Base de dados : MEDLINE
Pesquisa : D27.505.389.500.315 [Categoria DeCS]
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  1 / 28 MEDLINE  
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[PMID]:28870912
[Au] Autor:Pan PJ; Tsai JJ; Liu YC
[Ad] Endereço:Department of Physical Medicine and Rehabilitation, National Yang-Ming University Hospital, Yilan, Taiwan, R.O.C.
[Ti] Título:Amentoflavone Inhibits Metastatic Potential Through Suppression of ERK/NF-κB Activation in Osteosarcoma U2OS Cells.
[So] Source:Anticancer Res;37(9):4911-4918, 2017 09.
[Is] ISSN:1791-7530
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:AIM: The study goal was to investigate effect of amentoflavone on nuclear factor-κB (NF-κB)-modulated metastatic mechanism in osteosarcoma U2OS cells. U2OS cells were treated with amentoflavone, NF-κB inhibitor, protein kinase B (PKB or AKT) inhibitor or mitogen-activated protein kinase (MAPK) inhibitor. Change of cell viability, NF-κB activation, expression of metastasis-associated proteins, signal transduction, and cell migration and invasion were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, NF-κB reporter gene assay, western blotting, and cell migration and invasion assays. The results demonstrated that inhibition of activation of extracellular signal-regulated kinases (ERK) was a key point for suppression of NF-κB-modulated metastatic mechanism. Amentoflavone significantly inhibited NF-κB activation, ERK phosphorylation, expression of metastasis-associated proteins, and cell migration and invasion. Our findings indicate that amentoflavone reduces metastatic potential through suppression of ERK and NF-κB activation in osteosarcoma U2OS cells.
[Mh] Termos MeSH primário: Biflavonoides/farmacologia
Neoplasias Ósseas/tratamento farmacológico
Movimento Celular/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP2C9/farmacologia
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores
NF-kappa B/antagonistas & inibidores
Osteossarcoma/tratamento farmacológico
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Neoplasias Ósseas/metabolismo
Neoplasias Ósseas/patologia
Proliferação Celular/efeitos dos fármacos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Seres Humanos
NF-kappa B/metabolismo
Osteossarcoma/metabolismo
Osteossarcoma/secundário
Fosforilação/efeitos dos fármacos
Transdução de Sinais/efeitos dos fármacos
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biflavonoids); 0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (NF-kappa B); 9I1VC79L77 (amentoflavone); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171025
[Lr] Data última revisão:
171025
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE


  2 / 28 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


  3 / 28 MEDLINE  
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[PMID]:28135601
[Au] Autor:Poór M; Boda G; Needs PW; Kroon PA; Lemli B; Bencsik T
[Ad] Endereço:Department of Pharmacology, University of Pécs, Faculty of Pharmacy, Szigeti út 12, Pécs, H-7624, Hungary. Electronic address: poor.miklos@pte.hu.
[Ti] Título:Interaction of quercetin and its metabolites with warfarin: Displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme.
[So] Source:Biomed Pharmacother;88:574-581, 2017 Apr.
[Is] ISSN:1950-6007
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of these flavonoids on CYP2C9 enzyme were tested because the metabolic elimination of warfarin is catalysed principally by this enzyme. Herein, we demonstrate that each tested flavonoid metabolite can bind to human serum albumin (HSA) with high affinity, some with similar or even higher affinity than quercetin itself. Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C9/farmacologia
Citocromo P-450 CYP2C9/metabolismo
Metaboloma
Quercetina/metabolismo
Albumina Sérica/metabolismo
Varfarina/metabolismo
[Mh] Termos MeSH secundário: Diclofenaco/análogos & derivados
Diclofenaco/farmacologia
Interações Medicamentosas
Flavonoides/farmacologia
Seres Humanos
Metaboloma/efeitos dos fármacos
Quercetina/química
Espectrometria de Fluorescência
Ultrafiltração
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Flavonoids); 0 (Serum Albumin); 144O8QL0L1 (Diclofenac); 5Q7ZVV76EI (Warfarin); 9IKM0I5T1E (Quercetin); EC 1.14.13.- (Cytochrome P-450 CYP2C9); NJF5O599EF (4'-hydroxydiclofenac)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170131
[St] Status:MEDLINE


  4 / 28 MEDLINE  
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[PMID]:28167473
[Au] Autor:Sana T; Aslam B; Aslam N; Ashraf MM; Ashraf A; Malik TA; Niazi SG; Tahir IM; RiazurRehman M; Ahmed H
[Ad] Endereço:Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan.
[Ti] Título:Therapeutic effect of atorvastatin on kidney functions and urinary excretion of Glimepiride in healthy adult human male subjects.
[So] Source:Pak J Pharm Sci;29(6 Suppl):2321-2326, 2016 Nov.
[Is] ISSN:1011-601X
[Cp] País de publicação:Pakistan
[La] Idioma:eng
[Ab] Resumo:Glimepiride and atorvastatin in combination are commonly employed for treating the hyperglycemia and dyslipidemia, respectively, in patients of type 2 diabetes. The present study was designed to find out the influence of atorvastatin on urinary excretion and renal clearance of Glimepiride in healthy adult male volunteers. In each experimental subject, Glimepiride 2mg was given orally after an overnight fasting. Samples of blood and urine were taken at different specific time intervals. After a washout period of ten days, Glimepiride 2mg was co-administered with atorvastatin 20mg orally. Post-medication, blood and urine samples were collected following the same sampling schedule as for Glimepiride alone. The samples were analyzed for Glimepiride and creatinine concentration by HPLC-UV and Spectrophotometer, respectively. Mean (±SE) values for blood pH 7.445±0.05 and 7.382±0.05, urine pH 4.972±0.08 and 5.08±0.10, diuresis 0.0207±0.00 and 0.0237±0.00ml/min/kg, endogenous creatinine in plasma 9.048±0.33 and 8.613±0.024µg/ml, endogenous creatinine in urine 512.34±18.20 and 556.72±4.60µg/ml, Glimepiride plasma concentration 0.16069±0.00 and 0.3227±0.01µg/ml, Glimepiride urine concentration 1.5994±0.03 and 0.8665±0.04µg/ml, renal clearance of creatinine 1.224±0.09 and 1.550±0.09ml/min/kg, renal clearance of Glimepiride 0.2064±0.01 and 0.0641±0.00ml/min/kg and clearance ratio 0.1791±0.01 and 0.0414±0.00 were observed for Glimepiride alone and its concurrent administration with atorvastatin, respectively. Atorvastatin decreased the urinary excretion and renal clearance of Glimepiride due to which chances of hypoglycemia provokes and renal handling of Glimepiride involves back diffusion besides glomerular filtration and no influence of atorvastatin was seen on these mechanisms.
[Mh] Termos MeSH primário: Atorvastatina Cálcica/administração & dosagem
Inibidores do Citocromo P-450 CYP2C9/administração & dosagem
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
Hipoglicemiantes/urina
Rim/efeitos dos fármacos
Eliminação Renal/efeitos dos fármacos
Compostos de Sulfonilureia/urina
[Mh] Termos MeSH secundário: Adulto
Atorvastatina Cálcica/efeitos adversos
Cromatografia Líquida de Alta Pressão
Citocromo P-450 CYP2C9/metabolismo
Inibidores do Citocromo P-450 CYP2C9/efeitos adversos
Interações Medicamentosas
Voluntários Saudáveis
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos
Hipoglicemiantes/administração & dosagem
Hipoglicemiantes/farmacocinética
Rim/metabolismo
Masculino
Espectrofotometria Ultravioleta
Compostos de Sulfonilureia/administração & dosagem
Compostos de Sulfonilureia/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Hypoglycemic Agents); 0 (Sulfonylurea Compounds); 48A5M73Z4Q (Atorvastatin Calcium); 6KY687524K (glimepiride); EC 1.14.13.- (CYP2C9 protein, human); EC 1.14.13.- (Cytochrome P-450 CYP2C9)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE


  5 / 28 MEDLINE  
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[PMID]:27541271
[Au] Autor:Zak M; Yuen PW; Liu X; Patel S; Sampath D; Oeh J; Liederer BM; Wang W; O'Brien T; Xiao Y; Skelton N; Hua R; Sodhi J; Wang Y; Zhang L; Zhao G; Zheng X; Ho YC; Bair KW; Dragovich PS
[Ad] Endereço:Genentech Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
[Ti] Título:Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors.
[So] Source:J Med Chem;59(18):8345-68, 2016 Sep 22.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NAMPT inhibitors may show potential as therapeutics for oncology. Throughout our NAMPT inhibitor program, we found that exposed pyridines or related heterocyclic systems in the left-hand portion of the inhibitors are necessary pharmacophores for potent cellular NAMPT inhibition. However, when combined with a benzyl group in the center of the inhibitors, such pyridine-like moieties also led to consistent and potent inhibition of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis approach was used to identify central benzyl group replacements with increased Fsp3. A spirocyclic central motif was thus discovered that was combined with left-hand pyridines (or pyridine-like systems) to provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition. Further optimization of potency and ADME properties led to the discovery of compound 68, a highly potent NAMPT inhibitor with outstanding efficacy in a mouse tumor xenograft model and lacking measurable CYP2C9 inhibition at the concentrations tested.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2C9/metabolismo
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Nicotinamida Fosforribosiltransferase/antagonistas & inibidores
Piridinas/química
Piridinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/farmacologia
Antineoplásicos/uso terapêutico
Linhagem Celular Tumoral
Inibidores do Citocromo P-450 CYP2C9/química
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Descoberta de Drogas
Inibidores Enzimáticos/uso terapêutico
Feminino
Seres Humanos
Camundongos
Camundongos Nus
Modelos Moleculares
Neoplasias/tratamento farmacológico
Nicotinamida Fosforribosiltransferase/metabolismo
Piridinas/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Enzyme Inhibitors); 0 (Pyridines); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160820
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.6b00697


  6 / 28 MEDLINE  
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[PMID]:27473010
[Au] Autor:Torikai M; Ibara S; Ieiri S; Hamada T; Noguchi H; Sueyoshi K; Fukuda T; Abeyama K
[Ad] Endereço:Department of Pediatric Surgery, Research Field in Medical and Health Sciences, Medical and Dental Area, Research and Education Assembly, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan. motori@m.kufm.kagoshima-u.ac.jp.
[Ti] Título:Prophylactic efficacy of enteral miconazole administration for neonatal intestinal perforation and its potential mechanism.
[So] Source:Pediatr Surg Int;32(10):953-7, 2016 Oct.
[Is] ISSN:1437-9813
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Intestinal perforation (IP) is a fatal complication in extremely low birth weight infants (ELBWI). We started administrating enteral miconazole (MCZ) to ELBWI in 2002. Since then, the incidence of IP has significantly decreased. The aim of this study was to elucidate the prophylactic effect of MCZ for the treatment of neonatal IP, and to establish a new prophylactic concept for this disease. METHODS: In in vivo experiments, the effects of MCZ were examined histopathologically using a mouse model of intestinal ischemia. In in vitro experiments, the cytoprotective effect of MCZ against hypoxia was evaluated using Caco-2 intestinal cells, and its anti-inflammatory potential using a co-culture model of Caco-2 and HL60 cells. RESULTS: MCZ showed a tissue protective effect against intestinal ischemia. MCZ reduced high mobility group-box 1 (HMGB1) release in Caco-2 cells under hypoxic stress and attenuated the potential to activate co-cultured HL60 leukocytes with Caco-2 cells by suppressing interleukin-8 (IL-8). CONCLUSION: MCZ may have preventive roles in the clinical management of IP in ELBWI by the suppression of IL-8 and HMGB-1.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C9/uso terapêutico
Perfuração Intestinal/prevenção & controle
Miconazol/uso terapêutico
[Mh] Termos MeSH secundário: Animais
Células CACO-2/efeitos dos fármacos
Inibidores do Citocromo P-450 CYP2C9/administração & dosagem
Modelos Animais de Doenças
Seres Humanos
Intestinos/efeitos dos fármacos
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Miconazol/administração & dosagem
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 7NNO0D7S5M (Miconazole)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160731
[St] Status:MEDLINE
[do] DOI:10.1007/s00383-016-3946-6


  7 / 28 MEDLINE  
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[PMID]:27294921
[Au] Autor:Nembri S; Grisoni F; Consonni V; Todeschini R
[Ad] Endereço:Department of Earth and Environmental Sciences, University of Milano-Bicocca, P.za della Scienza 1, 20126 Milano, Italy. s.nembri@campus.unimib.it.
[Ti] Título:In Silico Prediction of Cytochrome P450-Drug Interaction: QSARs for CYP3A4 and CYP2C9.
[So] Source:Int J Mol Sci;17(6), 2016 Jun 09.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Cytochromes P450 (CYP) are the main actors in the oxidation of xenobiotics and play a crucial role in drug safety, persistence, bioactivation, and drug-drug/food-drug interaction. This work aims to develop Quantitative Structure-Activity Relationship (QSAR) models to predict the drug interaction with two of the most important CYP isoforms, namely 2C9 and 3A4. The presented models are calibrated on 9122 drug-like compounds, using three different modelling approaches and two types of molecular description (classical molecular descriptors and binary fingerprints). For each isoform, three classification models are presented, based on a different approach and with different advantages: (1) a very simple and interpretable classification tree; (2) a local (k-Nearest Neighbor) model based classical descriptors and; (3) a model based on a recently proposed local classifier (N-Nearest Neighbor) on binary fingerprints. The salient features of the work are (1) the thorough model validation and the applicability domain assessment; (2) the descriptor interpretation, which highlighted the crucial aspects of P450-drug interaction; and (3) the consensus aggregation of models, which largely increased the prediction accuracy.
[Mh] Termos MeSH primário: Inibidores do Citocromo P-450 CYP2C9/farmacologia
Citocromo P-450 CYP2C9/química
Inibidores do Citocromo P-450 CYP3A/farmacologia
Citocromo P-450 CYP3A/química
Relação Quantitativa Estrutura-Atividade
[Mh] Termos MeSH secundário: Animais
Simulação por Computador
Citocromo P-450 CYP2C9/metabolismo
Inibidores do Citocromo P-450 CYP2C9/química
Citocromo P-450 CYP3A/metabolismo
Inibidores do Citocromo P-450 CYP3A/química
Seres Humanos
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); EC 1.14.13.- (Cytochrome P-450 CYP2C9); EC 1.14.14.1 (Cytochrome P-450 CYP3A)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170315
[Lr] Data última revisão:
170315
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160614
[St] Status:MEDLINE


  8 / 28 MEDLINE  
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[PMID]:27287328
[Au] Autor:Wang Z; Gong Y; Zeng DL; Chen LG; Lin GT; Huang CK; Sun W; Chen MC; Hu GX; Chen RJ
[Ad] Endereço:Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
[Ti] Título:Inhibitory Effect of Apigenin on Losartan Metabolism and CYP2C9 Activity in vitro.
[So] Source:Pharmacology;98(3-4):183-9, 2016.
[Is] ISSN:1423-0313
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: CYP2C9 is one of the most important phase I drug-metabolizing enzymes in liver. The objective of this work was to investigate the effects of apigenin on the metabolism of losartan and human CYP2C9 and rat CYP2C11 activity in vitro. METHODS: Different concentrations of apigenin were added to a 100 mmol/l Tris-HCl reaction mixture containing 2 pmol/ml recombinant human CYP2C9.1, 0.25 mg/ml human liver microsomes or 0.5 mg/ml rat liver microsomes to determine the half maximal inhibition or a half-maximal inhibitory concentration (IC50) on the metabolism of losartan. In addition, diclofenac used as CYP2C9 substrate was performed to determine the effects of apigenin on CYP2C9. RESULTS: The results showed that apigenin has the inhibitory effect on the metabolism of losartan in vitro, the IC50 was 7.61, 4.10 and 11.07 µmol/l on recombinant CYP2C9 microsomes, human liver microsomes and rat liver microsomes, respectively. Meanwhile, apigenin's mode of action on human CYP2C9 activity was competitive for the substrate diclofenac. In contrast to its potent inhibition of CYP2C9 in humans (9.51 µmol/l), apigenin had lesser effects on CYP2C11 in rat (IC50 = 15.51 µmol/l). CONCLUSION: The observations imply that apigenin has the inhibitory effect on the metabolism of losartan and CYP2C9 activity in vitro. More attention should be paid as to when losartan should be administrated combined with apigenin.
[Mh] Termos MeSH primário: Apigenina/metabolismo
Apigenina/farmacologia
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Citocromo P-450 CYP2C9/metabolismo
Losartan/metabolismo
Losartan/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Interações Medicamentosas/fisiologia
Inibidores Enzimáticos/farmacologia
Seres Humanos
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Enzyme Inhibitors); 7V515PI7F6 (Apigenin); EC 1.14.13.- (Cytochrome P-450 CYP2C9); JMS50MPO89 (Losartan)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170316
[Lr] Data última revisão:
170316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160612
[St] Status:MEDLINE
[do] DOI:10.1159/000446808


  9 / 28 MEDLINE  
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[PMID]:27214159
[Au] Autor:Ohtani H; Hakoda R; Imaoka A; Akiyoshi T
[Ad] Endereço:Division of Clinical Pharmacy, Keio University Faculty of Pharmacy, 1-5-30, Shibakoen Minato-ku, Tokyo, 105-8512, Japan.
[Ti] Título:In silico evaluation of warfarin-bucolome therapy.
[So] Source:Biopharm Drug Dispos;37(4):233-42, 2016 May.
[Is] ISSN:1099-081X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Some reports have suggested that bucolome, an inhibitor of cytochrome P450 2C9, is useful for decreasing inter-patient variation in warfarin clearance. The purpose of the present study was to evaluate the utility of the concomitant administration of bucolome and warfarin using an in silico approach. METHODS: In vitro data regarding the enzymatic kinetics of (S)-warfarin and bucolome were collected from the literature. As a validation study, the geometric mean (GM) of the oral unbound clearance of (S)-warfarin and its inter-patient variation (assessed using the standard deviation of its natural logarithm (σ)) were predicted using a physiologically based population pharmacokinetic simulator (Simcyp(TM) ) and compared with clinical data. The utility of the concomitant administration was evaluated by comparing the GM and σ values predicted under various conditions (the prediction study). RESULTS AND DISCUSSION: The σ values in the presence and absence of bucolome were predicted to be 0.73 and 0.68, respectively, suggesting that bucolome might increase the inter-patient variation, as clinically observed. In the prediction study, the σ value of the bucolome co-administered group was greater in almost all of the examined conditions. In conclusion, the concomitant administration of bucolome might not be useful for reducing the inter-patient variation of (S)-warfarin pharmacokinetics. Copyright © 2016 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Anticoagulantes/farmacocinética
Barbitúricos/farmacologia
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Modelos Biológicos
Varfarina/farmacocinética
[Mh] Termos MeSH secundário: Simulação por Computador
Quimioterapia Combinada
Fluconazol/farmacologia
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticoagulants); 0 (Barbiturates); 0 (Cytochrome P-450 CYP2C9 Inhibitors); 5Q7ZVV76EI (Warfarin); 8VZV102JFY (Fluconazole); 9T08RAL174 (bucolome)
[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:160524
[St] Status:MEDLINE
[do] DOI:10.1002/bdd.2008


  10 / 28 MEDLINE  
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[PMID]:27154174
[Au] Autor:Malhi V; Colburn D; Williams SJ; Hop CE; Dresser MJ; Chandra P; Graham RA
[Ad] Endereço:Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. vmalhi@gmail.com.
[Ti] Título:A clinical drug-drug interaction study to evaluate the effect of a proton-pump inhibitor, a combined P-glycoprotein/cytochrome 450 enzyme (CYP)3A4 inhibitor, and a CYP2C9 inhibitor on the pharmacokinetics of vismodegib.
[So] Source:Cancer Chemother Pharmacol;78(1):41-9, 2016 Jul.
[Is] ISSN:1432-0843
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. METHODS: Cohorts included a control arm (n = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n = 24); itraconazole 200 mg (n = 22); or fluconazole 400 mg (n = 22). RESULTS: Area under the vismodegib concentration-time curve from zero to 24 h (AUC0-24h) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC0-24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. CONCLUSION: The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug-drug interaction. CLINICALTRIALS. GOV IDENTIFIER: NCT01772290.
[Mh] Termos MeSH primário: Anilidas/farmacocinética
Fluconazol/farmacologia
Itraconazol/farmacologia
Piridinas/farmacocinética
Rabeprazol/farmacologia
[Mh] Termos MeSH secundário: Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo
Anilidas/administração & dosagem
Área Sob a Curva
Inibidores do Citocromo P-450 CYP2C9/administração & dosagem
Inibidores do Citocromo P-450 CYP2C9/farmacologia
Inibidores do Citocromo P-450 CYP3A/administração & dosagem
Inibidores do Citocromo P-450 CYP3A/farmacologia
Interações Medicamentosas
Feminino
Fluconazol/administração & dosagem
Seres Humanos
Concentração de Íons de Hidrogênio
Itraconazol/administração & dosagem
Inibidores da Bomba de Prótons/administração & dosagem
Inibidores da Bomba de Prótons/farmacologia
Piridinas/administração & dosagem
Rabeprazol/administração & dosagem
Solubilidade
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (ATP-Binding Cassette, Sub-Family B, Member 1); 0 (Anilides); 0 (Cytochrome P-450 CYP2C9 Inhibitors); 0 (Cytochrome P-450 CYP3A Inhibitors); 0 (HhAntag691); 0 (Proton Pump Inhibitors); 0 (Pyridines); 304NUG5GF4 (Itraconazole); 32828355LL (Rabeprazole); 8VZV102JFY (Fluconazole)
[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:160508
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1007/s00280-016-3020-z



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