?g gDNA, followed by a decrease to 1.0×10(3) vg/?g gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections. PMID:24021025

Conlon, Thomas J; Erger, Kirsten; Porvasnik, Stacy; Cossette, Travis; Roberts, Cheryl; Combee, Lynn; Islam, Saleem; Kelley, Jeffry; Cloutier, Denise; Clément, Nathalie; Abernathy, Corinne R; Byrne, Barry J

2013-09-01

111

Irinotecan delivery by microbubble-assisted ultrasound - A pilot preclinical study  

NASA Astrophysics Data System (ADS)

Irinotecan is conventionally used for the treatment of colorectal cancer. However, its administration is associated with severe side effects. Targeted drug delivery using ultrasound (US) combined with microbubbles offers new opportunities to increase the therapeutic effectiveness of antitumor treatment and to reduce toxic exposure to healthy tissues. The objective of this study is to investigate the safety and efficacy of in-vivo delivery of irinotecan by microbubble-assisted US in human glioblastoma model (U-87 MG). In order to validate the potential of this new method in-vivo, subcutaneous tumors were implanted in the flank of nude mouse and treated when they reached a volume of 100 mm3. In the first study, the measured volumes with caliper and anatomic ultrasound imaging were compared for the monitoring and the quantification of tumor growth during 27 days. Ultrasound imaging measurements were positively correlated to caliper measurements. The tumor treatment consisted of an i.v. injection of irinotecan (20 mg/kg) followed one hour later by i.v. administration of MM1 microbubble and an US insonation using a single-element transducer operating at 1MHz (400 kPa, 10 kHz PRF 40% DC, 3 min). The therapeutic efficacy was evaluated for 39 days by measuring the tumor volume before and after treatment using a caliper and based on ultrasound images using an 18 MHz probe (Vevo 2100). Our results showed that anatomical ultrasound imaging was as efficient as caliper for the monitoring and the quantification of tumor growth. Moreover, irinotecan delivery by sonoporation induced a significant decrease of glioblastoma tumor volume and an increase of tumor-doubling time compared to the tumor treated by irinotecan alone. In conclusion, this novel therapeutic approach has promising features since it can be used to reduce the injected drug dose and to achieve a better therapeutic efficacy.

Escoffre, Jean-Michel; Novell, Anthony; Serrière, Sophie; Bouakaz, Ayache

2012-11-01

112

Radiopaque contrast media. XLIV - Preclinical studies with a new nonionic contrast agent.  

PubMed

L-5-alpha-hydroxypropionylamino-2,4,6-triiodoisophthalic acid di-(1,3-dihydroxy-2-propylamide), abbreviated Iopamidol, a new non-ionic water soluble contrast agent for angiography, myelography, ventriculography and for contrast reinforced computer-assisted axial tomography is described. Extensive preclinical testing showed favorable physico-chemical features of the new compound, low systemic toxicity, excellent cardiovascular and renal tolerability, very mild effects on the blood-brain barrier and on nervous tissue. PMID:923795

Felder, E; Pitrè, D; Tirone, P

1977-11-01

113

Studies of Rubella Vaccine Efficacy.  

National Technical Information Service (NTIS)

Contents: Vaccine trials - HPV-77, HPV-80, HPV-77/WI-38(6) and HPV-79/PRK-7; Challenge studies of HPV-77 and HPV-77 derived rubella vaccines; Reinfection rubella in an adult with naturally acquired rubella antibody; Ecology of HPV-77 DK-12 rubella vaccine...

B. Portnoy J. M. Leedom

1970-01-01

114

Synthesis, characterization and preclinical studies of two-photon-activated targeted PDT therapeutic triads  

NASA Astrophysics Data System (ADS)

Photodynamic therapy (PDT) continues to evolve into a mature clinical treatment of a variety of cancer types as well as age-related macular degeneration of the eye. However, there are still aspects of PDT that need to be improved in order for greater clinical acceptance. While a number of new PDT photo-sensitizers, sometimes referred to as second- or third- generation therapeutic agents, are currently under clinical investigation, the direct treatment through the skin of subcutaneous tumors deeper than 5 mm remains problematic. Currently approved PDT porphyrin photo-sensitizers, as well as several modified porphyrins (e.g. chlorins, bacteriochlorins, etc.) that are under clinical investigation can be activated at 630-730 nm, but none above 800 nm. It would be highly desirable if new PDT paradigms could be developed that would allow photo-activation deep in the tissue transparency window in the Near-infrared (NIR) above 800 nm to reduce scattering and absorption phenomena that reduce deep tissue PDT efficacy. Rasiris and MPA Technologies have developed new porphyrins that have greatly enhanced two-photon absorption ( P A ) cross-sections and can be activated deep in the NIR (ca. 780-850 nm). These porphyrins can be incorporated into a therapeutic triad that also employs an small molecule targeting agent that directs the triad to over-expressed tumor receptor sites, and a NIR onephoton imaging agent that allows tracking the delivery of the triad to the tumor site, as well as clearance of excess triad from healthy tissue prior to the start of PDT treatment. We are currently using these new triads in efficacy studies with a breast cancer cell line that has been transfected with luciferase genes that allow implanted tumor growth and post- PDT treatment efficacy studies in SCID mouse models by following the rise and decay of the bioluminescence signal. We have also designed highly absorbing and scattering collagen breast cancer phantoms in which we have demonstrated dramatic cell kill to a depth of at least 4 cm. We have also demonstrated that at the wavelength and laser fluences used in the treatment of implanted tumors in the mouse mammary fat pads, there is little, if any, damage to the skin or internal mouse organs. In addition, we have also demonstrated that the implanted tumors can be treated to a depth of more than 1 cm by direct radiation through the dorsal side of the mouse.

Spangler, C. W.; Starkey, J. R.; Rebane, A.; Meng, F.; Gong, A.; Drobizhev, M.

2006-03-01

115

Systematic Approach to Remediation in Basic Science Knowledge for Preclinical Students: A case study  

NASA Astrophysics Data System (ADS)

Remediation of pre-clerkship students for deficits in basic science knowledge should help them overcome their learning deficiencies prior to clerkship. However, very little is known about remediation in basic science knowledge during pre-clerkship. This study utilized the program theory framework to collect and organize mixed methods data of the remediation plan for pre-clerkship students who failed their basic science cognitive examinations in a Canadian medical school. This plan was analyzed using a logic model narrative approach and compared to literature on the learning theories. The analysis showed a remediation plan that was strong on governance and verification of scores, but lacked: clarity and transparency of communication, qualified remedial tutors, individualized diagnosis of learner's deficits, and student centered learning. Participants admitted uncertainty about the efficacy of the remediation process. A remediation framework is proposed that includes student-centered participation, individualized learning plan and activities, deliberate practice, feedback, reflection, and rigorous reassessment.

Amara, Francis

116

Preclinical assessment of the absorption and disposition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor GDC-0980 and prediction of its pharmacokinetics and efficacy in human.  

PubMed

(S)-1-{4-[2-(2-Amino-pyrimidin-5-yl)-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-piperazin-1-yl}-2-hydroxy-propan-1-one (GDC-0980) is a potent and selective inhibitor of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin, two key components of the PI3K pathway, the deregulation of which is associated with the development of many cancers. The objectives of these studies were to characterize the absorption and disposition of GDC-0980 and assess its efficacy in an MCF7-neo/HER2 human breast cancer xenograft model in immunocompromised mice. Studies in parental Madin-Darby canine kidney cells indicated that GDC-0980 had high permeability (P(app) = 18 × 10?? cm/s), suggesting good absorption potential. However, it was found to be a P-glycoprotein and breast cancer resistance protein substrate in transfected cells and in knockout mice studies. Plasma protein binding was low, with the fraction unbound ranging from 29 to 52% across species. GDC-0980 hepatic clearance (CL) was predicted to be low in all of the species tested from hepatocyte incubations. The plasma CL of GDC-0980 was low in mouse (6.30 ml · min?¹ · kg?¹), rat (15.4 ml · min?¹ · kg?¹), and dog (6.37 ml · min?¹ · kg?¹) and moderate in cynomolgus monkey (18.9 ml · min?¹ · kg?¹). Oral bioavailability ranged from 14.4% in monkey to 125% in dog. Predicted human plasma CL and volume of distribution using allometry were 5.1 ml · min?¹ · kg?¹ and 1.8 l/kg, respectively. Parameters estimated from the pharmacokinetic/pharmacodynamic modeling of the MCF7-neo/HER2 xenograft data indicated that the GDC-0980 plasma concentration required for tumor stasis was approximately 0.5 ?M. These parameters, combined with the predicted human pharmacokinetic profile, suggested that 55 mg once daily may be a clinically efficacious dose. GDC-0980 preclinical characterization and the predictions of its human properties supported its clinical development; it is currently in Phase II clinical trials. PMID:22696419

Salphati, Laurent; Pang, Jodie; Plise, Emile G; Lee, Leslie B; Olivero, Alan G; Prior, Wei Wei; Sampath, Deepak; Wong, Susan; Zhang, Xiaolin

2012-06-13

117

Creative Self-Efficacy: An Intervention Study  

ERIC Educational Resources Information Center

|This study examined the effects of creativity training on creative self-efficacy. We developed a creativity course based on social cognitive theory. The course was conducted in two formats: a five-day course and a condensed one-day course. Samples consisted of students and municipality employees (five-day course), and special education teachers…

Mathisen, Gro Ellen; Bronnick, Kolbjorn S.

2009-01-01

118

Long-term safety and efficacy of human-induced pluripotent stem cell (iPS) grafts in a preclinical model of retinitis pigmentosa.  

PubMed

The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell-based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65(rd12)/Rpe65(rd12) mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65(rd12)/Rpe65(rd12) mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss. PMID:22895806

Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H

2012-12-06

119

Long-term Safety and Efficacy of Human-Induced Pluripotent Stem Cell (iPS) Grafts in a Preclinical Model of Retinitis Pigmentosa  

PubMed Central

The U.S. Food and Drug Administration recently approved phase I/II clinical trials for embryonic stem (ES) cell–based retinal pigmented epithelium (RPE) transplantation, but this allograft transplantation requires lifelong immunosuppressive therapy. Autografts from patient-specific induced pluripotent stem (iPS) cells offer an alternative solution to this problem. However, more data are required to establish the safety and efficacy of iPS transplantation in animal models before moving iPS therapy into clinical trials. This study examines the efficacy of iPS transplantation in restoring functional vision in Rpe65rd12/Rpe65rd12 mice, a clinically relevant model of retinitis pigmentosa (RP). Human iPS cells were differentiated into morphologically and functionally RPE-like tissue. Quantitative real-time polymerase chain reaction (RT-PCR) and immunoblots confirmed RPE fate. The iPS-derived RPE cells were injected into the subretinal space of Rpe65rd12/Rpe65rd12 mice at 2 d postnatally. After transplantation, the long-term surviving iPS-derived RPE graft colocalized with the host native RPE cells and assimilated into the host retina without disruption. None of the mice receiving transplants developed tumors over their lifetimes. Furthermore, electroretinogram, a standard method for measuring efficacy in human trials, demonstrated improved visual function in recipients over the lifetime of this RP mouse model. Our study provides the first direct evidence of functional recovery in a clinically relevant model of retinal degeneration using iPS transplantation and supports the feasibility of autologous iPS cell transplantation for retinal and macular degenerations featuring significant RPE loss.

Li, Yao; Tsai, Yi-Ting; Hsu, Chun-Wei; Erol, Deniz; Yang, Jin; Wu, Wen-Hsuan; Davis, Richard J; Egli, Dieter; Tsang, Stephen H

2012-01-01

120

Aerosol measles vaccination in macaques: Preclinical studies of immune responses and safety  

Microsoft Academic Search

The comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston–Zagreb measles virus (MV) vaccine and compared different routes of administration in the immunocompetent and the immunocompromised host. Immunogenicity and protective efficacy of aerosol vaccination using devices similar to those previously

Rik L. de Swart; Thijs Kuiken; Jorge Fernandez-de Castro; Mark J. Papania; John V. Bennett; José L. Valdespino; Phil Minor; Clyde L. Witham; Selma Yüksel; Helma Vos; Geert van Amerongen; Albert D. M. E. Osterhaus

2006-01-01

121

Pre-Clinical Studies of Epigenetic Therapies Targeting Histone Modifiers in Lung Cancer  

PubMed Central

Treatment options for lung cancer patients have been generally limited to standard therapies or targeted interventions which involve a small number of known mutations. Although the targeted therapies are initially successful, they most often result in drug resistance, relapse, and mortality. We now know that the complexity of lung cancer comes not only from genomic changes, but also from aberrant epigenetic regulatory events. Epigenetic therapies have shown promise as single agents in the treatment of hematological malignancies but have yet to meet this expectation in solid tumors thus fostering researchers to pursue new approaches in the development and use of epigenetic interventions. Here, we review some recent pre-clinical findings involving the use of drugs targeting histone modifying enzymes both as single agents and as co-therapies against lung cancer. A greater understanding of the impact of these epigenetic compounds in lung cancer signaling is needed and further evaluation in vivo is warranted in several cases based on the pre-clinical activity of a subset of compounds discussed in this review, including drugs co-targeting HDACs and EGF receptor, targeting Brd4 and targeting Jumonji histone demethylases.

Huffman, Kenneth; Martinez, Elisabeth D.

2013-01-01

122

Preclinical Acute Toxicity Studies and Dosimetry Estimates of the Novel Sigma1 Receptor Radiotracer, [ 18 F]SFE  

Microsoft Academic Search

[18F]1-(2-Fluoroethyl)-4-[(4-cyanophenoxy)methyl]piperidine ([18F]SFE) is a novel, selective, high-affinity sigma-1 receptor radioligand that has been preclinically well characterized in rodents. To support an investigational new drug (IND) application for the first evaluation of [18F]SFE in humans, single-organ and whole-body radiation adsorbed doses associated with [18F]SFE injection were estimated from rat distribution data. In addition, single- and multiple-dose toxicity studies were conducted in

Rikki N. Waterhouse; Jun Zhao; Michael G. Stabin; Hanna Ng; Janice Schindler-Horvat; Raymond C. Chang; Jon C. Mirsalis

2006-01-01

123

Preclinical and clinical progress of particle-mediated DNA vaccines for infectious diseases  

Microsoft Academic Search

This review provides an overview of studies employing particle-mediated epidermal delivery (PMED) or the gene gun to administer DNA vaccines for infectious diseases in preclinical studies employing large animal models and in human clinical trials. It reviews the immunogenicity and protective efficacy of PMED DNA vaccines in nonhuman primates and swine and studies that have directly compared the effectiveness of

Deborah H. Fuller; Peter Loudon; Connie Schmaljohn

2006-01-01

124

Application of tetra-isopalmitoyl ascorbic acid in cosmetic formulations: stability studies and in vivo efficacy.  

PubMed

Liposoluble vitamin C derivatives, such as tetra-isopalmitoyl ascorbic acid (IPAA), are often used in dermocosmetic products due to their higher stability than vitamin C free form as well as its proposed effects in skin; however, there are no studies analyzing IPAA stability or its in vivo effects when present in dermocosmetic formulations. Thus, this study aimed to evaluate chemical stability and pre-clinical and clinical efficacy of dermocosmetic formulations containing IPAA in skin hydration and microrelief. Chemical stability of the formulations added with 1% IPAA was evaluated by heat stress during 35 days by HPLC. For pre-clinical evaluation, experimental formulations were topically applied on hairless skin mice during 5 days and animal skins were analyzed by non-invasive biophysic techniques (water content of stratum corneum, TEWL, viscoelasticity, and microrelief) and by histopathological studies. For clinical efficacy tests, the formulations were topically applied to the forearm and face of human volunteers, and 3h and 15 days after applications, the skins were evaluated by the same non-invasive techniques mentioned before. Results showed that formulations containing IPAA had medium stability and had pronounced moisturizing effects on stratum corneum and on viable epidermis. These formulations also improved skin microrelief especially in relation to skin smoothness and roughness. PMID:22974986

Maia Campos, Patrícia M B G; Gianeti, Mirela D; Camargo, Flávio B; Gaspar, Lorena R

2012-09-05

125

The Humanized NOD/SCID Mouse as a Preclinical Model to Study the Fate of Encapsulated Human Islets  

PubMed Central

Despite encouraging results in animal models, the transplantation of microencapsulated islets into humans has not yet reached the therapeutic level. Recent clinical trials using microencapsulated human islets in barium alginate showed the presence of dense fibrotic overgrowth around the microcapsules with no viable islets. The major reason for this is limited understanding of what occurs when encapsulated human islets are allografted. This warrants the need for a suitable small animal model. In this study, we investigated the usefulness of NOD/SCID mice reconstituted with human PBMCs (called humanized NOD/SCID mice) as a preclinical model. In this model, human T cell engraftment could be achieved, and CD45+ cells were observed in the spleen and peripheral blood. Though the engrafted T cells caused a small fibrotic overgrowth around the microencapsulated human islets, this failed to stop the encapsulated islets from functioning in the diabetic recipient mice. The ability of encapsulated islets to survive in this mouse model might partly be attributed to the presence of Th2 cytokines IL-4 and IL-10, which are known to induce graft tolerance. In conclusion, this study showed that the hu-NOD/SCID mouse is not a suitable preclinical model to study the allograft rejection mechanisms of encapsulated human islets. As another result, the maintained viability of transplanted islets on the NOD/SCID background emphasized a critical role of protective mechanisms in autoimmune diabetes transplanted subjects due to specific immunoregulatory effects provided by IL-4 and IL-10.

Vaithilingam, Vijayaganapathy; Oberholzer, Jose; Guillemin, Gilles J.; Tuch, Bernard E.

2010-01-01

126

Cardiac arterial spin labeling using segmented ECG-gated Look-Locker FAIR: variability and repeatability in preclinical studies.  

PubMed

MRI is important for the assessment of cardiac structure and function in preclinical studies of cardiac disease. Arterial spin labeling techniques can be used to measure perfusion noninvasively. In this study, an electrocardiogram-gated Look-Locker sequence with segmented k-space acquisition has been implemented to acquire single slice arterial spin labeling data sets in 15 min in the mouse heart. A data logger was introduced to improve data quality by: (1) allowing automated rejection of respiration-corrupted images, (2) providing additional prospective gating to improve consistency of acquisition timing, and (3) allowing the recombination of uncorrupted k-space lines from consecutive data sets to reduce respiration corruption. Finally, variability and repeatability of perfusion estimation within-session, between-session, between-animal, and between image rejection criteria were assessed in mice. The criterion used to reject images from the T(1) fit was shown to affect the perfusion estimation. These data showed that the between-animal coefficient of variability (24%) was greater than the between-session variability (17%) and within-session variability (11%). Furthermore, the magnitude of change in perfusion required to detect differences was 30% (within-session) and 55% (between-session) according to Bland-Altman repeatability analysis. These technique developments and repeatability statistics will provide a platform for future preclinical studies applying cardiac arterial spin labeling. PMID:22411842

Campbell-Washburn, Adrienne E; Price, Anthony N; Wells, Jack A; Thomas, David L; Ordidge, Roger J; Lythgoe, Mark F

2012-03-12

127

Evaluation of wound healing activity of Lantana camara L. - a preclinical study.  

PubMed

Lantana camara is used in herbal medicine for the treatment of skin itches, as an antiseptic for wounds, and externally for leprosy and scabies. The objective of our study was to investigate excision wound healing activity of the leaf extract of L. camara in rats. The animals were divided into two groups of 12 each in both the models. The test group animals were treated with the aqueous extract of L. camara (100 mg/kg/day) topically and the control group animals were left untreated. Wound healing efficacy was measured by determining the morphological and biochemical parameters. Wound healing time, wound contraction and synthesis of collagen were monitored periodically. Antimicrobial activities of the extract against the microorganisms were also assessed. Treatment of the wounds with extract enhanced significantly the rate of wound contraction (98%), synthesis of collagen and decreased mean wound healing time. These studies demonstrate that L. camara is effective in healing excision wounds in the experimental animal and could be evaluated as a therapeutic agent in tissue repair processes associated with skin injuries. PMID:18844241

Nayak, B Shivananda; Raju, S Sivachandra; Eversley, Mathew; Ramsubhag, Adash

2009-02-01

128

Novel direct factor IIa and Xa inhibitors: mechanisms of action and preclinical studies.  

PubMed

The need to overcome certain limitations of the existing anticoagulant agents (heparin, LMWH and VKAs) and to achieve more convenient long-term anticoagulation has fueled the quest for the "ideal anticoagulant", an agent that would exert at least similar antithrombotic effects with a substantially improved pharmacologic profile and significantly less bleeding complications. The major disadvantages of the traditional agents were the narrow therapeutic window with serious drug and food interactions and the need for regular blood monitoring. Coagulation factors IIa and Xa have proved the most attractive pharmacologic targets due to their key role in the coagulation process and the opportunity of blocking thrombin generation before the level of thrombin production that results in amplification of the anticoagulant effect while preserving some of thrombin hemostatic effect. This review summarizes the mechanism of action of some of the most promising novel oral direct factor IIa and Xa inhibitors with a focus on published preclinical trials that led to their clinical development. PMID:22564123

Deftereos, Spyridon; Anatoliotakis, Nikolaos; Giannopoulos, Georgios; Kaoukis, Andreas; Mavri, Maria; Pyrgakis, Vlasios; Stefanadis, Christodoulos

2012-08-01

129

Pre-clinical and preliminary dose-finding and safety studies to identify candidate antivenoms for treatment of envenoming by saw-scaled or carpet vipers (Echis ocellatus) in northern Nigeria.  

PubMed

The aim of this study was to identify candidate antivenoms with specific activity against the venom of the saw-scaled or carpet viper (Echis ocellatus) in northern Nigeria, where bites by this species cause great morbidity and mortality but where effective antivenoms have become scarce and unaffordable. Selected antivenoms were destined to be compared by randomised controlled clinical trials (RCTs). Standard pre-clinical neutralisation assays were carried out in rodents. We included two licensed antivenoms of established clinical efficacy and 6 candidate antivenoms. Although 6 of the tested antivenoms showed promising efficacy, all but 3 were excluded from further study because of inadequate pre-clinical efficacy or because they were unavailable or unaffordable for the anticipated RCTs. Median effective doses (ED(50)) of the remaining three candidate antivenoms suggested that the following doses might neutralise the maximum observed venom yield of 24.8 mg (dry weight) of venom milked from captive E. ocellatus: 10 ml of MicroPharm "EchiTAb G" (ET-G) antivenom; 30 ml of Instituto Clodomiro Picado "EchiTAb-Plus-ICP" (ET-Plus) antivenom; 50 ml of VacSera, Cairo "EgyVac" antivenom. A preliminary clinical dose-finding and safety study of these three antivenoms was carried out in 24 patients with incoagulable blood after E. ocellatus bites who were not severely envenomed. A 3+3 dose escalation design was employed. Initial doses of 10 ml ET-G and 30 ml ET-Plus restored blood coagulability in groups of 6 patients with early mild reactions (pruritus only) in not more than one third of them. EgyVac antivenom did not fulfil efficacy or safety criteria in 12 patients. On the basis of these results, ET-G and ET-Plus were selected for comparison in a RCT. PMID:19874841

Abubakar, S B; Abubakar, I S; Habib, A G; Nasidi, A; Durfa, N; Yusuf, P O; Larnyang, S; Garnvwa, J; Sokomba, E; Salako, L; Laing, G D; Theakston, R D G; Juszczak, E; Alder, N; Warrell, D A

2009-10-27

130

A Preclinical and Clinical Study of Lithium in Low-Grade Neuroendocrine Tumors  

PubMed Central

Background. Low-grade neuroendocrine tumors (NETs) respond poorly to chemotherapy; effective, less toxic therapies are needed. Glycogen synthase kinase (GSK)-3? has been shown to regulate growth and hormone production in NETs. Use of lithium chloride in murine models suppressed carcinoid cell growth, reduced GSK-3? levels, and reduced expression of chromogranin A. This study assessed the efficacy of lithium chloride in patients with NETs. Design. Eligible patients had low-grade NETs. A single-arm, open-label phase II design was used. Lithium was dosed at 300 mg orally three times daily, titrated to serum levels of 0.8–1.0 mmol/L. The primary endpoint was objective tumor response by the Response Evaluation Criteria in Solid Tumors. Secondary endpoints included overall survival, progression-free survival, GSK-3? phosphorylation, and toxicity. Results. Fifteen patients were enrolled between October 3, 2007 and July 17, 2008, six men and nine women. The median age was 58 years. Patient diagnoses were carcinoid tumor for eight patients, islet cell tumor for five patients, and two unknown primary sites. Eastern Cooperative Oncology Group performance status scores were 0 or 1. Two patients came off study because of side effects. The median progression-free survival interval was 4.50 months. There were no radiographic responses. Because of an early stopping rule requiring at least one objective response in the first 13 evaluable patients, the study was closed to further accrual. Patients had pre- and post-therapy biopsies. Conclusions. Lithium chloride was ineffective at obtaining radiographic responses in our 13 patients who were treated as part of this study. Based on the pre- and post-treatment tumor biopsies, lithium did not potently inhibit GSK-3? at serum levels used to treat bipolar disorders.

Kunnimalaiyaan, Muthusamy; Holen, Kyle D.; Ning, Li; Ndiaye, Mary; LoConte, Noelle K.; Mulkerin, Daniel L.; Schelman, William R.; Chen, Herbert

2011-01-01

131

Creative self-efficacy: An intervention study  

Microsoft Academic Search

This study examined the effects of creativity training on creative self-efficacy. We developed a creativity course based on social cognitive theory. The course was conducted in two formats: a five-day course and a condensed one-day course. Samples consisted of students and municipality employees (five-day course), and special education teachers (one-day course). Students from a mathematics and statistics course constituted a

Gro Ellen Mathisen; Kolbjorn S. Bronnick

2009-01-01

132

Latent Structure and Factorial Invariance of a Neuropsychological Test Battery for the Study of Preclinical Alzheimer's Disease  

PubMed Central

Objective To examine the latent structure of a test battery currently being used in a longitudinal study of asymptomatic middle-aged adults with a parental history of Alzheimer’s disease (AD) and test the invariance of the factor solution across subgroups defined by selected demographic variables and known genetic risk factors for AD. Method An exploratory factor analysis (EFA) and a sequence of confirmatory factor analyses (CFA) were conducted on 24 neuropsychological measures selected to provide a comprehensive estimate of cognitive abilities most likely to be affected in preclinical AD. Once the underlying latent model was defined and the structural validity established through model comparisons, a multi-group confirmatory factor analysis model was used to test for factorial invariance across groups. Results The EFA solution revealed a factor structure consisting of 5 constructs: verbal ability, visuo-spatial ability, speed & executive function, working memory, and verbal learning & memory. The CFA models provided support for the hypothesized 5-factor structure. Results indicated factorial invariance of the model across all groups examined. Conclusions Collectively, the results suggested a relatively strong psychometric basis for using the factor structure in clinical samples that match the characteristics of this cohort. This confirmed an invariant factor structure should prove useful in research aimed to detect the earliest cognitive signature of preclinical AD in similar middle aged cohorts.

Dowling, N. Maritza; Hermann, Bruce; La Rue, Asenath; Sager, Mark A.

2010-01-01

133

The effect of genistein aglycone on cancer and cancer risk: a review of in vitro, preclinical, and clinical studies.  

PubMed

In Asian epidemiological studies, health benefits, including reduced incidence of breast and prostate cancers, are attributed to soy food and isoflavone consumption. The recent increased intake of soy foods and supplements in the American diet has raised concerns about the possible estrogen-like effects of natural isoflavones and possible promotion or propagation of estrogen-sensitive cancers. These concerns are primarily based on in vitro and rodent data which suggest that genistein aglycone can stimulate tumor cell proliferation and growth in mice having deficient immune systems. In contrast, a recent nested case-control study and meta-analysis of numerous epidemiological studies show an inverse correlation between genistein intake and breast cancer risk. Furthermore, clinical studies in osteopenic and osteoporotic, postmenopausal women support the breast and uterine safety of purified naturally derived genistein administered for up to 3 years. In this review, we summarize the in vitro, preclinical and clinical evidence for the safety of natural genistein. PMID:19566600

Taylor, Christopher K; Levy, Robert M; Elliott, Jay C; Burnett, Bruce P

2009-07-01

134

Endoscopic minimally invasive thyroidectomy (eMIT): some clarifications regarding the idea, development, preclinical studies, and application in humans.  

PubMed

BACKGROUND: The transoral endoscopic approach for thyroid surgery was based on a previous attempt to reach the thyroid gland by an axilloscope. In contrast to this single-port access, endoscopic minimally invasive thyroidectomy (eMIT) uses three access points (sublingual and bivestibular). This results in a sufficient triangulation of instruments, making surgical procedures in the anterior neck region possible. METHODS: The idea and development of the eMIT technique are described in detail. Anatomic studies, the development of the surgical access in a cadaver study, and the animal study for safety and feasibility of this transoral endoscopic approach for surgery of the anterior neck are outlined. Also, the foundations and ethical aspects are addressed in the context of developing a surgical innovation, which resulted in the first clinical application of this technique in humans. RESULTS: The preclinical studies regarding endoscopic minimally invasive thyroidectomy proofed feasibility in a human cadaver studies as well as safety in a short-time survival animal study. The first clinical application in a 53-year old patient was successful without any significant complications; expected benefits (no postoperative pain or dysphagia, no visible scar) could be demonstrated. CONCLUSIONS: The eMIT technique represents a promising new surgical approach for endoscopic surgery in the anterior neck region. The whole development was based on principles for surgical innovation published after the authors' preclinical studies. At this writing, after an initial clinical study with humans, the time has come to compare this new technique with other endoscopic and minimally invasive approaches in a prospective randomized multicenter trial. PMID:20734066

Wilhelm, Thomas; Metzig, Andreas

2010-08-24

135

Targeted Toxins for Glioblastoma Multiforme: pre-clinical studies and clinical implementation  

PubMed Central

Glioblastoma multiforme (GBM) is most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM’s invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.

Candolfi, Marianela; Kroeger, Kurt M.; Xiong, Weidong; Liu, Chunyan; Puntel, Mariana; Yagiz, Kader; Ghulam Muhammad, AKM; Mineharu, Yohei; Foulad, David; Wibowo, Mia; Assi, Hikmat; Baker, Gregory J.; Lowenstein, Pedro R.; Castro, Maria G.

2011-01-01

136

[Classification of results of studying blood plasma with laser correlation spectroscopy based on semiotics of preclinical and clinical states].  

PubMed

The usage of laser correlation spectroscopy for verification of preclinical and clinical states is substantiated. Developed "semiotic" classifier for solving the problems of preclinical and clinical states is presented. The substantiation of biological algorithms as well as the mathematical support and software for the proposed classifier for the data of laser correlation spectroscopy of blood plasma are presented. PMID:9848161

Ternovo?, K S; Kryzhanovski?, G N; Musi?chuk, Iu I; Noskin, L A; Klopov, N V; Noskin, V A; Starodub, N F

137

Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer.  

PubMed

We have investigated protein kinase C (PKC) signaling, a putative differentiation-related and metastasis suppressor gene Cap43/NDRG1/Drg-1, and Y-box binding protein-1 (YB-1) to identify new molecular targeting for breast cancer. PKC is a family of serine/threonine kinases that is involved in the regulation of cell growth. We have demonstrated that PKC caused G(1) arrest in a breast cancer cell line through a mechanism involving a PKC-ERK MAPK-JNK-Rb protein signaling pathway. We have also characterized a novel mechanism through which all-trans retinoic acid (ATRA) and antineoplaston, anticancer drug, caused cell growth inhibition in breast cancer cells through effects on intracellular pathways. ATRA decreased the expression of PKCalpha, as well as reduced ERK MAPK phosphorylation, and consequently caused G(1) arrest. Antineoplaston caused the down-regulation of PKCalpha protein expression, resulting in inhibition of ERK MAPK phosphorylation, with resultant inhibition of Rb phosphorylation leading to G(1) arrest. PKC signaling represents a promising target for development of novel therapeutic agents. Cap43 is known as N-myc downstream-regulated gene 1 (NDRG1). Treatment with estradiol (E(2)) significantly decreased the expression of Cap43 in ER-alpha-positive breast cancer cell lines. Co-administration of tamoxifen abrogated the E(2)-induced downregulation of Cap43 in ER-alpha-positive cell lines. These results suggested that Cap43 may hold the potential of being a molecular marker to determine the therapeutic efficacy of anti-estrogenic anticancer agents in breast cancer. YB-1 is a member of the cold shock domain protein family. The expression of nuclear YB-1 was correlated with HER2 positively in clinical specimens of human breast cancer. Immunostaining studies showed that nuclear YB-1 expression was an independent prognostic factor of overall survival. Expression of nuclear YB-1 played an essential role in acquirement of malignant characteristics through HER2-dependent pathways in breast cancer patients. PKC, Cap43 and YB-1 may be useful in new molecular-targeting diagnosis and therapeutics in breast cancer. PMID:18224398

Fujii, Teruhiko; Yokoyama, Goro; Takahashi, Hiroki; Namoto, Roka; Nakagawa, Shino; Toh, Uhi; Kage, Masayoshi; Shirouzu, Kazuo; Kuwano, Michihiko

2008-01-01

138

Preclinical Prophylactic Efficacy Testing of Sm-p80-Based Vaccine in a Nonhuman Primate Model of Schistosoma mansoni Infection and Immunoglobulin G and E Responses to Sm-p80 in Human Serum Samples From an Area Where Schistosomiasis Is Endemic  

PubMed Central

The prophylactic efficacy of a schistosome antigen (Sm-p80) was tested in a nonhuman primate model, the baboon. Using a total of 28 baboons, different vaccination strategies were used including recombinant Sm-p80 protein formulated in Toll-like receptor 7 and Toll-like receptor 9 agonists, and DNA priming followed by boosting with protein plus adjuvants. Recombinant protein approaches provided levels of prophylactic efficacy of 52%–58%, whereas prime-boost approaches conferred 38%–47% protection in baboons. An appropriately balanced pro-inflammatory (T-helper 17 [Th17] and Th1) and anti-inflammatory (Th2) type of response was generated; the Th1 and Th17 types of immune responses appear to be indicative of increased prophylactic efficacy. Production and expression of several cytokines (interleukin 2 [IL-2], interferon ?, IL-12?, IL-1?, IL-6, and IL-22) were up-regulated in vaccinated animals. Human correlate studies revealed Sm-p80 reactivity with immunoglobulin G in human serum samples from schistosome-infected individuals. In addition, a complete lack of prevailing Sm-p80–specific immunoglobulin E in a high-risk or infected population was observed, thus minimizing the risk of hypersensitivity reaction following vaccination with Sm-p80 in humans. This study provided the proof of concept to move Sm-p80 forward into further preclinical development leading to human clinical trials.

Ahmad, Gul; Zhang, Weidong; Torben, Workineh; Ahrorov, Afzal; Damian, Raymond T.; Wolf, Roman F.; White, Gary L.; Carey, David W.; Mwinzi, Pauline N. M.; Ganley-Leal, Lisa; Kennedy, Ronald C.

2011-01-01

139

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement.  

PubMed

Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca(2+) mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia. PMID:23965381

Gregory, K J; Herman, E J; Ramsey, A J; Hammond, A S; Byun, N E; Stauffer, S R; Manka, J T; Jadhav, S; Bridges, T M; Weaver, C D; Niswender, C M; Steckler, T; Drinkenburg, W H; Ahnaou, A; Lavreysen, H; Macdonald, G J; Bartolomé, J M; Mackie, C; Hrupka, B J; Caron, M G; Daigle, T L; Lindsley, C W; Conn, P J; Jones, C K

2013-08-21

140

Safety and efficacy of commercially available demineralised bone matrix preparations: a critical review of clinical studies.  

PubMed

Demineralised bone matrix (DBM), a form of allograft, possesses the properties of osteoinductivity and osteoconductivity. A large body of data obtained from extensive preclinical studies have clearly supported the utility of DBM in human clinical settings. However, it is now recognized that various DBM configurations may differ considerably with regard to their bone inductive activity. Several factors could account for such variability, including the biologic properties of the graft, the host environment, and the methods of allograft preparation. The differing efficacy of DBM products may also depend on differences in particle size and shape, donor selection criteria, protocols for collection and storage, as well as DBM carrier materials. Several comparative studies have confirmed the differences in the osteoinductive potential of various DBM preparations. The purpose of the present review is to provide a critical overview of the current applications of DBM in a clinical setting. PMID:18224733

Drosos, Georgios I; Kazakos, Konstantinos I; Kouzoumpasis, Pavlos; Verettas, Dionisios-Alexandros

2007-09-01

141

Preclinical students: who are surgeons?  

Microsoft Academic Search

Introduction: We have previously demonstrated that even a brief intervention by surgeons can positively influence perceptions of preclinical medical students. The purpose of the present study was to determine the origin of negative perceptions regarding surgery and if perceptions differ between students with or without an interest in surgery (+surg or -surg). Methods: A qualitative study was performed by conducting

R. A. Kozar; K. D. Anderson; S. L. Escobar-Chaves; M. A. Thiel; S. I. Brundage

2003-01-01

142

In vitro preclinical lead optimisation technologies (PLOTs) in pharmaceutical development.  

PubMed

The explosion of genuine high throughput technologies has allowed large compound libraries to be screened with ever increasing biological specificity, exacerbating the problem of lead candidate selection for subsequent drug development. To avoid creating a bottleneck, compounds identified from the high throughput screens undergo lead optimisation, a medium-throughput screen which allows ranking in terms of their basic absorption, distribution, metabolism, excretion (ADME) and toxicological properties. The historical role of the preclinical scientist in the drug discovery/development continuum has been to perform ADME and toxicology studies, simply to support the regulatory submission of lead candidates. This situation is, however, changing with the development of preclinical lead optimisation technologies (Approaches to High Throughput Toxicity Screening, London, Atterwill et al., 1999) facilitating the selection of leading candidates, thereby bridging the gap between high throughput efficacy screens and traditional safety assessment programmes. PMID:12052652

Atterwill, Christopher K; Wing, Mark G

2002-02-28

143

Preclinical study of using multiphoton microscopy to diagnose liver cancer and differentiate benign and malignant liver lesions  

NASA Astrophysics Data System (ADS)

Recently, the miniaturized multiphoton microscopy (MPM) and multiphoton probe allow the clinical use of multiphoton endoscopy for diagnosing cancer via ``optical biopsy''. The purpose of this study was to establish MPM optical diagnostic features for liver cancer and evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis. Firstly, we performed a pilot study to establish the MPM diagnostic features by investigating 60 surgical specimens, and found that high-resolution MPM images clearly demonstrated apparent differences between benign and malignant liver lesions in terms of their tissue architecture and cell morphology. Cancer cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, were identified by MPM images, which were comparable to hematoxylin-eosin staining images. Secondly, we performed a blinded study to evaluate the sensitivity, specificity, and accuracy of MPM optical diagnosis by investigating another 164 specimens, and found that the sensitivity, specificity, and accuracy of MPM diagnosis was 96.32%, 96.43%, and 96.34%, respectively. In conclusion, it is feasible to use MPM to diagnose liver cancer and differentiate benign and malignant liver lesions. This preclinical study provides the groundwork for further using multiphoton endoscopy to perform real-time noninvasive ``optical biopsy'' for liver lesions in the near future.

Yan, Jun; Zhuo, Shuangmu; Chen, Gang; Wu, Xiufeng; Zhou, Dong; Xie, Shusen; Jiang, Jiahao; Ying, Mingang; Jia, Fan; Chen, Jianxin; Zhou, Jian

2012-02-01

144

Preclinical Studies of the Chinese Herbal Medicine formulation PHY906 as a Potential Adjunct to Radiation Therapy  

PubMed Central

Purpose/Objectives Abdominal and pelvic radiotherapy is limited by the radiosensitivity of the small and large intestine. PHY906, a state-of-the-art adaptation of a traditional Chinese medicine, decreased intestinal injury from chemotherapy in preclinical studies and is in clinical trials with chemotherapy. This project assessed whether PHY906 would also reduce intestinal injury from whole-abdomen irradiation in mice. Materials/Methods BALB/c mice received whole-abdomen irradiation (2 Gy/day) ± PHY906 by oral gavage twice daily for 4 days. Intestinal injury was assayed by physiological observations and histological studies. Effects of PHY906 on tumor radiation response were assayed in tumor growth studies. Results PHY906 decreased the toxicity of fractionated abdominal irradiation. Radiation alone produced marked blunting and loss of villi, crypt loss, crypt hyperplasia and irregular crypt morphology, which were reduced by PHY906. The radiation-induced reduction in viable crypt counts was also mitigated by PHY906. PHY906 did not alter radiation-induced weight loss, but resulted in more rapid recovery. PHY906 did not alter growth, local invasion or metastatic spread of EMT6 mouse mammary tumors or protect tumors from growth delays produced by single-dose and fractionated irradiation. Conclusion In this mouse model system, PHY906 decreased the toxicity of abdominal irradiation, without protecting tumors, thereby increasing the therapeutic ratio.

Rockwell, Sara; Grove, Tina A.; Liu, Yanfeng; Cheng, Yung-Chi; Higgins, Susan A; Booth, Carmen J

2013-01-01

145

Photodynamic therapy with the phthalocyanine photosensitizer Pc 4: The case experience with preclinical mechanistic and early clinical-translational studies  

SciTech Connect

Photodynamic therapy (PDT) is emerging as a promising non-invasive treatment for cancers. PDT involves either local or systemic administration of a photosensitizing drug, which preferentially localizes within the tumor, followed by illumination of the involved organ with light, usually from a laser source. Here, we provide a selective overview of our experience with PDT at Case Western Reserve University, specifically with the silicon phthalocyanine photosensitizer Pc 4. We first review our in vitro studies evaluating the mechanism of cell killing by Pc 4-PDT. Then we briefly describe our clinical experience in a Phase I trial of Pc 4-PDT and our preliminary translational studies evaluating the mechanisms behind tumor responses. Preclinical work identified (a) cardiolipin and the anti-apoptotic proteins Bcl-2 and Bcl-xL as targets of Pc 4-PDT, (b) the intrinsic pathway of apoptosis, with the key participation of caspase-3, as a central response of many human cancer cells to Pc 4-PDT, (c) signaling pathways that could modify apoptosis, and (d) a formulation by which Pc 4 could be applied topically to human skin and penetrate at least through the basal layer of the epidermis. Clinical-translational studies enabled us to develop an immunohistochemical assay for caspase-3 activation, using biopsies from patients treated with topical Pc 4 in a Phase I PDT trial for cutaneous T-cell lymphoma. Results suggest that this assay may be used as an early biomarker of clinical response.

Miller, Janine D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Baron, Elma D. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Louis-Stokes VA Medical Center, 10701 East Boulevard, Cleveland, OH 44106 (United States); Scull, Heather [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Skin Diseases Research Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Case Comprehensive Cancer Center, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Hsia, Andrew [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Berlin, Jeffrey C. [Department of Dermatology, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States); Department of Chemistry, Case Western Reserve University/University Hospitals of Cleveland, Cleveland, OH 44106 (United States)] (and others)

2007-11-01

146

Sequential therapy with JX-594, a targeted oncolytic poxvirus, followed by sorafenib in hepatocellular carcinoma: preclinical and clinical demonstration of combination efficacy.  

PubMed

JX-594 is a targeted and granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic poxvirus designed to selectively replicate in and destroy cancer cells through viral oncolysis and tumor-specific immunity. In a phase 1 trial, JX-594 injection into hepatocellular carcinoma (HCC) was well-tolerated and associated with viral replication, decreased tumor perfusion, and tumor necrosis. We hypothesized that JX-594 and sorafenib, a small molecule inhibitor of B-raf and vascular endothelial growth factor receptor (VEGFR) approved for HCC, would have clinical benefit in combination given their demonstrated efficacy in HCC patients and their complementary mechanisms-of-action. HCC cell lines were uniformly sensitive to JX-594. Anti-raf kinase effects of concurrent sorafenib inhibited JX-594 replication in vitro, whereas sequential therapy was superior to either agent alone in murine tumor models. We therefore explored pilot safety and efficacy of JX-594 followed by sorafenib in three HCC patients. In all three patients, sequential treatment was (i) well-tolerated, (ii) associated with significantly decreased tumor perfusion, and (iii) associated with objective tumor responses (Choi criteria; up to 100% necrosis). HCC historical control patients on sorafenib alone at the same institutions had no objective tumor responses (0 of 15). Treatment of HCC with JX-594 followed by sorafenib has antitumoral activity, and JX-594 may sensitize tumors to subsequent therapy with VEGF/VEGFR inhibitors. PMID:21427706

Heo, Jeong; Breitbach, Caroline J; Moon, Anne; Kim, Chang Won; Patt, Rick; Kim, Mi Kyung; Lee, Yu Kyung; Oh, Sung Yong; Woo, Hyun Young; Parato, Kelley; Rintoul, Julia; Falls, Theresa; Hickman, Theresa; Rhee, Byung-Geon; Bell, John C; Kirn, David H; Hwang, Tae-Ho

2011-03-22

147

Guidance for Industry: Efficacy Studies to Support Marketing of ...  

Center for Biologics Evaluation and Research (CBER)

... Guidance for Industry: Efficacy Studies to Support Marketing of Fibrin Sealant Products Manufactured for Commercial Use. ... More results from www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances

148

Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy  

PubMed Central

Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad-stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas.

Kim, Chae-Young; Park, Soon-Hye; Jeong, Moonsup; Kwon, O-Seo; Doh, Hyounmie; Kang, Su-Hyung; Robbins, Paul D.; Kim, Byong-Moon

2011-01-01

149

Re-Evaluate the Effect of Hyperbaric Oxygen Therapy in Cancer - A Preclinical Therapeutic Small Animal Model Study  

PubMed Central

Tumor hypoxia is a known driver of angiogenesis that also facilitates tumor growth. Moreover, poorly oxygenated central tumor area remains relatively radio or chemo resistant. HBO therapy is known to elevate the levels of dissolved oxygen and eliminates tumor hypoxia. It has been one of the modalities in cancer treatment; therefore its optimization is important. In this experimental study, no cancer enhancing effect was seen during the course of HBO therapy; however, post therapy there was an accelerated growth and progression of tumor. HBO treated mice lived shorter and the response to therapy was dose & tumor volume dependent. HBO therapy probably exert its effect on the cancer proliferating cells through multiple pathways such as increased DNA damage, apoptosis & geno-toxicity leading to slow cancer progression while post therapy tumorigenic effect could be due to impaired DNA repair mechanism, mutagenic effect & aneuploidy as well as altered blood supply & nutrients. Tumor growth reached plateau with time and this finding validated theoretical model predicting tumor reaching an asymptotic limit. While, marked asymmetry observed in tumor volume progression or cancer cell proliferation rate in each of the experimental C3H mouse suggested a need for an alternate small animal pre-clinical cancer therapeutic model.

Pande, Sneha; Sengupta, Amit; Srivastava, Anurag; Gude, Rajiv P.; Ingle, Arvind

2012-01-01

150

A review of preclinical and clinical studies using synthetic materials for meniscus replacement.  

PubMed

The emerging field of tissue engineering holds the promise to use bio-materials for meniscus injury repair, namely scaffold or meniscus implant. Many implants have been studied and several studies have been conducted to verify the safety and quality of scaffolds. Preliminary data support the idea that synthetic implants can provide an alternative to menyscectomy helping to preserve the cartilage and preventing arthritis in patient with menisci injuries. However, the prevalence of postoperative complications varies within studies. Further investigations are required to evaluate the role of these materials in the clinical practice. PMID:24016324

Longo, Umile Giuseppe; Rizzello, Giacomo; Berton, Alessandra; Fumo, Caterina; Battaglia, Giulio; Khan, Wasim S; Denaro, Vincenzo

2013-11-01

151

Preclinical Toxicology Study of Guanazole (Nsc 1895) Administered by 48-Hour Infusion in Dogs. Part III.  

National Technical Information Service (NTIS)

NSC 1895, Guanazole, Triazole 3,5-diamino-s, which shows strong antitumor activity against L1210 in mic3 when administered by the intraperitoneal route, and moderate activity by the intravenous, oral, intramuscular, and subcutaneous routes, has been studi...

P. E. Palm G. J. Kensler

1970-01-01

152

Remote ischaemic preconditioning protects against cardiopulmonary bypass-induced tissue injury: a preclinical study  

Microsoft Academic Search

Objectives: To test the hypothesis that remote ischaemic preconditioning (rIPC) reduces injury after cardiopulmonary bypass (CPB).Design: Randomised study with an experimental model of CPB (3 h CPB with 2 h of cardioplegic arrest). Twelve 15 kg pigs were randomly assigned to control or rIPC before CPB and followed up for 6 h.Intervention: rIPC was induced by four 5 min cycles

R K Kharbanda; J Li; I E Konstantinov; M M H Cheung; P A White; H Frndova; J Stokoe; P Cox; M Vogel; G Van Arsdell; R MacAllister; A N Redington

2006-01-01

153

Application of accelerator mass spectrometry to macromolecules: preclinical pharmacokinetic studies on a polybisphosphonate.  

PubMed

Data on the use of accelerator mass spectrometry (AMS) in conjunction with in vivo studies of macromolecular drugs are scarce. The present study shows the versatility of this technique when investigating the pharmacokinetics (PK) of a macromolecular drug candidate, a polybisphosphonate conjugate (ODX). The aforementioned is a polymer (molecular weight ~30?kDa) constituting a carbohydrate backbone with covalently linked ligands (aldendronate and aminoguanidine) and is intended for treatment of osteoporosis and the therapy of bone metastasis from prostate cancer. The conjugate is prepared through partial oxidation of the carbohydrate and sequential coupling of the ligands by reductive amination. (14)C was incorporated in the conjugate by means of coupling a commercially available (14)C-lysine in the conjugation sequence. Fifteen rats were injected intravenously with (14)C-labelled ODX (150?µg, 14?Bq/rat) and blood samples were collected at 1, 2, 4, 6, and 24?h post-injection (3 rats/time point). Liver, spleen and kidney samples were collected at 4 and 24?h post-injection. Blood from each time point (triplicate) were collected for AMS measurement determining the isotopic ratio ((14)C/(12)C) and consequently the drug concentration in blood. ODX showed a transient presence in blood circulation; 93% of the total dose was cleared from the circulation within 1?h. The half-life after 1?h was estimated to be about 3?h; 0.7% of the administered (14)C dose of ODX remained in circulation after 24?h. The major (14)C accumulation was in the liver, the spleen and the kidneys indicating the probable route of metabolism and excretion. This study demonstrates the versatility of AMS for pharmacological in vivo studies of macromolecules. Labelling with (14)C is relatively simple, inexpensive and the method requires minimal radioactivity, eliminating the need for radioprotection precautions in contrast to methods using scintillation counting. PMID:21818805

Salehpour, Mehran; Håkansson, Karl; Höglund, Urban; Grahn-Westin, Annika; Nilsson, Sten; Márquez, Marcela; Possnert, Göran; Holmberg, Anders R

2011-09-15

154

Preclinical Studies and Clinical Correlation of the Effect of Alkylating Dose1  

Microsoft Academic Search

Dose-response studies were performed with the alkylating agents (nitrogen mustard, \\/V,Ar'-bis(2-chloroethyl)-AI-nitrosourea, melphalan, cisplatin (CDDP), 4-hydroperoxycyclophosphamide (4-HC), and tri- methyleneiminethiophosphoramide) in both the MCF-7 human breast carcinoma cell line and the EMT6 and FSalIC murine tumor lines. Increasing selection pressure with the alkylating agents CDDP, mel phalan, and 4-HC In vitro produced low levels (6.5- to 9-fold) of drug resistance, despite

Emil Frei; Beverly A. Teicher; Sylvia A. Holden; Kathleen N. S. Cathcart; Yenyun Wang

1988-01-01

155

Issues in pharmaceutical development of thymosin alpha1 from preclinical studies through marketing.  

PubMed

SciClone Pharmaceuticals licensed the commercial and patent rights to thymosin alpha1, for geographical regions of the world excluding the United States and Europe, in the early 1990s. With this license, SciClone embarked on global drug development, and the issues encountered for thymosin alpha1 are reflective of the roller coaster of modern approval of pharmaceuticals. Most of the required toxicology studies had been completed prior to licensure, but some newer studies had to be conducted to obtain approvals in certain countries. The recent development of the "International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use" (ICH) guidelines allows for a clearer definition of the required battery of toxicology studies, although some countries still have not adopted these guidelines, and the local regulations have had to be understood and followed. Other hurdles include the complications that manufacturing requirements can differ between countries, and certain countries require local clinical experience trials in addition to SciClone's cumulative clinical data. A further obstacle was the pleiotropic nature of the mechanism of action of thymosin alpha1, with the resulting difficulty in the unraveling of its pharmacologic effects. With close attention to these regulatory details, SciClone has obtained approvals in more than 30 countries and has successfully begun commercial sales. PMID:17947591

Tuthill, Cynthia

2007-09-01

156

AAV-Mediated Gene Therapy for Choroideremia: Preclinical Studies in Personalized Models  

PubMed Central

Choroideremia (CHM) is an X- linked retinal degeneration that is symptomatic in the 1st or 2nd decade of life causing nyctalopia and loss of peripheral vision. The disease progresses through mid-life, when most patients become blind. CHM is a favorable target for gene augmentation therapy, as the disease is due to loss of function of a protein necessary for retinal cell health, Rab Escort Protein 1 (REP1).The CHM cDNA can be packaged in recombinant adeno-associated virus (rAAV), which has an established track record in human gene therapy studies, and, in addition, there are sensitive and quantitative assays to document REP1 activity. An animal model that accurately reflects the human condition is not available. In this study, we tested the ability to restore REP1 function in personalized in vitro models of CHM: lymphoblasts and induced pluripotent stems cells (iPSCs) from human patients. The initial step of evaluating safety of the treatment was carried out by evaluating for acute retinal histopathologic effects in normal-sighted mice and no obvious toxicity was identified. Delivery of the CHM cDNA to affected cells restores REP1 enzymatic activity and also restores proper protein trafficking. The gene transfer is efficient and the preliminary safety data are encouraging. These studies pave the way for a human clinical trial of gene therapy for CHM.

Vasireddy, Vidyullatha; Kohnke, Monika; Black, Aaron D.; Alexandrov, Krill; Zhou, Shangzhen; Maguire, Albert M.; Chung, Daniel C.; Mac, Helen; Sullivan, Lisa; Gadue, Paul; Bennicelli, Jeannette L.; French, Deborah L.; Bennett, Jean

2013-01-01

157

The Relationship between Lesson Study and Self-Efficacy  

ERIC Educational Resources Information Center

This article addresses a gap in the literature by developing a theory that bridges lesson study and self-efficacy. Since self-efficacy has been linked to student achievement, the theory is important as an explanatory mechanism linking lesson study to student achievement. The theory was developed using grounded theory based on primary source data…

Sibbald, Tim

2009-01-01

158

Minnelide reduces tumor burden in preclinical models of osteosarcoma.  

PubMed

Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-?B pathway. PMID:23499892

Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

2013-03-14

159

Preclinical antitumor activity of the oral platinum analog satraplatin  

Microsoft Academic Search

Purpose  Satraplatin is an orally available platinum analog. The purpose of this study was to better characterize satraplatin’s preclinical\\u000a antitumor efficacy in a variety of sensitive and resistant human tumor cell lines and in a prostate cancer xenograft model\\u000a and to evaluate the effect of satraplatin on PSA expression and\\/or secretion in a prostate cancer cell line.\\u000a \\u000a \\u000a \\u000a Methods  Satraplatin and its primary

Katja Wosikowski; Lou Lamphere; Gerhard Unteregger; Volker Jung; Faith Kaplan; Jimmy P. Xu; Benno Rattel; Maureen Caligiuri

2007-01-01

160

Balancing paediatric anaesthesia: preclinical insights into analgesia, hypnosis, neuroprotection, and neurotoxicity.  

PubMed

Logistical and ethical reasons make conducting clinical research in paediatric practice difficult, and therefore safe and efficacious advances are dependent on good preclinical research. For example, notable advances have been made in preclinical studies of pain processing that correlate well with patient data. Other areas of paediatric anaesthetic research remain in their infancy including mechanisms of anaesthesia and anaesthetic neuroprotection and neurotoxicity. Animal data have identified the potential 'double-edged' sword of administering anaesthetic agents in the young; although these agents can be neuroprotective in certain circumstances, they can be neurotoxic in others. The potential for this toxicity must be balanced against the importance of providing adequate anaesthesia for which there can be no compromise. We review the current state of preclinical research in paediatric anaesthesia and identify areas which require further exploration in order to provide the foundations for well-conducted clinical trials. PMID:18796440

Sanders, R D; Ma, D; Brooks, P; Maze, M

2008-09-16

161

Neural stem cell-mediated enzyme/prodrug therapy for glioma: preclinical studies.  

PubMed

High-grade gliomas are extremely difficult to treat because they are invasive and therefore not curable by surgical resection; the toxicity of current chemo- and radiation therapies limits the doses that can be used. Neural stem cells (NSCs) have inherent tumor-tropic properties that enable their use as delivery vehicles to target enzyme/prodrug therapy selectively to tumors. We used a cytosine deaminase (CD)-expressing clonal human NSC line, HB1.F3.CD, to home to gliomas in mice and locally convert the prodrug 5-fluorocytosine to the active chemotherapeutic 5-fluorouracil. In vitro studies confirmed that the NSCs have normal karyotype, tumor tropism, and CD expression, and are genetically and functionally stable. In vivo biodistribution studies demonstrated NSC retention of tumor tropism, even in mice pretreated with radiation or dexamethasone to mimic clinically relevant adjuvant therapies. We evaluated safety and toxicity after intracerebral administration of the NSCs in non-tumor-bearing and orthotopic glioma-bearing immunocompetent and immunodeficient mice. We detected no difference in toxicity associated with conversion of 5-fluorocytosine to 5-fluorouracil, no NSCs outside the brain, and no histological evidence of pathology or tumorigenesis attributable to the NSCs. The average tumor volume in mice that received HB1.F3.CD NSCs and 5-fluorocytosine was about one-third that of the average volume in control mice. On the basis of these results, we conclude that combination therapy with HB1.F3.CD NSCs and 5-fluorocytosine is safe, nontoxic, and effective in mice. These data have led to approval of a first-in-human study of an allogeneic NSC-mediated enzyme/prodrug-targeted cancer therapy in patients with recurrent high-grade glioma. PMID:23658244

Aboody, Karen S; Najbauer, Joseph; Metz, Marianne Z; D'Apuzzo, Massimo; Gutova, Margarita; Annala, Alexander J; Synold, Timothy W; Couture, Larry A; Blanchard, Suzette; Moats, Rex A; Garcia, Elizabeth; Aramburo, Soraya; Valenzuela, Valerie V; Frank, Richard T; Barish, Michael E; Brown, Christine E; Kim, Seung U; Badie, Behnam; Portnow, Jana

2013-05-01

162

Correlating preclinical animal studies and human clinical trials of a multifunctional, polymeric nanoparticle  

PubMed Central

Nanoparticles are currently being investigated in a number of human clinical trials. As information on how nanoparticles function in humans is difficult to obtain, animal studies that can be correlative to human behavior are needed to provide guidance for human clinical trials. Here, we report correlative studies on animals and humans for CRLX101, a 20- to 30-nm-diameter, multifunctional, polymeric nanoparticle containing camptothecin (CPT). CRLX101 is currently in phase 2 clinical trials, and human data from several of the clinical investigations are compared with results from multispecies animal studies. The pharmacokinetics of polymer-conjugated CPT (indicative of the CRLX101 nanoparticles) in mice, rats, dogs, and humans reveal that the area under the curve scales linearly with milligrams of CPT per square meter for all species. Plasma concentrations of unconjugated CPT released from CRLX101 in animals and humans are consistent with each other after accounting for differences in serum albumin binding of CPT. Urinary excretion of polymer-conjugated CPT occurs primarily within the initial 24 h after dosing in animals and humans. The urinary excretion dynamics of polymer-conjugated and unconjugated CPT appear similar between animals and humans. CRLX101 accumulates into solid tumors and releases CPT over a period of several days to give inhibition of its target in animal xenograft models of cancer and in the tumors of humans. Taken in total, the evidence provided from animal models on the CRLX101 mechanism of action suggests that the behavior of CRLX101 in animals is translatable to humans.

Eliasof, Scott; Lazarus, Douglas; Peters, Christian G.; Case, Roy I.; Cole, Roderic O.; Hwang, Jungyeon; Schluep, Thomas; Chao, Joseph; Lin, James; Yen, Yun; Han, Han; Wiley, Devin T.; Zuckerman, Jonathan E.; Davis, Mark E.

2013-01-01

163

A method for obtaining randomized block designs in preclinical studies with multiple quantitative blocking variables.  

PubMed

A method is proposed for block randomization of treatments to experimental units that can accommodate both multiple quantitative blocking variables and unbalanced designs. Hierarchical clustering in conjunction with leaf-order optimization is used to block experimental units in multivariate space. The method is illustrated in the context of a diabetic mouse assay. A simulation study is presented to explore the utility of the proposed randomization method relative to that of a completely randomized approach, both in the presence and absence of covariate adjustment. An example R function is provided to illustrate the implementation of the method. PMID:20572260

Iturria, Stephen J

164

Novel sugar esters proniosomes for transdermal delivery of vinpocetine: preclinical and clinical studies.  

PubMed

Vinpocetine (Vin) existing oral formulations suffer poor bioavailability (?7%) since Vin undergoes a marked first-pass effect (?75%) and its absorption is dissolution rate-limited. In this study, a novel sustained release proniosomal system was designed using sugar esters (SEs) as non-ionic surfactants in which proniosomes were converted to niosomes upon skin water hydration following topical application under occlusive conditions. Different in vitro aspects (encapsulation efficiency, vesicle size and shape, effect of occlusion, in vitro release, skin permeation and stability) were studied leading to an optimized formula that was assessed clinically for transdermal pharmacokinetics and skin irritation. All formulae exhibited high entrapment efficiencies, regardless of the surfactant HLB. Vesicle size analysis showed that all vesicles were in the range from 0.63 ?m to 2.52 ?m which favored efficient transdermal delivery. The extent of drug permeation through the skin from the optimized formula--containing laurate SE with shorter fatty acid chain length and high HLB--was quite high (91%) after 48 h under occlusive conditions. The extent of absorption of Vin from proniosomes was larger when compared to the oral tablet with a relative bioavailability (F(rel)) of 206%. Histopathological evaluation revealed only moderate skin irritation when using SEs compared to skin inflammation when using Tween 80. Sugar esters proniosomes may be a promising carrier for vinpocetine, especially due to their simple scaling up and their ability to control drug release. PMID:21056658

El-Laithy, Hanan M; Shoukry, Omar; Mahran, Laila G

2010-11-05

165

A preclinical study of the effects of seabuckthorn (Hippophae rhamnoides L.) leaf extract on cutaneous wound healing in albino rats.  

PubMed

Hippophae rhamnoides L. (family Elaeagnaceae), commonly known as seabuckthorn, is a wild shrub growing at high altitude (1200-4500 meters) in adverse climatic conditions. The aim of the present study was to evaluate healing potential of seabuckthorn leaves in a preclinical study on rats using a cutaneous excision-punch wound model. Four full-thickness excision-type wounds of 8.0 mm diameter were created on the dorsal surface of rats under aseptic conditions. The aqueous lyophilized extract of seabuckthorn leaves, at doses of 0.5%, 1.0%, and 1.5% w/v prepared in propylene glycol, were applied topically twice daily for 7 days. Control animals received the vehicle alone in an identical manner. Wound granulation tissues were excised on eighth day postwounding, and the hydroxyproline, hexosamine, total protein content, and antioxidant levels were determined. Wound surface area was also measured on the eighth day before wound excision to determine wound contraction. Topical application of 1.0% seabuckthorn leaf extract statistically significantly augmented the healing process, as evidenced by increases in the content of hydroxyproline and protein as well as the reduction in wound area when compared with similar effects in response to treatment using povidone-iodine ointment (standard care). The reduced glutathione, vitamin C, superoxide dismutase, catalase, and glutathione peroxidase activities showed significant increases in seabuckthorn leaf extract-treated wounds as compared to controls. The lipid peroxide levels were significantly decreased in leaf extract-treated wounds. The results suggest that aqueous leaf extract of seabuckthorn promotes wound healing, which may be due to increased antioxidant levels in the granulation tissue. PMID:15911921

Gupta, Asheesh; Kumar, Ratan; Pal, Karan; Banerjee, Pratul K; Sawhney, Ramesh C

2005-06-01

166

A gender study investigating physics self-efficacy  

NASA Astrophysics Data System (ADS)

The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively the influence of self-efficacy in predicting success and then to qualitatively explore the development of self-efficacy. In the initial quantitative studies, I explore the utility of self-efficacy in predicting the success of introductory physics students, both women and men. Results indicate that self-efficacy is a significant predictor of success for all students. I then disaggregate the data to examine how self-efficacy develops differently for women and men in the introductory physics course. Results show women rely on different sources of self-efficacy than do men, and that a particular instructional environment, Modeling Instruction, has a positive impact on these sources of self-efficacy. In the qualitative phase of the project, this dissertation focuses on the development of self-efficacy. Using the qualitative tool of microanalysis, I introduce a methodology for understanding how self-efficacy develops moment-by-moment using the lens of self-efficacy opportunities. I then use the characterizations of self-efficacy opportunities to focus on a particular course environment and to identify and describe a mechanism by which Modeling Instruction impacts student self-efficacy. Results indicate that the emphasizing the development and deployment of models affords opportunities to impact self-efficacy. The findings of this dissertation indicate that introducing key elements into the classroom, such as cooperative group work, model development and deployment, and interaction with the instructor, create a mechanism by which instructors can impact the self-efficacy of their students. Results from this study indicate that creating a model to impact the retention rates of women in physics should include attending to self-efficacy and designing activities in the classroom that create self-efficacy opportunities.

Sawtelle, Vashti

167

Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV2\\/8 Vector in the Mouse Model of Galactosialidosis  

Microsoft Academic Search

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein\\/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a

Huimin Hu; Elida Gomero; Erik Bonten; John T Gray; Jim Allay; Yanan Wu; Jianrong Wu; Christopher Calabrese; Arthur Nienhuis; Alessandra d'Azzo

2012-01-01

168

A novel injectable bioactive bone cement for spinal surgery: a developmental and preclinical study.  

PubMed

The injection of bone cement by minimally invasive techniques for the treatment of vertebral body fractures or for stabilization of an osteoporotic vertebral body is regarded as promising in spinal surgery. The purpose of this study was to develop a novel injectable bioactive bone cement to address such concerns. The cement was composed mainly of strontium-containing hydroxyapatite (Sr-HA) filler and Bisphenol A Diglycidylether Dimethacrylate (D-GMA) resin. The Sr-HA filler was prepared by precipitation and calcination, then analyzed with Fourier transform infrared (FTIR) spectra and X-ray diffraction (XRD) patterns. Samples of strontium-containing hydroxyapatite cement (SrHAC) were formed by a combination of powder filler and resin matrix, with the setting time and peak temperature recorded. Cell relative growth rate (RGR), Tetrazolium bromide (MTT), and haemolysis tests were used to detect initial in vitro biocompatibility of the new cement. In vitro spinal biomechanical testing and morphological observation after bone cement injection were performed on pig spines. Results indicate that the setting time and peak temperature of the cement was 15 min and 55 degrees C, respectively. Cytotoxicity of the cement was class 1 (no cytotoxicity) and haemolysis was 1% (no haemolysis). Stiffness after cement injection and fatigue loading were 112% and 95% of the intact bone, respectively, which is similar to that of natural bone. Radiopacity of SrHAC allowed easy radiographic imaging. The use of SrHAC cement is, thus, promising in spinal surgery. PMID:10906688

Li, Y W; Leong, J C; Lu, W W; Luk, K D; Cheung, K M; Chiu, K Y; Chow, S P

2000-10-01

169

Preclinical studies with zoledronic acid and other bisphosphonates: impact on the bone microenvironment.  

PubMed

The propensity for breast cancer cells to metastasize to bone and to induce osteolysis has long been recognized. Characteristics of both the tumor cells and the bone microenvironment contribute to this phenomenon. The presence of tumor in bone is associated with activation of osteoclasts, resulting in excessive bone resorption and subsequent osteolysis. Breast cancer cells and other tumor types influence osteoclastic bone resorption by increasing the number of osteoclasts and enhancing their resorptive activity. Parathyroid hormone-related peptide, in addition to its role in humorally mediated hypercalcemia, is secreted by metastatic breast cancer cells in bone in which it acts as a paracrine factor to stimulate osteoclasts. As bone matrix is broken down by activated osteoclasts, a rich supply of mitogenic factors is released, including insulin-like growth factors, bone morphogenetic proteins, and fibroblast growth factors. Transforming growth factor (TGF)-beta, one of the most abundant of the bone-derived factors, promotes increased production of parathyroid hormone-related peptide by tumor cells, establishing a "vicious cycle" leading to progressive tumor growth and bone destruction. Bisphosphonates interrupt this cycle by inhibiting osteoclasts, in part by inducing osteoclast apoptosis. In several animal models of breast cancer metastasis to bone, bisphosphonates decrease the number of new bone metastases and inhibit progression of existing lesions. A single 3 microg intravenous injection of zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ), a new highly potent bisphosphonate, prevented destruction of trabecular bone in an orthotopic mouse mammary tumor model. Tumor volume in bone was decreased by zoledronic acid in a dose-dependent manner in the same model, and tumor cell apoptosis was increased by zoledronic acid in bone metastases in the 4T1 murine model of mammary carcinoma metastasis. Zoledronic acid at a dose of 1.0 microg/d for 10 days also reduced bone lesion area in a nude mouse model with existing bone metastases. Although bisphosphonates, including zoledronic acid, are able to induce apoptosis in tumor cells in vitro, studies in animal models to date have generally not shown a reduction in nonosseous tumor. Therefore, bisphosphonate-associated tumor reduction in bone is most likely mediated by osteoclast inhibition or is related to high local concentrations of bisphosphonates in the bone compartment. PMID:11346863

Mundy, G R; Yoneda, T; Hiraga, T

2001-04-01

170

Monte Carlo simulation on pre-clinical irradiation: A heterogeneous phantom study on monoenergetic kilovoltage photon beams  

NASA Astrophysics Data System (ADS)

This study investigated radiation dose variations in pre-clinical irradiation due to the photon beam energy and presence of tissue heterogeneity. Based on the same mouse computed tomography image dataset, three phantoms namely, heterogeneous, homogeneous and bone homogeneous were used. These phantoms were generated by overriding the relative electron density of no voxel (heterogeneous), all voxel (homogeneous) and the bone voxel (bone homogeneous) to one. 360° photon arcs with beam energies of 50 - 1250 keV were used in mouse irradiations. Doses in the above phantoms were calculated using the EGSnrc-based DOSXYZnrc code through the DOSCTP. Monte Carlo simulations were carried out in parallel using multiple nodes in a high-performance computing cluster. It was found that the dose conformity increased with the increase of the photon beam energy from the keV to MeV range. For the heterogeneous mouse phantom, increasing the photon beam energy from 50 keV to 1250 keV increased seven times the dose deposited at the isocenter. For the bone dose enhancement, the mean dose was 2.7 times higher when the bone heterogeneity was not neglected using the 50 keV photon beams in the mouse irradiation. Bone dose enhancement affecting the mean dose was found in the photon beams with energy range of 50 - 200 keV and the dose enhancement decreased with an increase of the beam energy. Moreover, the MeV photon beam had a higher dose at the isocenter, and a better dose conformity compared to the keV beam.

Chow, James C. L.

2012-10-01

171

7?-methyl-19-nortestosterone vs. testosterone implants for hypogonadal osteoporosis: a preclinical study in the aged male orchidectomized rat model.  

PubMed

Overt male hypogonadism induces not only osteoporosis but also unfavourable changes in body composition, which can be prevented by testosterone (T) replacement. In this preclinical study, the potential of synthetic androgen 7?-methyl-19-nortestosterone (MENT) as alternative treatment for male hypogonadism was evaluated in comparison with T. Eleven-month-old male rats were orchidectomized (orch) and left untreated for 2-months. Subsequently, the effects of 4-month MENT (12 ?g/day) and T (72 ?g/day) treatment on bone, muscle and fat were analysed using microcomputed tomography, dual-energy X-ray absorptiometry, dynamic bone histomorphometry and muscle fibre typing. At the onset of treatment, orch rats were clearly hypogonadal. This was evidenced by significant reductions of androgen-sensitive organ weight, lean mass, cortical thickness and trabecular bone volume compared with sham-operated aged-matched controls (sham). MENT and T restored weight of androgen-sensitive organs to a similar extent, with a superior anabolic action of MENT on levator ani muscle. Both androgens not only fully rescued hypogonadal loss of lean mass but also restored muscle fibre type composition and trabecular bone volume. Cortical bone loss was similarly prevented by MENT and T, but without full recovery to sham. Both androgens stimulated periosteal bone formation, but with a stronger effect of T. By contrast, MENT more strongly suppressed endocortical bone formation and bone turnover rate and reduced fat mass and serum leptin to a greater extent than T. MENT and T are both effective replacement therapies to stimulate bone and muscle in hypogonadal rats, with stronger lipolytic action of MENT. PMID:21790658

Sinnesael, M; Callewaert, F; Morreels, M; Kumar, N; Sitruk-Ware, R; Van Proeyen, K; Hespel, P; Boonen, S; Claessens, F; Vanderschueren, D

2011-07-26

172

Drug Efficacy Testing in Mice  

PubMed Central

The traditional path of drug development passes from in vitro screening and response assessment to validation of drug efficacy in cell line xenografts. While xenografts have their merits, historically, more often than not, they have not served as an accurate predictor of drug efficacy in humans. The refinement and increased availability of genetically engineered mouse models (GEMMs) of cancer has made GEMMs an attractive avenue for the preclinical testing of therapeutic agents. The histopathologic and genetic resemblance of GEMMs to human cancer are an important measure to evaluate their suitability for pre-clinical studies and a number of studies using kinase inhibitors have now been performed in GEMMs. We have highlighted several of the salient advantages and challenges associated with GEMM studies. Well-characterized GEM models of human cancer should aide in the prioritization of both established and novel therapeutics.

Kim, William Y.

2013-01-01

173

Study of the Efficacy of Aerosol versus Nonaerosol Laundry Products.  

National Technical Information Service (NTIS)

The California Air Resources Board estimates that 6.6 tons of photochemically reactive organic compounds (PROC) are released into the environment in California every day because of the use of aerosol laundry products. The project studied the efficacy, eas...

R. R. Boggs B. Belmont

1987-01-01

174

In vitro preclinical lead optimisation technologies (PLOTs) in pharmaceutical development.  

PubMed

The explosion of genuine high throughput technologies has allowed large compound libraries to be screened with ever-increasing biological specificity, exacerbating the problem of lead candidate selection for subsequent drug development. To avoid creating a bottleneck, compounds identified from the high throughput screens undergo lead optimisation by employing medium-throughput screen which permits ranking in terms of their basic absorption, distribution, metabolism, excretion (ADME) and toxicological properties. The historical role of the CRO in the drug discovery/development continuum has been to perform efficacy and toxicology studies, simply to support the regulatory submission of lead candidates. This situation is, however, changing with the development of preclinical lead optimisation technologies facilitating the selection of leading candidates, thereby bridging the gap between high throughput efficacy screens and conventional safety assessment programmes. PMID:11105205

Atterwill, C K; Wing, M G

175

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2010 CFR

...Labeling Claims for Drugs in Drug Efficacy Study ...efficacy study evaluations in labeling and advertising. (a)(1...The results are compiled in âDrug Efficacy Study...require product and labeling changes. (3) Delays...

2010-04-01

176

21 CFR 201.200 - Disclosure of drug efficacy study evaluations in labeling and advertising.  

Code of Federal Regulations, 2010 CFR

...Labeling Claims for Drugs in Drug Efficacy Study ...efficacy study evaluations in labeling and advertising. (a)(1...The results are compiled in âDrug Efficacy Study...require product and labeling changes. (3) Delays...

2009-04-01

177

Phospholipogenic pharmaceuticals are associated with a higher incidence of histological findings than nonphospholipogenic pharmaceuticals in preclinical toxicology studies.  

PubMed

While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics. PMID:22745636

Barone, Linda R; Boyer, Scott; Damewood, James R; Fikes, James; Ciaccio, Paul J

2012-06-14

178

Phospholipogenic Pharmaceuticals Are Associated with a Higher Incidence of Histological Findings than Nonphospholipogenic Pharmaceuticals in Preclinical Toxicology Studies  

PubMed Central

While phospholipidosis is thought to be an adaptive response to chemical challenge, many phospholipogenic compounds are known to display adverse effects in preclinical species and humans. To investigate the link between phospholipogenic administration and incidence of preclinical histological signals, an internal AstraZeneca in vivo toxicology report database was searched to identify phospholipogenic and nonphospholipogenic compounds. The datasets assembled comprised 46 phospholipogenic and 62 nonphospholipogenic compounds. The phospholipogenic potential of these compounds was confirmed by a pathologist's interpretation and was supported by well-validated in silico and in vitro models. The phospholipogenic dataset contained 37 bases, 4 neutral compounds, 3 zwitterions, and 1 acid, whereas the nonphospholipogenic dataset contained 9 bases, 34 neutrals, 1 zwitterion, and 18 acids. Histologic findings were tracked for adrenal gland; bone marrow; kidney; liver; lung; lymph node; spleen; thymus; and reproductive organs. On average, plasma exposures were higher in animals dosed with the nonphospholipogenics. Phospholipogenics yielded proportionally more histologic changes (exclusive of phospholipidosis itself) in all organs. Statistically significant higher frequencies of liver necrosis, alveolitis/pneumonitis, as well as lymphocytolysis in the thymus, lymph nodes, and spleen occurred in response to phospholipogenics compared to that for nonphospholipogenics.

Barone, Linda R.; Boyer, Scott; Damewood, James R.; Fikes, James; Ciaccio, Paul J.

2012-01-01

179

Case studies for practical food effect assessments across BCS/BDDCS class compounds using in silico, in vitro, and preclinical in vivo data.  

PubMed

Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration-time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1-4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound's BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions. PMID:23139017

Heimbach, Tycho; Xia, Binfeng; Lin, Tsu-han; He, Handan

2012-11-10

180

Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: A preclinical study in a novel rat model  

SciTech Connect

Purpose: Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator. Methods and Materials: Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the 'scrotal hernia' was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation. Results: Orazipone significantly ameliorated histologic injury and transforming growth factor-{beta} immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation. Conclusions: This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.

Boerma, Marjan [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Wang, Junru [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Richter, Konrad K. [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States); Hauer-Jensen, Martin [Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States) and Department of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR (United States)]. E-mail: mhjensen@life.uams.edu

2006-10-01

181

Targeting therapy of hepatocellular carcinoma with doxorubicin prodrug PDOX increases anti-metastatic effect and reduces toxicity: a preclinical study  

PubMed Central

Background This study was to investigate the effects and safety of cathepsin B-cleavable doxorubicin (DOX)-prodrug (PDOX) for targeting therapy of metastatic human hepatocellular carcinoma (HCC) using DOX as a positive control drug. Methods The orthotopic nude mice model of highly metastatic HCC was established and the animals were randomized and treated with PDOX, DOX and saline, respectively. Hematology, biochemistry and tumor markers were studied. At autopsy, liver tumor weight and size, ascites, abdominal lymph nodes metastases, experimental peritoneal carcinomatosis index (ePCI), and tumor-host body weight ratio were investigated. Immunohistochemical studies and western blotting were done to investigate key molecules involved in the mechanism of action. Results Compared with Control, both PDOX and DOX could similarly and significantly reduce liver tumor weight and tumor volume by over 40%, ePCI values, retroperitoneal lymph node metastases and lung metastases and serum AFP levels (P?efficacy and reduced side effects especially cardio-toxicities in this HCC model.

2013-01-01

182

Sources of Self-Efficacy in Mathematics: A Validation Study  

ERIC Educational Resources Information Center

The purpose of this study was to develop and validate items with which to assess A. Bandura's (1997) theorized sources of self-efficacy among middle school mathematics students. Results from Phase 1 (N=1111) were used to develop and refine items for subsequent use. In Phase 2 of the study (N=824), a 39-item, four-factor exploratory model fit best.…

Usher, Ellen L.; Pajares, Frank

2009-01-01

183

Investigating the efficacy of practical skill teaching: a pilot-study comparing three educational methods.  

PubMed

Effective education of practical skills can alter clinician behaviour, positively influence patient outcomes, and reduce the risk of patient harm. This study compares the efficacy of two innovative practical skill teaching methods, against a traditional teaching method. Year three pre-clinical physiotherapy students consented to participate in a randomised controlled trial, with concealed allocation and blinded participants and outcome assessment. Each of the three randomly allocated groups were exposed to a different practical skills teaching method (traditional, pre-recorded video tutorial or student self-video) for two specific practical skills during the semester. Clinical performance was assessed using an objective structured clinical examination (OSCE). The students were also administered a questionnaire to gain the participants level of satisfaction with the teaching method, and their perceptions of the teaching methods educational value. There were no significant differences in clinical performance between the three practical skill teaching methods as measured in the OSCE, or for student ratings of satisfaction. A significant difference existed between the methods for the student ratings of perceived educational value, with the teaching approaches of pre-recorded video tutorial and student self-video being rated higher than 'traditional' live tutoring. Alternative teaching methods to traditional live tutoring can produce equivalent learning outcomes when applied to the practical skill development of undergraduate health professional students. The use of alternative practical skill teaching methods may allow for greater flexibility for both staff and infrastructure resource allocation. PMID:22354336

Maloney, Stephen; Storr, Michael; Paynter, Sophie; Morgan, Prue; Ilic, Dragan

2012-02-22

184

Isolated Lung Perfusion as an Adjuvant Treatment of Colorectal Cancer Lung Metastases: A Preclinical Study in a Pig Model  

PubMed Central

Background The lung is a frequent site of colorectal cancer (CRC) metastases. After surgical resection, lung metastases recurrences have been related to the presence of micrometastases, potentially accessible to a high dose chemotherapy administered via adjuvant isolated lung perfusion (ILP). We sought to determine in vitro the most efficient drug when administered to CRC cell lines during a short exposure and in vivo its immediate and delayed tolerance when administered via ILP. Methods First, efficacy of various cytotoxic molecules against a panel of human CRC cell lines was tested in vitro using cytotoxic assay after a 30-minute exposure. Then, early (operative) and delayed (1 month) tolerance of two concentrations of the molecule administered via ILP was tested on 19 adult pigs using hemodynamic, biological and histological criteria. Results In vitro, gemcitabine (GEM) was the most efficient drug against selected CRC cell lines. In vivo, GEM was administered via ILP at regular (20 µg/ml) or high (100 µg/ml) concentrations. GEM administration was associated with transient and dose-dependant pulmonary vasoconstriction, leading to a voluntary decrease in pump inflow in order to maintain a stable pulmonary artery pressure. After this modulation, ILP using GEM was not associated with any systemic leak, systemic damage, and acute or delayed histological pulmonary toxicity. Pharmacokinetics studies revealed dose-dependant uptake associated with heterogenous distribution of the molecule into the lung parenchyma, and persistent cytotoxicity of venous effluent. Conclusions GEM is effective against CRC cells even after a short exposure. ILP with GEM is a safe and reproducible technique.

Pages, Pierre-Benoit; Facy, Olivier; Mordant, Pierre; Ladoire, Sylvain; Magnin, Guy; Lokiec, Francois; Ghiringhelli, Francois; Bernard, Alain

2013-01-01

185

Pharmaceutical sales performance : A proposed study measuring behavioral aspects of self-efficacy as compared to general self-efficacy  

Microsoft Academic Search

Purpose – To date, a general self-efficacy concept has been the standard model for prediction of sales performance, and there has yet to be a published study that combines the three variables: sales performance, self-efficacy, and sales communication behaviors. It is proposed that a model which takes into account the behaviors of getting, giving, using, and planning, and the self-efficacy

Annette Ryerson

2008-01-01

186

The Efficacy of Math Coaching: An Evaluative Case Study  

ERIC Educational Resources Information Center

|There is a lack of implementation of instructional strategies to assist middle school teachers in improving mathematics education for their students. Coaching is one solution to this problem, but its impact on student achievement is unclear. This case study evaluated the relationship between coaching and teacher efficacy and the impact of these…

Dobbins, C. Neelie

2010-01-01

187

Year 3 ASK/FOSS Efficacy Study. CRESST Report 782  

ERIC Educational Resources Information Center

This efficacy study was designed to examine the traditional FOSS curriculum (Delta Publishing, Full Option Science System/FOSS, magnetism and electricity, structures of life, and water modules, 2005), and the new ASK/FOSS curriculum (magnetism and electricity, structures of life, and water modules, 2005), a revised version of the original FOSS…

Osmundson, Ellen; Dai, Yunyun; Herman, Joan

2011-01-01

188

Controlled Study of Prematurity Prevention: Efficacy and Costs.  

National Technical Information Service (NTIS)

The purpose of the randomized controlled study was to: assess the impact of a preterm birth prevention program applied in a sample of black inner-city women in Philadelphia; evaluate the efficacy of the risk screening tool as designed and attempt to impro...

D. M. Main

1988-01-01

189

Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.  

PubMed

Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD. PMID:19146880

Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram

2008-12-25

190

In vitro Immunogenicity Risk-assessment of Therapeutic Proteins in Preclinical Setting  

PubMed Central

Immunogenicity against therapeutic proteins is a clinical problem in the successful treatment of many diseases and as such, immunogenicity risk assessment in preclinical setting would be useful to improve safety and efficacy of protein based therapeutics in the product development stages. Here, we attempted a mechanism based in vitro studies as screening tool to capture clinically observed antibody based immune response against two representative therapeutic proteins; recombinant human Erythropoietin-alpha (rHuEPO) and recombinant Factor VIII (rFVIII). Flow cytometry was used to determine the maturation level of dendritic cells (DCs), a primary initiator of T-cell responses. Studies to capture T-lymphocyte proliferation upon challenge with free rFVIII were performed and secretion of immunomodulatory cytokines was analyzed by ELISA assay. These in vitro techniques could be used as risk assessment tool to determine the immunogenic potential of formulations of recombinant proteins in preclinical setting.

Gaitonde, Puneet; Balu-Iyer, Sathy V

2010-01-01

191

CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies  

PubMed Central

Established cell lines are utilized extensively to study tumor biology and preclinical therapeutic development; however, they may not accurately recapitulate the heterogeneity of their corresponding primary disease. B-cell tumor cells are especially difficult to maintain under conventional culture conditions, limiting access to samples that faithfully represent this disease for preclinical studies. Here, we used primary canine diffuse large B-cell lymphoma to establish a culture system that reliably supports the growth of these cells. CD40 ligand, either expressed by feeder cells or provided as a soluble two-trimeric form, was sufficient to support primary lymphoma cells in vitro. The tumor cells retained their original phenotype, clonality and known karyotypic abnormalities after extended expansion in culture. Finally, we illustrate the utility of the feeder cell-free culture system for comparable assessment of cytotoxicity using dog and human B-cell malignancies. We conclude this system has broad applications for in vitro preclinical development for B-cell malignancies.

Ito, Daisuke; Frantz, Aric M.; Williams, Christina; Thomas, Rachael; Burnett, Robert C.; Avery, Anne C.; Breen, Matthew; Mason, Nicola J.; O'Brien, Timothy D.; Modiano, Jaime F.

2013-01-01

192

[Studies of biologic activation associated with molecular receptor increase and tumor response in ChL6/L6 protocol patients; Studies in phantoms; Quantitative SPECT; Preclinical studies; and Clinical studies]. DOE annual report, 1994--95  

SciTech Connect

The authors describe results which have not yet been published from their associated studies listed in the title. For the first, they discuss Lym-1 single chain genetically engineered molecules, analysis of molecular genetic coded messages to enhance tumor response, and human dosimetry and therapeutic human use radiopharmaceuticals. Studies in phantoms includes a discussion of planar image quantitation, counts coincidence correction, organ studies, tumor studies, and {sup 90}Y quantitation with Bremsstrahlung imaging. The study on SPECT discusses attenuation correction and scatter correction. Preclinical studies investigated uptake of {sup 90}Y-BrE-3 in mice using autoradiography. Clinical studies discuss image quantitation verses counts from biopsy samples, S factors for radiation dose calculation, {sup 67}Cu imaging studies for lymphoma cancer, and {sup 111}In MoAb imaging studies for breast cancer to predict {sup 90}Y MoAb therapy.

DeNardo, S.J.

1995-12-31

193

Preclinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens  

Microsoft Academic Search

Human papillomavirus (HPV) E6 and E7 oncoproteins are attractive targets for T-cell-based immunotherapy of cervical intraepithelial neoplasia (CIN) and cancer. A newly designed vaccine, comprising the HPV16 L2, E6 and E7 as a single fusion protein (TA-CIN), was shown to elicit HPV16-specific CTL, T-helper cells and antibodies in a pre-clinical mouse model. These immune responses effectively prevented outgrowth of HPV16-positive

S. H. van der Burg; K. M. C. Kwappenberg; T. O'Neill; R. M. P. Brandt; C. J. M. Melief; J. K. Hickling; R. Offringa

2001-01-01

194

Gram-scale purification of flavonolignan diastereoisomers from Silybum marianum (Milk Thistle) extract in support of preclinical in vivo studies for prostate cancer chemoprevention.  

PubMed

Extracts of milk thistle ( Silybum marianum, Asteraceae), termed "silymarin," are used worldwide, primarily for hepatoprotective applications and recently for prostate cancer chemoprevention. Silymarin is a mixture of at least eight compounds, and four major constituents are a group of structurally related flavonolignans: silybin A, silybin B, isosilybin A, and isosilybin B. The initiation of IN VIVO studies to compare the respective preclinical activities of each compound required that gram quantities of these diastereoisomers be prepared. Procedures were developed and optimized to produce multigram-scale quantities of each of these in > 97 % purity. A hybrid chromatographic/precipitative technique was developed, whereby mixtures were chromatographed at high concentrations so as to induce formation of a precipitate in the column fractions, yielding samples that were more enriched in the desired compounds than would be obtained solely by the chromatographic steps alone. PMID:17948171

Graf, Tyler N; Wani, Mansukh C; Agarwal, Rajesh; Kroll, David J; Oberlies, Nicholas H

2007-10-18

195

Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development  

Microsoft Academic Search

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a

Alena V Savonenko; Tatiana Melnikova; Andrew Hiatt; Tong Li; Paul F Worley; Juan C Troncoso; Phil C Wong; Don L Price

2012-01-01

196

HIV Vaccine Development: Strategies for Preclinical and Clinical Investigation.  

PubMed

Abstract This article discusses HIV vaccine discovery and candidate vaccine testing in the context of current realities of funding and clinical trial practice. Lacking perfect animal models for testing candidate HIV vaccines, clinical investigators have proposed a strategy of iterative exploratory clinical trials in the model of cancer chemotherapy development. Problems with the appropriateness of this model to HIV vaccine development are discussed. Also, the future feasibility of this strategy in the context of increasing clinical trial costs and emerging new, efficacious prevention modalities is questioned. Strategies for making better use of animal models are presented as an alternative to iterative exploratory clinical efficacy testing. Some ways in which better data from preclinical studies can refine clinical product development are described. Finally, development of an HIV vaccine under the FDA's "Animal Rule" pathway to licensure when human efficacy studies are not feasible is discussed as a fall-back approach. Not making a preventive vaccine against HIV infection is simply not an option because eradication of AIDS will require a preventive vaccine. PMID:23379343

Shapiro, Stuart Z

2013-03-08

197

Preclinical Operative Dentistry Courses in Northern Europe and Scandinavia.  

ERIC Educational Resources Information Center

|This study compares teaching methods, time spent, and materials used in the existing preclinical teaching efforts of dental schools in 11 Northern European states (Belgium, Denmark, Eire, Finland, France, Germany, Netherlands, Norway, Sweden, Switzerland, and United Kingdom). Results reveal considerable variation in the teaching of preclinical

Wilson, N. H. F.; And Others

1993-01-01

198

Preclinical Imaging of Mammary Intraepithelial Neoplasia with Positron Emission Tomography  

Microsoft Academic Search

Small-animal imaging with positron emission tomography (PET) has become a valuable tool for evaluating preclinical models of breast cancer and other diseases. In this review, we examine a number of issues related to preclinical imaging studies with PET, using transgenic models of ductal carcinoma in situ and metastasis as specific examples. We discuss imaging components such as reconstruction, normalization, and

Craig K. Abbey; Alexander D. Borowsky; Jeffery P. Gregg; Robert D. Cardiff; Simon R. Cherry

2006-01-01

199

Use of zebrafish apoptosis assays for preclinical drug discovery.  

PubMed

Introduction: Apoptosis has become an important target for drug discovery. Although the mouse remains the animal model of choice for the preclinical assessment of drug toxicity and efficacy, zebrafish are increasingly used for early drug studies. Here, we describe approaches for assessing drug effects on apoptosis in transparent zebrafish. Areas covered: In this review, the authors discuss the drug effects on developmentally regulated apoptosis using microscopy. They also discuss the effects of neuroprotectants in a chemical induced disease model using morphometric image analysis. Finally, the authors review the effects of radioprotectants in irradiated whole animals using a conventional 96-well microplate format. Expert opinion: Several challenges have limited more widespread use of zebrafish as the organism of choice for drug screening. However, zebrafish do have a number of compelling inherent advantages including: rapid organogenesis, transparency, statistically significant numbers of animals per experiment and adaptability of cell-based methods. PMID:23964640

McGrath, Patricia; Seng, Wen Lin

2013-08-21

200

Preclinical computational models: predictors of tibial insert damage patterns in total knee arthroplasty: AAOS exhibit selection.  

PubMed

Computational models that predict clinical surface damage of the tibial insert during activities of daily living are emerging as powerful tools to assess the safety and efficacy of contemporary total knee arthroplasty designs. These models have the advantage of quickly determining the performance of new designs at low cost, and they allow direct comparison with the performance of classic, clinically successful designs. This study validated finite element and kinematic modeling predictions through comparison with preclinical physical testing results, damage patterns on retrieved tibial inserts, and clinically measured knee motion. There is a mounting body of evidence to support the role of computational modeling as a preclinical tool that enables the optimization of total knee arthroplasty designs and the auditing of component quality control before large-scale manufacturing is undertaken. PMID:22992885

Morra, Edward A; Heim, Christine S; Greenwald, A Seth

2012-09-19

201

A COMPARATIVE EFFICACY STUDY OF CENTBUTINDOLE AND HALOPERIDOL IN SCHIZOPHRENIA  

PubMed Central

A double blind study was undertaken to compare the efficacy between centbutindole and haloperidol. A total of 44 patients suffering from schizophrenia diagnosed in accordance to ICD-10 criteria were included. They were randomly assigned into two groups receiving centbutindole (4.5 mg) or haloperidol (15 mg) in two divided doses per day for six weeks. Each patient was evaluated on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale (CGI-S) and UKU side effect scale every week. Five patients (1 patient in centbutindole group, 4 patients in haloperidol group) dropped out due to various reasons. A total of 39 patients (21 patients in centbutindole group and 18 patients in haloperidol group) completed the study. The results revealed an early onset of therapeutic effect with centbutindole for both positive and negative symptoms. However, the efficacy was comparable between centibutindole and haloperidol from 3rd week onwards.

Singh, Harjeet; Srivastava, J.S.; Raghuvanshi, Charu; Dalal, P.K.; Asthana, O.P.

1999-01-01

202

Preclinical and clinical research on inflammation after intracerebral hemorrhage  

PubMed Central

Intracerebral hemorrhage (ICH) is one of the most lethal stroke subtypes. Despite the high morbidity and mortality associated with ICH, its pathophysiology has not been investigated as well as that of ischemic stroke. Available evidence from preclinical and clinical studies suggests that inflammatory mechanisms are involved in the progression of ICH-induced secondary brain injury. For example, in preclinical ICH models, microglial activation has been shown to occur within 1 h, much earlier than neutrophil infiltration. Recent advances in our understanding of neuroinflammatory pathways have revealed several new molecular targets, and related therapeutic strategies have been tested in preclinical ICH models. This review summarizes recent progress made in preclinical models of ICH, surveys preclinical and clinical studies of inflammatory cells (leukocytes, macrophages, microglia, and astrocytes) and inflammatory mediators (matrix metalloproteinases, nuclear factor erythroid 2-related factor 2, heme oxygenase, and iron), and highlights the emerging areas of therapeutic promise.

Wang, Jian

2010-01-01

203

Preclinical studies on targeted delivery of multiple IFN?2b to HLA-DR in diverse hematologic cancers.  

PubMed

The short circulating half-life and side effects of IFN? affect its dosing schedule and efficacy. Fusion of IFN? to a tumor-targeting mAb (mAb-IFN?) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFN? comprising tetrameric IFN?2b site-specifically linked to hL243 (humanized anti-HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFN? or a mixture comprising the parental mAb and IFN?. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFN? and hL243. C2-2b-2b induced more potent and longer-lasting IFN? signaling compared with nontargeted IFN?. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFN?, peginterferonalfa-2a, or a combination of hL243 and IFN?, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID:21680794

Rossi, Edmund A; Rossi, Diane L; Cardillo, Thomas M; Stein, Rhona; Goldenberg, David M; Chang, Chien-Hsing

2011-06-16

204

Personality and performance of preclinical medical students.  

PubMed

This study deals with personality variables of medical students in relation to their academic success in the preclinical stage. One hundred and one students completed the 16PF Questionnaire at the beginning of their medical course and the scores were analysed in relation to their marks obtained at the end of the 2-year preclinical stage. This study shows that the 16PF Questionnaire can be a useful instrument for identifying personality variables in candidates who are likely to have academic problems and those who are likely to do well in the preclinical stage of a medical course. Students of urban origin and the eldest in the family performed better in their preclinical years. Performance was not related to sex, ethnic group, family size of entrance qualification into medicine. Personality variables of being enthusiastic, venturesome, self-opinionated, imaginative, experimenting, resourceful and driven correlate positively with performance, whereas being self-assured has negative correlation. Problem students were more reserved, emotionally less stable and more apprehensive than non-problem students. PMID:8594392

Peng, R; Khaw, H H; Edariah, A B

1995-07-01

205

Preclinical Molecular Imaging of Tumor Angiogenesis  

PubMed Central

Angiogenesis, a course that new blood vessels grow from the existing vasculature, plays important roles both physiologically and pathologically. Angiogenesis can be switched on by growth factors secreted by tumor cells, and in turn supplies more oxygen and nutrition to the tumor. More and more preclinical studies and clinical trials have shown that inhibition of angiogenesis is an effective way to inhibit tumor growth, substantiating the development of anti-angiogenesis therapeutics. Imaging technologies accelerate the translation of preclinical research to the clinic. In oncology, various imaging modalities are widely applied to drug development, tumor early detection and therapy response monitoring. So far, several angiogenesis related imaging agents are promising in cancer diagnosis. However, more effective imaging agents with less side-effect still need to be pursued to visualize angiogenesis process non-invasively. The main purpose of this review is to summarize the recent progresses in preclinical molecular imaging of angiogenesis and to discuss the potential of the current preclinical probes specific to various angiogenesis targets including vascular endothelial growth factor and its receptors (VEGF/VEGFRs), integrin ?v?3 and matrix metalloproteinases (MMPs). It is predicable that related investigations in the field will benefit cancer research and quicken the anti-angiogenic drug development.

Zhu, Lei; Niu, Gang; Fang, Xuexun; Chen, Xiaoyuan

2010-01-01

206

Non-invasive molecular imaging for preclinical cancer therapeutic development.  

PubMed

Molecular and non-invasive imaging are rapidly emerging fields in preclinical cancer drug discovery. This is driven by the need to develop more efficacious and safer treatments, the advent of molecular-targeted therapeutics, and the requirements to reduce and refine current preclinical in vivo models. Such bioimaging strategies include MRI, PET, single positron emission computed tomography, ultrasound, and optical approaches such as bioluminescence and fluorescence imaging. These molecular imaging modalities have several advantages over traditional screening methods, not least the ability to quantitatively monitor pharmacodynamic changes at the cellular and molecular level in living animals non-invasively in real time. This review aims to provide an overview of non-invasive molecular imaging techniques, highlighting the strengths, limitations and versatility of these approaches in preclinical cancer drug discovery and development. PMID:23488622

O'Farrell, A C; Shnyder, S D; Marston, G; Coletta, P L; Gill, J H

2013-06-01

207

Early prediction of response to radiotherapy and androgen-deprivation therapy in prostate cancer by repeated functional MRI: a preclinical study  

PubMed Central

Background In modern cancer medicine, morphological magnetic resonance imaging (MRI) is routinely used in diagnostics, treatment planning and assessment of therapeutic efficacy. During the past decade, functional imaging techniques like diffusion-weighted (DW) MRI and dynamic contrast-enhanced (DCE) MRI have increasingly been included into imaging protocols, allowing extraction of intratumoral information of underlying vascular, molecular and physiological mechanisms, not available in morphological images. Separately, pre-treatment and early changes in functional parameters obtained from DWMRI and DCEMRI have shown potential in predicting therapy response. We hypothesized that the combination of several functional parameters increased the predictive power. Methods We challenged this hypothesis by using an artificial neural network (ANN) approach, exploiting nonlinear relationships between individual variables, which is particularly suitable in treatment response prediction involving complex cancer data. A clinical scenario was elicited by using 32 mice with human prostate carcinoma xenografts receiving combinations of androgen-deprivation therapy and/or radiotherapy. Pre-radiation and on days 1 and 9 following radiation three repeated DWMRI and DCEMRI acquisitions enabled derivation of the apparent diffusion coefficient (ADC) and the vascular biomarker Ktrans, which together with tumor volumes and the established biomarker prostate-specific antigen (PSA), were used as inputs to a back propagation neural network, independently and combined, in order to explore their feasibility of predicting individual treatment response measured as 30 days post-RT tumor volumes. Results ADC, volumes and PSA as inputs to the model revealed a correlation coefficient of 0.54 (p < 0.001) between predicted and measured treatment response, while Ktrans, volumes and PSA gave a correlation coefficient of 0.66 (p < 0.001). The combination of all parameters (ADC, Ktrans, volumes, PSA) successfully predicted treatment response with a correlation coefficient of 0.85 (p < 0.001). Conclusions We have in a preclinical investigation showed that the combination of early changes in several functional MRI parameters provides additional information about therapy response. If such an approach could be clinically validated, it may become a tool to help identifying non-responding patients early in treatment, allowing these patients to be considered for alternative treatment strategies, and, thus, providing a contribution to the development of individualized cancer therapy.

2011-01-01

208

The General Self-Efficacy Scale: Multicultural Validation Studies  

Microsoft Academic Search

General self-efficacy is the belief in one's competence to cope with a broad range of stressful or challenging demands, whereas specific self-efficacy is constrained to a particular task at hand. Relations between general self-efficacy and social cognitive variables (intention, implementation intentions, outcome expectancies, and self-regulation), behavior-specific self-efficacy, health behaviors, well-being, and coping strategies were examined among 1,933 respondents in 3

Aleksandra Luszczynska; Urte Scholz; Ralf Schwarzer

2005-01-01

209

Self-efficacy and interest: Experimental studies of optimal incompetence  

Microsoft Academic Search

How does self-efficacy affect interest? The interest-and-interests model assumes that factors that induce interest—novelty, complexity, conflict, and uncertainty—do so non-linearly. Self-efficacy should thus affect interest quadratically, because it reflects uncertainty about an activity’s outcome. When self-efficacy is low, interest is low because the activity’s outcome is certain. When self-efficacy is moderate, the person’s success on the task seems likely, but

Paul J. Silvia

2003-01-01

210

An Exploratory Study of Teacher Self-Efficacy Beliefs and Professional Learning Community  

ERIC Educational Resources Information Center

The exploratory study sought to examine the relationships between teachers' self-efficacy beliefs and professional learning community. Specifically, this study presents a quantitative analysis of the relationship between teachers' perceptions of self-efficacy and PLC implementation. The Teachers' Sense of Efficacy Scale (TSES) (long form)…

Romeo, Susan M.

2010-01-01

211

Preclinical Dose-Finding Study With a Liver-Tropic, Recombinant AAV-2/8 Vector in the Mouse Model of Galactosialidosis  

PubMed Central

Galactosialidosis (GS) is a lysosomal storage disease linked to deficiency of the protective protein/cathepsin A (PPCA). Similarly to GS patients, Ppca-null mice develop a systemic disease of the reticuloendothelial system, affecting most visceral organs and the nervous system. Symptoms include severe nephropathy, visceromegaly, infertility, progressive ataxia, and shortened life span. Here, we have conducted a preclinical, dose-finding study on a large cohort of GS mice injected intravenously at 1 month of age with increasing doses of a GMP-grade rAAV2/8 vector, expressing PPCA under the control of a liver-specific promoter. Treated mice, monitored for 16 weeks post-treatment, had normal physical appearance and behavior without discernable side effects. Despite the restricted expression of the transgene in the liver, immunohistochemical and biochemical analyses of other systemic organs, serum, and urine showed a dose-dependent, widespread correction of the disease phenotype, suggestive of a protein-mediated mechanism of cross-correction. A notable finding was that rAAV-treated GS mice showed high expression of PPCA in the reproductive organs, which resulted in reversal of their infertility. Together these results support the use of this rAAV-PPCA vector as a viable and safe method of gene delivery for the treatment of systemic disease in non-neuropathic GS patients.

Hu, Huimin; Gomero, Elida; Bonten, Erik; Gray, John T; Allay, Jim; Wu, Yanan; Wu, Jianrong; Calabrese, Christopher; Nienhuis, Arthur; d'Azzo, Alessandra

2012-01-01

212

Uruguay eHealth initiative: preliminary studies regarding an integrated approach to evaluate vascular age and preclinical atherosclerosis (CUiiDARTE project).  

PubMed

In this work we present an initiative to develop a national (Uruguayan) program to evaluate vascular age and to detect pre-clinical atherosclerosis using: gold-standard technologies; complimentary and integrative approaches to asses arterial functional and structural indexes; data bases systems to process, analyze and determine normal and reference values and to identify the most sensitive markers of vascular changes for different ages. We evaluated, in a Uruguayan population complementary structural and functional vascular parameters that associate aging-related changes and are considered markers of sub-clinical atherosclerosis. Traditional CV risk factors were assessed. The subjects (n=281) were submitted to non-invasive vascular studies to evaluate: 1) Common carotid artery (CCA) intima-media thickness and diameter waveforms, 2) CCA stiffness, 3) aortic stiffness (pulse wave velocity) and 4) peripheral and central pressure pulse wave derived parameters. Age groups: 21-30, 31-40, 41-50, 51-60, and 61-70 years-old. Age-related profiles were obtained for the different vascular parameters, and their utility to assess vascular changes in young, middle-aged and old subjects was evaluated. The work has the strength of being the first that uses, in Latin-America an integrative approach to characterize vascular aging-related changes. PMID:22254442

Armentano, Ricardo L; Bia, Daniel; Zócalo, Yanina; Torrado, Juan; Farro, Ignacio; Farro, Federico; Florio, Lucía; Olascoaga, Alicia; Alallon, Walter; Negreira, Carlos; Lluberas, Ricardo

2011-01-01

213

Transplantation of umbilical cord-derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives.  

PubMed

The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates. PMID:22430384

Dalous, Jérémie; Larghero, Jérome; Baud, Olivier

2012-02-08

214

Preclinical studies of [ 99mTc]DTPA-mannosyl-dextran? ? ? Supported in part by National Cancer Institute Grant CA72751 and University of California Breast Cancer Research Program Grants 2RB0018 and 4IB0051  

Microsoft Academic Search

We report the preclinical testing of a synthetic receptor-binding macromolecule, [99mTc]DTPA-mannosyl-dextran (36 kDa, 8 DTPA and 55 mannosyl units per dextran, KD = 0.12 nM), for sentinel node detection. Nonclinical safety studies included cardiac pharmacology safety studies, acute toxicology and pathology studies at 50 and 500 times the scaled human dose in both rats and rabbits after foot pad administration,

Carl K Hoh; Anne M Wallace; David R Vera

2003-01-01

215

21 CFR 310.6 - Applicability of ânew drugâ or safety or effectiveness findings in drug efficacy study...  

Code of Federal Regulations, 2010 CFR

...or effectiveness findings in drug efficacy study implementation notices and...or effectiveness findings in drug efficacy study implementation notices and...the Federal Register as Drug Efficacy Study Implementation (DESI)...

2009-04-01

216

Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication  

Microsoft Academic Search

1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus in- fection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg\\/kg\\/day, and the no-effect dose in a 1-month monkey study was 180 mg\\/kg\\/day. Toxic effects were limited to increases in liver weights, neutrophils,

George W. Koszalka; Nelson W. Johnson; Steven S. Good; Leslie Boyd; Stanley C. Chamberlain; Leroy B. Townsend; John C. Drach; Karen K. Biron

2002-01-01

217

In vitro studies on radioprotective efficacy of silymarin against ?-irradiation.  

PubMed

Abstract Purpose: Silymarin has been widely exploited for its hepatoprotective activities. This study aimed to evaluate the protective efficacy of silymarin against ?-radiation. Materials and methods: The radioprotective properties of silymarin were studied using different assays. Cytotoxicity of silymarin on Human embryonic kidney (HEK) cells was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. Protective efficacy against ?-radiation was assessed by studying reduction in micronuclei frequency and free radical generation using 2',7'-dichlorodihydroflurescin diacetate (H2DCFDA). Radiation-induced apoptosis was estimated by Annexin V-PI (propidium iodide) analysis and cell cycle analysis. ?-radiation induced changes in mitochondrial membrane potential (MMP) and DNA damage was estimated employing flow-cytometry and comet assay respectively. Results: MTT assay and Annexin V-PI studies showed that pre-incubation of HEK cells with silymarin protected them from ?-irradiation. Significant reduction in apoptosis (76.36%) was observed. Silymarin also decreased the percentage of radiation-induced micronuclei (> 69%) (p < 0.05 ). Measurement of intracellular reactive oxygen species (ROS) by H2DCFDA revealed a reduction in ROS (21%) at 0.5 h. Cell cycle analysis revealed G1 block in the unirradiated control, which declined in the silymarin pretreated irradiated group (0.5 h). Silymarin treatment resulted in a significant increase in MMP (2 h) against the radiation control. Moreover, the presence of silymarin during irradiation significantly decreased the DNA damage (as measured by comet assay). Conclusions: Protection against radiation-induced cell-death and DNA damage by silymarin could be attributed to a reduction in ROS induced by ?-radiation. In vitro experiments on HEK cells explicitly prove that silymarin is a promising, effective and safe radiation countermeasure agent. PMID:23078259

Adhikari, Manish; Dhaker, Atlar; Adhikari, Jawahar; Ivanov, Veselin; Singh, Vijay; Chawla, Raman; Kumar, Raj; Sharma, Rakesh; Karamalakova, Yana; Gadjeva, Veselina; Arora, Rajesh

2013-01-10

218

Teacher Self-Efficacy and Teacher Burnout: A Study of Relations  

ERIC Educational Resources Information Center

|The purpose of this study was partly to test the factor structure of a recently developed Norwegian scale for measuring teacher self-efficacy and partly to explore relations between teachers' perception of the school context, teacher self-efficacy, collective teacher efficacy, teacher burnout, teacher job satisfaction, and teachers' beliefs that…

Skaalvik, Einar M.; Skaalvik, Sidsel

2010-01-01

219

Teacher self-efficacy and teacher burnout: A study of relations  

Microsoft Academic Search

The purpose of this study was partly to test the factor structure of a recently developed Norwegian scale for measuring teacher self-efficacy and partly to explore relations between teachers' perception of the school context, teacher self-efficacy, collective teacher efficacy, teacher burnout, teacher job satisfaction, and teachers' beliefs that factors external to teaching puts limitations to what they can accomplish. Participants

Einar M. Skaalvik; Sidsel Skaalvik

2010-01-01

220

The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies  

Microsoft Academic Search

Epidemiologic studies indicate that children exposed to early adverse experiences are at increased risk for the development of depression, anxiety disorders, or both. Persistent sensitization of central nervous system (CNS) circuits as a consequence of early life stress, which are integrally involved in the regulation of stress and emotion, may represent the underlying biological substrate of an increased vulnerability to

Christine Heim; Charles B. Nemeroff

2001-01-01

221

Preclinical toxicology studies for new drugs and vaccines. Annual report, 15 November 1991-14 November 1992  

SciTech Connect

The purpose of this study is to determine specific target organ toxicity, dose-response relationships, and a no adverse effect level of WR6026 in Beagle dogs following thirteen weeks of daily oral administration. In addition, the reversibility of these toxic effects over a 90-day recovery period will be assessed. Treatment was initiated on 5/7/92. Necropsies were conducted on 8/6-7/92 and 11/5-6/92 after the three month treatment period and a three month recovery period, respectively.

Levine, B.S.

1992-12-07

222

Preclinical Alzheimer disease --the challenges ahead  

PubMed Central

There is growing recognition that the pathophysiological process of Alzheimer disease (AD) begins many years prior to clinically obvious symptoms, and the concept of a presymptomatic or preclinical stage of AD is becoming more widely accepted. Advances in biomarker studies have enabled detection of AD pathology in vivo in clinically normal older individuals. The predictive value of these biomarkers at the individual patient level, however, remains to be elucidated. The ultimate goal of identifying individuals in the preclinical stages of AD is to facilitate early intervention to delay and perhaps even prevent emergence of the clinical syndrome. A number of challenges remain to be overcome before this concept can be validated and translated into clinical practice.

Sperling, Reisa A.; Karlawish, Jason; Johnson, Keith A.

2013-01-01

223

Fibrillar amyloid correlates of preclinical cognitive decline.  

PubMed

BACKGROUND: It is not known whether preclinical cognitive decline is associated with fibrillar ?-amyloid (A?) deposition irrespective of apolipoprotein E (APOE) ?4 status. METHODS: From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ?4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVRs), reflecting fibrillar A? burden. RESULTS: At P < .005 (uncorrected), decliners had significantly greater DVRs in comparison to nondecliners. CONCLUSIONS: Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ?4 genotype. PMID:23583233

Stonnington, Cynthia M; Chen, Kewei; Lee, Wendy; Locke, Dona E C; Dueck, Amylou C; Liu, Xiaofen; Roontiva, Auttawut; Fleisher, Adam S; Caselli, Richard J; Reiman, Eric M

2013-04-11

224

Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women's Health Initiative observational study  

PubMed Central

Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months prior to diagnosis from 28 triple-negative cases and 28 matched controls from the Women’s Health Initiative Observational Study were equally divided into a training set and a test set and interrogated using a customized antibody array. Data were available on 889 antibodies, and in the training set statistically significant differences in case vs. control signals were observed for 93 (10.5%) antibodies at p<0.05. Of these 93 candidates, 29 were confirmed in the test set at p<0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98%, sensitivity ranged from 4% to 68% with ?20 candidates having a sensitivity 20% and 6 having a sensitivity ?40%. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p=0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p=0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to follow-up on promising candidates in larger sample sizes and to better understand their potential biological importance as our understanding of the etiology of triple-negative breast cancer continues to grow.

Li, Christopher I.; Mirus, Justin E.; Zhang, Yuzheng; Ramirez, Arturo B.; Ladd, Jon J.; Prentice, Ross L.; McIntosh, Martin; Hanash, Samir M.; Lampe, Paul D.

2012-01-01

225

A rapid and sensitive LC-MS/MS assay for the determination of berbamine in rat plasma with application to preclinical pharmacokinetic study.  

PubMed

Berbamine (BBM), a natural compound from Chinese herb Berberis amurensis, has recently received a great deal of attention due to its anti-leukemia activity. In this study, a rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of BBM in rat plasma was developed for the first time. Caffeine was used as an internal standard. Chromatographic separation was performed on an ODS column with gradient elution using methanol-1% formic acid as mobile phase at a flow rate of 0.3mL/min. Quantification was through tandem mass spectrometry with positive electrospray ionization (ESI) and multiple reaction monitoring (MRM) at m/z 305.2?566.3 and 195.1?138.0 for BBM and IS, respectively. The lower limit of quantification was 1ng/mL with a linear range of 1-1000ng/mL. The intra- and inter-day assay precision (RSD) ranged from 2.0-6.4% to 2.5-5.5%, respectively, and the intra- and inter-day assay accuracy (RE) was between -5.8-6.0% and -6.5-1.4%, respectively. The validated method was successfully applied to the preclinical pharmacokinetic studies of BBM in rats. The elimination half-lives (t1/2) were (472.4±66.1), (509.6±97.0) and (486.2±94.6) min after single intravenous administration of 2, 4 and 8mg/kg BBM, respectively. The area under the plasma concentration versus time curve (AUC0-24h) and initial plasma concentration (C0) were linearly related to dose. PMID:23660248

Liu, Qingwang; Wang, Junsong; Yang, Lei; Jia, Yuanwei; Kong, Lingyi

2013-04-17

226

Standardized extracts from hawthorn leaves and flowers in the treatment of cardiovascular disorders--preclinical and clinical studies.  

PubMed

Extracts from different parts of hawthorn plants (Crataegus spp.) are used worldwide for the treatment of cardiovascular diseases. So far, almost all clinical studies have been conducted with standardized hydroalcoholic extracts from leaves and flowers. These trials with more than 4000 patients have provided evidence for clinical benefits in the therapy of mild chronic heart failure. Besides cardiotonic effects, recent pharmacological investigations indicate that hawthorn extracts also possess cardio- and vasoprotective properties. Thus, these extracts may also be employed in the prophylactic and therapeutic treatment of such conditions as endothelial dysfunction, atherosclerosis, coronary heart disease, or prevention of restenosis/reocclusion following peripheral endovascular treatment. In this review the pharmacological and clinical data relating to these standardized extracts are summarized. PMID:21384315

Koch, Egon; Malek, Fathi Abdul

2011-03-07

227

Fluorine-18-fluorodeoxygglucose-guided breast cancer surgery with a positron-sensitive probe: Validation in preclinical studies  

SciTech Connect

In this study, the feasibility of utilizing 2-deoxy-2-fluoro-d-glucose (FDG) in conjunction with a positron-sensitive intraoperative probe to guide breast tumor excision was investigated. The probe was constructed with a plastic scintillator tip coupled to a photomultiplier tube with fiber optic cable. Anticipated resolution degradation was evaluated by measurement of line spread functions in the presence of background radiation. Realistic photon background distributions were simulated with a human torso phantom and a cardiac insert. The relationship between resolution and energy threshold was measured to find the optimal discriminator settings. In addition, probe sensitivity as a function of energy threshold was determined for various size-simulated tumors. Finally, the ability to localize breast cancers in vivo was tested in a rodent model. Mammary rat tumors implanted in Lewis rats were examined after injection with FDG; these results were correlated with those of histologic analyses. Measurements of line spread functions indicated that resolution could be maximized in a realistic background photon environment by increasing the energy threshold to levels at or above the Compton continuum edge (340 keV). At this setting, the probe`s sensitivity was determined to be 58 and 11 cps/{mu}Ci for 3.18- and 6.35-mm diameter simulated tumors, respectively. Probe readings correlated well with histologic results; the probe was generally able to discriminate between tumor and normal tissue. This study indicates that breast cancer surgery guided by a positron-sensitive probe warrants future evaluation in breast-conserving surgery of patients with breast cancer. 23 refs., 5 figs.

Raylman, R.R.; Fisher, S.J.; Brown, R.S.; Ethier, S.P.; Wahl, R.L. [Univ. of Michigan Medical Center, Ann Arbor, MI (United States)

1995-10-01

228

A comparative study of students' performance in preclinical physiology assessed by multiple choice and short essay questions.  

PubMed

This study was designed to compare the performance of medical students in physiology when assessed by multiple choice questions (MCQs) and short essay questions (SEQs). The study also examined the influence of factors such as age, sex, O/level grades and JAMB scores on performance in the MCQs and SEQs. A structured questionnaire was administered to 264 medical students' four months before the Part I MBBS examination. Apart from personal data of each student, the questionnaire sought information on the JAMB scores and GCE O' Level grades of each student in English Language, Biology, Chemistry, Physics and Mathematics. The physiology syllabus was divided into five parts and the students were administered separate examinations (tests) on each part. Each test consisted of MCQs and SEQs. The performance in MCQs and SEQs were compared. Also, the effects of JAMB scores and GCE O/level grades on the performance in both the MCQs and SEQs were assessed. The results showed that the students performed better in all MCQ tests than in the SEQs. JAMB scores and O' level English Language grade had no significant effect on students' performance in MCQs and SEQs. However O' level grades in Biology, Chemistry, Physics and Mathematics had significant effects on performance in MCQs and SEQs. Inadequate knowledge of physiology and inability to present information in a logical sequence are believed to be major factors contributing to the poorer performance in the SEQs compared with MCQs. In view of the finding of significant association between performance in MCQs and SEQs and GCE O/level grades in science subjects and mathematics, it was recommended that both JAMB results and the GCE results in the four O/level subjects above may be considered when selecting candidates for admission into the medical schools. PMID:11713989

Oyebola, D D; Adewoye, O E; Iyaniwura, J O; Alada, A R; Fasanmade, A A; Raji, Y

229

Pre-clinical study of in vivo magnetic resonance-guided bubble-enhanced heating in pig liver.  

PubMed

Bubble-enhanced heating (BEH) can be exploited to increase heating efficiency in treatment of liver tumors with non-invasive high-intensity focused ultrasound (HIFU). The objectives of this study were: (i) to demonstrate the feasibility of increasing the heating efficiency of sonication exploiting BEH in pig liver in vivo using a clinical platform; (ii) to determine the acoustic threshold for such effects with real-time, motion-compensated magnetic resonance-guided thermometry; and (iii) to compare the heating patterns and thermal lesion characteristics resulting from continuous sonication and sonication including a burst pulse. The threshold acoustic power for generation of BEH in pig liver in vivo was determined using sonication of 0.5-s duration ("burst pulse") under real-time magnetic resonance thermometry. In a second step, experimental sonication composed of a burst pulse followed by continuous sonication (14.5 s) was compared with conventional sonication (15 s) of identical energy (1.8 kJ). Modification of the heating pattern at the targeted region located at a liver depth between 20 and 25 mm required 600-800 acoustic watts. The experimental group exhibited near-spherical heating with 40% mean enhancement of the maximal temperature rise as compared with the conventional sonication group, a mean shift of 7 ± 3.3 mm toward the transducer and reduction of the post-focal temperature increase. Magnetic resonance thermometry can be exploited to control acoustic BEH in vivo in the liver. By use of experimental sonication, more efficient heating can be achieved while protecting tissues located beyond the focal point. PMID:23562012

Elbes, Delphine; Denost, Quentin; Laurent, Christophe; Trillaud, Hervé; Rullier, Anne; Quesson, Bruno

2013-04-03

230

[The opioid tramadol demonstrates excitatory properties of non-opioid character--a preclinical study using alfentanil as a comparison].  

PubMed

Tramadol, an analgesic with mean potency one tenth that of morphine is used regularly for the treatment of chronic and postoperative pain. Previous reports have indicated that tramadol may induce seizure activity when given together with a selective serotonin reuptake inhibitor (SSRI). Therefore, its major mode of action may be questioned which purportedly is due to binding with the opioid receptor and partly due to the inhibition of monoamine reuptake. We therefore set out to study its potential in inducing seizure activity and to quantify its effect on EEG-power spectra and on the central modulation of sensory afferents in awake and trained dogs (n=7). In order to demonstrate if opioid receptors mediated these effects, incremental doses of tramadol were given which was followed by naloxone for possible reversal. After a wash-out period the same animals were exposed to graded doses of alfentanil, a pure mu-receptor agonist. Again this was followed by the opioid antagonist naloxone for reversal.The electroencephalogram (EEG) and the event-related evoked potentials (SEP) were used to demonstrate possible excitatory effects. In order to derive the SEP the front paw was stimulated electrically (Digi Stim II trade mark ) while the evoked potentials were picked up contralaterally from the somatosensory cortex using stick-on electrodes. 256 sweeps were averaged (Lifescan) and the peak-to-peak amplitude was measured to demonstrate CNS excitation compared to control (%). Additionally, the raw electroencephalogram was viewed for epileptogenic changes and its power computed into the various power bands alpha, beta, delta und theta using FFT over a time epoch of 60 s. Following control, graded doses of either tramadol (2-5-10 mg/kg i.v.) or alfentanil (10-30-60 microg/kg i.v.) were given every 15 min while the EEG and the SEP were recorded. Thereafter naloxone (20 microg/kg i.v.) was injected for reversal. Tramadol did not suppress the amplitude of the SEP at any dose. High doses (>5 mg/kg i.v.) resulted in an increase (+100%) of the amplitude of the evoked potential. This was accompanied by short-term muscle fibrillations, and a short-term spike-and-wave activity in the EEG followed by a long-lasting theta-dominance. These effects could not be reversed by naloxone. In contrast to tramadol, alfentanil induced a dose-related depression of amplitude in the SEP with a maximum of 82% suggesting a depressive effect of modulation of afferents in the sensory cortex. This effect was fully naloxone reversible and was followed by a rebound in amplitude of the SEP together with an increase in fast beta-waves in the EEG. Tramadol very little mediates its central action via the mu-opioid receptor as the present effects were not naloxone reversible. Consistent with the results is the very low affinity of tramadol to the opioid receptor which is several thousand times less than that of morphine. Most likely, inhibition of central norepinephrine and serotonin reuptake as well as the reduction in 5-HT-turnover may contribute to the effects of tramadol. Due to the monoamine reuptake inhibition an increase in transmission may result, triggering off excitatory phenomena with spike-and-wave activity in the CNS. Such excitatory effects, however, may only be seen when tramadol is used in doses exceeding the therapeutic range. PMID:12799988

Freye, E; Latasch, L; Von Bredow, G; Neruda, B

1998-02-28

231

Preclinical electrogastrography in experimental pigs  

PubMed Central

Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology.

Kvetina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kunes, Martin; Bures, Jan; Tacheci, Ilja; Rejchrt, Stanislav; Kopacova, Marcela

2010-01-01

232

Preclinical Pharmacology and Toxicology Studies  

Cancer.gov

OF RECEIPT for determining TIMELY DELIVERY is the address provided for the OFFICE OF ACQUISITIONS. IF YOUR PROPOSAL IS NOT RECEIVED BY THE CONTRACTING OFFICER OR HIS DESIGNEE AT THE PLACE AND TIME SPECIFIED FOR THE OFFICE OF ACQUISITIONS, THEN IT WILL BE CONSIDERED LATE AND HANDLED IN ACCORDANCE WITH subparagraph (c)(3) of FAR Clause 52.215-1, Instructions to Offerors--Competitive Acquisition," LOCATED IN SECTION L.1. OF THIS SOLICITATION. 10.

233

Sibutramine in weight control: a dose-ranging, efficacy study.  

PubMed

We tested the safety and efficacy of sibutramine, 5 and 20 mg, and placebo on weight loss. Medication was added to caloric restriction, behavior modification, and exercise in a parallel-group, double-blind clinical trial. Participants were 130% to 180% of ideal body weight and in good health. The study lasted 12 weeks over Thanksgiving, Christmas, and New Year's Day. Weight loss during 8 weeks of study medication was: placebo, 1.4 +/- 2.1 kg (n = 19); 5 mg sibutramine, 2.9 +/- 2.3 kg (n = 18); and 20 mg sibutramine, 5.0 +/- 2.7 kg (n = 18) (p less than 0.05 sibutramine, 5 and 20 mg, versus placebo; p less than 0.05 sibutramine, 20 mg versus 5 mg). There is a significant dose-effect relationship. Five participants left the study before completion, all because of adverse events; placebo (one patient), 5 mg sibutramine (one patient), and 20 mg sibutramine (three patients). Sleep difficulties were noted by eight participants (20 mg sibutramine, seven patients; 5 mg, one patient; and placebo, no patients). Six of 21 participants receiving 20 mg complained of irritability, unusual impatience, or "excitation." Sibutramine, 5 and 20 mg, added to a multimodal program assisted participants in losing weight. PMID:1914367

Weintraub, M; Rubio, A; Golik, A; Byrne, L; Scheinbaum, M L

1991-09-01

234

Advances in Preclinical SPECT Instrumentation  

PubMed Central

Preclinical SPECT imaging of rodents is both in demand and very demanding. The need for high spatial resolution in combination with good sensitivity has given rise to considerable innovation in the areas of detectors, collimation, acquisition geometry, and image reconstruction. Some of the developments described herein are beginning to carry over into clinical imaging as well.

Peterson, Todd E.; Shokouhi, Sepideh

2012-01-01

235

Efficacy of Zolpidem for Dystonia: A Study Among Different Subtypes  

PubMed Central

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (?1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20?mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2?±?7.9 to 5.5?±?5.0 (P?=?0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor.

Miyazaki, Yoshimichi; Sako, Wataru; Asanuma, Kotaro; Izumi, Yuishin; Miki, Tetsuro; Kaji, Ryuji

2012-01-01

236

Development of a preclinical model of ischemic cardiomyopathy in swine  

PubMed Central

A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dtmax) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.

Ishikawa, Kiyotake; Ladage, Dennis; Takewa, Yoshiaki; Yaniz, Elisa; Chen, Jiqiu; Tilemann, Lisa; Sakata, Susumu; Badimon, Juan J.; Kawase, Yoshiaki

2011-01-01

237

Lost in translation: preclinical studies on 3,4-methylenedioxymethamphetamine provide information on mechanisms of action, but do not allow accurate prediction of adverse events in humans  

PubMed Central

3,4-Methylenedioxymethamphetamine (MDMA) induces both acute adverse effects and long-term neurotoxic loss of brain 5-HT neurones in laboratory animals. However, when choosing doses, most preclinical studies have paid little attention to the pharmacokinetics of the drug in humans or animals. The recreational use of MDMA and current clinical investigations of the drug for therapeutic purposes demand better translational pharmacology to allow accurate risk assessment of its ability to induce adverse events. Recent pharmacokinetic studies on MDMA in animals and humans are reviewed and indicate that the risks following MDMA ingestion should be re-evaluated. Acute behavioural and body temperature changes result from rapid MDMA-induced monoamine release, whereas long-term neurotoxicity is primarily caused by metabolites of the drug. Therefore acute physiological changes in humans are fairly accurately mimicked in animals by appropriate dosing, although allometric dosing calculations have little value. Long-term changes require MDMA to be metabolized in a similar manner in experimental animals and humans. However, the rate of metabolism of MDMA and its major metabolites is slower in humans than rats or monkeys, potentially allowing endogenous neuroprotective mechanisms to function in a species specific manner. Furthermore acute hyperthermia in humans probably limits the chance of recreational users ingesting sufficient MDMA to produce neurotoxicity, unlike in the rat. MDMA also inhibits the major enzyme responsible for its metabolism in humans thereby also assisting in preventing neurotoxicity. These observations question whether MDMA alone produces long-term 5-HT neurotoxicity in human brain, although when taken in combination with other recreational drugs it may induce neurotoxicity. LINKED ARTICLES This article is commented on by Parrott, pp. 1518–1520 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.01941.x and to view the the rebuttal by the authors (Green et al., pp. 1521–1522 of this issue) visit http://dx.doi.org/10.1111/j.1476-5381.2012.01940.x

Green, AR; King, MV; Shortall, SE; Fone, KCF

2012-01-01

238

Typhoid fever vaccines: a meta›analysis of studies on efficacy and toxicity  

Microsoft Academic Search

Objective: To estimate the efficacy and toxicity of typhoid fever vaccines. Design: Meta›analysis of randomised efficacy trials and both randomised and non›randomised toxicity studies of the parenteral whole cell, oral Ty21a, and parenteral Vi vaccines. Subjects: 1 866 951 subjects in 17 efficacy trials; 11 204 subjects in 20 toxicity studies. Main outcome measures: Pooled estimates of three year cumulative

Eric A Engels; Matthew E Falagas; Joseph Lau; Michael L Bennish

1998-01-01

239

A Study Strategies Self-Efficacy Instrument for Use with Community College Students  

Microsoft Academic Search

Theories of self-efficacy and self-regulation were used to examine scores from an instrument that measures self-efficacy for using self-regulatory study strategies. The authors investigated the dimensionality of responses to the Study Skills Self-Efficacy Scale using exploratory factor analysis and Rasch measurement. They also investigated the utility of the Rasch measures in differentiating between groups of students who report being academically

Bethany B. Silver; Everett V. Smith; Barbara A. Greene

2001-01-01

240

The relationship between efficacy and methodology in studies investigating EMDR treatment of PTSD  

Microsoft Academic Search

The controlled treatment outcome studies that examined the efficacy of EMDR in the treatment of posttraumatic stress disorder have yielded a range of results, with the efficacy of EMDR varying across studies. The current study sought to determine if differences in outcome were related to methodological differences. The research was reviewed to identify meth- odological strengths, weaknesses, and empirical findings.

Louise Maxfield; Lee Hyer

2002-01-01

241

The efficacy of citalopram in the treatment of premature ejaculation: a placebo-controlled study  

Microsoft Academic Search

Background: Despite the limited number of available study comparing of their efficacy, selective serotonin re-uptake inhibitors (SSRI) have been thought to have beneficial effects for the patients with premature ejaculation. In the present study, we decided to examine the efficacy of citalopram, an SSRI, in the treatment of premature ejaculation.Method: The study was consisted of 26 married patients diagnosed with

M Atmaca; M Kuloglu; E Tezcan; A Semercioz

2002-01-01

242

Genetic Modification of Risk Assessment Based on Staging of Preclinical Type 1 Diabetes in Siblings of Affected Children  

Microsoft Academic Search

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposi- tion affects the natural course of preclinical diabetes in ini- tially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based

S. MRENA; K. SAVOLA; P. KULMALA; H. REIJONEN; J. ILONEN; H. K. ÅKERBLOM; M. KNIP

2010-01-01

243

Self-efficacy after bariatric surgery for obesity. A population-based cohort study  

Microsoft Academic Search

Background: Eating behaviors often predict outcomes after bariatric surgery, and in this regard, self-efficacy has been shown to predict long-term behavior. We examined current eating self-efficacy in post-bariatric surgery patients comparing them to obese non-surgery patients to determine whether weight loss is associated with increased self-efficacy in post-bariatric surgery patients. Methods: We performed a population-based study of patients evaluated for

John A. Batsis; Matthew M. Clark; Karen Grothe; Francisco Lopez-Jimenez; Maria L. Collazo-Clavell; Virend K. Somers; Michael G. Sarr

2009-01-01

244

Efficacy of Counseling and Psychotherapy in Schools: A Meta-Analytic Review of Treatment Outcome Studies  

ERIC Educational Resources Information Center

|This study investigated the efficacy of counseling and psychotherapy interventions for youth in schools. Data were examined for 107 studies that included 132 treatment interventions. Overall efficacy was d = 0.45 and was significantly different from zero. Interventions for adolescents outperformed those of children, treatment groups that were…

Baskin, Thomas W.; Slaten, Christopher D.; Crosby, Nicole R.; Pufahl, Tiffany; Schneller, Cali L.; Ladell, Monica

2010-01-01

245

A Study on the Correlation between Self Efficacy and Foreign Language Learning Anxiety  

ERIC Educational Resources Information Center

Anxiety in language learning is one of the less researched areas; that is why this study explores whether the anxiety level of foreign language learners is related to their self efficacy levels. For this purpose, 100 participants joined the study and the Foreign Language Learning Anxiety Scale and The Self Efficacy Scale were administered to them.…

Cubukcu, Feryal

2008-01-01

246

A STUDY ON THE CORRELATION BETWEEN SELF EFFICACY AND FOREIGN LANGUAGE LEARNING ANXIETY  

Microsoft Academic Search

Anxiety in language learning is one of the less researched areas; that is why this study explores whether the anxiety level of foreign language learners is related to their self efficacy levels. For this purpose, 100 participants joined the study and the Foreign language Learning Anxiety Scale and The Self Efficacy Scale were administered to them. The results show that

Feryal ÇUBUKÇU

247

A Season Long Case Study Investigation of Collective Efficacy In Male Intercollegiate Basketball  

Microsoft Academic Search

Collective efficacy is defined as a group's shared belief, which emerges from an aggregation of individual group members' perception of the group's capabilities to succeed at a given task (Bandura, 1986). The present study used a case study design to explore the relationships between collective efficacy and performance over the course of one season. It was hypothesized that there would

David MacLean; Philip Sullivan

2003-01-01

248

Comparative in vitro efficacy of antimicrobial shampoos: a pilot study.  

PubMed

This study compared the antimicrobial efficacy of shampoos against meticillin-sensitive Staphylococcus pseudintermedius (MSSP), meticillin-resistant S. pseudintermedius (MRSP), antibiotic-sensitive Pseudomonas aeruginosa (PA), multidrug-resistant P. aeruginosa (MDR-PA) and Malassezia pachydermatis. Three isolates were incubated for 10, 30 and 60 min with each shampoo diluted in phosphate-buffered saline. Aliquots were then incubated for 16-18 h on sheep blood agar (bacteria) or for 3 days on Sabouraud's dextrose agar (Malassezia). The minimal bactericidal concentrations (MBCs) for chlorhexidine products (Malaseb(®), Pyoderm(®)/Microbex(®) and Hibiscrub(®)) were 1:1,024-1:2,048 for MSSP and MRSP, 1:512-1:1,024 for PA and MDR-PA, and 1:2,048-1:5,096 for Malassezia at all time points. The MBCs for benzoyl peroxide (Paxcutol(®)) for MSSP and MRSP were 1:2-1:8 at 10 min, and 1:256 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and 1:512-1:1,024 dilutions were effective against Malassezia at all time points. The MBCs for ethyl lactate (Etiderm(®)) for MSSP and MRSP were 1:2 at 10 min, and 1:2-1:16 after 30 and 60 min. A 1:2 dilution was effective against Pseudomonas, and a 1:512 dilution was effective against Malassezia at all time points. Chloroxylenol (Coatex(®)) and acetic acid-boric acid (Malacetic(®)) were not effective against MSSP, MRSP or Pseudomonas. Both were effective against Malassezia at 1:8-1:16 dilution at 10 min, and at 1:8-1:32 dilution after 30 and 60 min. In conclusion, chlorhexidine appeared to be the most effective topical biocide, and MRSP and MDR-PA were no less susceptible than antibiotic-sensitive organisms. These results should, however, be confirmed with larger numbers of isolates. PMID:21777309

Young, Rebecca; Buckley, Laura; McEwan, Neil; Nuttall, Tim

2011-07-21

249

A Gender Study Investigating Physics Self-Efficacy  

ERIC Educational Resources Information Center

|The underrepresentation of women in physics has been well documented and a source of concern for both policy makers and educators. My dissertation focuses on understanding the role self-efficacy plays in retaining students, particularly women, in introductory physics. I use an explanatory mixed methods approach to first investigate quantitatively…

Sawtelle, Vashti

2011-01-01

250

Preclinical pharmacology of docetaxel.  

PubMed

Docetaxel is a taxoid cytotoxic agent which promotes tubulin assembly into microtubles and inhibits their depolymerisation. In vitro, docetaxel reduces murine and human tumour cell survival by 50% at concentrations of 4-35 ng/ml, with a greater cytotoxic effect on proliferating than on non-proliferating cells. In vivo, docetaxel is schedule-independent. Over 80% of murine transplantable tumours were found to be very docetaxel sensitive, with complete regression of advanced stage tumours. Activity was also observed in > 90% of advanced stage human tumour xenografts in mice. In combination therapy studies, synergism with 5-fluorouracil, cyclophosphamide and etoposide was observed in vivo. Docetaxel exhibited linear pharmacokinetics and long tumour retention in tumour-bearing mice; plasma protein binding ranged from 76 to 89%. In toxicological studies in mice and dogs, docetaxel produced haematological, gastrointestinal and neuromotor toxicity. The dog was found to be the most sensitive species to the toxic effects of docetaxel. PMID:7577097

Bissery, M C

1995-01-01

251

Preclinical multimodality phantom design for quality assurance of tumor size measurement  

PubMed Central

Background Evaluation of changes in tumor size from images acquired by ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI) is a common measure of cancer chemotherapy efficacy. Tumor size measurement based on either the World Health Organization (WHO) criteria or the Response Evaluation Criteria in Solid Tumors (RECIST) is the only imaging biomarker for anti-cancer drug testing presently approved by the United States Food and Drug Administration (FDA). The aim of this paper was to design and test a quality assurance phantom with the capability of monitoring tumor size changes with multiple preclinical imaging scanners (US, CT and MRI) in order to facilitate preclinical anti-cancer drug testing. Methods Three phantoms (Gammex/UTHSCSA Mark 1, Gammex/UTHSCSA Mark 2 and UTHSCSA multimodality tumor measurement phantom) containing tumor-simulating test objects were designed and constructed. All three phantoms were scanned in US, CT and MRI devices. The size of test objects in the phantoms was measured from the US, CT and MRI images. RECIST, WHO and volume analyses were performed. Results The smaller phantom size, simplified design and better test object CT contrast of the UTHSCSA multimodality tumor measurement phantom allowed scanning of the phantom in preclinical US, CT and MRI scanners compared with only limited preclinical scanning capability of Mark 1 and Mark 2 phantoms. For all imaging modalities, RECIST and WHO errors were reduced for UTHSCSA multimodality tumor measurement phantom (?1.69 ± 0.33%) compared with both Mark 1 (? -7.56 ± 6.52%) and Mark 2 (? 5.66 ± 1.41%) phantoms. For the UTHSCSA multimodality tumor measurement phantom, measured tumor volumes were highly correlated with NIST traceable design volumes for US (R2 = 1.000, p < 0.0001), CT (R2 = 0.9999, p < 0.0001) and MRI (R2 = 0.9998, p < 0.0001). Conclusions The UTHSCSA multimodality tumor measurement phantom described in this study can potentially be a useful quality assurance tool for verifying radiologic assessment of tumor size change during preclinical anti-cancer therapy testing with multiple imaging modalities.

2011-01-01

252

Changes in self-efficacy and dietary adherence: the impact on weight loss in the PREFER study  

Microsoft Academic Search

Findings from studies examining self-efficacy and its relationship to weight loss have been inconsistent. We examined self-efficacy\\u000a specific to changing eating behaviors in the PREFER trial, an 18-month behavioral weight-loss study, to determine if self-efficacy\\u000a and dietary adherence were associated with weight change, and what impact self-efficacy had on weight change after controlling\\u000a for adherence. Measurements included the weight efficacy

Melanie T. Warziski; Susan M. Sereika; Mindi A. Styn; Lora E. Burke

2008-01-01

253

A preclinical and clinical review of aflibercept for the management of cancer.  

PubMed

Aflibercept, also known as vascular endothelial growth factor (VEGF)-Trap, is a recombinant, decoy receptor fusion protein, rationally designed to block angiogenesis by targeting not only all forms of VEGF-A, but also VEGF-B and placental growth factor. It inhibits VEGF-induced angiogenesis in preclinical models. In tumor models, aflibercept is associated with the reduction of tumor vasculature and size, and the inhibition of ascites formation. Clinical studies are investigating the use of aflibercept alone and in combination with other antineoplastic therapies for the treatment of various cancers. Phase I and II studies have provided proof of principle, and support the continuing clinical investigation of aflibercept. Results from the phase III study, VITAL, of aflibercept in the second-line setting in patients with advanced non-small cell lung cancer [NCT00532155] demonstrated efficacy in progression-free survival and overall objective response rate, but overall survival was not significantly improved. A full report awaits publication. The Phase III VANILLA trial in metastatic pancreatic cancer [NCT00574275] showed no improvement in overall survival. Most recently, the phase III VELOUR study [NCT00561470] of aflibercept plus FOLFIRI compared with placebo plus FOLFIRI in patients with metastatic colorectal cancer following failure of an oxaliplatin regimen showed significant improvements in overall survival, progression-free survival, and response rate and the complete results have been submitted to a peer-reviewed journal. This review summarizes preclinical and clinical data for aflibercept and discusses future directions and clinical trials for this agent. PMID:22264850

Gaya, Andrew; Tse, Vivien

2012-01-20

254

Estimating Influenza Vaccine Efficacy From Challenge and Community-based Study Data  

Microsoft Academic Search

In this paper, the authors provide estimates of 4 measures of vaccine efficacy for live, attenuated and inactivated influenza vaccine based on secondary analysis of 5 experimental influenza challenge studies in seronegative adults and community-based vaccine trials. The 4 vaccine efficacy measures are for susceptibility (VES), symp- tomatic illness given infection (VEP), infection and illness (VESP), and infectiousness (VEI). The

Nicole E. Basta; M. Elizabeth Halloran; Laura Matrajt; Ira M. Longini

2008-01-01

255

Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors  

ERIC Educational Resources Information Center

The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that…

Morris, David B.; Usher, Ellen L.

2011-01-01

256

A Confirmatory Study of Rating Scale Category Effectiveness for the Coaching Efficacy Scale  

ERIC Educational Resources Information Center

|This study extended validity evidence for measures of coaching efficacy derived from the Coaching Efficacy Scale (CES) by testing the rating scale categorizations suggested in previous research. Previous research provided evidence for the effectiveness of a four-category (4-CAT) structure for high school and collegiate sports coaches; it also…

Myers, Nicholas D.; Feltz, Deborah L.; Wolfe, Edward W.

2008-01-01

257

A Survey Study of Chinese In-Service Teachers' Self-Efficacy about Inclusive Education  

ERIC Educational Resources Information Center

|A survey study was conducted to a total of 323 in-service teachers (110 special education teachers and 213 general education teachers) in Shanghai regarding their self-efficacy and concerns about inclusive education. Multivariate analysis results reveal that special teachers have significantly higher self-efficacy about inclusive education than…

Wang, Mian; Zan, Fei; Liu, Jiaqiu; Liu, Chunling; Sharma, Umesh

2012-01-01

258

Developing Teaching Self-Efficacy in Research Institutions: A Study of Award-Winning Professors  

ERIC Educational Resources Information Center

|The purpose of this study was to assess the sources of award-wining research professors' (six women; six men) teaching self-efficacy through the framework of Bandura's (1986) social cognitive theory. Semi-structured interviews revealed that mastery experiences and social persuasions were particularly influential sources of self-efficacy and that…

Morris, David B.; Usher, Ellen L.

2011-01-01

259

Academic Self-Efficacy as a Predictor of College Outcomes: Two Incremental Validity Studies  

ERIC Educational Resources Information Center

|A growing body of literature supports the relationship between students' self-efficacy beliefs for academic tasks and milestones and their academic performance. Not surprisingly, some researchers have investigated the role that academic self-efficacy beliefs play in predicting college success. Two incremental validity studies were conducted to…

Gore, Paul A. Jr

2006-01-01

260

Organizational Structure, Collegial Trust, and College Faculty Teaching Efficacy: A Case Study  

ERIC Educational Resources Information Center

|The purpose of this mixed-method study was to explore the relationship between faculty self-efficacy, organizational structure, and collegial trust. The concepts of teacher self-efficacy, organizational structure, and collegial trust were used to investigate any possible empirical relationships existing between these variables in a private,…

Okpogba, Desmond

2011-01-01

261

Spinal cord stimulation in chronic intractable angina pectoris: A randomized, controlled efficacy study  

Microsoft Academic Search

Background Spinal cord stimulation is known to be a successful treatment for chronic intractable angina pectoris. Its effect may be anti-ischemic. It is uncertain if the clinical effect is partly caused by a placebo effect of surgery for implantation of a stimulator. In this study, clinical efficacy is investigated, together with a possible placebo effect. Methods and Results Efficacy of

Raymond W. M. Hautvast; Mike J. L. DeJongste; Michiel J. Staal; Wiek H. van Gilst; K. I. Lie

1998-01-01

262

Tyrosine kinase inhibitor (TKI)-induced cardiotoxicity: approaches to narrow the gaps between preclinical safety evaluation and clinical outcome.  

PubMed

Although therapies targeted to inhibit the activity of certain tyrosine kinases (TK) have helped advance cancer therapy in recent years, reports of cardiac toxicity following treatment with tyrosine kinase inhibitors (TKIs) were unexpected and not well predicted by preclinical studies. Such clinical findings exposed gaps in current preclinical drug testing for predicting the development of cardiac toxicities in humans. These gaps included a lack of a comprehensive TKI mechanism of action determination and appropriate cardiac functional evaluation. New preclinical approaches are suggested to address these issues. In addition to tyrosine kinase inhibition, other factors that may play a role in drug-induced cardiac effects should be assessed, such as unintended secondary targets of TKIs, toxic drug metabolites and drug accumulation in the heart. Both on-target and off-target toxic effects of TKIs on cultured cardiac myocytes have now been shown to be detectable, providing a rationale for using cardiomyocytes as a screening tool to study potential TKI-mediated cardiotoxicity. Incorporating isolated perfused heart methodology to chronic/subchronic rodent studies or including echocardiography in chronic large animal toxicity studies may improve the detection of changes in cardiac function over current methods, and they may eventually become a routine tool for screening drugs with suspected cardiotoxic potential. Further, assessing drug toxicity and efficacy together in an animal model of disease is highly informative for candidate drug selection, and should be encouraged to assess specific safety endpoints, such as cardiovascular function. Together, these approaches will help better close the gaps between preclinical testing and clinical outcomes. PMID:22961481

Yang, Baichun; Papoian, Thomas

2012-09-10

263

Development of a Preclinical Therapeutic Model of Human Brain Metastasis with Chemoradiotherapy  

PubMed Central

Currently, survival of breast cancer patients with brain metastasis ranges from 2 to 16 months. In experimental brain metastasis studies, only 10% of lesions with the highest permeability exhibited cytotoxic responses to paclitaxel or doxorubicin. Therefore, radiation is the most frequently used treatment, and sensitizing agents, which synergize with radiation, can improve the efficacy of the therapy. In this study we used 435-Br1 cells containing the fluorescent protein (eGFP) gene and the photinus luciferase (PLuc) gene to develop a new brain metastatic cell model in mice through five in vivo/in vitro rounds. BR-eGFP-CMV/Luc-V5 brain metastatic cells induce parenchymal brain metastasis within 60.8 ± 13.8 days of intracarotid injection in all mice. We used this model to standardize a preclinical chemoradiotherapy protocol comprising three 5.5 Gy fractions delivered on consecutive days (overall dose of 16.5 Gy) which improved survival with regard to controls (60.29 ± 8.65 vs. 47.20 ± 11.14). Moreover, the combination of radiotherapy with temozolomide, 60 mg/Kg/day orally for five consecutive days doubled survival time of the mice 121.56 ± 52.53 days (Kaplan-Meier Curve, p < 0.001). This new preclinical chemoradiotherapy protocol proved useful for the study of radiation response/resistance in brain metastasis, either alone or in combination with new sensitizing agents.

Martinez-Aranda, Antonio; Hernandez, Vanessa; Picon, Cristina; Modolell, Ignasi; Sierra, Angels

2013-01-01

264

Appraisal of cognition in preclinical Alzheimer's disease: a conceptual review  

PubMed Central

SUMMARY Biomarker evidence and clinical observations support the hypothesis that there is a diagnosable condition termed preclinical Alzheimer’s disease (AD). Recently, a workgroup convened under the auspices of the National Institute on Aging and the Alzheimer’s Association proposed a framework for defining preclinical AD. The definition was based on the presence of biomarkers that are indicative of the AD pathophysiological process. In the context of abnormal AD biomarkers, the workgroup postulated that ‘subtle cognitive changes’ occurred as well. Based on studies of genetically at-risk individuals and those destined to become demented, who were observed while still cognitively normal, low performance on learning and memory functions may be the earliest cognitive manifestations of preclinical AD, at the group level at least. It is not clear whether subtle cognitive decline can be detected reliably on an individual basis. Preclinical AD cognitive changes could be diagnosed by traditional neuropsychological testing, computerized testing, assessments of subjective memory loss, assessments of levels of participation in cognitively stimulating activities and direct measurement of activity using recently developed monitoring technology. Confounding effects of normal aging, test–retest variability, variations in educational attainment, as well as the presence of other brain diseases make diagnosing cognitive decline due to preclinical AD challenging.

Knopman, David S; Caselli, Richard J

2012-01-01

265

Five decades of progress in hematopoietic cell transplantation based on the preclinical canine model  

PubMed Central

The preclinical canine model has proved valuable for the development of principles and techniques of hematopoietic cell transplantation (HCT) applicable to human patients. Studies in random-bred dogs concerning the impact of histocompatibility barriers on engraftment and graft-versus-host disease, the kinetics of immunological reconstitution, the efficacy of various pre-transplant conditioning regimens, post-transplantation immunosuppression protocols, treatment of malignant diseases, and graft-versus-tumor effects have advanced HCT from an investigational therapy with uncertain clinical benefit half a century ago to an important treatment choice for thousands of patients treated annually in transplantation centers worldwide. More recent preclinical canine studies have resulted in the clinical translation of nonmyeloablative, minimally invasive transplantation protocols that have extended allogeneic HCT to include older human patients with malignant and non-malignant, acquired or inherited hematological disorders, and those with comorbid conditions. Here we review the contributions of the canine model to modern HCT and describe the usefulness of HCT for the treatment of canine hematological disorders.

Lupu, Marilena; Storb, Rainer

2009-01-01

266

Primer on preclinical instruction and evaluation.  

PubMed

This review summarizes the available literature for both instruction and evaluation of the novice dental and dental hygiene preclinical student. Effective instruction for dental and dental hygiene instrumentation requires knowledge of motor skills theory and mechanisms of fine motor skills attainment. The novice learner requires small, explicit steps that clearly define production. Prior to any performance, the skill to be performed should be envisioned accurately by the learner. Timely, precise feedback from the instructor to the learner contributes to learning. Novices are unable to judge their performance accurately, so self-assessment skills must be taught. Repetition enhances motor performance. Instruction is supported through well-designed evaluation instruments containing explicit criteria arranged in the correct order of production. Assessment tools should be designed to aid in providing specific, immediate feedback. Well-designed assessments may also aid in calibration of instructors. Examples of evaluation instruments are found in the literature, and several are reviewed in this article. For those responsible for preclinical performance assessment, application of current motor skills theory and development of appropriate instruction and evaluation instruments may result in improved student performance. Studies also indicate the instructional environment in the dental clinical setting may be less stressful if evaluation is based on achievement of target levels rather than multiple daily grades. PMID:19289728

Hauser, Anna Marie; Bowen, Denise M

2009-03-01

267

Minimally invasive neuroradiologic model of preclinical transient middle cerebral artery occlusion in canines  

PubMed Central

Stroke is currently the third leading cause of death in the United States, with approximately 780,000 Americans affected by a new or recurring stroke each year. Although a variety of therapeutic approaches have shown promise in small-animal models of stroke, the vast majority of clinical trials to test the efficacy of such modalities have failed. To bridge the translational gap between laboratory and clinical research, we developed a preclinical model of acute ischemic stroke in dogs. Using a minimally invasive endovascular approach, a platinum coil was intravascularly guided through the vertebrobasilar system under C-arm fluoroscopy to occlude the M1 segment of the middle cerebral artery (MCA) for 1 h. The approach included femoral artery catheterization to access the MCA and therefore eliminated the occurrence of head trauma associated with other preclinical stroke models relying on transorbital or craniectomy approaches. After 1 h of focal MCA ischemia, the coil was retrieved to cause reperfusion, which was verified by arteriograms. At 24 h, T2-weighted coronal magnetic resonance (MR) images were acquired and processed for three-dimensional reconstruction of the brain and its vasculature. Infarction, limited to the area at risk, was noted. Two independent observers calculated the mean percentage hemispherical lesion volumes as follows: observer 1, 30.9 ± 2.1%; observer 2, 31.2 ± 4.3%. Infarct-affected changes in histology were determined by hematoxylin and eosin as well as by Fluoro-Jade staining. This work reports the successful development of a powerful preclinical model of stroke that lends itself to the study of biologic mechanisms as well as to testing experimental therapeutics.

Rink, Cameron; Christoforidis, Greg; Abduljalil, Amir; Kontzialis, Marinos; Bergdall, Valerie; Roy, Sashwati; Khanna, Savita; Slivka, Andrew; Knopp, Michael; Sen, Chandan K.

2008-01-01

268

Science teaching self-efficacy in a primary school: A case study  

NASA Astrophysics Data System (ADS)

Bandura's theory of self-efficacy predicts that teachers with high, self-efficacy should persist longer, provide a greater academic focus in child-centred classrooms and exhibit different types of feedback than teachers who have lower self-efficacy. This paper reports on the science teaching self-efficacy in a group of teachers at a state primary school. The research was conducted in two stages using firstly the Science Teaching Efficacy Beliefs Instrument (STEBI-A) to identify cases, and secondly, a semistructured interview coupled with classroom observations. Thirty seven teaching staff were surveyed with the STEBI-A instrument. The five highest and five lowest scoring teachers on the personal science teaching self-efficacy subscale of the STEBI-A were interviewed. The analysis of interviews and observations indicated that teachers with high personal science teaching self-efficacy have had a long interest in science and a relatively strong background of formal science studies with opportunities for exploring out of school activities. Although they may have experienced negative science experiences in their own schooling other ameliorating factors existed which maintained their interest. Their instructional strategies in science lessons were more child-centred than those reported by teachers with lower personal science teaching self-efficacy. The implications of the results for the inservice training of teachers are discussed.

de Laat, Jenny; Watters, James J.

1995-12-01

269

The influence of achievement goal orientation, self-efficacy on allocation of study time  

Microsoft Academic Search

The influence of achievement goal orientation and self-efficacy on allocation of study time are explored in this study. 96 senior high School students are investigated through RJR paradigm and materials (meaningful and meaningless associated Chinese word-pairs). The result shows that: (1) Achievement goal orientation has prominent influence on allocation of study time. (2) Self-efficacy has prominent influence on allocation of

Shuhua Su; Gongxiang Chen

2010-01-01

270

A cross cultural study of gender-role orientation and entrepreneurial self-efficacy  

Microsoft Academic Search

The study of gender differences in entrepreneurial self-efficacy to date has produced inconclusive results. Cross-cultural\\u000a studies are virtually non-existent. The present study seeks to understand the complex interplay of biological sex, socialized\\u000a gender-roles, and culture on entrepreneurial self-efficacy and motivation to become an entrepreneur. Findings indicate that\\u000a among American business students the traditional view of “entrepreneur as male” is fading.

Stephen L. Mueller; Mary Conway Dato-on

271

1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate.  

PubMed

Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC(50) = 4.7 ?M). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC(50) > 30 ?M). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate. PMID:22335555

Ramnauth, Jailall; Renton, Paul; Dove, Peter; Annedi, Subhash C; Speed, Joanne; Silverman, Sarah; Mladenova, Gabriela; Maddaford, Shawn P; Zinghini, Salvatore; Rakhit, Suman; Andrews, John; Lee, David K H; Zhang, Dongqin; Porreca, Frank

2012-03-01

272

Preclinical research in treatment of pancreatic cancer.  

PubMed

Pancreatic adenocarcinoma is an aggressive type of malignancy and remains a treatment-refractory cancer. Because of the few treatment options, understanding of the molecular mechanisms is necessary, for new drugs be developed against molecular targets. Two of the novel, promising regimens against molecular targets, NVP-BEZ235 and MSK-777, were examined in three preclinical studies performed in human pancreatic cell lines and mouse models and presented in the 2013 ASCO Annual Meeting. Two of the studies evaluated the role of NVP-BEZ235, an oral phosphatidylinositol-3-kinase (PI3K) inhibitor, in pancreatic cancer treatment, alone and in combination with nab-paclitaxel (Abstract #e15007) or gemcitabine (Abstract #e15070). The third study presents the effectiveness of the novel cell division cycle 7 (Cdc7) kinase inhibitor, MSK-777 (Abstract #e15059). All studies demonstrated promising results and further investigation is ongoing. PMID:23846933

Skoura, Evangelia; Syrigos, Konstantinos N; Saif, Muhammad Wasif

2013-07-10

273

Microenvironmental Influence on Pre-Clinical Activity of Polo-Like Kinase Inhibition in Multiple Myeloma: Implications for Clinical Translation  

PubMed Central

Polo-like kinases (PLKs) play an important role in cell cycle progression, checkpoint control and mitosis. The high mitotic index and chromosomal instability of advanced cancers suggest that PLK inhibitors may be an attractive therapeutic option for presently incurable advanced neoplasias with systemic involvement, such as multiple myeloma (MM). We studied the PLK 1, 2, 3 inhibitor BI 2536 and observed potent (IC50<40 nM) and rapid (commitment to cell death <24 hrs) in vitro activity against MM cells in isolation, as well as in vivo activity against a traditional subcutaneous xenograft mouse model. Tumor cells in MM patients, however, don't exist in isolation, but reside in and interact with the bone microenvironment. Therefore conventional in vitro and in vivo preclinical assays don't take into account how interactions between MM cells and the bone microenvironment can potentially confer drug resistance. To probe this question, we performed tumor cell compartment-specific bioluminescence imaging assays to compare the preclinical anti-MM activity of BI 2536 in vitro in the presence vs. absence of stromal cells or osteoclasts. We observed that the presence of these bone marrow non-malignant cells led to decreased anti-MM activity of BI 2536. We further validated these results in an orthotopic in vivo mouse model of diffuse MM bone lesions where tumor cells interact with non-malignant cells of the bone microenvironment. We again observed that BI 2536 had decreased activity in this in vivo model of tumor-bone microenvironment interactions highlighting that, despite BI 2536's promising activity in conventional assays, its lack of activity in microenvironmental models raises concerns for its clinical development for MM. More broadly, preclinical drug testing in the absence of relevant tumor microenvironment interactions may overestimate potential clinical activity, thus explaining at least in part the gap between preclinical vs. clinical efficacy in MM and other cancers.

McMillin, Douglas W.; Delmore, Jake; Negri, Joseph; Ooi, Melissa; Klippel, Steffen; Miduturu, Chandrasekhar V.; Gray, Nathanael S.; Richardson, Paul G.; Anderson, Kenneth C.; Kung, Andrew L.; Mitsiades, Constantine S.

2011-01-01

274

Self-efficacy is mainly genetic, not learned: a multiple-rater twin study on the causal structure of general self-efficacy in young people.  

PubMed

Social learning theory postulates that self-efficacy is learned through the person's interaction with his/her physical and social environment. In this genetically informative, population-based, multi-informant study of 1,394 adolescent twin pairs, self-efficacy was modeled as one latent psychometric self-efficacy factor with genetic and environmental effects common to all informants, as well as for effects specific for each informant. The results showed that 75% of variation in self-efficacy was due to genetic factors. Non-shared environmental causes explained the remaining 25% of the variance in the latent factor, with no effect of common environment. Some informant-specific effects were also found. The present study challenges the theoretical assumption of learning as the dominant etiological factor behind self-efficacy in young people. PMID:23601253

Waaktaar, Trine; Torgersen, Svenn

2013-04-22

275

The pre-clinical assessment of rapamycin-eluting, durable polymer-free stent coating concepts.  

PubMed

All four currently FDA-approved drug-eluting stents (DESs) contain a durable polymeric coating which can negatively impact vascular healing processes and eventually lead to adverse cardiac events. Aim of this study was the pre-clinical assessment of two novel rapamycin-eluting stent (RES) coating technologies that abstain from use of a durable polymer. Two distinctive RES coating technologies were evaluated in vitro and in the porcine coronary artery stent model. The R-poly(S) stent platform elutes rapamycin from a biodegradable polymer that is top coated with the resin shellac to minimize the amount of polymer. The R-pro(S) stent platform allows dual drug release of rapamycin and probucol, blended by shellac. HPLC-based determination of pharmacokinetics indicated drug release for more than 28 days. At 30 days, neointimal formation was found to be significantly decreased for both DESs compared to bare-metal stents. Assessment of vascular healing revealed absence of increased inflammation in both DESs, which is commonly observed in DES with non-erodible polymeric coating. In conclusion, the pre-clinical assessment of RESs with resin-based or dual drug coating indicated an adequate efficacy profile as well as a beneficial effect for vascular healing processes. These results encourage the transfer of these technologies to clinical evaluation. PMID:18990438

Steigerwald, Kristin; Merl, Sabine; Kastrati, Adnan; Wieczorek, Anna; Vorpahl, Marc; Mannhold, Raimund; Vogeser, Michael; Hausleiter, Jörg; Joner, Michael; Schömig, Albert; Wessely, Rainer

2008-11-05

276

77 FR 12310 - Drugs for Human Use; Drug Efficacy Study Implementation; Prescription Drugs That Contained...  

Federal Register 2010, 2011, 2012, 2013

...DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-1978-N-0441] (formerly 78N-0324); DESI 10392] Drugs for Human Use; Drug Efficacy Study Implementation; Prescription...

2012-02-29

277

A multilevel study on the relationships between work characteristics, self-efficacy, collective efficacy, and organizational citizenship behavior: the case of Taiwanese police duty-executing organizations.  

PubMed

Public security, traffic management, and service for the people are the 3 major functions of policing in Taiwan. This definition encompasses not only the traditional job characteristics, but also the level of contextual characteristics and social characteristics because of police work's characteristics and its frequent interaction with the public. Thus, the present study conducted a multilevel model analysis by taking self-efficacy and collective efficacy as the mediating variables. The purpose was to investigate the influences of motivational work characteristics (knowledge-oriented) and social work characteristics (socially and contextually oriented) of work-design model on the police officers' organizational citizenship behavior (OCB), by using first-line police officers in Taiwan as the research objects. The study showed not only that knowledge characteristics will influence the self-efficacy of a police officer and that self-efficacy can in turn influence individual police officers' OCB, but also the contextual effect of social characteristics, contextual characteristics, and collective efficacy on self-efficacy and individuals' OCB. Additionally, there was a crosslevel moderating effect from contextual characteristics on the relationship between knowledge characteristics and self-efficacy and the relationship between self-efficacy and the individuals' OCB. The authors conclude the article with research implications. PMID:21834327

Chen, Chun-Hsi Vivian; Kao, Rui-Hsin

278

Teacher efficacy: A comparative study of Hong Kong and Shanghai Primary in-service teachers  

Microsoft Academic Search

Teachers beliefs about their ability to affect students’ performance is an important part of professionalism. This study compared\\u000a 725 Hong Kong and 575 Shanghai primary in-service teachers on their teacher efficacy. Two Chinese versions of the 12-item\\u000a Teachers’ Sense of Efficacy Scale were used in this study since some wordings of the Hong Kong version of the Scale (HK-TSE)\\u000a were

Hoi Yan Cheung

2008-01-01

279

Effects of dose and schedule on the efficacy of Ethyol: preclinical studies 1 1 The authors are employees and shareholders of MedImmune Inc  

Microsoft Academic Search

The chemo- and radioprotectant drug amifostine (Ethyol; MedImmune, Inc, Gaithersburg, MD) is approved for intravenous (IV) administration; however, the subcutaneous (SC) route is being explored as a practical alternative. We have previously reported equivalence between IV and SC administration using a rat model of radioprotection and active metabolite (WR-1065) tissue pharmacokinetics. To examine the more clinically relevant fractionated and hyperfractionated

David R Cassatt; Christine A Fazenbaker; Gizachew Kifle; Christine M Bachy

2003-01-01

280

Pomegranate Extracts in the Management of Men's Urologic Health: Scientific Rationale and Preclinical and Clinical Data  

PubMed Central

Multiple strands of research provide growing evidence that diet, nutrition, and life style play a role in the development and the course of urological diseases. Numerous micronutrients and polyphenols found in soy, green tea, and many fruits and vegetables have been described to impact diseases including erectile dysfunction, benign prostatic hyperplasia, and prostate cancer. However, oftentimes these reports lack both a scientific rationale and supportive evidence base. The efficacy of pomegranate, on the other hand, in the modulation of central biological processes like inflammation, hypoxia, and oxidative stress that are important in the pathogenesis of urological maladies has been robustly demonstrated in preclinical in vitro and in vivo studies. Moreover, clinical trials have further supported its use in the treatment of several diseases, in particular in the management of prostate cancer. Herein, we critically review the scientific knowledge about the current role and future prospects for the use of pomegranate extracts in the therapy of erectile dysfunction, benign prostatic hyperplasia, and prostate cancer.

N., Kroeger; A. S., Belldegrun; A. J., Pantuck

2013-01-01

281

MEMS-enabled implantable drug infusion pumps for laboratory animal research, preclinical, and clinical applications  

PubMed Central

Innovation in implantable drug delivery devices is needed for novel pharmaceutical compounds such as certain biologics, gene therapy, and other small molecules that are not suitable for administration by oral, topical, or intravenous routes. This invasive dosing scheme seeks to directly bypass physiological barriers presented by the human body, release the appropriate drug amount at the site of treatment, and maintain the drug bioavailability for the required duration of administration to achieve drug efficacy. Advances in microtechnologies have led to novel MEMS-enabled implantable drug infusion pumps with unique performance and feature sets. In vivo demonstration of micropumps for laboratory animal research and preclinical studies include acute rapid radiolabeling, short-term delivery of nanomedicine for cancer treatment, and chronic ocular drug dosing. Investigation of MEMS actuators, valves, and other microstructures for on-demand dosing control may enable next generation implantable pumps with high performance within a miniaturized form factor for clinical applications.

Meng, Ellis; Hoang, Tuan

2012-01-01

282

Paclitaxel coated balloons for coronary artery interventions: a comprehensive review of preclinical and clinical data.  

PubMed

After the "mechanical era" in interventional cardiology (represented by balloon angioplasty and bare metal stent implantation), arrived the "local dispensing" era, began with the intracoronary delivery of antithrombotic or antirestenotic drugs. However, even drug eluting stents have some pitfalls and cannot be used in all clinical subsets. In this article we will review the significant data on the paclitaxel-coated balloons for the treatment of coronary artery disease. Particularly, we will review the rationale of this new treatment strategy, the preclinical data and will focus on available clinical studies in humans. After the initial boost of the paclitaxel coated balloons with the Paccocath technology in in-stent restenotic lesions, the experimentation of newer devices in native coronary arteries raised some concerns on their efficacy and safety. We will comment on this topic trying to understand the reasons of this failure, and will discuss on possible future developments and applications for these devices for the treatment of coronary artery disease. PMID:21955612

Cortese, Bernardo; Bertoletti, Alessandra

2011-09-28

283

A novel fusion protein containing the receptor binding domains of C. difficile toxin A and toxin B elicits protective immunity against lethal toxin and spore challenge in preclinical efficacy models.  

PubMed

Antibodies targeting the Clostridium difficile toxin A and toxin B confer protective immunity to C. difficile associated disease in animal models and provided protection against recurrent C. difficile disease in human subjects. These antibodies are directed against the receptor binding domains (RBD) located in the carboxy-terminal portion of both toxins and inhibit binding of the toxins to their receptors. We have constructed a recombinant fusion protein containing portions of the RBD from both toxin A and toxin B and expressed it in Escherichia coli. The fusion protein induced high levels of serum antibodies to both toxins A and B capable of neutralizing toxin activity both in vitro and in vivo. In a hamster C. difficile infection model, immunization with the fusion protein reduced disease severity and conferred significant protection against a lethal dose of C. difficile spores. Our studies demonstrate the potential of the fusion protein as a vaccine that could provide protection from C. difficile disease in humans. PMID:22537987

Tian, Jing-Hui; Fuhrmann, Steven R; Kluepfel-Stahl, Stefanie; Carman, Robert J; Ellingsworth, Larry; Flyer, David C

2012-04-23

284

From type 2 diabetes to antioxidant activity: a systematic review of the safety and efficacy of common and cassia cinnamon bark  

Microsoft Academic Search

Common (Cinnamomum verum, C. zeylanicum) and cassia (C. aromaticum) cinnamon have a long history of use as spices and flavouring agents. A number of pharmacological and clinical effects have been observed with their use. The objective of this study was to systematically review the scientific literature for preclinical and clinical evidence of safety, efficacy, and pharmacological activity of common and

Jean-Jacques Dugoua; Dugald Seely; Dan Perri; Kieran Cooley; Taryn Forelli; Edward Mills; Gideon Koren

2007-01-01

285

Identification and Characterization of Psoralen and Isopsoralen as Potent CYP1A2 Reversible and Time-Dependent Inhibitors in Human and Rat Preclinical Studies.  

PubMed

Naturally occurring furanocoumarin compounds psoralen (PRN) and isopsoralen (IPRN) are bioactive constituents found in herbaceous plants. They are widely used as active ingredients in several Chinese herbal medicines. In this study, the CYP1A2 inhibitory potential of PRN and IPRN was investigated in rats in vitro and in vivo as well as in human liver microsomes. Both compounds exhibited reversible and time-dependent inhibition toward rat microsomal cyp1a2. The IC50, kinact, and KI values were 10.4 ± 1.4 ?M, 0.060 ± 0.002 min(-1), and 1.13 ± 0.12 ?M for PRN, and 7.1 ± 0.6 ?M, 0.10 ± 0.01 min(-1), and 1.95 ± 0.31 ?M for IPRN, respectively. In human liver microsomal incubations, potent reversible CYP1A2 inhibition was observed for both compounds, with IC50 values of 0.26 ± 0.01 ?M and 0.22 ± 0.03 ?M for PRN and IPRN, respectively. However, time-dependent inhibition was only observed for IPRN, with kinact and KI values of 0.050 ± 0.002 min(-1) and 0.40 ± 0.06 ?M, respectively. Coadministration with PRN or IPRN significantly inhibited cyp1a2 activity in rats, with the area under the curve (AUC) of phenacetin increasing more than 5-fold. Simcyp simulation predicted that PRN would cause 1.71- and 2.12-fold increases in the phenacetin AUC in healthy volunteers and smokers, respectively. IPRN, on the other hand, would result in 3.24- and 5.01-fold increases in phenacetin AUCs in healthy volunteers and smokers, respectively. These findings represent the first detailed report comparing the potential drug-drug interactions of PRN and IPRN, and provide useful information for balancing safe and efficacious doses of PRN and IPRN. PMID:23975028

Zhuang, Xiao-Mei; Zhong, Yu-Huan; Xiao, Wei-Bin; Li, Hua; Lu, Chuang

2013-08-23

286

Induction and Efficacy: A Case Study of New Zealand Newly Qualified Secondary Science Teachers  

NASA Astrophysics Data System (ADS)

This paper reports on 20 newly qualified secondary science teachers (NQSSTs) participating in a New Zealand study on teachers' early professional learning. The focus of our study is how these new teachers were nurtured to become competent science teachers, confident of their ability to positively influence student learning. Based on responses to a graduating questionnaire and three interviews across their first 18 months of teaching, we look at the effect of induction and contextual factors on the teachers' efficacy. While the NQSSTs overall reported relatively constant ratings of self-efficacy, they demonstrated different patterns of declared efficacy across this 18-month period. Findings regarding the influence of induction practices and contextual factors on the efficacy of these teachers are mixed.

Haigh, Mavis A.; Anthony, Glenda J.

2012-10-01

287

Comparison of Student and Faculty Evaluators in Preclinical Operative Dentistry.  

ERIC Educational Resources Information Center

|In a study of the reliability of evaluation of laboratory techniques by recent dental graduates versus faculty, wide variance was found in student evaluations. However, faculty evaluations were consistent with each other only 40 percent of the time. Questions are raised about the general system of preclinical evaluation. (MSE)|

Hinkelman, Kenneth W.; And Others

1982-01-01

288

A short-term increase in cancer risk associated with daytime napping is likely to reflect pre-clinical disease: prospective cohort study  

PubMed Central

Background: Sleep disturbance, a correlate of which is daytime napping, has been hypothesised to be associated with risk of breast and other cancers. Methods: We estimated relative risks (RR) of breast and other invasive cancers by the reported frequency of daytime napping in a large prospective cohort of middle-aged women in the UK. Results: During an average of 7.4 years of follow-up, 20?058 breast cancers and 31?856 other cancers were diagnosed. Over the first 4 years of follow-up, daytime napping (sometimes/usually vs rarely/never) was associated with slightly increased risks of breast cancer (RR=1.10, 95% CI 1.06–1.15) and of other cancers (RR=1.12, 1.08–1.15), but the RRs decreased significantly with increasing follow-up time (P=0.001 and P=0.01, respectively, for trend). Four or more years after baseline, there was no elevated risk of breast cancer (RR=1.00, 0.96–1.05), and only marginally greater risk of other cancers (RR=1.04, 1.01–1.07). Conclusion: The effect of pre-clinical disease is a likely explanation for the short-term increased risk of breast and other cancers associated with daytime napping.

Cairns, B J; Travis, R C; Wang, X-S; Reeves, G K; Green, J; Beral, V

2012-01-01

289

Sirtuin and pan-class I/II deacetylase (DAC) inhibition is synergistic in preclinical models and clinical studies of lymphoma.  

PubMed

Understanding the molecular pathogenesis of lymphoma has led to paradigm-changing treatment opportunities. One example involves tailoring specific agents based on the cell of origin in aggressive lymphomas. Germinal center (GC)-derived diffuse large B-cell lymphoma (DLBCL) is known to be driven by an addiction to Bcl6, whereas the activated B-cell (ABC) subtype is driven by nuclear factor ?B. In the GC subtype, there is a critical inverse relationship between Bcl6 and p53, the functional status of which is linked to each transcription factor's degree of acetylation. Deacetylation of Bcl6 is required for its transcriptional repressor effects allowing for the oncogene to drive lymphomagenesis. Conversely, acetylation of p53 is activating when class III deacetylases (DACs), or sirtuins, are inhibited by niacinamide. Treatment of DLBCL cell lines with pan-DAC inhibitors in combination with niacinamide produces synergistic cytotoxicity in GC over ABC subtypes. This correlated with acetylation of both Bcl6 and p53. This combination also produced remissions in a spontaneous aggressive B-cell lymphoma mouse model expressing Bcl6. In a phase 1 proof-of-principle clinical trial, 24% of patients with relapsed or refractory lymphoma attained a response to vorinostat and niacinamide, and 57% experienced disease stabilization. We report herein on the preclinical and clinical activity of this targeted strategy in aggressive lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT00691210. PMID:23913470

Amengual, Jennifer E; Clark-Garvey, Sean; Kalac, Matko; Scotto, Luigi; Marchi, Enrica; Neylon, Ellen; Johannet, Paul; Wei, Ying; Zain, Jasmine; O'Connor, Owen A

2013-08-02

290

Preclinical efficacy of a carboxylesterase 2-activated prodrug of doxazolidine.  

PubMed

Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small-cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homologue, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment. PMID:19634903

Barthel, Benjamin L; Zhang, Zhiyong; Rudnicki, Daniel L; Coldren, Christopher D; Polinkovsky, Margaret; Sun, Hengrui; Koch, Gary G; Chan, Daniel C F; Koch, Tad H

2009-12-10

291

Preclinical Efficacy of a Carboxylesterase 2-Activated Prodrug of Doxazolidine  

PubMed Central

Doxazolidine (Doxaz) is a functionally distinct formaldehyde conjugate of doxorubicin (Dox) that induces cancer cell death in Dox-sensitive and resistant cells. Pentyl PABC-Doxaz (PPD) is a prodrug of Doxaz that is activated by carboxylesterase 2 (CES2), which is expressed by liver, non-small cell lung, colon, pancreatic, renal, and thyroid cancer cells. Here, we demonstrate that in two murine models, PPD was effective at slowing tumor growth and demonstrated markedly reduced cardiotoxic and nephrotoxic effects, as well as better tolerance, relative to Dox. Hepatotoxicity, consistent with liver expression of the murine CES2 homolog, was induced by PPD. Unlike irinotecan, a clinical CES2-activated prodrug, PPD produced no visible gastrointestinal damage. Finally, we demonstrate that cellular response to PPD may be predicted with good accuracy using CES2 expression and Doxaz sensitivity, suggesting that these metrics may be useful as clinical biomarkers for sensitivity of a specific tumor to PPD treatment.

Barthel, Benjamin L.; Zhang, Zhiyong; Rudnicki, Daniel L.; Coldren, Christopher D.; Polinkovsky, Margaret; Sun, Hengrui; Koch, Gary G.; Chan, Daniel C.F.; Koch, Tad H.

2009-01-01

292

Toward making the invisible visible: Studying science teaching self-efficacy beliefs  

NASA Astrophysics Data System (ADS)

This dissertation consists of two articles to be submitted for publication. The first, a literature review, makes visible common influences on science teaching self-efficacy beliefs and also points to potentially invisible validation concerns regarding the instrument used. The second investigates the participants' invisible science teaching self-efficacy beliefs and, through the use of a more focused interview, makes those beliefs visible. Science teaching self-efficacy beliefs are science teachers' perceptions of their abilities to teach science effectively. The construct "teaching self-efficacy" originated in social cognitive theory (Bandura, 1977). The first article reviews the mixed results from teaching self-efficacy research in science contexts. The review focuses upon factors that facilitate or inhibit the development of self-efficacy beliefs among science teachers across stages of their careers. Although many studies of science teaching self-efficacy beliefs have utilized the Science Teaching Efficacy Belief Instrument - STEBI (Enochs & Riggs, 1990; Riggs & Enochs, 1990), this review also includes non-STEBI studies in order to represent diverse lines of research methodology. The review's findings indicate that antecedent factors such as science activities in and out of school, teacher preparation, science teaching experiences and supportive job contexts are significant influences on the development of science teaching self-efficacy beliefs. The review also indicates that the majority of these studies are short term and rely on a single STEBI administration with the collection of antecedent/demographic and/or interview data. The second article documents a study that responded to the above literature review findings. This study utilized multiple STEBI administrations during the preservice and beginning year of teaching for two science teachers. Rather than general questions, these participants were asked item specific, yet open-ended, questions to determine what events or experiences the participants felt influenced their survey answers. This methodological approach was chosen to add clarity to the STEBI scores and to add another layer in the ongoing process of instrument validation. Unlike some studies in science teaching self-efficacy, both participants' STEBI scores continued to increase as they transitioned from preservice to beginning teachers. The participant responses to the focused interview probes also validated their STEBI scores 77% of the time.

Perkins, Catherine J.

293

Application of peripheral-blood-derived endothelial progenitor cell for treating ischemia-reperfusion injury and infarction: a preclinical study in rat models  

PubMed Central

Background Our aim was to explore the therapeutic effects of peripheral blood-derived endothelial progenitor cells (PB-EPC) in cardiac ischemia-reperfusion infarction models in rats and in in vitro culture systems. Methods Rat models of ischemia reperfusion and myocardial infarction were developed using male, Sprague–Dawley rats. Cardiomyocyte and endothelial cell cultures were also established. Therapeutic effects of PB-EPCs were examined in vivo and in vitro in both models. Rats underwent either cardiac ischemia-reperfusion (n?=?40) or infarction (n?=?56) surgeries and were transplanted with genetically modified EPCs. Treatment efficacy in the ischemia-reperfusion group was measured by infarct size, myocardial contraction velocity, and myeloperoxidase activity after transplantation. Cardiomyocyte survival and endothelial cell apoptosis were investigated in vitro. Vascular growth-associated protein expression and cardiac function were evaluated in the myocardial infarction group by western blot and echocardiography, respectively. Results Infarct size and myeloperoxidase activity were significantly decreased in the ischemia-reperfusion group, whereas myocardial contractility was significantly increased in the EPC and T?4 groups compared with that in the control group. In contrast, no differences were found between EPC?+?shRNA T?4 and control groups. Rates of cardiomyocyte survival and endothelial cell apoptosis were significantly higher and lower, respectively, in the EPC and T?4 groups than in the control group, whereas no differences were found between the EPC?+?shRNA T?4 and control group. Four weeks after myocardial infarction, cardiac function was significantly better in the EPC group than in the control group. Expressions of PDGF, VEGF, and Flk-1 were significantly higher in EPC group than in control group. Conclusions Study findings suggest that PB-EPCs are able to protect cardiomyocytes from ischemia-reperfusion or infarction-induced damage via a T?4-mediated mechanism. EPCs may also provide protection through increased expression of proteins involved in mediating vascular growth. Autologous peripheral-blood-derived EPCs are readily available for efficient therapeutic use without the concerns of graft rejection.

2013-01-01

294

Efficacy of a communication and stress management training on medical residents' self-efficacy, stress to communicate and burnout: a randomized controlled study.  

PubMed

This is a longitudinal randomized controlled study investigating the efficacy of a communication and stress management skills training programme on medical residents' self-efficacy to communicate and to manage stress in interviews, stress to communicate in interviews, and burnout. Ninety-six medical residents participated. Results showed a statistically significant increase in self-efficacy and decrease in stress to communicate. No changes were noted in burnout. Results of this training may encourage its compulsory organization in the medical curriculum. Further research is required to examine whether a programme associating person-directed and organization-directed interventions could have an impact on residents' burnout. PMID:20453053

Bragard, Isabelle; Etienne, Anne-Marie; Merckaert, Isabelle; Libert, Yves; Razavi, Darius

2010-05-07

295

A Cross-Sectional Study of Engineering Students' Self-Efficacy by Gender, Ethnicity, Year, and Transfer Status  

ERIC Educational Resources Information Center

|This is a cross-sectional study of 519 undergraduate engineering majors' self-efficacy beliefs at a large, research extensive, Midwestern university. Engineering self-efficacy is an individual's belief in his or her ability to successfully negotiate the academic hurdles of the engineering program. Engineering self-efficacy was obtained from four…

Concannon, James P.; Barrow, Lloyd H.

2009-01-01

296

Registration of challenging pre-clinical brain images.  

PubMed

The size and complexity of brain imaging studies in pre-clinical populations are increasing, and automated image analysis pipelines are urgently required. Pre-clinical populations can be subjected to controlled interventions (e.g., targeted lesions), which significantly change the appearance of the brain obtained by imaging. Existing systems for registration (the systematic alignment of scans into a consistent anatomical coordinate system), which assume image similarity to a reference scan, may fail when applied to these images. However, affine registration is a particularly vital pre-processing step for subsequent image analysis which is assumed to be an effective procedure in recent literature describing sophisticated techniques such as manifold learning. Therefore, in this paper, we present an affine registration solution that uses a graphical model of a population to decompose difficult pairwise registrations into a composition of steps using other members of the population. We developed this methodology in the context of a pre-clinical model of stroke in which large, variable hyper-intense lesions significantly impact registration performance. We tested this technique systematically in a simulated human population of brain tumour images before applying it to pre-clinical models of Parkinson's disease and stroke. PMID:23558335

Crum, William R; Modo, Michel; Vernon, Anthony C; Barker, Gareth J; Williams, Steven C R

2013-04-01

297

Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma.  

PubMed

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic. PMID:24030150

Matthews, G M; Lefebure, M; Doyle, M A; Shortt, J; Ellul, J; Chesi, M; Banks, K M; Vidacs, E; Faulkner, D; Atadja, P; Bergsagel, P L; Johnstone, R W

2013-09-12

298

Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma  

PubMed Central

Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.

Matthews, G M; Lefebure, M; Doyle, M A; Shortt, J; Ellul, J; Chesi, M; Banks, K-M; Vidacs, E; Faulkner, D; Atadja, P; Bergsagel, P L; Johnstone, R W

2013-01-01

299

Preservice Elementary Teachers' Development of Self-Efficacy and Confidence to Teach Science: A Case Study  

NASA Astrophysics Data System (ADS)

This study examines the self-efficacy of one preservice elementary school teacher (Kasey) during and after her participation in Science in Childhood Education—a 16-week, elementary preservice science methods course. The case study of this teacher is situated in the context of the class as a whole. This is accomplished through interviewing the one teacher and examining artifacts and observations of the entire class. The results of these experiences are studied to determine what changes have taken place in the participants' self-efficacy in science teaching as well as the one preservice teacher in greater detail. Because self efficacy is influential to student learning, the results of this study have significant implications for the design of elementary teacher education programs and the support of elementary teachers in teaching science.

Gunning, Amanda M.; Mensah, Felicia Moore

2011-03-01

300

Syndecan-1 antigen, a promising new target for triple-negative breast cancer immuno-PET and radioimmunotherapy. A preclinical study on MDA-MB-468 xenograft tumors  

PubMed Central

Background Overexpression of syndecan-1 (CD138) in breast carcinoma correlates with a poor prognosis and an aggressive phenotype. The objective of this study was to evaluate the potential of targeting CD138 by immuno-PET imaging and radioimmunotherapy (RIT) using the antihuman syndecan-1 B-B4 mAb radiolabeled with either 124I or 131I in nude mice engrafted with the triple-negative MDA-MB-468 breast cancer cell line. Method The immunoreactivity of 125I-B-B4 (80%) was determined, and the affinity of 125I-B-B4 and the expression of CD138 on MDA-MB-468 was measured in vitro by Scatchard analysis. CD138 expression on established tumors was confirmed by immunohistochemistry. A biodistribution study was performed in mice with subcutaneous MDA-MB-468 and 125I-B-B4 at 4, 24, 48, 72, and 96 h after injection and compared with an isotype-matched control. Tumor uptake of B-B4 was evaluated in vivo by immuno-PET imaging using the 124I-B-B4 mAb. The maximum tolerated dose (MTD) was determined from mice treated with 131I-B-B4 and the RIT efficacy evaluated. Results 125I-B-B4 affinity was in the nanomolar range (Kd = 4.39 ± 1.10 nM). CD138 expression on MDA-MB-468 cells was quite low (Bmax = 1.19 × 104 ± 9.27 × 102 epitopes/cell) but all expressed CD138 in vivo as determined by immunohistochemistry. The tumor uptake of 125I-B-B4 peaked at 14% injected dose (ID) per gram at 24 h and was higher than that of the isotype-matched control mAb (5% ID per gram at 24 h). Immuno-PET performed with 124I-B-B4 on tumor-bearing mice confirmed the specificity of B-B4 uptake and its retention within the tumor. The MTD was reached at 22.2 MBq. All mice treated with RIT (n = 8) as a single treatment at the MTD experienced a partial (n = 3) or complete (n = 5) response, with three of them remaining tumor-free 95 days after treatment. Conclusion These results demonstrate that RIT with 131I-B-B4 could be considered for the treatment of metastatic triple-negative breast cancer that cannot benefit from hormone therapy or anti-Her2/neu immunotherapy. Immuno-PET for visualizing CD138-expressing tumors with 124I-B-B4 reinforces the interest of this mAb for diagnosis and quantitative imaging.

2011-01-01

301

Lesson study: Professional development and its impact on science teacher self-efficacy  

NASA Astrophysics Data System (ADS)

This study focuses on an analysis of a professional development program known as lesson study via data obtained during an in-service professional development program for secondary school science teachers. The purpose of this study was to examine the self-efficacy beliefs of one group of science teachers related to their experiences in a lesson study. Another purpose for this research, aligned with the first, included a theoretical analysis of the lesson study construct to see if its design promoted positive self-efficacy beliefs of its participants. The research is framed within the context of social constructivism and self-efficacy and is qualitative in nature and utilized descriptive analysis as a means of research. Case studies were conducted detailing two of the six participants. Data sources included researcher field notes and transcriptions of all planning and debriefing sessions; individual interviews with each participant and the schools' principal; a participant questionnaire, and the Science Teaching Efficacy Belief Instrument. Themes that emerged included the positive perceptions of lesson study as a collaborative and teacher-centered experience; the understanding that lesson study can instill a sense of professionalism to those who participate in the process; the sense that discussing student learning using objective observations from classroom is a powerful way to assess learning and uncover personal teacher beliefs; and the insight that the time commitment that lesson study requires can inhibit teachers and schools from sustaining it as a form of on-going professional development. Although these themes are consistent with the research on lesson study in Japan and elsewhere in the United States, they also extend the research on self-efficacy and science teacher professional development. In the end, this study supported some of the conclusions of the self-efficacy research as it relates to professional development while also adding that interpersonal relationships is a relevant consideration in the development of science teacher's self-efficacy. From this study, it is apparent that teachers who are collaboratively involved in a supportive setting such as lesson study can increase their level of self-efficacy and thus improve their teaching practice.

Roberts, Megan Rae

302

Outcomes of usual chiropractic, harm & efficacy, the ouch study: study protocol for a randomized controlled trial  

PubMed Central

Background Previous studies have demonstrated that adverse events occur during chiropractic treatment. However, because of these studies design we do not know the frequency and extent of these events when compared to sham treatment. The principal aims of this study are to establish the frequency and severity of adverse effects from short term usual chiropractic treatment of the spine when compared to a sham treatment group. The secondary aim of this study is to establish the efficacy of usual short term chiropractic care for spinal pain when compared to a sham intervention. Methods One hundred and eighty participants will be randomly allocated to either usual chiropractic care or a sham intervention group. To be considered for inclusion the participants must have experienced non-specific spinal pain for at least one week. The study will be conducted at the clinics of registered chiropractors in Western Australia. Participants in each group will receive two treatments at intervals no less than one week. For the usual chiropractic care group, the selection of therapeutic techniques will be left to the chiropractors' discretion. For the sham intervention group, de-tuned ultrasound and de-tuned activator treatment will be applied by the chiropractors to the regions where spinal pain is experienced. Adverse events will be assessed two days after each appointment using a questionnaire developed for this study. The efficacy of short term chiropractic care for spinal pain will be examined at two week follow-up by assessing pain, physical function, minimum acceptable outcome, and satisfaction with care, with the use of the following outcome measures: Numerical Rating Scale, Functional Rating Index, Neck Disability Index, Minimum Acceptable Outcome Questionnaire, Oswestry Disability Index, and a global measure of treatment satisfaction. The statistician, outcome assessor, and participants will be blinded to treatment allocation. Trial registration Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000542998

2011-01-01

303

Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide  

PubMed Central

AIMS To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans. METHODS An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non-linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles. RESULTS Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54 µg g?1 were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations from 13.9 to 52.8 µg g?1 (n = 4, LY2181308 750 mg) were observed associated with a median survivin mRNA and protein inhibition of 20% ± 34 (SD) (n = 9) and 23% ± 63 (SD) (n = 10), respectively. The human PK parameters were adequately estimated: central Vd, 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00) l h?1, peripheral Vds, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922) l, mean elimination clearance 23.1 l h?1 (5.6, 33.4) and mean terminal half-life, 32.7 days (range 22–52 days). CONCLUSION The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750 mg.

Callies, Sophie; Andre, Valerie; Patel, Bharvin; Waters, David; Francis, Paul; Burgess, Michael; Lahn, Michael

2011-01-01

304

Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors  

NASA Astrophysics Data System (ADS)

Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.

Urbán, Patricia; Estelrich, Joan; Adeva, Alberto; Cortés, Alfred; Fernàndez-Busquets, Xavier

2011-12-01

305

Opinions on the preclinical evaluation of novel therapies for spinal cord injury: a comparison between researchers and spinal cord-injured individuals.  

PubMed

We previously conducted a survey to gather the opinions and perspectives of scientific and clinical researchers on what levels of preclinical evidence were needed to justify translating a promising neuroprotective or neuroregenerative therapy in spinal cord injury (SCI) into a human clinical trial (Kwon et al., 2010 ). Here we conducted an analogous survey of individuals living with SCI in which we gathered their expectations for the levels of preclinical evidence achieved by researchers in substantiating the neuroprotective and neuroregenerative therapies being offered to them in clinical trials. In total, 214 individuals with SCI completed the survey, and their responses were compared to the responses of the 235 scientists and clinicians who completed our previous survey. SCI individuals were more likely than SCI researchers to opine that demonstrating efficacy and safety in rodent models of SCI alone is sufficient to proceed with clinical trials. However, SCI individuals also reported strong support for large animal and primate model studies, and in the case of the latter, were actually more in agreement for the need for primate studies than researchers. SCI individuals also reported strong support for independent replication studies. In general, individuals with SCI had high expectations for the levels of preclinical evidence required to justify translating novel therapies into clinical trials. These expectations should be considered in the decisions to translate specific experimental therapies for SCI. PMID:22776047

Kwon, Brian K; Ghag, Arvindera; Reichl, Leilani; Dvorak, Marcel F; Illes, Judy; Tetzlaff, Wolfram

2012-09-20

306

Leukotrienes as Modifiers of Preclinical Atherosclerosis?  

PubMed Central

Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis.

Riccioni, Graziano; Back, Magnus

2012-01-01

307

Preclinical Considerations for Products Regulated in OCTGT  

Center for Biologics Evaluation and Research (CBER)

... Allen Wensky provides a basic overview of preclinical considerations that make up one of the three key elements of an IND submission. -. ... More results from www.fda.gov/biologicsbloodvaccines/newsevents

308

Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.  

PubMed

Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey. PMID:15500257

Koll, R; Buhr, M; Dieter, R; Pabst, H; Predel, H G; Petrowicz, O; Giannetti, B; Klingenburg, S; Staiger, C

2004-09-01

309

Longitudinal Study: Efficacy of Online Technology Tools for Instructional Use.  

National Technical Information Service (NTIS)

Studies show that the student population (secondary and post secondary) is becoming increasingly more technologically savvy. Use of the internet, computers, MP3 players, and other technologies along with online gaming has increased tremendously amongst th...

M. D. Uenking

2011-01-01

310

The Relevance of Pharmacokinetic Studies in Designing Efficacy Trials in Juvenile Major Depression  

Microsoft Academic Search

Introduction: Identifying evidence-based dosing strategies is a key part of new drug develop- ment in pediatric populations. Pharmacokinetic (PK) studies can provide important information regarding how best to dose medications in children and adolescents. Utilizing scientifically supported dosing strategies provides the best chance for any given drug to demonstrate both efficacy and acceptable tolerability in definitive, placebo-controlled studies. Methods: Results

Robert L. Findling; Nora K. McNamara; Robert J. Stansbrey; Norah C. Feeny; Christopher M. Young; Franco V. Peric; Eric A. Youngstrom

2006-01-01

311

Case Study: Influence of Tracking on Achievement, Self-Efficacy and Instruction  

ERIC Educational Resources Information Center

|Focusing on a suburban Philadelphia high school's social studies classes, this research study investigated the influence of tracking on student achievement, on teachers' and students' perceptions of self-efficacy, and on teachers' instructional practices in the classroom. In order to address these research questions, the researcher used a…

Butz, Toni R.

2011-01-01

312

Efficacy of a cognitive training programme for mild cognitive impairment: Results of a randomised controlled study  

Microsoft Academic Search

This study aimed to determine the efficacy of cognitive training in a 10-week randomised controlled study involving 22 individuals presenting with mild cognitive impairment of the amnestic type (MCI-A). Participants in the experimental group (n = 11) learned face–name associations using a paradigm combining errorless (EL) learning and spaced retrieval (SR) whereas participants in the control group (n = 11)

Léonie Jean; Martine Simard; Sandra Wiederkehr; Marie-Ève Bergeron; Yves Turgeon; Carol Hudon; Isabelle Tremblay; Robert van Reekum

2010-01-01

313

Career Development Interventions and Academic Self-Efficacy and Motivation: A Pilot Study.  

ERIC Educational Resources Information Center

|The impact of career development interventions on career and technical education (CTE) students' academic self-efficacy and motivation was explored in a pilot study that elicited responses from 293 students at 20 high schools across the United States. The study included a literature review, survey of high school seniors that examined 44…

Dykeman, Cass; Wood, Chris; Ingram, Michael; Herr, Edwin L.

314

Examining Culturally Responsive Teaching Self-Efficacy in a Preservice Social Studies Education Course  

ERIC Educational Resources Information Center

|In a preexperimental study of preservice practitioners' professional dispositions, we examined the relationship between an innovative culturally responsive teaching model in a social studies methods course and teacher candidates' culturally responsive teaching self-efficacy. Findings indicate preservice teachers exposed to an in-depth culturally…

Fitchett, Paul G.; Starker, Tehia V.; Salyers, Beth

2012-01-01

315

The Interplay between Motivation, Self-Efficacy, and Approaches to Studying  

ERIC Educational Resources Information Center

|Background: The strategies students adopt in their study are influenced by a number of social-cognitive factors and impact upon their academic performance. Aims: The present study examined the interrelationships between motivation orientation (intrinsic and extrinsic), self-efficacy (in reading academic texts and essay writing), and approaches to…

Prat-Sala, Merce; Redford, Paul

2010-01-01

316

Efficacy of Eight Months of Nightly Zolpidem: A Prospective Placebo-Controlled Study  

PubMed Central

Study Objectives: To evaluate the long-term (8 months) efficacy of zolpidem in adults with chronic primary insomnia using polysomnography. Design: Randomized, double-blind, placebo-controlled clinical trial. Setting: Sleep disorders and research center. Participants: Healthy participants (n = 91), ages 23-70, meeting DSM-IV-TR criteria for primary insomnia. Interventions: Nightly zolpidem, 10 mg (5 mg for patients > 60 yrs) or placebo 30 minutes before bedtime for 8 months. Measurements and Results: Polysomnographic sleep parameters and morning subject assessments of sleep on 2 nights in months 1 and 8. Relative to placebo, zolpidem significantly increased overall total sleep time and sleep efficiency, reduced sleep latency and wake after sleep onset when assessed at months 1 and 8. Overall, subjective evaluations of efficacy were not shown among treatment groups. Conclusions: In adults with primary insomnia, nightly zolpidem administration remained efficacious across 8 months of nightly use. Clinical Trial Information: ClinicalTrials.gov Identifier: NCT01006525; Trial Name: Safety and Efficacy of Chronic Hypnotic Use; http://clinicaltrials.gov/ct2/show/NCT01006525. Citation: Randall S; Roehrs TA; Roth T. Efficacy of eight months of nightly zolpidem: a prospective placebo-controlled study. SLEEP 2012;35(11):1551-1557.

Randall, Surilla; Roehrs, Timothy A.; Roth, Thomas

2012-01-01

317

Postmarketing Surveillance Study of the Efficacy and Safety of Phentermine in Patients with Obesity  

PubMed Central

Background Obesity is a complex problem that is now considered a chronic metabolic disease. In Korea, phentermine has been widely used for the treatment of obesity in the primary care setting since 2004. However, there have been very few studies on the safety and efficacy of phentermine. To investigate the safety and efficacy of this drug, a postmarketing surveillance study was performed. Methods A total of 795 patients with obesity (body mass index ? 25 kg/m2) were enrolled from 30 primary care centers in Korea from September 2006 to November 2007. Patients were examined to ascertain safety and efficacy at 4-, 8-, and 12-week intervals. The criterion for efficacy was defined as a weight loss ? 5% of body weight. Results Of the 795 enrolled patients, 735 (92.5%) were evaluated in safety assessments and 711 (89.4%) was included in efficacy assessments. A total of 266 adverse events (AEs) were reported by 218 patients (30.6%), and no serious AEs were reported. Among 711 patients, 324 patients (45.6%) lost ? 5% of their body weight. The mean weight loss was 3.8 ± 4.0 kg. Conclusion AEs are commonly associated with phentermine, even though phentermine is effective for weight loss and relatively well-tolerated.

Kim, Hyun Ok; Lee, Jung Ah; Suh, Hee Won; Kim, Bum Soo; Ahn, Eun Sook; Roh, Young Jun; Jung, Seong Gil; Kim, Jin Mok; Kang, Moon Kuk; Ahn, In Soon; Park, Young Gyu

2013-01-01

318

Preclinical toxicological evaluation of sertraline hydrochloride.  

PubMed

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with other serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drugtreated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk. PMID:9598298

Davies, T S; Klowe, W M

1998-05-01

319

Preclinical toxicological evaluation of sertraline hydrochloride.  

PubMed

The toxicity profile of the antidepressant drug sertraline was determined in a series of preclinical studies in mice, rats, rabbits and dogs. Acute, subchronic, reproductive, chronic and carcinogenicity studies were conducted by the oral route. The highest doses tested in these studies were the maximum tolerated doses based on clinical signs, decreased food consumption, body weight effects, organ weight changes or clinical/anatomical pathology findings. Genetic toxicity studies were also performed. The liver was identified as a target organ in the mouse, rat and dog. The observed liver findings were consistent with hepatic xenobiotic-metabolizing enzyme induction and included hepatomegaly, hepatocellular hypertrophy, slightly increased serum transaminase activity and proliferation of smooth endoplasmic reticulum. Hepatocellular fatty change, a minimal toxic effect, was seen in mice and rats. There was no teratogenicity in studies conducted at maternally toxic doses in rats and rabbits. Decreased neonatal survival and growth observed in these studies have been previously reported in reproduction studies with serotonin reuptake inhibitors. Sertraline was not genotoxic in an extensive battery of tests. Carcinogenicity tests were negative in rats, while benign liver tumors were slightly increased in drug-treated male mice. Liver tumors were considered secondary to the enzyme inducing potential of sertraline and not indicative of human risk. PMID:10048942

Davies, T S; Kluwe, W M

1998-11-01

320

Preclinical Data of Eluting Stents  

Microsoft Academic Search

The concept of using stents coated with agents that could potentially inhibit neointimal hyperplasia has emerged and drug-eluting\\u000a stents (DES) represent one of the fastest growing fields in interventional cardiology today. Different animal models have\\u000a been used in order to test the safety and efficacy of DES. The drug-eluting coatings contain antimitotic (e.g., sirolimus\\u000a [SRL], SRL analogs, paclitaxel, and actinomycin),

Antonio Colombo; Alaide Chieffo

321

Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases.  

PubMed

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy. PMID:23971871

Morimoto, Bruce H; Fox, Anthony W; Stewart, Alistair J; Gold, Michael

2013-08-24

322

Legislature agrees to fund study of marijuana efficacy.  

PubMed

California could be the first State to conduct a research study on medical uses for marijuana under the "Medical Research Act of 1999". S.B. 847 would authorize a three-year program, administered by the University of California, to study which methods of ingesting marijuana are most effective in treating pain and side effects of treatments for AIDS, cancer, glaucoma and seizures. The sponsor of the bill, Sen. John Vasconcellos, initially wanted $1 million in annual funding, but the program will be funded through the normal appropriations process. PMID:11367022

1999-10-01

323

Discourse-Based Language Intervention: An Efficacy Study.  

ERIC Educational Resources Information Center

This study of a 5-year-old girl with sensorineural hearing loss examined the effect of supplementing a pragmatically based procedure of focused stimulation with structured opportunities for verbal practice using vertical constructions. Results indicated that focused stimulation was an effective treatment procedure, especially when enhanced by the…

Skarakis-Doyle, Elizabeth; Murphy, Lisa

1995-01-01

324

Antidepressant efficacy of tranylcypromine isomers: A controlled study  

Microsoft Academic Search

Summary The (+)- and (-)-isomers of the monoamine oxidase inhibitor (MAO-I) tranylcypromine (TCP) were administered separately in a double-blind controlled study to 20 depressed patients. The Hamilton Depression Rating Scale, the AMP-system and the Bf-s self-rating questionnaire were used for documentation of psychopathological state and autonomic side effects.

H.-W. Moises; H. Beckmann

1981-01-01

325

Community Education for Stroke Awareness An Efficacy Study  

Microsoft Academic Search

Background and Purpose—This study examined the effectiveness of a slide\\/audio community education program aimed at increasing knowledge of stroke risk factors, stroke warning signs, and action needed when stroke warning signs occur. The program targets audiences at higher risk for stroke, especially individuals who are black or .50 years of age. Methods—Subjects were 657 adults living in the community or

Erica B. Stern; MaryEllen Berman; Juliann J. Thomas; Arthur C. Klassen

326

Studies examining the efficacy of ankle foot orthoses should report activity level and mechanical evidence.  

PubMed

Ankle Foot Orthoses (AFOs) to promote walking ability are a common treatment in patients with neurological or muscular diseases. However, guidelines on the prescription of AFOs are currently based on a low level of evidence regarding their efficacy. Recent studies aiming to demonstrate the efficacy of wearing an AFO in respect to walking ability are not always conclusive. In this paper it is argued to recognize two levels of evidence related to the ICF levels. Activity level evidence expresses the gain in walking ability for the patient, while mechanical evidence expresses the correct functioning of the AFO. Used in combination for the purpose of evaluating the efficacy of orthotic treatment, a conjunct improvement at both levels reinforces the treatment algorithm that is used. Conversely, conflicting outcomes will challenge current treatment algorithms and the supposed working mechanism of the AFO. A treatment algorithm must use relevant information as an input, derived from measurements with a high precision. Its result will be a specific AFO that matches the patient's needs, specified by the mechanical characterization of the AFO footwear combination. It is concluded that research on the efficacy of AFOs should use parameters from two levels of evidence, to prove the efficacy of a treatment algorithm, i.e., how to prescribe a well-matched AFO. PMID:20738235

Harlaar, Jaap; Brehm, Merel; Becher, Jules G; Bregman, Daan J J; Buurke, Jaap; Holtkamp, Fred; De Groot, Vincent; Nollet, Frans

2010-09-01

327

Joint modeling of clinical efficacy and safety with an application to diabetes studies.  

PubMed

The purpose of drug development is to evaluate a drug's efficacy and safety profile. For a personalized medicine, it is important for patients and health care providers to understand the efficacy and safety trade-off when selecting a dose for a patient. In this article, we propose three different methods for jointly modeling the clinical safety and efficacy endpoints. These three methods model the correlation relationship in three different ways: modeling the joint distribution by a copula method, modeling conditional distributions, and modeling their correlations through individual means by a hierarchical model. We compare these three methods through simulations and apply these methods to a data set from a diabetes study. PMID:23957521

Zhao, Yang; Shen, Wei; Fu, Haoda

2013-01-01

328

Lifetime depressive and somatic symptoms as preclinical markers of late-onset depression  

Microsoft Academic Search

.   Background: Several risk factors of depression, i. e., female gender and life-stress, have been identified. Few studies have focussed\\u000a on symptoms as preclinical markers of depression. In these studies current symptoms like dysphoria, tiredness and increased\\u000a appetite predicted later depression. Even though of possible interest for treatment, no study focussed on lifetime symptoms\\u000a as preclinical markers of depression. Consequently,

Sandra Hein; Marzia Bonsignore; Katrin Barkow; Frank Jessen; Ursula Ptok; Reinhard Heun

2003-01-01

329

New cast for a new era: preclinical cancer drug development revisited.  

PubMed

Molecularly targeted agents promise to revolutionize therapeutics by reducing morbidity and mortality in patients with cancer. However, despite an urgent need for more effective anticancer compounds, current preclinical drug evaluations largely fail to satisfy the demand. New preclinical strategies, including the improvement of sophisticated mouse models and co-clinical study designs, are being used to augment the predictive value of animal-based translational cancer research. Here, we review the development of successful preclinical antineoplastic agents, their associated limitations, and alternative methods to predict clinical outcomes. PMID:23999436

Herter-Sprie, Grit S; Kung, Andrew L; Wong, Kwok-Kin

2013-09-03

330

Mouse Model of Cervicovaginal Toxicity and Inflammation for Preclinical Evaluation of Topical Vaginal Microbicides  

PubMed Central

Clinical trials evaluating the efficacy of nonoxynol-9 (N-9) as a topical microbicide concluded that N-9 offers no in vivo protection against human immunodeficiency virus type 1 (HIV-1) infection, despite demonstrated in vitro inactivation of HIV-1 by N-9. These trials emphasize the need for better model systems to determine candidate microbicide effectiveness and safety in a preclinical setting. To that end, time-dependent in vitro cytotoxicity, as well as in vivo toxicity and inflammation, associated with N-9 exposure were characterized with the goal of validating a mouse model of microbicide toxicity. In vitro studies using submerged cell cultures indicated that human cervical epithelial cells were inherently more sensitive to N-9-mediated damage than human vaginal epithelial cells. These results correlated with in vivo findings obtained by using Swiss Webster mice in which intravaginal inoculation of 1% N-9 or Conceptrol gel (containing 4% N-9) resulted in selective and acute disruption of the cervical columnar epithelial cells 2 h postapplication accompanied by intense inflammatory infiltrates within the lamina propria. Although damage to the cervical epithelium was apparent out to 8 h postapplication, these tissues resembled control tissue by 24 h postapplication. In contrast, minimal damage and infiltration were associated with both short- and long-term exposure of the vaginal mucosa to either N-9 or Conceptrol. These analyses were extended to examine the relative toxicity of polyethylene hexamethylene biguanide (PEHMB), a polybiguanide compound under evaluation as a candidate topical microbicide. In similar studies, in vivo exposure to 1% PEHMB caused minimal damage and inflammation of the genital mucosa, a finding consistent with the demonstration that PEHMB was >350-fold less cytotoxic than N-9 in vitro. Collectively, these studies highlight the murine model of toxicity as a valuable tool for the preclinical assessment of toxicity and inflammation associated with exposure to candidate topical microbicides.

Catalone, Bradley J.; Kish-Catalone, Tina M.; Budgeon, Lynn R.; Neely, Elizabeth B.; Ferguson, Maelee; Krebs, Fred C.; Howett, Mary K.; Labib, Mohamed; Rando, Robert; Wigdahl, Brian

2004-01-01

331

Herbimycin A in the treatment of experimental proliferative vitreoretinopathy: toxicity and efficacy study  

Microsoft Academic Search

Background: Proliferative vitreoretinopathy (PVR) is partially caused by peptide growth factors, stimulating the cell by binding to a\\u000a transmembrane tyrosine kinase receptor. We studied the effects of herbimycin A (HA), a tyrosine kinase inhibitor, in PVR.?\\u000a Methods: Toxicity studies: Electroretinography and histological studies were performed after intravitreal injection of HA. Efficacy\\u000a studies: Homologous rabbit dermal fibroblasts were injected intravitreally, followed

Kazuyuki Imai; Anat Loewenstein; Barba Koroma; Rhonda Grebe; Eugene de Juan Jr

2000-01-01

332

Exercise Self-Efficacy and Perceived Wellness among College Students in a Basic Studies Course  

ERIC Educational Resources Information Center

|University basic studies courses provide a valuable opportunity for facilitating the knowledge, skills, and beliefs that develop healthy behaviors to last a lifetime. Belief in one's ability to participate in physical activity, exercise self-efficacy, is a psychological construct that has had a documented impact on physical activity. Although…

Sidman, Cara L.; D'Abundo, Michelle Lee; Hritz, Nancy

2009-01-01

333

Integrated Family and Cognitive-Behavioral Therapy for adolescent substance abusers: a Stage I efficacy study  

Microsoft Academic Search

This study evaluated the efficacy of Integrated Family and Cognitive-Behavioral Therapy (IFCBT), a multisystems treatment for adolescent drug abuse, versus a Drugs Harm Psychoeducation curriculum (DHPE). A randomized controlled trial assessed youth and parents at baseline and at 1, 3 and 6-month posttreatment points. Youth participants (N=43) met diagnostic criteria for one or more psychoactive substance use disorders with most

William W. Latimer; Ken C. Winters; Thomas D'Zurilla; Mike Nichols

2003-01-01

334

Comparison of the antimanic efficacy of carbamazepine and chlorpromazine: A double-blind controlled study  

Microsoft Academic Search

A multiinstitutional cooperative study comparing carbamazepine (Tegretol) with chlorpromazine was performed using a controlled, double-blind trial design. In a series of 63 cases of endogenous manic psychosis, carbamazepine's clinical utility and efficacy, characteristics of therapeutic effect, and side effects were evaluated. Carbamazepine and chlorpromazine were given by a fixed, but flexible, method at an equipotent ratio of 2:1, starting from

Teruo Okuma; Kazutoyo Inanaga; Saburo Otsuki; Keisuke Sarai; Ryo Takahashi; Hidefumi Hazama; Atsuyoshi Mori; Masasuke Watanabe

1979-01-01

335

THE FELDENKRAIS METHOD IN THE TREATMENT OF CHRONIC PAIN: A STUDY OF EFFICACY AND COST EFFECTIVENESS  

Microsoft Academic Search

A preliminary study was undertaken to determine both the efficacy and cost effectiveness of the Feldenkrais Method for treatment of Medicaid recipients with chronic pain at the Santa Barbara Regional Health Authority (SBRHA). SBRHA staff wished to offer treatment for chronic pain patients beyond what is provided for in the Medicaid scope of benefits. Conventional intensive chronic pain treatment programs

David Bearman; Steven Shafarman

336

Safety and antiulcer efficacy studies of Achillea millefolium L. after chronic treatment in Wistar rats  

Microsoft Academic Search

Achillea millefolium L. (Asteraceae), popularly known as yarrow, has been used in folk medicine to treat complaints such as inflammation, pain, wounds, hemorrhages and gastrointestinal disturbances. The aim of the present study was to assess the safety and efficacy of the aqueous extract (AE) of the plant after chronic exposure. Indeed, the AE was effective in protecting the gastric mucosa

Ana Maria Cavalcanti; Cristiane Hatsuko Baggio; Cristina Setim Freitas; Lia Rieck; Renato Silva de Sousa; José Eduardo Da Silva-Santos; Sonia Mesia-Vela; Maria Consuelo Andrade Marques

2006-01-01

337

Self-Efficacy and Vocational Outcome Expectations for Adolescents of Lower Socioeconomic Status: A Pilot Study  

ERIC Educational Resources Information Center

Relationships between contextual support, perceived educational barriers, and vocational/educational self-efficacy and outcome expectations were examined for a group of 114 ninth graders from lower socioeconomic backgrounds. Results of this exploratory pilot study indicated that sibling and peer support accounted for a significant amount of…

Ali, Saba Rasheed; McWhirter, Ellen Hawley; Chronister, Krista M.

2005-01-01

338

A Study of Teachers' Sense of Efficacy. Final Report, Executive Summary.  

ERIC Educational Resources Information Center

A conceptual framework for the study of teachers' sense of efficacy was used to determine the extent to which teachers believed they could influence student learning. The framework was based on an extensive review of research literature on teaching, an ethnographic comparison of 2 organizationally different middle schools, and a process-product…

Ashton, Patricia T.; And Others

339

Evaluating the Efficacy of the Valsalva Maneuver on Venous Cannulation Pain: A Prospective, Randomized Study  

Microsoft Academic Search

Pain associated with venous cannula is a distressing symptom. We evaluated the efficacy of the Valsalva maneuver on pain associated with venous cannulation. Seventy-five adults, ASA physical status I and II, either sex, undergoing elective surgery, were included in this study. Patients were randomized into 3 groups of 25 each. Group I (C): control; Group II (V): blew into sphygmomanometer

Anil Agarwal; P. K. Sinha; Manish Tandon; Sanjay Dhiraaj; Uttam Singh

2005-01-01

340

PRELIMINARY STUDY OF THERAPEUTIC EFFICACY OF A NEW FASCIOLICIDAL DRUG DERIVED FROMCOMMIPHORA MOLMOL(MYRRH)  

Microsoft Academic Search

Myrrh (from the stem of the Commiphora molmoltree) is an oleo gum resin that may prove efficacious for the treatment of fascioliasis. We studied 7 patients who were passing Fasciola eggs in their stools and treated them with myrrh. The drug (a formulation consisting of 8 parts of resin and 3.5 parts of volatile oils, all extracted from myrrh) was

AHMED MASSOUD; SAWSAN EL SISI; OSAMA SALAMA; AFAF MASSOUD

341

Study of the efficacy of aerosol versus nonaerosol laundry products. Final report  

Microsoft Academic Search

The California Air Resources Board estimates that 6.6 tons of photochemically reactive organic compounds (PROC) are released into the environment in California every day because of the use of aerosol laundry products. The project studied the efficacy, ease of product use, and PROC content for three major brands of pre-wash stain removers in available product forms and for five starch

R. R. Boggs; B. Belmont

1987-01-01

342

A Mixed-Method Study: Assessing the BAR Model's Impact on Preservice Teachers' Efficacy Beliefs  

ERIC Educational Resources Information Center

This study took place at a mid-sized, Midwestern university located in a mid-sized town. The researchers developed the BAR model to teach mathematics methods both in the classroom and in the field. The preservice teachers took Enochs, Smith, and Huinker's Mathematics Teaching Efficacy Beliefs Instrument (MTEBI) on the first and last day of class.…

Rethlefsen, Ann Lyle; Park, Hyesung

2011-01-01

343

A comparative study of self-efficacy, outcome expectancy, and retention of beginning urban science teachers  

NASA Astrophysics Data System (ADS)

The purpose of the multi-tiered study presented is to compare the effect of credentialing route on the self-efficacy, outcome expectancy, and retention of beginning urban science teachers serving students in a large urban school district in Southern California. Candidates from one traditional, university-based teacher education program and from two alternative programs, the Teach for America and District Intern Programs, were surveyed and interviewed during the second semester of their first year of teaching. To determine the potential of a difference in self-efficacy and outcome expectancy, the study gave teachers a modified version of the Science Teachers' Efficacy Belief Instrument (STEBI), developed and validated by Riggs and Enochs (1989). Two representative candidates from each program were then interviewed in order to probe for deeper understanding of possible sources of their efficacy and outcome expectancy. The final part of the study is an evaluation of retention data from the three programs, each to triangulate this information with data collected from the surveys, and comparing these retention rates with published data. The study provides data on unresearched questions about traditionally and alternatively credentialed science teachers in urban settings in California.

Klein, Nina

344

Multicentric Double-Blind Study Comparing Efficacy and Safety of Minaprine and Imipramine in Dysthymic Disorders  

Microsoft Academic Search

This multicentre study compares the therapeutic efficacy and safety of minaprine (200 mg) to that of imipramine (50, 75, 100 mg) in the treatment of patients over 40 years suffering from dysthymic disorders as diagnosed according to DSM III. After 4–7 days on placebo, 67 patients were randomly assigned to receive either drug for a period of 6 weeks in

E. Salzmann; J. L. Robin

1995-01-01

345

A Mixed-Method Study: Assessing the BAR Model's Impact on Preservice Teachers' Efficacy Beliefs  

ERIC Educational Resources Information Center

|This study took place at a mid-sized, Midwestern university located in a mid-sized town. The researchers developed the BAR model to teach mathematics methods both in the classroom and in the field. The preservice teachers took Enochs, Smith, and Huinker's Mathematics Teaching Efficacy Beliefs Instrument (MTEBI) on the first and last day of class.…

Rethlefsen, Ann Lyle; Park, Hyesung

2011-01-01

346

The COACH prompting system to assist older adults with dementia through handwashing: An efficacy study  

Microsoft Academic Search

BACKGROUND: Many older adults with dementia require constant assistance from a caregiver when completing activities of daily living (ADL). This study examines the efficacy of a computerized device intended to assist people with dementia through ADL, while reducing caregiver burden. The device, called COACH, uses artificial intelligence to autonomously guide an older adult with dementia through the ADL using audio

Alex Mihailidis; Jennifer N Boger; Tammy Craig; Jesse Hoey

2008-01-01

347

Preclinical Toxicology of Nsc 1895 Administered By 24-Hour Infusion in Dogs. Part II.  

National Technical Information Service (NTIS)

NSC 1895, Guanazole, Triazole 3, 5-diamino-s, which shows strong antitumor activity has been studied for preclinical toxicological effects following weekly 24-hour infusions in young adult beagle dogs. At all dosage levels, clinical signs of toxicity were...

P. E. Palm M. S. Nick C. J. Kensler D. A. Cooney R. D. Davis

1969-01-01

348

Preclinical Toxicology of Nsc 17251E Administered by Oral Route in Dogs. Part II.  

National Technical Information Service (NTIS)

NSC 17251E* has been studied for preclinical toxicological effects following repeated oral administration in young adult beagle dogs. All animals survived the 28-day treatment, and no serious clinical signs of toxicity were noted with dosages of 168, 336,...

P. E. Palm M. S. Nick C. J. Kensler D. A. Cooney R. D. Davis

1969-01-01

349

Key treatment studies of lithium in manic-depressive illness: efficacy and side effects.  

PubMed

Lithium is the most extensively studied single psychopharmacologic agent. This review summarizes efficacy results of key studies in manic-depressive illness, the increasingly practical findings regarding predictors of response, and the implications of the increasingly better understood adverse effect profile of lithium. A recent well-designed study confirms earlier studies regarding the marked effectiveness of lithium in alleviation of acute mania. Early maintenance studies of marked superiority of lithium over placebo have been countered by recent open reports of lesser effectiveness. A recent randomized study provides support for the efficacy of lithium in maintenance therapy, but a satisfactory assessment of the effectiveness of lithium for maintenance and its optimal role requires further study. Many of the adverse effects of lithium can be addressed by dosage reduction, use of sustained-release lithium, or combination therapy. PMID:9674932

Bowden, C L

1998-01-01

350

Preclinical evaluation of skin substitutes.  

PubMed

The important requirements of a skin substitute such as water vapour permeability, adherence to the excised wound surface, oxygen permeability, mechanical properties, impermeability to micro-organisms and exudate soaking capacity have been highlighted. Two commercial synthetic skin substitutes, Bioclusive and Geliperm, have been used to establish the preclinical assessment procedures for skin substitutes. Two in vitro techniques, the 'Water Cup' and the 'Inverted Cup,' and two in vivo methods involving a 'Ventilated Hygrometer Chamber' system and an Evaporimeter have been employed to assess and compare the water vapour permeability of the skin substitutes under controlled conditions. An Evaporimeter, which is very simple to operate, provides more accurate results. A simple test has been designed to evaluate the early adherence of the skin substitutes to the excised wound surface of rats. The pulling force and the peeling force required to remove the membrane from the wound surface have been measured and these forces have been found to depend upon the composition of the membrane. An oxygen permeability cell has been fabricated which measures the dissolved oxygen permeability of the skin substitutes. The detection of oxygen is based on the electrocatalytic reduction of oxygen at the surface of a noble metal. The tensile properties of the skin substitutes have been measured by an International Standard procedure and both the skin prostheses are associated with some drawbacks. An in vitro method of testing the microbial permeability of the skin substitutes has been designed which simulates an oozing colonized wound that a skin substitute faces in cases of septicaemia. Both the test materials were impermeable to both bacteria and fungi and will provide an effective barrier. The effectiveness of the skin substitutes to absorb wound exudate from the wound surface has been evaluated by soaking the pieces of the membranes in water, plasma and serum and observing their weight gain. The soaking capacity depends upon the composition and nature of the material. The procedures developed have been employed to evaluate a hydrogel type synthetic skin substitute recently formulated in our laboratory. PMID:2275766

Nangia, A; Hung, C T

1990-10-01

351

Passive and Oxymetazoline-Enhanced Delivery with a Lens Device: Pharmacokinetics and Efficacy Studies with Rabbits  

PubMed Central

Abstract Purpose The aims of this study were to assess the trans-scleral delivery of dexamethasone phosphate (DexP) with a prototype lens device and a formulation comprising a vasoconstrictor and to determine the efficacy of this delivery system in treating experimentally induced uveitis in a rabbit model. Methods Passive trans-scleral delivery was performed on New Zealand white rabbits in vivo, using the lens device and a formulation of 0.034 M oxymetazoline (OMZ, the vasoconstrictor) and 0.5 M of dexamethasone sodium phosphate (DexNaP). Trans-scleral delivery of DexP without OMZ was the control. The amounts of DexP delivered into the eye and its distributions in the eye were determined by dissection of the eye and high-performance liquid chromatography assay in the pharmacokinetics study. The efficacy of the DexP delivery system in treating lipopolysaccharide-induced uveitis was also evaluated in the rabbit model in vivo. The effect of OMZ upon DexP delivery and its treatment efficacy was studied by comparing the DexP results with and without OMZ. Results In the pharmacokinetics study, the amounts of DexP delivered into the eye using the lens system with OMZ were significantly higher than those without OMZ. The results in the efficacy study showed a better treatment outcome with OMZ to relieve the symptoms of endotoxin-induced uveitis in rabbits. Conclusions The potential of vasoconstrictors to enhance eye disease treatments in passive trans-scleral drug delivery was demonstrated. The higher DexP level in the eye and the improvement of the outcome in the efficacy study in the presence of the vasoconstrictor are consistent with the hypothesis that the vasoconstrictor enhances drug delivery by decreasing clearance.

Miller, David J.; Tuitupou, Anthony L.; Kochambilli, Rajan P.; Papangkorn, Kongnara; Mix, Donald C.; Higuchi, William I.; Higuchi, John W.

2008-01-01

352

CTLA-4 blockade in tumor models: an overview of preclinical and translational research.  

PubMed

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address. PMID:23390376

Grosso, Joseph F; Jure-Kunkel, Maria N

2013-01-22

353

CTLA-4 blockade in tumor models: an overview of preclinical and translational research  

PubMed Central

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a key negative regulator of T cell activation. A complex integration of positive and negative co-stimulatory signals in the well-defined B7:CD28/CTLA-4 pathway modulates the generation and maintenance of immune responses. Inhibiting negative regulation through binding of CTLA-4 has been shown to promote stimulation of adaptive immunity and potentiation of T cell activation. CTLA-4-blocking antibodies have demonstrated efficacy in various murine malignancy models when administered as monotherapy; additionally, they have shown synergistic anti-tumor activity when utilized with other agents, such as vaccines, chemotherapy, and radiation. Preclinical studies have supported the rationale for current clinical development of anti-CTLA-4 antibodies, including ipilimumab and tremelimumab, as novel therapeutic strategies to augment anti-tumor immunity in cancer. Both ipilimumab and tremelimumab have been evaluated extensively in melanoma; notably, ipilimumab was recently approved as monotherapy for the treatment of advanced melanoma. Tremelimumab is currently undergoing evaluation in phase II trials as monotherapy in melanoma and malignant mesothelioma, while ipilimumab is under clinical investigation in phase II and III trials in various tumor types, including in melanoma, prostate, and lung cancers as monotherapy and with other therapeutic modalities, such as chemotherapy and radiation. In this review, we will provide a detailed overview of preclinical advances that have delineated many features of CTLA-4 and have helped define its role in T cell response. We will also highlight clinical application of anti-CTLA-4 therapy in cancer and describe knowledge gaps that future studies may address.

Grosso, Joseph F.; Jure-Kunkel, Maria N.

2013-01-01

354

Preclinical safety of recombinant human thrombin.  

PubMed

Recombinant human thrombin (rhThrombin) is being developed as an alternative to thrombin products purified from pooled human or bovine plasma, which are currently marketed for topical hemostasis. Preclinical studies of rhThrombin were conducted prior to its evaluation as a topical adjunct to surgical hemostasis in clinical trials. No overt clinical pathology or signs were observed in cynomolgus monkeys following implantation of a gelatin sponge containing either rhThrombin or bovine thrombin to a surgical liver wound, and similar gross and microscopic wound healing characteristics were observed over an eight-week recovery period with either compound. Repeated subcutaneous injections of rhThrombin or bovine thrombin to cynomolgus monkeys produced no treatment-related effects. Whereas no monkeys demonstrated anti-rhThrombin antibody seroconversion, specific anti-bovine antibodies were detected in all tested monkeys exposed to bovine thrombin. Addition of rhThrombin or bovine thrombin to mouse fibroblast cells resulted in expected detachment and shape change. Topical application of rhThrombin to rabbits did not cause irritation to the eye, normal skin, or abraded skin. These studies showed that topical, subcutaneous, or implanted rhThrombin was minimally immunogenic, safe, and well tolerated in nonclinical models, and supported the clinical evaluation of rhThrombin in a variety of surgical settings. PMID:16971028

Heffernan, Jane K; Ponce, Rafael A; Zuckerman, Linda A; Volpone, John P; Visich, Jennifer; Giste, Erika E; Jenkins, Nancy; Boster, Dan; Pederson, Susan; Knitter, Glenn; Palmer, Thomas; Wills, Margaret; Early, Richard J; Rogge, Mark C

2006-09-12

355

Efficacy and tolerability of policosanol in elderly patients with type II hypercholesterolemia: a 12-month study  

Microsoft Academic Search

This study reports the results of a 12-month, multicenter, randomized, double-blind, placebo-controlled study of the efficacy, safety, and tolerability of policosanol at daily doses of 10 mg in the treatment of elderly patients with type II hypercholesterolemia. The study included 62 elderly patients of both sexes with total cholesterol and low-density lipoprotein cholesterol (LDL-C) not controlled sufficiently during a diet-only

Gladys Castaño; Miguel Canetti; Marta Moreira; Leonel Tula; Rosa Más; José Illnait; Lilla Fernández; Julio C. Fernández; Eduardo Díaz

1995-01-01

356

A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: design of the RENEW study.  

PubMed

Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina. PMID:23708155

Povsic, Thomas J; Junge, Candice; Nada, Adel; Schatz, Richard A; Harrington, Robert A; Davidson, Charles J; Fortuin, F David; Kereiakes, Dean J; Mendelsohn, Farrell O; Sherman, Warren; Schaer, Gary L; White, Christopher J; Stewart, Duncan; Story, Kenneth; Losordo, Douglas W; Henry, Timothy D

2013-04-19

357

Methodology to investigate androgen-sensitive and castration-resistant human prostate cancer xenografts in preclinical setting.  

PubMed

Understanding the biology of prostate cancer and the roles of androgen receptor in prostate cancer progression is essential to the development of novel therapeutic strategies to effectively attack and eradicate this disease. Preclinical, in vivo, studies are critical to further evaluate potential clinical relevance of in vitro findings. Ideally, in vivo studies should employ models that mimic characteristics of prostate cancer from early diagnosis through the period of castration-resistant metastases. In this chapter we describe methodologies used to grow human prostate cancer xenografts in mice. In this setting, roles of androgen receptor signaling in prostate cancer progression and efficacy of novel treatment modalities, including those affecting androgen receptor signaling, can be investigated. PMID:21796533

Nguyen, Holly M; Corey, Eva

2011-01-01

358

Update of the Stroke Therapy Academic Industry Roundtable Preclinical Recommendations  

PubMed Central

The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies. Although recognized as reasonable, they have not been closely followed nor rigorously validated. Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation. The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate. The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest. After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia. Another consideration is the use of clinically relevant biomarkers in animal studies. Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success.

Fisher, Marc; Feuerstein, Giora; Howells, David W.; Hurn, Patricia D.; Kent, Thomas A.; Savitz, Sean I.; Lo, Eng H.

2010-01-01

359

Preclinical Models for Neuroblastoma: Establishing a Baseline for Treatment  

PubMed Central

Background Preclinical models of pediatric cancers are essential for testing new chemotherapeutic combinations for clinical trials. The most widely used genetic model for preclinical testing of neuroblastoma is the TH-MYCN mouse. This neuroblastoma-prone mouse recapitulates many of the features of human neuroblastoma. Limitations of this model include the low frequency of bone marrow metastasis, the lack of information on whether the gene expression patterns in this system parallels human neuroblastomas, the relatively slow rate of tumor formation and variability in tumor penetrance on different genetic backgrounds. As an alternative, preclinical studies are frequently performed using human cell lines xenografted into immunocompromised mice, either as flank implant or orthtotopically. Drawbacks of this system include the use of cell lines that have been in culture for years, the inappropriate microenvironment of the flank or difficult, time consuming surgery for orthotopic transplants and the absence of an intact immune system. Principal Findings Here we characterize and optimize both systems to increase their utility for preclinical studies. We show that TH-MYCN mice develop tumors in the paraspinal ganglia, but not in the adrenal, with cellular and gene expression patterns similar to human NB. In addition, we present a new ultrasound guided, minimally invasive orthotopic xenograft method. This injection technique is rapid, provides accurate targeting of the injected cells and leads to efficient engraftment. We also demonstrate that tumors can be detected, monitored and quantified prior to visualization using ultrasound, MRI and bioluminescence. Finally we develop and test a “standard of care” chemotherapy regimen. This protocol, which is based on current treatments for neuroblastoma, provides a baseline for comparison of new therapeutic agents. Significance The studies suggest that use of both the TH-NMYC model of neuroblastoma and the orthotopic xenograft model provide the optimal combination for testing new chemotherapies for this devastating childhood cancer.

Federico, Sara; Bradley, Cori L.; Brennan, Rachel; Zhang, Jiakun; Johnson, Melissa D.; Sedlacik, Jan; Inoue, Madoka; Zhang, Ziwei M.; Frase, Sharon; Rehg, Jerold E.; Hillenbrand, Claudia M.; Finkelstein, David; Calabrese, Christopher; Dyer, Michael A.; Lahti, Jill M.

2011-01-01

360

Executive functions in clinical and preclinical Alzheimer's disease.  

PubMed

Executive functions is an umbrella term describing a wide range of higher order processes that allow the flexible modification of thought and behaviour in response to changing cognitive or environmental contexts. Impairment of executive functions is common in neurodegenerative disorders such as Alzheimer's disease. These deficits negatively affect everyday activities and hamper the ability to cope with other cognitive or behavioural disorders. In this paper, we propose a synthesis of the knowledge on executive impairments in clinical and preclinical Alzheimer's disease, mostly leaning on the current studies made in this domain. We made some propositions for neuropsychological assessment of executive functions in preclinical and clinical phases of Alzheimer's disease. We hope that this overview will provide a useful insight into an area that is still insufficiently explored in the field of the neuropsychology of Alzheimer's disease. PMID:24011643

Allain, P; Etcharry-Bouyx, F; Verny, C

2013-09-05

361

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement  

PubMed Central

Objectives: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). Materials and Methods: In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. Results: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. Conclusion: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.

Ali, Rashid; Ali, Raisuddin; Jaimini, Abhinav; Nishad, Dhruv Kumar; Mittal, Gaurav; Chaurasia, Om Prakash; Kumar, Raj; Bhatnagar, Aseem; Singh, Shashi Bala

2012-01-01

362

Preclinical trials in Duchenne dystrophy: what animal models can tell us about potential drug effectiveness  

Microsoft Academic Search

The symptomatic pharmacological therapy of Duchenne dystrophy is poor, glucocorticoids being the sole compounds showing a certain efficacy, although their use is restricted by serious side effects. Pre-clinical trials of prompt-to-use drugs need reliable animal models of the human disease to predict drug effectiveness in patients. The exercised mdx mouse develops a typical pattern of muscle weakness in vivo, which

Annamaria De Luca; Sabata Pierno; Antonella Liantonio; Diana Conte Camerino

2002-01-01

363

Immunobiology of human mucin 1 in a preclinical ovarian tumor model.  

PubMed

Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1(+/-) as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-ras(G12D/+)) and the floxed Pten gene (Pten/(loxP/loxP)). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1-MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies. PMID:22964632

Budiu, R A; Elishaev, E; Brozick, J; Lee, M; Edwards, R P; Kalinski, P; Vlad, A M

2012-09-10

364

Role Models, Approaches to Studying, and Self-Efficacy in Forensic and Mainstream High School Students: A Pilot Study  

ERIC Educational Resources Information Center

|This study investigated the relationships between role models, approaches to studying, and self-efficacy in students attending a high school specialising in educating those with emotional and behavioural difficulties (EBD, n = 30) and students attending a mainstream high school (n = 41) in the UK. Types and quantity of role models held by…

Skidmore, Michael; Dede, Yemi U.; Moneta, Giovanni B.

2009-01-01

365

A review of the preclinical and clinical data of newer intranasal steroids used in the treatment of allergic rhinitis  

Microsoft Academic Search

The anti-inflammatory activity of corticosteroids has prompted the exploration of their use in the treatment of allergic rhinitis. The development of intranasal steroids has resulted in several agents with quick actions, localized effects, and great efficacy in the treatment of seasonal allergic rhinitis and the prophylactic management of perennial rhinitis. This article presents a concise review of the preclinical and

William R. Lumry

1999-01-01

366

Preclinical Evaluation of Pharmacotherapies for Treatment of Cocaine and Opioid Abuse Using Drug Self-Administration Procedures  

Microsoft Academic Search

Drug abuse is a major public health problem, and the relationship between intravenous drug abuse and AIDS underscores the need for more effective treatment medications. Animal models of drug self-administration are useful to systematically evaluate new treatment medications and predict clinical efficacy. This review summarizes the status of preclinical evaluations of medications for treatment of cocaine and opiate abuse. The

Nancy K Mello; S Stevens Negus

1996-01-01

367

Metacognitive Training for Schizophrenia Patients (MCT): A Pilot Study on Feasibility, Treatment Adherence, and Subjective Efficacy  

Microsoft Academic Search

Objectives: A plethora of studies has confirmed that several cognitive biases (e.g., attributional style, jumping to conclu- sions, bias against disconfirmatory evidence, theory of mind, over-confidence in errors, need for closure, and low self- esteem) may play a pathogenetic role in the emergence and\\/or maintenance of the disorder, particularly delusions. The present study explored the safety, acceptance and subjective efficacy

Steffen Moritz; Todd S. Woodward

368

The efficacy of erythropoietin on acute spinal cord injury. An experimental study on a rat model  

Microsoft Academic Search

Introduction  The accumulated knowledge of erythropoietin (EPO) interaction in neural injury has led to potentially novel therapeutic strategies.\\u000a Previous experimental studies of recombinant human EPO (rhEPO) administration have shown favorable results after central and\\u000a peripheral neural injury. In the present study we used the aneurysmal clip model to evaluate the efficacy of two different\\u000a regimes of rhEPO administration on the functional

Vasileios A. Kontogeorgakos; Spyridon Voulgaris; Anastasios V. Korompilias; Marios Vekris; Konstantinos S. Polyzoidis; Konstantinos Bourantas; Alexandros E. Beris

2009-01-01

369

Self-Efficacy and Equine Assisted Therapy: A Single Subject Study  

Microsoft Academic Search

Equine Assisted Therapy (EAT) is growing in popularity as an alternative to traditional talk therapy in treating a range of presenting concerns; however, there is little empirical research to support its use. In this study, the author added to the body of empirical literature on EAT’s impact on self-efficacy. This study was a single subject A-B-A-B design wherein the subject

Jessica H. Geddes

2010-01-01

370

Self-efficacy, Training Effectiveness, and Deception Detection: A Longitudinal Study of Lie Detection Training  

Microsoft Academic Search

\\u000a Studies examining the ability to detection deception have consistently found that humans tend to be poor detectors. In this\\u000a study, we examine the roles of self-efficacy and training over time. We conducted a field experiment at a military training\\u000a center involving 119 service members. The subjects were given two sessions of deception detection training. Their performance\\u000a history, perceived effectiveness of

Kent Marett; David P. Biros; Monti L. Knode

2004-01-01

371

A preclinical rodent model of radiation induced lung injury for medical countermeasure screening in accordance with the FDA animal rule  

PubMed Central

The purpose of pre-clinical murine model development is to establish that the pathophysiological outcome of our rodent model of radiation-induced lung injury is sufficiently representative of the anticipated pulmonary response in the human population. This objective is based on concerns that the C57BL/6J strain may not be the most appropriate preclinical model of lethal radiation lung injury in humans. In this study, we assessed this issue by evaluating the relationship between morbidity (pulmonary function, histopathologic damage) and mortality among three strains of mice, C57BL/6J, CBA/J, and C57L/J. These different strains display variations in latency and phenotypic expression of radiation-induced lung damage. By comparing the response of each strain to the human pulmonary response, we established an appropriate animal model(s) of human radiation-induced pulmonary injury. Observations in the C57L/J and CBA/J murine models can be extrapolated to the human lung for evaluation of mechanisms of action of radiation as well as future efficacy testing and approving agents that fall under the “Animal Rule” of the US Food and Drug Administration (FDA) (21 CFR Parts 314 and 601).

Jackson, Isabel L.; Xu, Puting; Hadley, Caroline; Katz, Barry P.; McGurk, Ross; Down, Julian D.; Vujaskovic, Zeljko

2012-01-01

372

Factors associated with self-efficacy for managing recovery in the trauma intensive care population: A prospective cohort study.  

PubMed

OBJECTIVE: The aim of this paper was to identify factors associated with self-efficacy for managing recovery in the trauma intensive care population. INTRODUCTION: Injury accounts for 6.5% of disease burden in Australia, with similar levels being reported in other developed countries. While some studies regarding self-efficacy have identified a relationship to patient recovery post acute injury, others have been inconclusive. This study will identify factors associated with self-efficacy for managing recovery in the trauma intensive care population. METHODS: A prospective cohort study of patients aged ?18 years, admitted to a metropolitan tertiary hospital in South East Queensland between June 2008 and August 2010 for the acute treatment of injury. Demographic, injury, acute care and psychosocial factors were considered. The primary outcome was self-efficacy measured by the 6-item self-efficacy scale (SES) 1 and 6 months post hospital discharge. All factors significant (p<0.10) on univariate analysis were included in multivariable modelling where p<0.05 was considered significant. RESULTS: A total of 88 patients were included. The mean self-efficacy score at 1 and 6 months was similar (6.8 vs 6.9 respectively). Self-efficacy at 1 month, psychological distress (K-10) Score and illness perception (K10) Score accounted for 68.4% (adjusted R(2)) of the variance in 6 month self-efficacy (F3,75)=57.17, p<0.001. Illness perception was the strongest contributor to 6 month self-efficacy (beta=-0.516), followed by psychological distress (beta=-0.243) and self-efficacy at 1 month (beta=0.205). CONCLUSION: Significant factors associated with self-efficacy for managing recovery at 6 months included 1 month self-efficacy, illness perception and psychological distress. To promote patient recovery, screening patients at 1 month in order to commence relevant interventions could be beneficial. PMID:23747123

Connolly, Fiona R; Aitken, Leanne M; Tower, Marion; Macfarlane, Bonnie

2013-06-01

373

A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs.  

PubMed

The failure rate of randomized phase III oncology clinical trials is extremely high, even when preceded by encouraging preclinical studies and phase II trial results of the same therapy. Thus, there is considerable effort being made to improve the predictive clinical potential of preclinical models, in addition to improving phase II trial design. With respect to the former, preclinical models have historically relied heavily on treatment of primary spontaneous or transplanted tumors rather than the more common and therapeutically challenging clinical trial circumstance of advanced metastatic disease. Here, we show that the oral antiangiogenic tyrosine kinase inhibitor (TKI), sunitinib, which failed to meet primary or secondary survival endpoints in 4 separate phase III metastatic breast cancer (MBC) trials, either alone or with chemotherapy, similarly failed to show monotherapy or combination chemotherapy efficacy in a model of postsurgical advanced MBC using a metastatic variant of the MDA-MB-231 triple-negative human breast cancer. In contrast, the drug was effective when used to treat established orthotopic primary tumors. Similar results were obtained with pazopanib monotherapy, another antiangiogenic oral TKI. However, when an antibody targeting the VEGF pathway (DC101) was tested, it showed a trend in modestly improving the efficacy of paclitaxel therapy, thus resembling to a degree prior phase III clinical results of bevacizumab plus paclitaxel in MBC. Our results suggest the potential value of treating postsurgical advanced metastatic disease as a possible strategy to improve preclinical models for predicting outcomes in patients with metastatic disease. PMID:23610448

Guerin, Eric; Man, Shan; Xu, Ping; Kerbel, Robert S

2013-04-22

374

A solution for archiving and retrieving preclinical molecular imaging data in PACS using a DICOM gateway  

NASA Astrophysics Data System (ADS)

Advances in biology, computer technology and imaging technology have given rise to a scientific specialty referred to as molecular imaging, which is the in vivo imaging of cellular and molecular pathways using contrast-enhancing targeting agents. Increasing amounts of molecular imaging research are being performed at pre-clinical stages, generating diverse datasets that are unstructured and thereby lacking in archiving and distribution solutions. Since PACS in radiology is a mature clinical archiving solution, a method is proposed to convert current imaging files from preclinical molecular imaging studies into DICOM formats for archival and retrieval from PACS systems. A web-based DICOM gateway is presented with an emphasis on metadata mapping in the DICOM header, system connectivity, and overall user workflow. This effort to conform preclinical imaging data to the DICOM standard is necessary to utilize current PACS solutions for preclinical imaging data content archiving and distribution.

Lee, Jasper; Liu, Bihui; Liu, Brent

2011-03-01

375

Characterization of a preclinical model of chronic ischemic wound  

PubMed Central

Chronic ischemic wounds presenting at wound clinics are heterogeneous with respect to etiology, age of the wound, and other factors complicating wound healing. In addition, there are ethical challenges associated with collecting repeated biopsies from a patient to develop an understanding of the temporal dynamics of the mechanisms underlying chronic wounds. The need for a preclinical model of ischemic wound is therefore compelling. The porcine model is widely accepted as an excellent preclinical model for human wounds. A full-thickness bipedicle flap approach was adopted to cause skin ischemia. Closure of excisional wounds placed on ischemic tissue was severely impaired resulting in chronic wounds. Histologically, ischemic wounds suffered from impaired re-epithelialization, delayed macrophage recruitment and poorer endothelial cell abundance and organization. Compared with the pair-matched nonischemic wound, unique aspects of the ischemic wound biology were examined on days 3, 7, 14, and 28 by systematic screening of the wound tissue transcriptome using high-density porcine GeneChips. Ischemia markedly potentiated the expression of arginase-1, a cytosolic enzyme that metabolizes the precursor of nitric oxide l-arginine. Ischemia also induced the SOD2 in the wound tissue perhaps as survival response of the challenged tissue. Human chronic wounds also demonstrated elevated expression of SOD2 and arginase-1. This study provides a thorough database that may serve as a valuable reference tool to develop novel hypotheses aiming to elucidate the biology of ischemic chronic wounds in a preclinical setting.

Roy, Sashwati; Biswas, Sabyasachi; Khanna, Savita; Gordillo, Gayle; Bergdall, Valerie; Green, Jeanne; Marsh, Clay B.; Gould, Lisa J.; Sen, Chandan K.

2009-01-01

376

Imaging technologies for preclinical models of bone and joint disorders  

PubMed Central

Preclinical models for musculoskeletal disorders are critical for understanding the pathogenesis of bone and joint disorders in humans and the development of effective therapies. The assessment of these models primarily relies on morphological analysis which remains time consuming and costly, requiring large numbers of animals to be tested through different stages of the disease. The implementation of preclinical imaging represents a keystone in the refinement of animal models allowing longitudinal studies and enabling a powerful, non-invasive and clinically translatable way for monitoring disease progression in real time. Our aim is to highlight examples that demonstrate the advantages and limitations of different imaging modalities including magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging. All of which are in current use in preclinical skeletal research. MRI can provide high resolution of soft tissue structures, but imaging requires comparatively long acquisition times; hence, animals require long-term anaesthesia. CT is extensively used in bone and joint disorders providing excellent spatial resolution and good contrast for bone imaging. Despite its excellent structural assessment of mineralized structures, CT does not provide in vivo functional information of ongoing biological processes. Nuclear medicine is a very promising tool for investigating functional and molecular processes in vivo with new tracers becoming available as biomarkers. The combined use of imaging modalities also holds significant potential for the assessment of disease pathogenesis in animal models of musculoskeletal disorders, minimising the use of conventional invasive methods and animal redundancy.

2011-01-01

377

Efficacy and safety of butterbur herbal extract Ze 339 in seasonal allergic rhinitis: Postmarketing surveillance study  

Microsoft Academic Search

The efficacy and safety of the butterbur leaf extract Ze 339 (carbon dioxide extract from the leaves ofPetasites hybridus L., 8 mg petasines per tablet) were tested in patients with seasonal allergic rhinitis. In an open postmarketing surveillance\\u000a study, 580 patients were treated with an average of 2 tablets of Ze 339 daily for 2 weeks. Symptoms of rhinorrhea, sneezing,

Robert Käufeler; Wolfgang Polasek; Axel Brattström; Uwe Koetter

2006-01-01

378

A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses  

Microsoft Academic Search

Abstract—Background: Teriflunomide, a dihydro-orotate dehydrogenase inhibitor, has immunomodulatory effects, in- cluding the ability to suppress experimental allergic encephalomyelitis. In this randomized, double-blind, placebo- controlled Phase II study, the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis (MS) with,relapses. Methods: Patients (n,179) with,relapsing–remitting MS (n,157) or secondary,progressive,MS with relapses (n 22) were randomized to receive placebo, teriflunomide

P. W. O'Connor; D. Li; M. S. Freedman; G. P. A. Rice; C. Confavreux

2006-01-01

379

A Study of the Mathematics Teaching Efficacy Beliefs of Primary Teachers  

Microsoft Academic Search

The affective domain has in recent years attracted much attention from the mathematics research community; empirical data\\u000a seem to increasingly support expert opinion that affect plays a decisive role in the process of cognitive development. One\\u000a of the less researched dimensions of the affective domain is teachers’ beliefs about the efficacy of their mathematics teaching.\\u000a Though there are studies examining

George Philippou; Constantinos Christou

380

Long-term efficacy of Botulinum toxin in classical achalasia: a prospective study  

Microsoft Academic Search

OBJECTIVE:We sought to examine the long-term efficacy of intrasphincteric Botulinum toxin A injection in a prospective cohort study of 30 patients with achalasia.METHODS:Thirty patients with classical achalasia were treated with intrasphincteric Botulinum toxin A injection. Follow-up consisted of clinical assessment, symptom scoring, and postinjection manometry.RESULTS:Symptomatic improvement for >3 months was seen in 23 of 30 patients (77%). Of the 23

Jeff Kolbasnik; William E. Waterfall; Beth Fachnie; Ying Chen; Gervais Tougas

1999-01-01

381

A Nicotine Mouth Spray for Smoking Cessation: A Pilot Study of Preference, Safety and Efficacy  

Microsoft Academic Search

Background: Various formulations of nicotine replacement therapy are commercially available. Objectives: It was the aim of this study to test preference, safety and efficacy of a new nicotine mouth spray (1 mg\\/actuation; NicoNovum). Methods: One hundred healthy smokers wanting to quit (mean age 43.1 ± 11.2 years) were included. They were given the mouth spray, as well as 2-mg nicotine

C. T. Bolliger; X. van Biljon; A. Axelsson

2007-01-01

382

An adjudicated hermeneutic single-case efficacy design study of experiential therapy for panic\\/phobia  

Microsoft Academic Search

This article illustrates the application of an adjudicated form of hermeneutic single-case efficacy design, a critical-reflective method for inferring change and therapeutic influence in single therapy cases. The client was a 61-year-old European-American male diagnosed with panic and bridge phobia. He was seen for 23 sessions of individual process-experiential\\/emotion-focused therapy. In this study, affirmative and skeptic teams of researchers developed

Robert Elliott; Rhea Partyka; Rebecca Alperin; Robert Dobrenski; John Wagner; Stanley B. Messer; Jeanne C. Watson; Louis G. Castonguay

2009-01-01

383

Contraceptive efficacy of bioabsorbable pellets of norethindrone (NET) as subcutaneous implants: Phase II clinical study  

Microsoft Academic Search

The contraceptive efficacy of norethindrone (NET) fused pellets was evaluated over 12 months in a Phase II clinical study with three and four pellets, each pellet containing 35 mg of NET. Volunteers were healthy, fertile, sexually active women. The release rate of NET from three and four pellets, respectively, was 150.3±7.2µg and 212.5±8.6µg NET\\/day. Following the implantation of NET pellets,

M. Singh; B. B. Saxena; R. Landesman; W. J. Ledger

1985-01-01

384

Pharmacokinetic Characteristics, Efficacy, and Safety of Buccal Testosterone in Hypogonadal Males: A Pilot Study  

Microsoft Academic Search

Transbuccal administration of drugs provides an easy route of administration. To test the safety and efficacy of a novel testosterone (T) product, we performed a randomized, double blind, placebo-con- trolled study in a parallel design. Men with serum T levels below 250 ng\\/dL were administered either an active buccal tablet containing 10 mg T( n5 7) or a buccal placebo

ADRIAN S. DOBS; DONALD R. HOOVER; MIN-CHI CHEN; RICHARD ALLEN

385

Preclinical and clinical antiallergic effect of olopatadine 0.2% solution 24 hours after topical ocular administration.  

PubMed

Pharmacologic studies examined the potential of a solution containing olopatadine to maintain and extend antiallergic efficacy after single topical ocular drop administration over 24 hours. Results of these preclinical experiments conducted in guinea pigs indicated that olopatadine 0.2% (wt/vol) solution was significantly effective 24 hours after dosing. This concentration of olopatadine provided significantly more efficacy than Patanol (olopatadine 0.1%) 24 hours after administration while being as effective as Patanol (olopatadine 0.1%) 5 minutes after administration. Results from a human conjunctival allergen challenge trial in sensitive subjects confirmed clinical efficacy of olopatadine 0.2% solution over 24 hours. When individuals were challenged with antigen at onset, 16 and 24 hours after drug administration onto the eye, significant reductions were observed in the scores for active drug as compared with placebo for pruritus (77, 77, and 61%), conjunctival redness (35, 28, and 20%), and chemosis (53, 41, and 31%), respectively. These data suggest that topically applied olopatadine 0.2% solution will be an effective once-a-day therapy for allergic conjunctivitis. PMID:15055565

Vogelson, Cullen T; Abelson, Mark B; Pasquine, Terri; Stephens, Donna M; Gamache, Daniel A; Gross, Robert D; Robertson, Stella M; Yanni, John M

386

Insights from pre-clinical studies for new combination treatment regimens with the Bcr-Abl kinase inhibitor imatinib mesylate (Gleevec\\/Glivec) in chronic myelogenous leukemia: a translational perspective  

Microsoft Academic Search

Clinical phase I\\/II studies with the Abl kinase inhibitor imatinib mesylate (Gleevec\\/Glivec, formerly STI571) for the treatment for chronic myelogenous leukemia (CML) demonstrated the safety and the remarkable efficacy of this molecularly targeted agent. However, a significant proportion of patients treated in the chronic phase of the disease after having failed interferon alpha (IFN) remain predominantly Philadelphia chromosome positive (Ph+),

P La Rosée; M E O’Dwyer; BJ Druker

2002-01-01

387

A Comparison of the ?2/3/5 Selective Positive Allosteric Modulators L-838,417 and TPA023 in Preclinical Models of Inflammatory and Neuropathic Pain  

PubMed Central

GABAA receptors containing ?2/3 subunits are current targets in the battle to develop new pain medications, as they are expressed in the spinal cord where increasing inhibitory drive should result in analgesia. However, this approach is prone to a range of side effects including sedation, cognitive impairment, and abuse as a consequence of the widespread influence of GABA. The ability to make subtype selective low-efficacy benzodiazepine compounds, which potentiate the action of GABA at specific ? subunits, has the potential to reduce this side effect profile. In this study, we have investigated the effects of the medium-efficacy positive allosteric modulator (PAM) L-838,417 and the low-efficacy PAM TPA023 in a number of preclinical inflammatory and neuropathic pain models. We conclude that either the higher level of efficacy at ?2/3 or efficacy at ?5 is required for compounds to have a significant analgesic effect in a range of models, and, therefore, although the side-effect profile of compounds can be reduced compared to typical benzodiazepines, it is unlikely that it can be completely eliminated.

Nickolls, Sarah; Mace, Hannah; Fish, Rebecca; Edye, Michelle; Gurrell, Rachel; Ivarsson, Magnus; Pitcher, Tom; Tanimoto-Mori, Sachi; Richardson, Denise; Sweatman, Catherine; Nicholson, Janet; Ward, Cameron; Jinks, John; Bell, Christine; Young, Kimberly; Rees, Huw; Moss, Andrew; Kinloch, Ross; McMurray, Gordon

2011-01-01

388

Post-marketing surveillance study of the safety and efficacy of sildenafil prescribed in primary care to erectile dysfunction patients  

Microsoft Academic Search

In order to investigate the safety and efficacy of sildenafil prescribed in primary care, a post-marketing surveillance study was undertaken. A total of 651 men with erectile dysfunction (ED) were enrolled from 31 family physicians in Korea from December 1999 to July 2002. Patients were regularly followed up to ascertain the safety and efficacy of sildenafil. Of the 651 patients

S Sunwoo; Y S Kim; B L Cho; K S Cheon; H G Seo; M K Rho; Y S Cheong; M H Hong; S W Kim; D H Kim

2005-01-01

389

Exploring the Influence of Teacher Collaboration on Teacher Self-Efficacy: A Single Case Study of a Charter High School  

ERIC Educational Resources Information Center

|Teachers who work in isolation may experience low self-efficacy. Research shows an association between high self-efficacy and positive outcomes for teachers, such as teacher longevity and higher instructional effectiveness. While some studies have suggested that a collaborative teaching environment can decrease teacher attrition and increase…

McGuire, Brian David

2011-01-01

390

Adult Attachment, Social Self-Efficacy, Self-Disclosure, Loneliness, and Subsequent Depression for Freshman College Students: A Longitudinal Study  

ERIC Educational Resources Information Center

This longitudinal study examined whether social self-efficacy and self-disclosure serve as mediators between attachment and feelings of loneliness and subsequent depression. Participants were 308 freshmen at a large Midwestern university. Results indicated that social self-efficacy mediated the association between attachment anxiety and feelings…

Wei, Meifen; Russel, Daniel W.; Zakalik, Robyn A.

2005-01-01

391

Efficacy of Thematic Units on Language and Literacy: A Collaborative Study of a Shelter Unit Intervention with Struggling First Graders  

ERIC Educational Resources Information Center

|The purpose of this study was to examine the efficacy of using thematic units in small group instructional settings for struggling readers to increase oral language in the areas of receptive, expressive, and written vocabulary. This research examined the efficacy of using thematic units in small group instructional settings for struggling readers…

Hale, Suzan L.

2010-01-01

392

Explaining Perceptions of Principal Leadership Behaviors that Enhance Middle School Teacher Self-Efficacy: A Mixed Methods Study  

ERIC Educational Resources Information Center

Teachers are primarily responsible for the educational achievement of all students. Past research has shown that Teacher Self-Efficacy plays a large role in academic success of students. This study investigates various levels of teacher efficacy and the individual perceptions of teacher in regards to principal leadership behaviors, specifically,…

Charf, Michelle R.

2009-01-01

393

Efficacy of Atomoxetine in Children with Severe Autistic Disorders and Symptoms of ADHD: An Open-Label Study  

ERIC Educational Resources Information Center

|Objective: This study aims to examine the efficacy of atomoxetine in treating symptoms of attention deficit hyperactivity disorder (ADHD) in children with severe autistic disorder. Method: Children with severe autistic disorder who had symptoms of ADHD were given atomoxetine for 10 weeks. The efficacy of atomoxetine was evaluated by using the…

Charnsil, Chawanun

2011-01-01

394

A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma  

PubMed Central

Summary Purpose Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody–drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Ley) antigen, conjugated to doxorubicin. Ley is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Ley-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients. Experimental design Sixty-two patients with recurrent or metastatic NSCLC expressing Ley, one or two prior chemotherapy regimens, and PS ? 2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life. Results Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A. Conclusions SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.

Ross, Helen J.; Hart, Lowell L.; Swanson, Paul M.; Rarick, Mark U.; Figlin, Robert A.; Jacobs, Andrew D.; McCune, David E.; Rosenberg, Arthur H.; Baron, Ari D.; Grove, Laurie E.; Thorn, Michael D.; Miller, Dennis M.; Drachman, Jonathan G.; Rudin, Charles M.

2013-01-01

395

Environmental context effects on alcohol-related outcome expectancies, efficacy, and norms: A field study.  

PubMed

The purpose of this study was to examine the effect of environmental contexts on alcohol norms, expectancies, and efficacy ratings. University students (n = 177) recruited via opportunity sampling completed questionnaires in either university lecture theaters or in a student bar. Positive social, fun, and tension reduction outcome expectancies were higher and social drink refusal self efficacy was lower in those participants questioned in a student bar relative to those questioned in a university lecture theater. These differences were found while controlling for between-groups variations in typical alcohol consumption quantities. Although hitherto largely unexamined by research, context appears to be a potentially important moderator of alcohol-related cognitions. Such findings require further exploration to inform more effective intervention approaches and have implications for the validity of existing literature. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID:24059833

Monk, Rebecca L; Heim, Derek

2013-09-01

396

Efficacy of ayurvedic health care system: a study in a community.  

PubMed

This study is aimed at evaluating the efficacy of the Ayurvedic system, especially for chronic diseases. Assessment of the subjective relief feed back was done on the lines as suggested in Caraka Samhita, one of the oldest classical Ayurvedic texts. An inter-disciplinary research work involving ancient medical learning and hi-tech modern electronic data processing unit evaluate the efficacy of the Ayurvedic treatment in a closed community. 80 percent of the respondents were in the relief range of 75% to 100%, while overall relief in terms of regaining positive health in addition to attending complaint relief is over 70% in all diseases groups, as reported by the respondents in this Programme. PMID:22556503

Nagaraju, V; Sriram, P

1990-07-01

397

EFFICACY OF AYURVEDIC HEALTH CARE SYSTEM: A STUDY IN A COMMUNITY  

PubMed Central

This study is aimed at evaluating the efficacy of the Ayurvedic system, especially for chronic diseases. Assessment of the subjective relief feed back was done on the lines as suggested in Caraka Samhita, one of the oldest classical Ayurvedic texts. An inter-disciplinary research work involving ancient medical learning and hi-tech modern electronic data processing unit evaluate the efficacy of the Ayurvedic treatment in a closed community. 80 percent of the respondents were in the relief range of 75% to 100%, while overall relief in terms of regaining positive health in addition to attending complaint relief is over 70% in all diseases groups, as reported by the respondents in this Programme.

Nagaraju, V.; Sriram, P.

1990-01-01

398

Tolerance and Efficacy of Sodium Oxybate in Childhood Narcolepsy with Cataplexy: A Retrospective Study  

PubMed Central

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy. Citation: Lecendreux M; Poli F; Oudiette D; Benazzouz F; Donjacour CEHM; Franceschini C; Finotti E; Pizza F; Bruni O; Plazzi G. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. SLEEP 2012;35(5):709-711.

Lecendreux, Michel; Poli, Francesca; Oudiette, Delphine; Benazzouz, Fatima; Donjacour, Claire E.H.M; Franceschini, Christian; Finotti, Elena; Pizza, Fabio; Bruni, Oliviero; Plazzi, Giuseppe

2012-01-01

399

Efficacy assessment of SNP sets for genome-wide disease association studies  

PubMed Central

The power of a genome-wide disease association study depends critically upon the properties of the marker set used, particularly the number and physical spacing of markers, and the level of inter-marker association due to linkage disequilibrium. Extending our previously devised theoretical framework for the entropy-based selection of genetic markers, we have developed a local measure of the efficacy of a marker set, relative to including a maximally polymorphic single nucleotide polymorphism (SNP) at the map position of interest. Using this quantitative criterion, we evaluated five currently available SNP sets, namely Affymetrix 100K and 500K, and Illumina 100K, 300K and 550K in the CEU, YRI and JPT + CHB HapMap populations. At 50% relative efficacy, the commercial marker sets cover between 19 and 68% of the human genome, depending upon the population under study. An optimal technology-independent 500K marker set constructed from HapMap for Caucasians, in contrast, would achieve 73% coverage at the same relative efficacy.

Wollstein, Andreas; Herrmann, Alexander; Wittig, Michael; Nothnagel, Michael; Franke, Andre; Nurnberg, Peter; Schreiber, Stefan; Krawczak, Michael; Hampe, Jochen

2007-01-01

400

Pharmacokinetic-pharmacodynamic determinants of oseltamivir efficacy using data from phase 2 inoculation studies.  

PubMed

Given the limited understanding about pharmacokinetic-pharmacodynamic (PK-PD) determinants of oseltamivir efficacy, data from two phase 2 influenza virus inoculation studies were evaluated. Healthy volunteers in studies 1 and 2 were experimentally infected with influenza A/Texas (the concentration of neuraminidase inhibitor which reduced neuraminidase activity by 50% [IC(50)] = 0.18 nM) or B/Yamagata (IC(50) = 16.76 nM), respectively. In study 1, 80 subjects received 20, 100, or 200 mg of oral oseltamivir twice daily (BID), 200 mg oseltamivir once daily, or placebo for 5 days. In study 2, 60 subjects received 75 or 150 mg of oral oseltamivir BID or placebo for 5 days. Oseltamivir carboxylate (OC) (active metabolite) PK was evaluated using individual PK data and a population PK model to derive individual values for area under the concentration-time curve from 0 to 24 h (AUC(0-24)), minimum concentration of OC in plasma (C(min)), and maximum concentration of OC in plasma (C(max)). Exposure-response relationships were evaluated for continuous (area under composite symptom score curve [AUCSC], area under the viral titer curve, and peak viral titer) and time-to-event (alleviation of composite symptom scores and cessation of viral shedding) efficacy endpoints. Univariable analyses suggested the existence of intuitive and highly statistically significant relationships between OC AUC(0-24 )evaluated as a 3-group variable and AUCSC, time to alleviation of composite symptom scores, and time to cessation of viral shedding. The upper OC AUC(0-24) threshold (~14,000 ng · h/ml) was similar among these endpoints. Multivariable analyses failed to demonstrate the influence of study/strain on efficacy endpoints. These results provide the first demonstration of exposure-response relationships for efficacy for oseltamivir against influenza and suggest that OC exposures beyond those achieved with the approved oseltamivir dosing regimen will provide enhanced efficacy. The clinical applicability of these observations requires further investigation. PMID:23669386

Rayner, C R; Bulik, C C; Kamal, M A; Reynolds, D K; Toovey, S; Hammel, J P; Smith, P F; Bhavnani, S M; Van Wart, S A; Ambrose, P G; F