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1.
Int J Toxicol ; 36(4): 340-349, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28578602

RESUMO

There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed. A regulatory perspective on common reasons for a molecule to fail in its forward progress was presented. In addition, situations arise when a third-party advisory committee can provide input to help overcome issues identified by a regulatory agency. Using examples from the private and public domain, presentations centered on how to repurpose a molecule and when more science is needed.


Assuntos
Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Terapêutica/normas , Animais , Indústria Farmacêutica/normas , Humanos
2.
Clin Transl Sci ; 15(7): 1581-1591, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35478436

RESUMO

Launched in May 2012 as part of the New Therapeutic Uses program, the National Center for Advancing Translational Sciences (NCATS)' National Institutes of Health (NIH)-Industry Partnerships initiative fostered collaboration between pharmaceutical companies and the biomedical research community to advance therapeutic development. Over the 10-year life of the initiative, the industry partners included: AstraZeneca; AbbVie (formerly Abbott); Bristol-Myers Squibb; Eli Lilly and Company; GlaxoSmithKline; Janssen Pharmaceutical Research & Development, L.L.C.; Pfizer; Sanofi; and Mereo (out licensed assets). The initiative provided researchers at academic medical centers with a rare opportunity to propose clinical trials to test ideas for new therapeutic uses for a selection of clinic-ready and often previously proprietary experimental pharmaceutical assets that were provided by industry partners. Here, we describe the process by which collaborations between pharmaceutical companies with viable experimental assets and academic researchers with ideas for new uses of those assets were established; and how NCATS/NIH funding supported not only phase I and II clinical trials as well as any nonclinical studies needed before testing in a new patient population, it also provided an opportunity for testing innovative outcome measures for proof-of-concept trials. Although the program did not demonstrate improved success rates for phase II clinical trials, this collaboration model leverages the strengths of each party and with a focus toward evaluating an innovative outcome measure, could be used to reduce patient burden and trial costs, and improve patient engagement.


Assuntos
Centros Médicos Acadêmicos , Humanos , Preparações Farmacêuticas
3.
Nat Rev Drug Discov ; 14(12): 833-41, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26585533

RESUMO

A new model for translational research and drug repositioning has recently been established based on three-way partnerships between public funders, the pharmaceutical industry and academic investigators. Through two pioneering initiatives - one involving the Medical Research Council in the United Kingdom and one involving the National Center for Advancing Translational Sciences of the National Institutes of Health in the United States - new investigations of highly characterized investigational compounds have been funded and are leading to the exploration of known mechanisms in new disease areas. This model has been extended beyond these first two initiatives. Here, we discuss the progress to date and the unique requirements and challenges for this model.


Assuntos
Pesquisa Biomédica , Indústria Farmacêutica , Reposicionamento de Medicamentos , Regulamentação Governamental , Comunicação Interdisciplinar , Pesquisa Translacional Biomédica , Comportamento Cooperativo , Reposicionamento de Medicamentos/métodos , Reposicionamento de Medicamentos/tendências , Programas Governamentais/métodos , Programas Governamentais/organização & administração , Humanos , Modelos Organizacionais , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendências
4.
J Med Chem ; 47(5): 1085-97, 2004 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-14971889

RESUMO

The design and synthesis of a series of 11,12-cyclic carbamate derivatives of 6-O-methylerythromycin A that are novel, nonpeptide LHRH antagonists, is described. The macrolide antagonist 1, discovered during a screen of our chemical repository, was compared to a macrocyclic peptide antagonist 2 using molecular modeling, thus providing a model for the design of more potent antagonists. Medicinal chemistry efforts to find a replacement for cladinose at position 3 of the erythronolide core provided a series of oxazolidinone carbamates that were equally as active as the cladinose-containing parent macrolides. The descladinose LHRH antagonist 14 has 1-2 nM affinity for both rat and human LHRH receptors and is a potent inhibitor of LH release (pA2 = 8.76) in vitro. In vivo, 14 was found to produce a dose-dependent suppression of LH in male castrate rats via both i.v. and p.o. dosing.


Assuntos
Eritromicina/análogos & derivados , Eritromicina/síntese química , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hexoses/síntese química , Administração Oral , Animais , Células Cultivadas , Cricetinae , Desenho de Fármacos , Eritromicina/farmacologia , Hormônio Liberador de Gonadotropina/sangue , Hormônio Liberador de Gonadotropina/metabolismo , Hexoses/farmacologia , Humanos , Injeções Intravenosas , Masculino , Modelos Moleculares , Orquiectomia , Hipófise/citologia , Hipófise/metabolismo , Ratos , Relação Estrutura-Atividade
5.
Eur J Pharmacol ; 435(1): 73-7, 2002 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-11790380

RESUMO

Bimoclomol is a new compound that improves cell survival under experimental stress conditions partly by increasing intracellular heat shock proteins (HSPs). HSPs, especially HSP70, play a cytoprotective role in the rat heart. Rat neonatal cardiomyocytes were used to determine the ability of bimoclomol to induce HSP70 and affect cell survival across a broad concentration range (0.01-100 microM). Bimoclomol significantly elevated HSP70 levels at concentrations ranging from 0.01 to 10 microM, depending on the time of exposure. Pretreatment with bimoclomol for 24 h significantly increased survival of cells. There was a significant correlation between the increased levels of HSP70 and the increase in cell survival as a result of the treatment with bimoclomol. In conclusion, bimoclomol improved cell survival in rat neonatal cardiomyocytes, in part, by increasing the levels of HSP70. This cytoprotection began at the relatively low concentration of 0.1 microM, which is a concentration that can be achieved clinically.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Coração/efeitos dos fármacos , Imidas/farmacologia , Miocárdio/metabolismo , Substâncias Protetoras/farmacologia , Piridinas/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Coração/fisiologia , Ratos
6.
Eur J Pharmacol ; 435(1): 79-83, 2002 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-11790381

RESUMO

Bimoclomol has been shown to increase an inducible member of the heat shock protein 70 family (HSP70) and cytoprotect in vitro. Here, we addressed whether oral pretreatment of rats with bimoclomol could elevate myocardial HSP70 and reduce infarct size in a rat model of ischemia and reperfusion. Rats were pretreated with bimoclomol at 3, 6 or 18 h or with 42 degrees thermal stress 24 h before ischemia. Infarct size was significantly decreased 6 h after oral administration of bimoclomol and 24 h after thermal stress. Left ventricles from a separate group of rats were examined for HSP70 levels. Western blots showed a significant increase in HSP70 6 h after oral administration of bimoclomol and 24 h after thermal stress. There was a significant correlation (P<0.05) between HSP70 induction and infarct size reduction, whether produced by thermal stress or oral administration of bimoclomol. Thus, bimoclomol can increase HSP70 and reduce infarct size in a rat model of ischemia and reperfusion.


Assuntos
Proteínas de Choque Térmico HSP70/metabolismo , Imidas/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Miocárdio/metabolismo , Substâncias Protetoras/uso terapêutico , Piridinas/uso terapêutico , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Frequência Cardíaca/efeitos dos fármacos , Infarto do Miocárdio/fisiopatologia , Ratos
7.
J Pharmacol Toxicol Methods ; 49(1): 31-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14670692

RESUMO

INTRODUCTION: Many therapeutic agents stimulate histamine release from mast cells, which results in a decrease in blood pressure. The purpose of this study is to establish a method to determine if the mechanism of action, or one of the mechanisms, of hypotensive compounds is related to the release of histamine. The method was developed using a novel hypotensive compound, SC-372. METHODS: In Inactin anesthetized rats, after intravenous administration of SC-372 (0.3-7 mg/kg), the 2 and 7 mg/kg resulted in a dose-dependent decrease in blood pressure. Histamine (0.1 and 1 mg/kg) was injected intravenously to establish whether histamine release was the mechanism of action for the hypotension induced by SC-372. Compound 48/80 (0.1 mg/kg, promotes histamine release) and Cromolyn (1 mg/kg/min, [5 min], prevents histamine release from mast cells) were characterized and used intravenously in combination with/or compared to SC-372. RESULTS: Histamine resulted in a decrease in blood pressure that was unaffected by Cromolyn (1 mg/kg). Administration of Compound 48/80 resulted in a rapid reduction of systemic blood pressure. Intravenous infusion of Cromolyn prior to the injection of Compound 48/80 significantly attentuated the hypotensive response and the increase in histamine levels in the plasma. Intravenous administration of SC-372 resulted in a rapid reduction in blood pressure with a profile similar to that of Compound 48/80. When the rats were treated with Cromolyn prior to the administration of SC-372, both the blood pressure and plasma histamine levels were maintained at their pretreatment control levels. DISCUSSION: These data indicate that Compound 48/80 and Cromolyn can be used in rats to screen for histamine release-dependent drug-induced hypotension and suggest that the rapid decrease in blood pressure caused by SC-372 may result from histamine release from mast cells.


Assuntos
Guanidinas/efeitos adversos , Liberação de Histamina/efeitos dos fármacos , Hipotensão/induzido quimicamente , Pirazinas/efeitos adversos , Animais , Cromolina Sódica/efeitos adversos , Cromolina Sódica/farmacologia , Guanidinas/farmacologia , Hipotensão/fisiopatologia , Injeções Intravenosas , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , p-Metoxi-N-metilfenetilamina/efeitos adversos , p-Metoxi-N-metilfenetilamina/farmacologia
8.
Drug Discov Today ; 17(9-10): 419-24, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22227532

RESUMO

In an effort to uncover systematic learnings that can be applied to improve compound survival, an analysis was performed on data from Phase II decisions for 44 programs at Pfizer. It was found that not only were the majority of failures caused by lack of efficacy but also that, in a large number of cases (43%), it was not possible to conclude whether the mechanism had been tested adequately. A key finding was that an integrated understanding of the fundamental pharmacokinetic/pharmacodynamic principles of exposure at the site of action, target binding and expression of functional pharmacological activity (termed together as the 'three Pillars of survival') all determine the likelihood of candidate survival in Phase II trials and improve the chance of progression to Phase III.


Assuntos
Ensaios Clínicos Fase II como Assunto , Avaliação de Medicamentos , Preparações Farmacêuticas/metabolismo , Farmacocinética , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antagonistas dos Receptores CCR5 , Cicloexanos/farmacologia , Cicloexanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Maraviroc , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Receptores de Dopamina D3/agonistas , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Disfunções Sexuais Fisiológicas/metabolismo , Triazóis/farmacologia , Triazóis/uso terapêutico
9.
ACS Med Chem Lett ; 1(2): 59-63, 2010 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900177

RESUMO

Hematopoietic prostaglandin D synthase (HPGDS) is primarly expressed in mast cells, antigen-presenting cells, and Th-2 cells. HPGDS converts PGH2 into PGD2, a mediator thought to play a pivotal role in airway allergy and inflammatory processes. In this letter, we report the discovery of an orally potent and selective inhibitor of HPGDS that reduces the antigen-induced response in allergic sheep.

10.
J Cardiovasc Pharmacol ; 41(5): 714-9, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12717101

RESUMO

Reactive oxygen species (ROS) have been implicated as important mediators of cellular damage during ischemia/reperfusion. AEOL10113 is a low-molecular-weight superoxide dismutase mimetic that has dismutase activity against ROS. The objective of this study was to test the cardioprotective efficacy of postischemic administration of AEOL10113 in a rat model of left ventricular ischemia and reperfusion. Left ventricular infarction was produced by 25 min of left coronary artery occlusion followed by 3 h of reperfusion. Infarct size (IS) is reported as IS/area at risk (AAR). The control group had an IS/AAR of 67.5 +/- 2.6%. Postischemic administration of AEOL10113 beginning 5 min prior to reperfusion at doses of 0.03, 0.1, and 0.3 mg/kg resulted in an IS/AAR of 69.3 +/- 3.4%, 57.8 +/- 3.3% (P < 0.05), and 55.0 +/- 2.9% (P < 0.05), respectively. Preischemic administration of AEOL10113 beginning 5 min prior to occlusion at a dose of 0.3 mg/kg resulted in an IS/AAR of 44.2 +/- 5.9% (P < 0.0125). AAR as a percentage of the left ventricle and rate-pressure product were unaffected by any dose tested. The data from this study demonstrate that pre- and postischemic administration of AEOL10113 reduces IS in a rat model of myocardial ischemia and reperfusion.


Assuntos
Hemodinâmica/efeitos dos fármacos , Metaloporfirinas/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/complicações , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Masculino , Metaloporfirinas/química , Metaloporfirinas/farmacologia , Mimetismo Molecular , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/etiologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/química , Fatores de Tempo
11.
Am J Physiol Heart Circ Physiol ; 283(4): H1555-61, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12234809

RESUMO

The role of endothelin-B (ET(B)) receptors in circulatory homeostasis is ambiguous, reflecting vasodilator and constrictor effects ascribed to the receptor and diuretic and natriuretic responses that could oppose the hypertensive effects of ET excess. With the use of conscious, telemetry-instrumented cynomolgus monkeys, we characterized the hypertension produced by ET(B) blockade and the role of ET(A) receptors in mediating this response. Mean arterial pressure (MAP) and heart rate (HR) were measured 24 h/day for 24 days under control conditions and during administration of the ET(B)-selective antagonist A-192621 (0.1, 1.0, and 10 mg/kg bid, 4 days/dose) followed by coadministration of the ET(A) antagonist atrasentan (5 mg/kg bid) + A-192621 (10 mg/kg bid) for another 4 days. High-dose ET(B) blockade increased MAP from 79 +/- 3 (control) to 87 +/- 3 and 89 +/- 3 mmHg on the first and fourth day, respectively; HR was unchanged, and plasma ET-1 concentration increased from 2.1 +/- 0.3 pg/ml (control) to 7.24 +/- 0.99 and 11.03 +/- 2.37 pg/ml. Atrasentan + A-192621 (10 mg/kg) decreased MAP from hypertensive levels (89 +/- 3) to 75 +/- 2 and 71 +/- 4 mmHg on the first and fourth day, respectively; plasma ET-1 and HR increased to 26.64 +/- 3.72 and 28.65 +/- 2.89 pg/ml and 113 +/- 5 (control) to 132 +/- 5 and 133 +/- 7 beats/min. Thus systemic ET(B) blockade produces a sustained hypertension in conscious nonhuman primates, which is mediated by ET(A) receptors. These data suggest an importance clearance function for ET(B) receptors, one that influences arterial pressure homeostasis indirectly by reducing plasma ET-1 levels and minimizing ET(A) activation.


Assuntos
Antagonistas dos Receptores de Endotelina , Hipertensão/fisiopatologia , Receptores de Endotelina/fisiologia , Animais , Antineoplásicos/farmacologia , Atrasentana , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estado de Consciência , Endotelina-1/sangue , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Homeostase , Hipertensão/induzido quimicamente , Macaca fascicularis , Masculino , Pirrolidinas/farmacologia , Receptor de Endotelina A , Receptor de Endotelina B , Telemetria
12.
J Magn Reson Imaging ; 16(3): 277-83, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12205583

RESUMO

PURPOSE: To evaluate the feasibility of using dynamic contrast-enhanced magnetic resonance imaging (MRI) for assessment of muscle perfusion in a rat model of hind-limb ischemia. MATERIALS AND METHODS: The acute alteration and chronic recovery in muscle perfusion and perfusion reserve after femoral artery ligation were quantified using the maximum Gd-DTPA uptake rate obtained by a T(1)-weighted gradient-recalled echo sequence. Radionuclide-labeled microsphere blood flow measurements were performed for comparison with the MR perfusion measurement on a separate set of animals. RESULTS: After femoral artery ligation, a significant reduction in resting muscle perfusion was only observed at 1 hour post-ligation during the 28-day follow-up period. Muscle perfusion reserve was severely diminished following the ligation. Despite significant recovery over time, perfusion reserve to the ligated limb reached only 63% of the perfusion capacity in the unaffected limb by 42 days post ligation. A strong correlation (r = 0.86) between MR perfusion and microsphere blood flow measurements was observed for evaluation of relative changes in muscle perfusion. CONCLUSION: Dynamic contrast-enhanced MRI with Gd-DTPA is useful to assess time-dependent changes in muscle perfusion and perfusion reserve in this hind-limb ischemia model.


Assuntos
Gadolínio DTPA , Isquemia/patologia , Imageamento por Ressonância Magnética/métodos , Músculo Esquelético/irrigação sanguínea , Doenças Vasculares Periféricas/fisiopatologia , Animais , Meios de Contraste , Artéria Femoral/cirurgia , Membro Posterior , Processamento de Imagem Assistida por Computador , Ligadura , Microesferas , Ratos , Ratos Sprague-Dawley
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