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Pesquisa : D08.244.453.491.500.500 [Categoria DeCS]
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[PMID]:28973596
[Au] Autor:Emery JD
[Ad] Endereço:Department of General Practice and Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia.
[Ti] Título:Pharmacogenomic Testing and Warfarin: What Evidence Has the GIFT Trial Provided?
[So] Source:JAMA;318(12):1110-1112, 2017 09 26.
[Is] ISSN:1538-3598
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Testes Farmacogenômicos
Varfarina
[Mh] Termos MeSH secundário: Anticoagulantes
Citocromo P-450 CYP2C9
Seres Humanos
Farmacogenética
[Pt] Tipo de publicação:EDITORIAL; COMMENT
[Nm] Nome de substância:
0 (Anticoagulants); 5Q7ZVV76EI (Warfarin); EC 1.14.13.- (Cytochrome P-450 CYP2C9)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171012
[Lr] Data última revisão:
171012
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1001/jama.2017.11465


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[PMID]:28972767
[Au] Autor:Maekawa K; Adachi M; Matsuzawa Y; Zhang Q; Kuroki R; Saito Y; Shah MB
[Ad] Endereço:Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women's College of Liberal Arts , Kodo, Kyotanabe, Kyoto 610-0395, Japan.
[Ti] Título:Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9.
[So] Source:Biochemistry;56(41):5476-5480, 2017 Oct 17.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Single-nucleotide polymorphisms in drug-metabolizing cytochrome P450 (CYP) enzymes are important contributors to interindividual differences in drug metabolism leading to adverse drug reactions. Despite their extensive characterization and importance in pharmacogenetics of clinical drugs, the structural basis of CYP polymorphisms has remained scant. Here we report the crystal structures of human CYP2C9 and its polymorphic variants, *3 (I359L) and *30 (A477T), with an antihypertensive drug losartan. The structures show distinct interaction and occupation of losartan in the active site, the access channel, and the peripheral binding site. The I359L substitution located far from the active site remarkably altered the residue side chains near the active site and the access channel, whereas the T477 substitution illustrated hydrogen-bonding interaction with the reoriented side chain of Q214. The results yield structural insights into the reduced catalytic activity of the CYP2C9 variants and have important implications for understanding genetic polymorphisms in CYP-mediated drug metabolism.
[Mh] Termos MeSH primário: Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo
Anti-Hipertensivos/metabolismo
Citocromo P-450 CYP2C9/genética
Losartan/metabolismo
Modelos Moleculares
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Alelos
Sítio Alostérico
Substituição de Aminoácidos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química
Anti-Hipertensivos/química
Sítios de Ligação
Domínio Catalítico
Cristalografia por Raios X
Citocromo P-450 CYP2C9/química
Citocromo P-450 CYP2C9/metabolismo
Seres Humanos
Ligações de Hidrogênio
Ligantes
Losartan/química
Conformação Molecular
Conformação Proteica
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiotensin II Type 1 Receptor Blockers); 0 (Antihypertensive Agents); 0 (Ligands); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); JMS50MPO89 (Losartan)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00795


  3 / 2182 MEDLINE  
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[PMID]:28817838
[Au] Autor:Lévi F; Karaboué A; Saffroy R; Desterke C; Boige V; Smith D; Hebbar M; Innominato P; Taieb J; Carvalho C; Guimbaud R; Focan C; Bouchahda M; Adam R; Ducreux M; Milano G; Lemoine A
[Ad] Endereço:INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.
[Ti] Título:Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).
[So] Source:Br J Cancer;117(7):965-973, 2017 Sep 26.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1). RESULTS: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763). CONCLUSION: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
Arilamina N-Acetiltransferase/genética
Neoplasias Colorretais/genética
Neoplasias Hepáticas/tratamento farmacológico
Neoplasias Hepáticas/genética
Vitamina K Epóxido Redutases/genética
[Mh] Termos MeSH secundário: Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
Administração Intravenosa
Adulto
Idoso
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
Camptotecina/administração & dosagem
Camptotecina/análogos & derivados
Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética
Cetuximab/administração & dosagem
Neoplasias Colorretais/patologia
Citocromo P-450 CYP2C19/genética
Citocromo P-450 CYP2C9/genética
Diarreia/induzido quimicamente
Diarreia/genética
Intervalo Livre de Doença
Feminino
Fluoruracila/administração & dosagem
Glucuronosiltransferase/genética
Hepatectomia
Artéria Hepática
Seres Humanos
Infusões Intra-Arteriais
Neoplasias Hepáticas/secundário
Neoplasias Hepáticas/cirurgia
Masculino
Meia-Idade
Neutropenia/induzido quimicamente
Neutropenia/genética
Compostos Organoplatínicos/administração & dosagem
Farmacogenética
Polimorfismo de Nucleotídeo Único
Taxa de Sobrevida
Resultado do Tratamento
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ABCB1 protein, human); 0 (ATP Binding Cassette Transporter, Sub-Family B); 0 (Catecholamine Plasma Membrane Transport Proteins); 0 (Organoplatinum Compounds); 0 (Slc22a1 protein, mouse); 04ZR38536J (oxaliplatin); 7673326042 (irinotecan); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.17.4.4 (VKORC1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 2.4.1.- (UDP-glucuronosyltransferase, UGT1A6); EC 2.4.1.17 (Glucuronosyltransferase); PQX0D8J21J (Cetuximab); U3P01618RT (Fluorouracil); XT3Z54Z28A (Camptothecin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170818
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.278


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[PMID]:28689179
[Au] Autor:Vandell AG; Walker J; Brown KS; Zhang G; Lin M; Grosso MA; Mercuri MF
[Ad] Endereço:Translational Medicine Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
[Ti] Título:Genetics and clinical response to warfarin and edoxaban in patients with venous thromboembolism.
[So] Source:Heart;103(22):1800-1805, 2017 Nov.
[Is] ISSN:1468-201X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin. METHODS: Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in and genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes. An exploratory analysis was also conducted comparing normal responders to pooled sensitive responders (ie, sensitive and highly sensitive responders). RESULTS: The analysis included 47.7% (3956/8292) of the patients in Hokusai VTE. Among 1978 patients randomised to warfarin, 63.0% (1247) were normal responders, 34.1% (675) were sensitive responders and 2.8% (56) were highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders had heparin therapy discontinued earlier (p<0.001), had a decreased final weekly warfarin dose (p<0.001), spent more time overanticoagulated (p<0.001) and had an increased bleeding risk with warfarin (sensitive responders HR 1.38 [95% CI 1.11 to 1.71], p=0.0035; highly sensitive responders 1.79 [1.09 to 2.99]; p=0.0252). CONCLUSION: In this study, and genotypes identified patients with VTE at increased bleeding risk with warfarin. TRIAL REGISTRATION NUMBER: NCT00986154.
[Mh] Termos MeSH primário: Anticoagulantes/efeitos adversos
Coagulação Sanguínea/efeitos dos fármacos
Citocromo P-450 CYP2C9/genética
Inibidores do Fator Xa/efeitos adversos
Hemorragia/genética
Variantes Farmacogenômicos
Piridinas/efeitos adversos
Tiazóis/efeitos adversos
Tromboembolia Venosa/tratamento farmacológico
Vitamina K Epóxido Redutases/genética
Varfarina/efeitos adversos
[Mh] Termos MeSH secundário: Adulto
Idoso
Citocromo P-450 CYP2C9/metabolismo
Método Duplo-Cego
Monitoramento de Medicamentos
Feminino
Predisposição Genética para Doença
Hemorragia/induzido quimicamente
Hemorragia/diagnóstico
Seres Humanos
Masculino
Meia-Idade
Farmacogenética
Fenótipo
Medição de Risco
Fatores de Risco
Fatores de Tempo
Resultado do Tratamento
Tromboembolia Venosa/sangue
Tromboembolia Venosa/diagnóstico
Tromboembolia Venosa/genética
Vitamina K Epóxido Redutases/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Factor Xa Inhibitors); 0 (Pyridines); 0 (Thiazoles); 5Q7ZVV76EI (Warfarin); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.17.4.4 (VKORC1 protein, human); EC 1.17.4.4 (Vitamin K Epoxide Reductases); NDU3J18APO (edoxaban)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170710
[St] Status:MEDLINE
[do] DOI:10.1136/heartjnl-2016-310901


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[PMID]:28687336
[Au] Autor:Polonikov A; Kharchenko A; Bykanova M; Sirotina S; Ponomarenko I; Bocharova A; Vagaytseva K; Stepanov V; Bushueva O; Churnosov M; Solodilova M
[Ad] Endereço:Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx St., Kursk 305041, Russian Federation; Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya St., K
[Ti] Título:Polymorphisms of CYP2C8, CYP2C9 and CYP2C19 and risk of coronary heart disease in Russian population.
[So] Source:Gene;627:451-459, 2017 Sep 05.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study. DNA samples from all study participants were genotyped for six common SNPs rs7909236, rs1934953 of CYP2C8, rs9332242, rs4918758 and rs61886769 of CYP2C9 and rs4244285 of CYP2C19 using by the Mass-ARRAY 4 system. SNP rs4918758 of CYP2C9 was associated with decreased risk of CHD (codominant model) at a borderline significance with odds ratio adjusted for sex and age 0.61 (95% CI: 0.41-0.92, P=0.038, Q=0.20). SNP rs9332242 of CYP2C9 showed a trend towards association with increased CHD risk in cigarette smokers (P=0.049, Q=0.29). Log-likelihood ratio test (LRT) pointed out epistatic interactions between rs9332242 and rs61886769 of CYP2C9 (codominant model, P =0.02), however, this P-value did not survive after correction for multiple tests. Bioinformatic analysis revealed a regulatory potential for a majority of the investigated SNPs. Our preliminary results demonstrate that polymorphisms of genes encoding CYP2C subfamily represent potential genetic markers of CHD susceptibility. Further studies are required to substantiate the contribution of these genes to the disease risk.
[Mh] Termos MeSH primário: Doença das Coronárias/genética
Citocromo P-450 CYP2C19/genética
Citocromo P-450 CYP2C8/genética
Citocromo P-450 CYP2C9/genética
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Idoso
Estudos de Casos e Controles
Feminino
Seres Humanos
Masculino
Meia-Idade
Federação Russa
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP2C8)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170709
[St] Status:MEDLINE


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[PMID]:28682065
[Au] Autor:Swain NA; Batchelor D; Beaudoin S; Bechle BM; Bradley PA; Brown AD; Brown B; Butcher KJ; Butt RP; Chapman ML; Denton S; Ellis D; Galan SRG; Gaulier SM; Greener BS; de Groot MJ; Glossop MS; Gurrell IK; Hannam J; Johnson MS; Lin Z; Markworth CJ; Marron BE; Millan DS; Nakagawa S; Pike A; Printzenhoff D; Rawson DJ; Ransley SJ; Reister SM; Sasaki K; Storer RI; Stupple PA; West CW
[Ti] Título:Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of Na 1.7.
[So] Source:J Med Chem;60(16):7029-7042, 2017 Aug 24.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective Na 1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective Na 1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
[Mh] Termos MeSH primário: Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Éteres Fenílicos/farmacologia
Sulfonamidas/farmacologia
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Citocromo P-450 CYP2C9/metabolismo
Inibidores do Citocromo P-450 CYP2C9/síntese química
Inibidores do Citocromo P-450 CYP2C9/química
Inibidores do Citocromo P-450 CYP2C9/farmacocinética
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/síntese química
Inibidores do Citocromo P-450 CYP3A/química
Inibidores do Citocromo P-450 CYP3A/farmacocinética
Inibidores do Citocromo P-450 CYP3A/farmacologia
Desenho de Drogas
Seres Humanos
Microssomos Hepáticos/metabolismo
Canal de Sódio Disparado por Voltagem NAV1.7/química
Éteres Fenílicos/síntese química
Éteres Fenílicos/química
Éteres Fenílicos/farmacocinética
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/química
Sulfonamidas/farmacocinética
Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química
Bloqueadores do Canal de Sódio Disparado por Voltagem/química
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (PF-05089771); 0 (Phenyl Ethers); 0 (SCN9A protein, human); 0 (Sulfonamides); 0 (Voltage-Gated Sodium Channel Blockers); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170707
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00598


  7 / 2182 MEDLINE  
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[PMID]:28520411
[Au] Autor:de Bruyn Kops C; Friedrich NO; Kirchmair J
[Ad] Endereço:Faculty of Mathematics, Informatics and Natural Sciences, Department of Computer Science, Center for Bioinformatics, Universität Hamburg , Hamburg 20146, Germany.
[Ti] Título:Alignment-Based Prediction of Sites of Metabolism.
[So] Source:J Chem Inf Model;57(6):1258-1264, 2017 Jun 26.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Prediction of metabolically labile atom positions in a molecule (sites of metabolism) is a key component of the simulation of xenobiotic metabolism as a whole, providing crucial information for the development of safe and effective drugs. In 2008, an exploratory study was published in which sites of metabolism were derived based on molecular shape- and chemical feature-based alignment to a molecule whose site of metabolism (SoM) had been determined by experiments. We present a detailed analysis of the breadth of applicability of alignment-based SoM prediction, including transfer of the approach from a structure- to ligand-based method and extension of the applicability of the models from cytochrome P450 2C9 to all cytochrome P450 isozymes involved in drug metabolism. We evaluate the effect of molecular similarity of the query and reference molecules on the ability of this approach to accurately predict SoMs. In addition, we combine the alignment-based method with a leading chemical reactivity model to take reactivity into account. The combined model yielded superior performance in comparison to the alignment-based approach and the reactivity models with an average area under the receiver operating characteristic curve of 0.85 in cross-validation experiments. In particular, early enrichment was improved, as evidenced by higher BEDROC scores (mean BEDROC = 0.59 for α = 20.0, mean BEDROC = 0.73 for α = 80.5).
[Mh] Termos MeSH primário: Biologia Computacional/métodos
Xenobióticos/metabolismo
[Mh] Termos MeSH secundário: Citocromo P-450 CYP2C9/metabolismo
Modelos Moleculares
Conformação Molecular
Xenobióticos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Xenobiotics); EC 1.14.13.- (Cytochrome P-450 CYP2C9)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170921
[Lr] Data última revisão:
170921
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00165


  8 / 2182 MEDLINE  
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[PMID]:28414290
[Au] Autor:Ershov PV; Yablokov EO; Mezentsev YV; Kalushskiy LA; Florinskaya AV; Veselovsky AV; Gnedenko OV; Gilep AA; Usanov SA; Medvedev AE; Ivanov AS
[Ad] Endereço:Institute of Biomedical Chemistry, Moscow, Russia.
[Ti] Título:[The effect of isatin on protein-protein interactions between cytochrome b5 and cytochromes P450].
[Ti] Título:Vliianie izatina na vzaimodeistvie tsitokhroma b5 s tsitokhromami R450..
[So] Source:Biomed Khim;63(2):170-175, 2017 Mar.
[Is] ISSN:2310-6972
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Cytochromes P450 (CYP) are involved in numerous biochemical processes including metabolism of xenobiotics, biosynthesis of cholesterol, steroid hormones etc. Since some CYP catalyze indol oxidation to isatin, we have hypothesized that isatin can regulate protein-protein interactions (PPI) between components of the CYP system thus representing a (negative?) feedback mechanism. The aim of this study was to investigate a possible effect of isatin on interaction of human CYP with cytochrome b5 (CYB5A). Using the optical biosensor test system employing surface plasmon resonance (SPR) we have investigated interaction of immobilized CYB5A with various CYP in the absence and in the presence of isatin. The SPR-based experiments have shown that a high concentration of isatin (270 mM) increases Kd values for complexes CYB5A/CYP3А5 and CYB5A/CYP3A4 (twofold and threefold, respectively), but has no influence on complex formation between CYB5A and other CYP (including indol-metabolizing CYP2C19 and CYP2E1). Isatin injection to the optical biosensor chip with the preformed molecular complex CYB5A/CYP3A4 caused a 30%-increase in its dissociation rate. Molecular docking manipulations have shown that isatin can influence interaction of CYP3А5 or CYP3A4 with CYB5A acting at the contact region of CYB5A/CYP.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2C19/química
Citocromo P-450 CYP2E1/química
Citocromo P-450 CYP3A/química
Citocromos b5/química
Isatina/química
[Mh] Termos MeSH secundário: Sítios de Ligação
Enzima de Clivagem da Cadeia Lateral do Colesterol/química
Citocromo P-450 CYP2C9/química
Seres Humanos
Cinética
Simulação de Acoplamento Molecular
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Proteínas Recombinantes/química
Soluções
Esteroide 11-beta-Hidroxilase/química
Esteroide 17-alfa-Hidroxilase/química
Ressonância de Plasmônio de Superfície
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 0 (Solutions); 82X95S7M06 (Isatin); 9035-39-6 (Cytochromes b5); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.13.- (Cytochrome P-450 CYP2E1); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (CYP2C19 protein, human); EC 1.14.14.1 (CYP3A5 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C19); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.14.15.4 (Steroid 11-beta-Hydroxylase); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170418
[St] Status:MEDLINE
[do] DOI:10.18097/PBMC20176302170


  9 / 2182 MEDLINE  
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[PMID]:28403136
[Au] Autor:Wang Y; Yi XD; Lu HL
[Ad] Endereço:Department of Orthopaedics, Peking University First Hospital, Beijing, China (mainland).
[Ti] Título:Influence of CYP2C9 and COX-2 Genetic Polymorphisms on Clinical Efficacy of Non-Steroidal Anti-Inflammatory Drugs in Treatment of Ankylosing Spondylitis.
[So] Source:Med Sci Monit;23:1775-1782, 2017 Apr 12.
[Is] ISSN:1643-3750
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND The aim of this study was to evaluate the relationships of CYP2C9 and COX-2 genetic polymorphisms with therapeutic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) in treatment of ankylosing spondylitis (AS). MATERIAL AND METHODS We enrolled 130 AS inpatients and outpatients in the Arthritis and Rheumatism Department of Peking University First Hospital and 106 healthy people getting routine check-ups between September 2013 and July 2014. CYP2C9 and COX-2 genetic polymorphisms were detected by PCR-RFLP. All AS patients underwent medical treatment and 12-week follow-up treatment. Score differences of BASDAI, ASAS20, ASAS50, and ASAS70 for AS patients with different genotypes before and after treatment were compared. RESULTS In terms of COX-2-1290A/G and -1195G/A gene polymorphism genotype and allele frequency, the case group and control group were obviously different (all P<0.05), but CYP2C9*3 polymorphism genotype and allele frequency were not statistically different between the 2 groups (P>0.05). AS patients had improved BASDAI, ASAS20, ASAS50, and ASAS70 scores after they received NSAID treatment (all P<0.05). Furthermore, the efficacy of NSAID in treatment of AS and COX-2 gene -1290A/G and -1195G/A polymorphism were associated (all P<0.05), but it is not associated with CYP2C9 *3 polymorphism (all P>0.05). CONCLUSIONS COX-2-1290A/G and -1195G/A polymorphism may increase AS risk and they both can be considered as biological indicators for prediction of efficacy of NSAIDs in treatment of AS.
[Mh] Termos MeSH primário: Ciclo-Oxigenase 2/genética
Citocromo P-450 CYP2C9/genética
Espondilite Anquilosante/genética
[Mh] Termos MeSH secundário: Adulto
Anti-Inflamatórios não Esteroides/uso terapêutico
Ciclo-Oxigenase 2/metabolismo
Citocromo P-450 CYP2C9/metabolismo
Feminino
Frequência do Gene
Predisposição Genética para Doença
Genótipo
Seres Humanos
Masculino
Polimorfismo de Nucleotídeo Único
Espondilite Anquilosante/tratamento farmacológico
Espondilite Anquilosante/enzimologia
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (PTGS2 protein, human)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170622
[Lr] Data última revisão:
170622
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE


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[PMID]:28385504
[Au] Autor:Wu W; Li Z; Yang G; Teng M; Qin J; Hu Z; Hou L; Shen L; Dong H; Zhang Y; Li J; Chen S; Tian J; Zhang J; Ye L
[Ad] Endereço:WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, People's Republic of China.
[Ti] Título:The discovery of tetrahydropyridine analogs as hNav1.7 selective inhibitors for analgesia.
[So] Source:Bioorg Med Chem Lett;27(10):2210-2215, 2017 05 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:hNav1.7 small molecular inhibitors have attracted lots of attention by its unique analgesic effect. Herein, we report the design and synthesis of a novel series of tetrahydropyridine analogs as hNav1.7 inhibitors for analgesia. Detail structural-activity relationship (SAR) studies were undertaken towards improving hNav1.7 activity, in vitro ADME, and in vivo PK profiles. These efforts resulted in the identification of compound (-)-15h, a highly potent and selective hNav1.7 inhibitor with good ADME and PK profiles.
[Mh] Termos MeSH primário: Analgésicos/química
Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo
Piridinas/química
Sulfonamidas/química
Bloqueadores do Canal de Sódio Disparado por Voltagem/química
[Mh] Termos MeSH secundário: Analgésicos/síntese química
Analgésicos/farmacocinética
Animais
Sítios de Ligação
Citocromo P-450 CYP2C9/química
Citocromo P-450 CYP2C9/metabolismo
Desenho de Drogas
Meia-Vida
Seres Humanos
Concentração Inibidora 50
Simulação de Acoplamento Molecular
Canal de Sódio Disparado por Voltagem NAV1.7/química
Estrutura Terciária de Proteína
Piridinas/síntese química
Piridinas/farmacocinética
Ratos
Relação Estrutura-Atividade
Sulfonamidas/síntese química
Sulfonamidas/farmacocinética
Bloqueadores do Canal de Sódio Disparado por Voltagem/síntese química
Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Analgesics); 0 (NAV1.7 Voltage-Gated Sodium Channel); 0 (Pyridines); 0 (Sulfonamides); 0 (Voltage-Gated Sodium Channel Blockers); EC 1.14.13.- (Cytochrome P-450 CYP2C9); NH9L3PP67S (pyridine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170408
[St] Status:MEDLINE



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