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[PMID]:28829844
[Au] Autor:Vu KT; Zhang F; Hulleman JD
[Ad] Endereço:Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
[Ti] Título:Conditional, Genetically Encoded, Small Molecule-Regulated Inhibition of NFκB Signaling in RPE Cells.
[So] Source:Invest Ophthalmol Vis Sci;58(10):4126-4137, 2017 Aug 01.
[Is] ISSN:1552-5783
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Purpose: Nuclear factor κB (NFκB) is a ubiquitously expressed, proinflammatory transcription factor that controls the expression of genes involved in cell survival, angiogenesis, complement activation, and inflammation. Studies have implicated NFκB-dependent cytokines or complement-related factors as being detrimentally involved in retinal diseases, thus making inhibition of NFκB signaling a potential therapeutic target. We sought to develop a conditional and reversible method that could regulate pathogenic NFκB signaling by the addition of a small molecule. Methods: We developed a genetically based, trimethoprim (TMP)-regulated approach that conditionally inhibits NFκB signaling by fusing a destabilized dihydrofolate reductase (DHFR) domain to an inhibitor of NFκB, IκBα, in ARPE-19 cells. We then challenged ARPE-19 cells with a number of stimuli that have been demonstrated to trigger NFκB signaling, including LPS, TNFα, IL-1α, and A2E. Western blotting, electrophoretic mobility shift assay, quantitative PCR, ELISA, and NFκB reporter assays were used to evaluate the effectiveness of this DHFR-IκBα approach. Results: This destabilized domain approach, coupled with doxycycline-inducibility, allowed for accurate control over the abundance of DHFR-IκBα. Stabilization of DHFR-IκBα with TMP prevented IL-1α-, A2E-, LPS-, and TNFα-induced NFκB-mediated upregulation and release of the proinflammatory cytokines IL-1ß and IL-6 from ARPE-19 cells (by as much as 93%). This strategy is dosable, completely reversible, and can be cycled "on" or "off" within the same cell population repeatedly to confer protection at desired time points. Conclusions: These studies lay the groundwork for the use of destabilized domains in retinal pigment epithelium (RPE) cells in vivo and in this context, demonstrate their utility for preventing inflammatory signaling.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C8/farmacologia
NF-kappa B/antagonistas & inibidores
Epitélio Pigmentado da Retina/metabolismo
Tetra-Hidrofolato Desidrogenase/farmacologia
Trimetoprima/farmacologia
[Mh] Termos MeSH secundário: Western Blotting
Sobrevivência Celular/efeitos dos fármacos
Células Cultivadas
Inibidores do Citocromo P-450 CYP2C8/química
Ensaio de Desvio de Mobilidade Eletroforética
Ensaio de Imunoadsorção Enzimática
Regulação da Expressão Gênica/efeitos dos fármacos
Seres Humanos
NF-kappa B/metabolismo
Domínios Proteicos/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Tetra-Hidrofolato Desidrogenase/química
Trimetoprima/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (NF-kappa B); AN164J8Y0X (Trimethoprim); EC 1.5.1.3 (Tetrahydrofolate Dehydrogenase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE
[do] DOI:10.1167/iovs.17-22133


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[PMID]:27548563
[Au] Autor:Tornio A; Neuvonen PJ; Niemi M; Backman JT
[Ad] Endereço:a Department of Clinical Pharmacology , University of Helsinki and Helsinki University Hospital , Helsinki , Finland.
[Ti] Título:Role of gemfibrozil as an inhibitor of CYP2C8 and membrane transporters.
[So] Source:Expert Opin Drug Metab Toxicol;13(1):83-95, 2017 Jan.
[Is] ISSN:1744-7607
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Cytochrome P450 (CYP) 2C8 is a drug metabolizing enzyme of major importance. The lipid-lowering drug gemfibrozil has been identified as a strong inhibitor of CYP2C8 in vivo. This effect is due to mechanism-based inhibition of CYP2C8 by gemfibrozil 1-O-ß-glucuronide. In vivo, gemfibrozil is a fairly selective CYP2C8 inhibitor, which lacks significant inhibitory effect on other CYP enzymes. Gemfibrozil can, however, have a smaller but clinically meaningful inhibitory effect on membrane transporters, such as organic anion transporting polypeptide 1B1 and organic anion transporter 3. Areas covered: This review describes the inhibitory effects of gemfibrozil on CYP enzymes and membrane transporters. The clinical drug interactions caused by gemfibrozil and the different mechanisms contributing to the interactions are reviewed in detail. Expert opinion: Gemfibrozil is a useful probe inhibitor of CYP2C8 in vivo, but its effect on membrane transporters has to be taken into account in study design and interpretation. Moreover, gemfibrozil could be used to boost the pharmacokinetics of CYP2C8 substrate drugs. Identification of gemfibrozil 1-O-ß-glucuronide as a potent mechanism-based inhibitor of CYP2C8 has led to recognition of glucuronide metabolites as perpetrators of drug-drug interactions. Recently, also acyl glucuronide metabolites of clopidogrel and deleobuvir have been shown to strongly inhibit CYP2C8.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C8/farmacologia
Genfibrozila/farmacologia
Proteínas de Membrana Transportadoras/efeitos dos fármacos
[Mh] Termos MeSH secundário: Citocromo P-450 CYP2C8/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP2C8/metabolismo
Interações Medicamentosas
Genfibrozila/análogos & derivados
Genfibrozila/metabolismo
Glucuronatos/metabolismo
Glucuronatos/farmacologia
Seres Humanos
Hipolipemiantes/metabolismo
Hipolipemiantes/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Glucuronates); 0 (Hypolipidemic Agents); 0 (Membrane Transport Proteins); 91683-38-4 (gemfibrozil 1-O-acylglucuronide); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170210
[Lr] Data última revisão:
170210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160823
[St] Status:MEDLINE


  3 / 10 MEDLINE  
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[PMID]:27417579
[Au] Autor:Gong Y; Fu Z; Edin ML; Liu CH; Wang Z; Shao Z; Fredrick TW; Saba NJ; Morss PC; Burnim SB; Meng SS; Lih FB; Lee KS; Moran EP; SanGiovanni JP; Hellström A; Hammock BD; Zeldin DC; Smith LE
[Ad] Endereço:From the Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, MA (Y.G., Z.F., C.-H.L., Z.W., Z.S., T.W.F., N.J.S., P.C.M., S.B.B., S.S.M., E.P.M., L.E.H.S.); Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Healt
[Ti] Título:Cytochrome P450 Oxidase 2C Inhibition Adds to ω-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization.
[So] Source:Arterioscler Thromb Vasc Biol;36(9):1919-27, 2016 Sep.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30% and 20%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36% and 39% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Inibidores da Angiogênese/farmacologia
Neovascularização de Coroide/prevenção & controle
Inibidores do Citocromo P-450 CYP2C8/farmacologia
Citocromo P-450 CYP2C8/metabolismo
Ácidos Graxos Ômega-3/farmacologia
Quinolinas/farmacologia
Neovascularização Retiniana/prevenção & controle
Retinopatia da Prematuridade/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Aorta/efeitos dos fármacos
Aorta/enzimologia
Células Cultivadas
Neovascularização de Coroide/enzimologia
Neovascularização de Coroide/genética
Neovascularização de Coroide/fisiopatologia
Citocromo P-450 CYP2C8/genética
Modelos Animais de Doenças
Células Endoteliais/efeitos dos fármacos
Células Endoteliais/enzimologia
Ácidos Graxos Ômega-3/metabolismo
Genótipo
Seres Humanos
Hiperóxia/complicações
Lasers
Camundongos Endogâmicos C57BL
Camundongos Transgênicos
Neovascularização Fisiológica/efeitos dos fármacos
Fenótipo
Neovascularização Retiniana/enzimologia
Neovascularização Retiniana/genética
Neovascularização Retiniana/fisiopatologia
Retinopatia da Prematuridade/enzimologia
Retinopatia da Prematuridade/genética
Retinopatia da Prematuridade/fisiopatologia
Técnicas de Cultura de Tecidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Angiogenesis Inhibitors); 0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Fatty Acids, Omega-3); 0 (Quinolines); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); MHM278SD3E (montelukast)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160716
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.307558


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[PMID]:26663350
[Au] Autor:Yang SJ; Kim BJ; Mo L; Han HK
[Ad] Endereço:BK21 Plus Project Team, College of Pharmacy, Dongguk University-Seoul, Dongguk-ro-32, Ilsan-Donggu, Goyang, 410-820, Korea.
[Ti] Título:Alteration of the intravenous and oral pharmacokinetics of valsartan via the concurrent use of gemfibrozil in rats.
[So] Source:Biopharm Drug Dispos;37(5):245-51, 2016 Jul.
[Is] ISSN:1099-081X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The present study aimed to examine the potential pharmacokinetic drug interaction between valsartan and gemfibrozil. Compared with the control given valsartan (10 mg/kg) alone, the concurrent use of gemfibrozil (10 mg/kg) significantly (p < 0.05) increased the oral exposure of valsartan in rats. In the presence of gemfibrozil, the Cmax and AUC of oral valsartan increased by 1.7- and 2.5-fold, respectively. Consequently, the oral bioavailability of valsartan was significantly higher (p < 0.05) in the presence of gemfibrozil compared with that of the control group. Furthermore, the intravenous pharmacokinetics of valsartan (1 mg/kg) was also altered by pretreatment with oral gemfibrozil (10 mg/kg). The plasma clearance of valsartan was decreased by two-fold in the presence of gemfibrozil, while the plasma half-life was not altered. In contrast, both the oral and intravenous pharmacokinetics of gemfibrozil were not affected by the concurrent use of valsartan. The cellular uptake of valsartan and gemfibrozil was also investigated by using cells overexpressing OATP1B1 or OATP1B3. Gemfibrozil and gemfibrozil 1-O-ß glucuronide inhibited the cellular uptake of valsartan with IC50 values (µm) of 39.3 and 20.4, respectively, in MDCK/OATP1B1, while they were less interactive with OATP1B3. The cellular uptake of gemfibrozil was not affected by co-incubation with valsartan in both cells. Taken together, the present study suggests the potential drug interaction between valsartan and gemfibrozil, at least in part, via the OATP1B1-mediated transport pathways during hepatic uptake. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Genfibrozila/farmacocinética
Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo
Valsartana/farmacocinética
[Mh] Termos MeSH secundário: Administração Intravenosa
Administração Oral
Bloqueadores do Receptor Tipo 1 de Angiotensina II/sangue
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacocinética
Animais
Anti-Hipertensivos/sangue
Anti-Hipertensivos/farmacocinética
Inibidores do Citocromo P-450 CYP2C8/sangue
Inibidores do Citocromo P-450 CYP2C8/farmacocinética
Cães
Interações Medicamentosas
Genfibrozila/sangue
Hipolipemiantes/sangue
Hipolipemiantes/farmacocinética
Fígado/metabolismo
Células Madin Darby de Rim Canino
Masculino
Transportadores de Ânions Orgânicos Sódio-Independentes/antagonistas & inibidores
Transportadores de Ânions Orgânicos Sódio-Independentes/genética
Ratos Sprague-Dawley
Valsartana/sangue
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin II Type 1 Receptor Blockers); 0 (Antihypertensive Agents); 0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Hypolipidemic Agents); 0 (Organic Anion Transporters, Sodium-Independent); 80M03YXJ7I (Valsartan); Q8X02027X3 (Gemfibrozil)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170127
[Lr] Data última revisão:
170127
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE
[do] DOI:10.1002/bdd.2001


  5 / 10 MEDLINE  
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[PMID]:26446447
[Au] Autor:Bergmann TK; Filppula AM; Launiainen T; Nielsen F; Backman J; Brosen K
[Ti] Título:Neurotoxicity and low paclitaxel clearance associated with concomitant clopidogrel therapy in a 60-year-old Caucasian woman with ovarian carcinoma.
[So] Source:Br J Clin Pharmacol;81(2):313-5, 2016 Feb.
[Is] ISSN:1365-2125
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIM: The aim of the present case report was to describe a novel pharmacokinetic drug­drug interaction between the antiplatelet agent clopidogrel and the antineoplastic agent paclitaxel. METHODS: The patient was identified in a previously described cohort of 93 patients with ovarian carcinoma treated with paclitaxel. The effect of clopidogrel acyl-ß-D-glucuronide on the metabolism of paclitaxel was assessed in human liver microsomes. The analysis of clopidogrel in plasma and the quantification of paclitaxel and 6-hydroxypaclitaxel in in vitro samples were performed by liquid chromatography tandem mass spectrometry. RESULTS: The patient was a 60-year-old female treated with an unknown dose of clopidogrel at the time of paclitaxel therapy. Clopidogrel was present in all three of the plasma samples obtained during paclitaxel dosing. Estimated unbound paclitaxel clearance was 238 l h−1, which was only 62% of the cohort geometric mean (385 l h−1; range 176­726). She was hospitalized three times, developed severe neuropathy and paclitaxel treatment was subsequently discontinued. In vitro, 30-min preincubation with 100 µM clopidogrel acyl-ß-D-glucuronide inhibited the depletion rate of 0.5 µM paclitaxel by 51% and the formation rate of 6-hydroxypaclitaxel by 77%. CONCLUSION: This is the first report of a clopidogrel­paclitaxel interaction, suggesting that clinically used doses of clopidogrel can reduce the cytochrome P450 2C8 (CYP2C8)-mediated systemic clearance of paclitaxel, leading to an increased risk of paclitaxel toxicity. Caution should be exercised whenever the simultaneous use of paclitaxel and clopidogrel cannot be avoided.
[Mh] Termos MeSH primário: Antineoplásicos Fitogênicos/efeitos adversos
Inibidores do Citocromo P-450 CYP2C8/sangue
Síndromes Neurotóxicas/etiologia
Neoplasias Ovarianas/tratamento farmacológico
Paclitaxel/efeitos adversos
Ticlopidina/análogos & derivados
[Mh] Termos MeSH secundário: Antineoplásicos Fitogênicos/administração & dosagem
Antineoplásicos Fitogênicos/sangue
Antineoplásicos Fitogênicos/uso terapêutico
Hidrocarboneto de Aril Hidroxilases/metabolismo
Citocromo P-450 CYP2C8/metabolismo
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem
Inibidores do Citocromo P-450 CYP2C8/uso terapêutico
Interações Medicamentosas
Feminino
Seres Humanos
Meia-Idade
Síndromes Neurotóxicas/sangue
Neoplasias Ovarianas/sangue
Paclitaxel/administração & dosagem
Paclitaxel/sangue
Paclitaxel/uso terapêutico
Ticlopidina/administração & dosagem
Ticlopidina/sangue
Ticlopidina/uso terapêutico
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents, Phytogenic); 0 (Cytochrome P-450 CYP2C8 Inhibitors); A74586SNO7 (clopidogrel); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); OM90ZUW7M1 (Ticlopidine); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151009
[St] Status:MEDLINE


  6 / 10 MEDLINE  
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[PMID]:26195223
[Au] Autor:Takagi M; Sakamoto M; Itoh T; Fujiwara R
[Ad] Endereço:School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
[Ti] Título:Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.
[So] Source:Drug Metab Pharmacokinet;30(4):288-94, 2015 Aug.
[Is] ISSN:1880-0920
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 µM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo.
[Mh] Termos MeSH primário: Hidrocarboneto de Aril Hidroxilases/metabolismo
Citocromo P-450 CYP2C8/metabolismo
Interações Medicamentosas/fisiologia
Genfibrozila/metabolismo
Glucuronídeos/metabolismo
Hipolipemiantes/metabolismo
Tiazolidinedionas/metabolismo
[Mh] Termos MeSH secundário: Área Sob a Curva
Claritromicina/metabolismo
Inibidores do Citocromo P-450 CYP2C8/metabolismo
Eritromicina/metabolismo
Glucuronosiltransferase/metabolismo
Seres Humanos
Microssomos Hepáticos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Glucuronides); 0 (Hypolipidemic Agents); 0 (Thiazolidinediones); 63937KV33D (Erythromycin); EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 2.4.1.17 (Glucuronosyltransferase); H1250JIK0A (Clarithromycin); Q8X02027X3 (Gemfibrozil); X4OV71U42S (pioglitazone)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:150808
[Lr] Data última revisão:
150808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150722
[St] Status:MEDLINE


  7 / 10 MEDLINE  
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Registro de Ensaios Clínicos
PubMed Central Texto completo
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[PMID]:25929560
[Au] Autor:Gibbons JA; de Vries M; Krauwinkel W; Ohtsu Y; Noukens J; van der Walt JS; Mol R; Mordenti J; Ouatas T
[Ad] Endereço:Medivation, Inc., 525 Market Street, 36th Floor, San Francisco, CA, 94105, USA. Jackie.Gibbons@medivation.com.
[Ti] Título:Pharmacokinetic Drug Interaction Studies with Enzalutamide.
[So] Source:Clin Pharmacokinet;54(10):1057-69, 2015 Oct.
[Is] ISSN:1179-1926
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND OBJECTIVES: Two phase I drug interaction studies were performed with oral enzalutamide, which is approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). METHODS: A parallel-treatment design (n = 41) was used to evaluate the effects of a strong cytochrome P450 (CYP) 2C8 inhibitor (oral gemfibrozil 600 mg twice daily) or strong CYP3A4 inhibitor (oral itraconazole 200 mg once daily) on the pharmacokinetics of enzalutamide and its active metabolite N-desmethyl enzalutamide after a single dose of enzalutamide (160 mg). A single-sequence crossover design (n = 14) was used to determine the effects of enzalutamide 160 mg/day on the pharmacokinetics of a single oral dose of sensitive substrates for CYP2C8 (pioglitazone 30 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), or CYP3A4 (midazolam 2 mg). RESULTS: Coadministration of gemfibrozil increased the composite area under the plasma concentration-time curve from time zero to infinity (AUC∞) of enzalutamide plus active metabolite by 2.2-fold, and coadministration of itraconazole increased the composite AUC∞ by 1.3-fold. Enzalutamide did not affect exposure to oral pioglitazone. Enzalutamide reduced the AUC∞ of oral S-warfarin, omeprazole, and midazolam by 56, 70, and 86 %, respectively; therefore, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of CYP3A4. CONCLUSIONS: If a patient requires coadministration of a strong CYP2C8 inhibitor with enzalutamide, then the enzalutamide dose should be reduced to 80 mg/day. It is recommended to avoid concomitant use of enzalutamide with narrow therapeutic index drugs metabolized by CYP2C9, CYP2C19, or CYP3A4, as enzalutamide may decrease their exposure.
[Mh] Termos MeSH primário: Feniltioidantoína/análogos & derivados
Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico
Neoplasias de Próstata Resistentes à Castração/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Idoso de 80 Anos ou mais
Estudos Cross-Over
Inibidores do Citocromo P-450 CYP2C8/administração & dosagem
Inibidores do Citocromo P-450 CYP2C8/farmacocinética
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/farmacocinética
Interações Medicamentosas
Seres Humanos
Masculino
Midazolam/farmacocinética
Meia-Idade
Feniltioidantoína/administração & dosagem
Feniltioidantoína/farmacocinética
Neoplasias de Próstata Resistentes à Castração/enzimologia
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (MDV 3100); 2010-15-3 (Phenylthiohydantoin); R60L0SM5BC (Midazolam)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150502
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1007/s40262-015-0283-1


  8 / 10 MEDLINE  
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Texto completo
[PMID]:25449654
[Au] Autor:Suttle AB; Grossmann KF; Ouellet D; Richards-Peterson LE; Aktan G; Gordon MS; LoRusso PM; Infante JR; Sharma S; Kendra K; Patel M; Pant S; Arkenau HT; Middleton MR; Blackman SC; Botbyl J; Carson SW
[Ad] Endereço:GlaxoSmithKline, Research Triangle Park, NC, USA.
[Ti] Título:Assessment of the drug interaction potential and single- and repeat-dose pharmacokinetics of the BRAF inhibitor dabrafenib.
[So] Source:J Clin Pharmacol;55(4):392-400, 2015 Apr.
[Is] ISSN:1552-4604
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The induction of CYP2C9 by dabrafenib using S-warfarin as a probe and the effects of a CYP3A inhibitor (ketoconazole) and a CYP2C8 inhibitor (gemfibrozil) on dabrafenib pharmacokinetics were evaluated in patients with BRAF V600 mutation-positive tumors. Dabrafenib single- and repeat-dose pharmacokinetics were also evaluated. S-warfarin AUC(0- ∞) decreased 37% and Cmax increased 18% with dabrafenib. Dabrafenib AUC(0- τ) and C(max) increased 71% and 33%, respectively, with ketoconazole. Hydroxy- and desmethyl-dabrafenib AUC(0-τ) increased 82% and 68%, respectively, and AUC for carboxy-dabrafenib decreased 16%. Dabrafenib AUC(0-τ) increased 47%, with no change in C(max), after gemfibrozil co-administration. Gemfibrozil did not affect systemic exposure to dabrafenib metabolites. Single- and repeat-dose dabrafenib pharmacokinetics were consistent with previous reports. All cohorts used the commercial capsules. More-frequent monitoring of international normalized ratios is recommended in patients receiving warfarin during initiation or discontinuation of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A or CYP2C8 is recommended during treatment with dabrafenib.
[Mh] Termos MeSH primário: Genfibrozila/farmacologia
Imidazóis/administração & dosagem
Imidazóis/farmacocinética
Cetoconazol/farmacologia
Oximas/administração & dosagem
Oximas/farmacocinética
Inibidores de Proteínas Quinases/administração & dosagem
Inibidores de Proteínas Quinases/farmacocinética
Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores
[Mh] Termos MeSH secundário: Anticoagulantes/farmacocinética
Inibidores do Citocromo P-450 CYP2C8/farmacologia
Inibidores do Citocromo P-450 CYP3A/farmacologia
Interações Medicamentosas
Feminino
Seres Humanos
Imidazóis/metabolismo
Imidazóis/farmacologia
Masculino
Meia-Idade
Oximas/metabolismo
Oximas/farmacologia
Inibidores de Proteínas Quinases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Varfarina/farmacocinética
[Pt] Tipo de publicação:CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Cytochrome P-450 CYP2C8 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Imidazoles); 0 (Oximes); 0 (Protein Kinase Inhibitors); 5Q7ZVV76EI (Warfarin); EC 2.7.11.1 (BRAF protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins B-raf); Q8X02027X3 (Gemfibrozil); QGP4HA4G1B (dabrafenib); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150313
[Lr] Data última revisão:
150313
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141203
[St] Status:MEDLINE
[do] DOI:10.1002/jcph.437


  9 / 10 MEDLINE  
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[PMID]:25361939
[Au] Autor:Fucci N; Pascali VL
[Ad] Endereço:Institute of Public Health, Section of Legal Medicine, Università Cattolica del Sacro Cuore, Largo F. Vito, Rome, Italy nadiafucci@rm.unicatt.it.
[Ti] Título:Acute morphine and cocaine related death after trimethoprim-adultered cocaine abuse.
[So] Source:Ann Clin Lab Sci;44(4):499-501, 2014.
[Is] ISSN:1550-8080
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Over the last few decades, cocaine and morphine (heroin) have been among the primary causes of deaths related to drug abuse. Cocaine is frequently altered by dilution, substitution, contamination, and adulteration. Trimethoprim has never been identified in the powders of cocaine, making this the first post-mortem case report in which the presence of this compound is described. The case reported here is that of a 46-year-old woman with a history of cocaine and morphine abuse who was found dead inside her bathroom. The police found the corpse next to a syringe, with a telephone card containing trace of cocaine on the sink. Toxicological analysis was performed, and drug levels were measured by means of gas chromatography/mass spectrometry. In addition to the presence of cocaine and smaller alkaloids, trimethoprim was also detected on the syringe and telephone card and in the woman's nasal mucosa. Trimethoprim analysis is very quick and easy and can be added to the routine analysis of drugs of abuse seized on the illicit market to obtain more information.
[Mh] Termos MeSH primário: Transtornos Relacionados ao Uso de Cocaína/diagnóstico
Transtornos Relacionados ao Uso de Cocaína/mortalidade
Cocaína
Inibidores do Citocromo P-450 CYP2C8
Morfina
Trimetoprima
[Mh] Termos MeSH secundário: Cocaína/sangue
Cocaína/urina
Feminino
Cromatografia Gasosa-Espectrometria de Massas
Seres Humanos
Masculino
Morfina/sangue
Morfina/urina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C8 Inhibitors); 76I7G6D29C (Morphine); AN164J8Y0X (Trimethoprim); I5Y540LHVR (Cocaine)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141102
[St] Status:MEDLINE


  10 / 10 MEDLINE  
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[PMID]:25177037
[Au] Autor:Mukai Y; Toda T; Hayakawa T; Eliasson E; Rane A; Inotsume N
[Ad] Endereço:Division of Clinical Pharmacology, Hokkaido Pharmaceutical University School of Pharmacy.
[Ti] Título:Losartan competitively inhibits CYP2C8-dependent paclitaxel metabolism in vitro.
[So] Source:Biol Pharm Bull;37(9):1550-4, 2014.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The present study aimed to characterize the inhibitory effects of losartan, an angiotensin II receptor blocker, on CYP2C8. Inhibition experiments were based on human lymphoblast-expressed recombinant CYP2C8 (rCYP2C8) and paclitaxel as a CYP2C8 substrate. The disappearance of paclitaxel (initial concentration: 7.5 µmol/L) was monitored over time at different concentrations of losartan (0, 100, 500 and 1000 µmol/L). For Dixon and Cornish-Bowden plots, various concentrations of losartan (final concentration: 0, 50, 100 and 250 µmol/L) and paclitaxel (final concentration: 3.75, 7.5 and 15 µmol/L) were used. Losartan exhibited significant inhibitory effects on paclitaxel disappearance at losartan concentrations of ≥100 µmol/L (p<0.05). Losartan at 50 µmol/L inhibited the disappearance of paclitaxel by about 60%. Both plots showed that losartan exerted competitive inhibition of rCYP2C8, and its apparent Ki value was estimated to be 40.7 µmol/L. The degree of inhibition (R value) for rCYP2C8 after oral administration of losartan (100 mg) was estimated to be 1.2, using the maximum hepatic input total blood concentration (7.3 µmol/L). The present results show that losartan acts as a competitive inhibitor of CYP2C8-dependent drug metabolism in vitro. Subjects with a low clearance of losartan, resulting in a high average systemic blood concentration of losartan after repeated oral administration, should be carefully monitored for possible adverse reactions during co-medication with CYP2C8 substrate drugs.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C8/farmacologia
Citocromo P-450 CYP2C8/metabolismo
Losartan/farmacologia
Paclitaxel/farmacologia
[Mh] Termos MeSH secundário: Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia
Anti-Hipertensivos/farmacologia
Antineoplásicos Fitogênicos/farmacologia
Células Cultivadas
Interações Medicamentosas
Seres Humanos
Microssomos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin II Type 1 Receptor Blockers); 0 (Antihypertensive Agents); 0 (Antineoplastic Agents, Phytogenic); 0 (Cytochrome P-450 CYP2C8 Inhibitors); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); JMS50MPO89 (Losartan); P88XT4IS4D (Paclitaxel)
[Em] Mês de entrada:1505
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140902
[St] Status:MEDLINE



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