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[PMID]:28671458
[Au] Autor:Ho SY; Alam J; Jeyaraj DA; Wang W; Lin GR; Ang SH; Tan ESW; Lee MA; Ke Z; Madan B; Virshup DM; Ding LJ; Manoharan V; Chew YS; Low CB; Pendharkar V; Sangthongpitag K; Hill J; Keller TH; Poulsen A
[Ad] Endereço:Experimental Therapeutics Centre , 31 Biopolis Way, No. 03-01 Nanos, 138669, Singapore.
[Ti] Título:Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors.
[So] Source:J Med Chem;60(15):6678-6692, 2017 Aug 10.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Porcupine is an O-acyltransferase that regulates Wnt secretion. Inhibiting porcupine may block the Wnt pathway which is often dysregulated in various cancers. Consequently porcupine inhibitors are thought to be promising oncology therapeutics. A high throughput screen against porcupine revealed several potent hits that were confirmed to be Wnt pathway inhibitors in secondary assays. We developed a pharmacophore model and used the putative bioactive conformation of a xanthine inhibitor for scaffold hopping. The resulting maleimide scaffold was optimized to subnanomolar potency while retaining good physical druglike properties. A preclinical development candidate was selected for which extensive in vitro and in vivo profiling is reported.
[Mh] Termos MeSH primário: Aciltransferases/antagonistas & inibidores
Antineoplásicos/farmacologia
Maleimidas/farmacologia
Proteínas de Membrana/antagonistas & inibidores
Piridazinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/administração & dosagem
Antineoplásicos/síntese química
Antineoplásicos/farmacocinética
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP1A2/administração & dosagem
Inibidores do Citocromo P-450 CYP1A2/síntese química
Inibidores do Citocromo P-450 CYP1A2/farmacocinética
Inibidores do Citocromo P-450 CYP1A2/farmacologia
Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Inibidores do Citocromo P-450 CYP2D6/síntese química
Inibidores do Citocromo P-450 CYP2D6/farmacocinética
Inibidores do Citocromo P-450 CYP2D6/farmacologia
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/farmacocinética
Inibidores do Citocromo P-450 CYP3A/farmacologia
Feminino
Células HEK293
Ensaios de Triagem em Larga Escala
Seres Humanos
Maleimidas/administração & dosagem
Maleimidas/síntese química
Maleimidas/farmacocinética
Camundongos Endogâmicos BALB C
Camundongos Nus
Microssomos Hepáticos/metabolismo
Piridazinas/administração & dosagem
Piridazinas/síntese química
Piridazinas/farmacocinética
Ratos
Relação Estrutura-Atividade
Via de Sinalização Wnt
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(6-cyclopropyl-5,7-dioxo-2,3,4,5,6,7-hexahydro-1H-pyrrolo(3,4-b)pyridin-1-yl)-N-(6-(pyridin-3-yl)pyridazin-3-yl)acetamide); 0 (Antineoplastic Agents); 0 (Cytochrome P-450 CYP1A2 Inhibitors); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Maleimides); 0 (Membrane Proteins); 0 (Pyridazines); EC 2.3.- (Acyltransferases); EC 2.3.1.- (PORCN protein, human); EC 2.3.1.- (Porcn protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00662


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[PMID]:28659160
[Au] Autor:Jamshidfar S; Ardakani YH; Lavasani H; Rouini M
[Ad] Endereço:Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
[Ti] Título:Inhibition of mirtazapine metabolism by Ecstasy (MDMA) in isolated perfused rat liver model.
[So] Source:Daru;25(1):16, 2017 Jun 28.
[Is] ISSN:2008-2231
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N-desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. METHODS: The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 µg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. RESULTS: Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC of the parent drug demonstrated 50% increase and AUC of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CL ) and intrinsic clearance (Cl ) showed 20% and 60% decrease in treatment group compared to control group. CONCLUSION: All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In conclusion, this study is the first investigation of MRZ metabolism in presence of MDMA in isolated perfused rat liver model.
[Mh] Termos MeSH primário: Antidepressivos/metabolismo
Fígado/metabolismo
Mianserina/análogos & derivados
N-Metil-3,4-Metilenodioxianfetamina/farmacologia
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/farmacologia
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/farmacologia
Fígado/efeitos dos fármacos
Masculino
Mianserina/antagonistas & inibidores
Mianserina/metabolismo
N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 250PJI13LM (Mianserin); A051Q2099Q (mirtazapine); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1186/s40199-017-0183-z


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[PMID]:28347660
[Au] Autor:Niwa T; Shizuku M; Yamano K
[Ad] Endereço:School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan. Electronic address: tniwa@shujitsu.ac.jp.
[Ti] Título:Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.
[So] Source:Arch Biochem Biophys;620:23-27, 2017 Apr 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K ) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/química
Citocromo P-450 CYP2D6/genética
Dopamina/química
Polimorfismo Genético
Tiramina/química
[Mh] Termos MeSH secundário: Animais
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/química
Dopamina/genética
Dopamina/metabolismo
Seres Humanos
Quinidina/química
Quinina/química
Ratos
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Tiramina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Recombinant Proteins); A7V27PHC7A (Quinine); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); ITX08688JL (Quinidine); VTD58H1Z2X (Dopamine); X8ZC7V0OX3 (Tyramine)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170428
[Lr] Data última revisão:
170428
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170329
[St] Status:MEDLINE


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[PMID]:28129313
[Au] Autor:Dong YH; Bykov K; Choudhry NK; Donneyong MM; Huybrechts KF; Levin R; Schneeweiss S; Gagne JJ
[Ad] Endereço:From the *Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA; †Faculty of Pharmacy, National Yang-Ming University, Taipei, Taiwan; ‡Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA; and §Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH.
[Ti] Título:Clinical Outcomes of Concomitant Use of Warfarin and Selective Serotonin Reuptake Inhibitors: A Multidatabase Observational Cohort Study.
[So] Source:J Clin Psychopharmacol;37(2):200-209, 2017 Apr.
[Is] ISSN:1533-712X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. METHODS: We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases. Patients were followed for up to 180 days as long as they were exposed to both warfarin and their index SSRI groups. Cox regression models were used to estimate hazard ratios and 95% confidence intervals for bleeding events, ischemic or thromboembolic events, and mortality comparing patients treated with SSRIs that are potent CYP2C9 inhibitors (fluoxetine, fluvoxamine) with those treated with other SSRIs after propensity score matching. FINDINGS: The eligible cohort comprised 52,129 patients. Hazard ratios were 1.14 (95% confidence interval [CI], 0.94-1.38) for bleeding events, 1.03 (95% CI, 0.87-1.21) for ischemic or thromboembolic events, and 0.90 (95% CI, 0.72-1.14) for mortality. Results were consistent across individual component outcomes, different warfarin stabilization periods, and subgroup analyses. CONCLUSIONS: Patients concomitantly treated with warfarin and SSRIs that are potent CYP2C9 inhibitors had comparable rates of bleeding events, ischemic or thromboembolic events, and mortality as did patients cotreated with warfarin and other SSRIs, although small but potentially meaningful effects on bleeding cannot be completely excluded. SSRI inhibition of CYP2C9 does not appear to affect major safety or effectiveness outcomes of warfarin treatment in clinical practice, where patients may be closely monitored.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2D6/efeitos adversos
Inibidores da Captação de Serotonina/efeitos adversos
Varfarina/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Idoso
Estudos de Coortes
Bases de Dados Factuais
Interações Medicamentosas
Quimioterapia Combinada
Feminino
Seres Humanos
Masculino
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE; OBSERVATIONAL STUDY
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Serotonin Uptake Inhibitors); 5Q7ZVV76EI (Warfarin)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170626
[Lr] Data última revisão:
170626
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE
[do] DOI:10.1097/JCP.0000000000000658


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[PMID]:27046219
[Au] Autor:Ma SP; Tsai CJ; Chang CC; Hsu WY
[Ad] Endereço:Department of Psychiatry, Changhua Christian Hospital, Changhua, Taiwan.
[Ti] Título:Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient.
[So] Source:Psychogeriatrics;17(2):130-132, 2017 Mar.
[Is] ISSN:1479-8301
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Delirium is common in daily practice. Drug-induced delirium constitutes approximately one-third of all cases of delirium. In cases characterized by the limited efficacy of a single antidepressant, a combination of two antidepressants is required, which may induce a complex drug-drug interaction. We reviewed a case of duloxetine- and bupropion-related delirium in an elderly male patient in our clinical practice. The patient was diagnosed with major depressive disorder and was treated with duloxetine. However, he developed delirium 10 days after bupropion was added to his treatment regimen. Three days after the cessation of bupropion, his delirious condition gradually improved. Duloxetine and bupropion are both cytochrome P450 2D6 inhibitors that may result in a higher level of hydroxybupropion. An increased level of hydroxybupropion may cause the elevation of dopamine and a risk of subsequent delirium. We should be aware of the risk of delirium induced by drug-drug interactions.
[Mh] Termos MeSH primário: Antidepressivos de Segunda Geração/uso terapêutico
Bupropiona/efeitos adversos
Inibidores do Citocromo P-450 CYP2D6/efeitos adversos
Delírio/induzido quimicamente
Transtorno Depressivo Maior/tratamento farmacológico
Cloridrato de Duloxetina/uso terapêutico
[Mh] Termos MeSH secundário: Idoso de 80 Anos ou mais
Antidepressivos de Segunda Geração/administração & dosagem
Bupropiona/administração & dosagem
Bupropiona/uso terapêutico
Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Inibidores do Citocromo P-450 CYP2D6/uso terapêutico
Transtorno Depressivo Maior/diagnóstico
Relação Dose-Resposta a Droga
Interações Medicamentosas
Cloridrato de Duloxetina/administração & dosagem
Cloridrato de Duloxetina/efeitos adversos
Seres Humanos
Masculino
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS
[Nm] Nome de substância:
0 (Antidepressive Agents, Second-Generation); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 01ZG3TPX31 (Bupropion); 9044SC542W (Duloxetine Hydrochloride)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170330
[Lr] Data última revisão:
170330
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160406
[St] Status:MEDLINE
[do] DOI:10.1111/psyg.12202


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[PMID]:27875319
[Au] Autor:Athukuri BL; Neerati P
[Ti] Título:Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition.
[So] Source:Drug Metab Pers Ther;31(4):229-234, 2016 Dec 01.
[Is] ISSN:2363-8915
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Cytochrome P450-2D6 (CYP2D6), a member of the CYP450 mixed function oxidase system, is an important CYP isoform with regard to herbal-drug interactions and is responsible for the metabolism of nearly 25% of drugs. Until now, studies on the effects of various phytochemicals on CYP2D6 activity in vivo have been very rare. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. In the present study, the effects of gallic acid and ellagic acid pretreatment on intestinal transport and oral bioavailability of metoprolol were investigated. METHODS: The intestinal transport of metoprolol was assessed by conducting an in situ single pass intestinal perfusion (SPIP) study. The bioavailability study was conducted to evaluate the pharmacokinetic parameters of orally administered metoprolol in rats. RESULTS: After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of metoprolol was observed at the ileum part of rat intestine. A significant improvement in the peak plasma concentration (Cmax) and area under the serum concentration-time profile (AUC) and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid. CONCLUSIONS: Gallic acid and ellagic acid significantly enhanced the oral bioavailability of metoprolol by inhibiting CYP2D6-mediated metabolism in the rat liver. Hence, adverse herbal-drug interactions may result with concomitant ingestion of gallic acid and ellagic acid supplements and drugs that are CYP2D6 substrates. The clinical assessment of these interactions should be further investigated in human volunteers.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Inibidores do Citocromo P-450 CYP2D6/farmacocinética
Citocromo P-450 CYP2D6/metabolismo
Ácido Elágico/farmacocinética
Ácido Gálico/farmacocinética
Fígado/metabolismo
Metoprolol/farmacocinética
[Mh] Termos MeSH secundário: Administração Oral
Animais
Disponibilidade Biológica
Relação Dose-Resposta a Droga
Ácido Elágico/administração & dosagem
Ácido Gálico/administração & dosagem
Fígado/enzimologia
Masculino
Metoprolol/administração & dosagem
Microssomos Hepáticos/enzimologia
Ratos
Ratos Wistar
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 19YRN3ZS9P (Ellagic Acid); 632XD903SP (Gallic Acid); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); GEB06NHM23 (Metoprolol)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161123
[St] Status:MEDLINE


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[PMID]:27616730
[Au] Autor:Corpas-López V; Merino-Espinosa G; López-Viota M; Gijón-Robles P; Morillas-Mancilla MJ; López-Viota J; Díaz-Sáez V; Morillas-Márquez F; Navarro Moll MC; Martín-Sánchez J
[Ti] Título:Topical Treatment of Leishmania tropica Infection Using (-)-α-Bisabolol Ointment in a Hamster Model: Effectiveness and Safety Assessment.
[So] Source:J Nat Prod;79(9):2403-7, 2016 Sep 23.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There is currently no reliable treatment for the management of cutaneous leishmaniasis, and intralesional antimonial injections remain the main treatment. The present work aims at evaluating the antileishmanial effectiveness and safety of (-)-α-bisabolol (1) in a novel topical formulation on a cutaneous leishmaniasis model involving Leishmania tropica-infected Syrian hamsters. The topical treatment with 1 reduced lesion thickness to 56% at 2.5%, showing a higher efficacy than the reference control, meglumine antimoniate. Other regimens (ointment at 1% and 5% and oral treatment at 200 mg/kg) reduced the footpad thickness as well. The skin parasite load decreased after the experiment in all treatment groups, particularly in those animals treated with the 2.5% formulation (83.2%). Treatment with (-)-α-bisabolol at different concentrations or through an oral route did not lead to the appearance of toxicity or side effects in healthy hamsters or infected animals. Therefore, topical (-)-α-bisabolol was more effective than meglumine antimoniate in this cutaneous leishmaniasis model without showing toxicity effects on the hamsters. These results are of great interest and might be used for the development of alternatives for the treatment of cutaneous leishmaniasis, either in monotherapy or in combination with other drugs whose skin permeability could be enhanced by this sesquiterpene.
[Mh] Termos MeSH primário: Antiprotozoários/uso terapêutico
Inibidores do Citocromo P-450 CYP2D6/uso terapêutico
Leishmania tropica/efeitos dos fármacos
Meglumina/uso terapêutico
Compostos Organometálicos/uso terapêutico
Sesquiterpenos/uso terapêutico
[Mh] Termos MeSH secundário: Administração Oral
Animais
Cricetinae
Inibidores do Citocromo P-450 CYP2D6/química
Modelos Animais de Doenças
Injeções Intralesionais
Leishmaniose Cutânea/tratamento farmacológico
Masculino
Estrutura Molecular
Sesquiterpenos/química
Pele
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Organometallic Compounds); 0 (Sesquiterpenes); 24WE03BX2T (bisabolol); 6HG8UB2MUY (Meglumine); 75G4TW236W (meglumine antimoniate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170627
[Lr] Data última revisão:
170627
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160913
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.6b00740


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[PMID]:27606885
[Au] Autor:Rackelmann N; Matter H; Englert H; Follmann M; Maier T; Weston J; Arndt P; Heyse W; Mertsch K; Wirth K; Bialy L
[Ad] Endereço:Sanofi-Aventis Deutschland GmbH, R&D , D-65926, Frankfurt am Main, Germany.
[Ti] Título:Discovery and Optimization of 1-Phenoxy-2-aminoindanes as Potent, Selective, and Orally Bioavailable Inhibitors of the Na /H Exchanger Type 3 (NHE3).
[So] Source:J Med Chem;59(19):8812-8829, 2016 Oct 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The design, synthesis, and structure-activity relationship of 1-phenoxy-2-aminoindanes as inhibitors of the Na /H exchanger type 3 (NHE3) are described based on a hit from high-throughput screening (HTS). The chemical optimization resulted in the discovery of potent, selective, and orally bioavailable NHE3 inhibitors with 13d as best compound, showing high in vitro permeability and lacking CYP2D6 inhibition as main optimization parameters. Aligning 1-phenoxy-2-aminoindanes onto the X-ray structure of 13d then provided 3D-QSAR models for NHE3 inhibition capturing guidelines for optimization. These models showed good correlation coefficients and allowed for activity estimation. In silico ADMET models for Caco-2 permeability and CYP2D6 inhibition were also successfully applied for this series. Moreover, docking into the CYP2D6 X-ray structure provided a reliable alignment for 3D-QSAR models. Finally 13d, renamed as SAR197, was characterized in vitro and by in vivo pharmacokinetic (PK) and pharmacological studies to unveil its potential for reduction of obstructive sleep apneas.
[Mh] Termos MeSH primário: Indanos/química
Indanos/farmacologia
Trocadores de Sódio-Hidrogênio/antagonistas & inibidores
[Mh] Termos MeSH secundário: Administração Oral
Animais
Células CACO-2
Cristalografia por Raios X
Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP2D6/administração & dosagem
Inibidores do Citocromo P-450 CYP2D6/química
Inibidores do Citocromo P-450 CYP2D6/farmacocinética
Inibidores do Citocromo P-450 CYP2D6/farmacologia
Desenho de Drogas
Descoberta de Drogas
Seres Humanos
Indanos/administração & dosagem
Indanos/farmacocinética
Modelos Moleculares
Relação Quantitativa Estrutura-Atividade
Ratos Sprague-Dawley
Trocador 3 de Sódio-Hidrogênio
Trocadores de Sódio-Hidrogênio/química
Trocadores de Sódio-Hidrogênio/metabolismo
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Indans); 0 (SLC9A3 protein, human); 0 (Slc9a3 protein, rat); 0 (Sodium-Hydrogen Exchanger 3); 0 (Sodium-Hydrogen Exchangers); 1P810SQ3EY (2-aminoindan); EC 1.14.14.1 (Cytochrome P-450 CYP2D6)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160909
[St] Status:MEDLINE


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[PMID]:27136621
[Au] Autor:Zane LT; Chanda S; Coronado D; Del Rosso J
[Ad] Endereço:Anacor Pharmaceuticals, Inc.. lzane@anacor.com.
[Ti] Título:Antifungal agents for onychomycosis: new treatment strategies to improve safety.
[So] Source:Dermatol Online J;22(3), 2016 Mar 16.
[Is] ISSN:1087-2108
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Onychomycosis is a common and difficult-to-treat fungal infection of the nail unit that gradually leads to dystrophic changes of the nail plate and nail bed. If untreated, infection progresses and may lead to discomfort, reduced quality of life, and risk of complications in patients with comorbid conditions (eg, diabetes, human immunodeficiency virus, peripheral vascular disease). Onychomycosis treatments are designed to eradicate causative pathogens (most commonly Trichophyton rubrum and Trichophyton mentagrophytes), restore healthy nails, and prevent recurrence or spread of infection. Given the deep-seated nature of most cases of onychomycosis, an effective antifungal agent needs to achieve and maintain sufficient drug concentrations throughout the nail unit for the duration of healthy nail in-growth. Oral antifungal drugs are the most effective available therapy and are generally well tolerated, but may be limited by safety concerns and the potential for drug-drug interactions (DDIs). Thus, treating physicians and pharmacists must be cognizant of a patient's current medications; indeed, it may not be feasible to treat onychomycosis in patients with diabetes, heart disease, or depression because of the risk for DDIs. Current topical therapy is not associated with risk of DDIs. Tavaborole and efinaconazole, two recently approved topical agents, have demonstrated good nail penetration and high negative culture rates in clinical trials of patients with onychomycosis. This article provides the treating physician and pharmacist with information on the safety and effectiveness of current oral (allylamine, azole) and topical (ciclopirox, efinaconazole, tavaborole) treatment to aid in making informed treatment decisions based on the unique characteristics (medication history, comorbidities, nature of onychomycosis) of each patient.
[Mh] Termos MeSH primário: Antifúngicos/efeitos adversos
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Inibidores do Citocromo P-450 CYP2D6/efeitos adversos
Inibidores do Citocromo P-450 CYP3A/efeitos adversos
Onicomicose/tratamento farmacológico
[Mh] Termos MeSH secundário: Administração Oral
Administração Tópica
Compostos de Boro/efeitos adversos
Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos
Interações Medicamentosas
Seres Humanos
Itraconazol/efeitos adversos
Naftalenos/efeitos adversos
Piridonas/efeitos adversos
Triazóis/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antifungal Agents); 0 (Boron Compounds); 0 (Bridged Bicyclo Compounds, Heterocyclic); 0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (Naphthalenes); 0 (Pyridones); 0 (Triazoles); 19W019ZDRJ (ciclopirox); 304NUG5GF4 (Itraconazole); G7RIW8S0XP (terbinafine); J82SB7FXWB (efinaconazole); K124A4EUQ3 (tavaborole)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160503
[St] Status:MEDLINE


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Texto completo
[PMID]:27006091
[Au] Autor:Borkar RM; Bhandi MM; Dubey AP; Ganga Reddy V; Komirishetty P; Nandekar PP; Sangamwar AT; Kamal A; Banerjee SK; Srinivas R
[Ad] Endereço:National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, India.
[Ti] Título:An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug-drug and drug-herb interaction by LC-ESI/MS/MS.
[So] Source:Biomed Chromatogr;30(10):1556-72, 2016 Oct.
[Is] ISSN:1099-0801
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aim of the present study was to evaluate the contribution of metabolites to drug-drug interaction and drug-herb interaction using the inhibition of CYP2D6 and CYP3A4 by metoprolol (MET) and its metabolites. The peak concentrations of unbound plasma concentration of MET, α-hydroxy metoprolol (HM), O-desmethyl metoprolol (ODM) and N-desisopropyl metoprolol (DIM) were 90.37 ± 2.69, 33.32 ± 1.92, 16.93 ± 1.70 and 7.96 ± 0.94 ng/mL, respectively. The metabolites identified, HM and ODM, had a ratio of metabolic area under the concentration-time curve (AUC) to parent AUC of ≥0.25 when either total or unbound concentration of metabolite was considered. In vitro CYP2D6 and CYP3A4 inhibition by MET, HM and ODM study revealed that MET, HM and ODM were not inhibitors of CYP3A4-catalyzed midazolam metabolism and CYP2D6-catalyzed dextromethorphan metabolism. However, DIM only met the criteria of >10% of the total drug related material and <25% of the parent using unbound concentrations. If CYP inhibition testing is solely based on metabolite exposure, DIM metabolite would probably not be considered. However, the present study has demonstrated that DIM contributes significantly to in vitro drug-drug interaction. Copyright © 2016 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2D6/farmacologia
Citocromo P-450 CYP2D6/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP3A/farmacologia
Citocromo P-450 CYP3A/efeitos dos fármacos
Metoprolol/farmacologia
Espectrometria de Massas por Ionização por Electrospray/métodos
Espectrometria de Massas em Tandem/métodos
[Mh] Termos MeSH secundário: Área Sob a Curva
Inibidores do Citocromo P-450 CYP2D6/metabolismo
Inibidores do Citocromo P-450 CYP3A/metabolismo
Interações Medicamentosas
Seres Humanos
Metoprolol/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2D6 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); EC 1.14.14.1 (Cytochrome P-450 CYP3A); GEB06NHM23 (Metoprolol)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170130
[Lr] Data última revisão:
170130
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160324
[St] Status:MEDLINE
[do] DOI:10.1002/bmc.3721



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