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[PMID]:27723808
[Au] Autor:Sasaoka S; Matsui T; Hane Y; Abe J; Ueda N; Motooka Y; Hatahira H; Fukuda A; Naganuma M; Hasegawa S; Kinosada Y; Nakamura M
[Ad] Endereço:Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu-shi, Gifu, Japan.
[Ti] Título:Time-to-Onset Analysis of Drug-Induced Long QT Syndrome Based on a Spontaneous Reporting System for Adverse Drug Events.
[So] Source:PLoS One;11(10):e0164309, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database. For signal detection, we used the reporting odds ratio (ROR). Furthermore, we analyzed the time-to-onset data and assessed the hazard type using the Weibull shape parameter. The RORs (95% confidence interval) for bepridil, amiodarone, pilsicainide, nilotinib, disopyramide, arsenic trioxide, clarithromycin, cibenzoline, donepezil, famotidine, sulpiride, and nifekalant were 174.4 (148.6-204.6), 17.3 (14.7-20.4), 52.0 (43.4-62.4), 13.9 (11.5-16.7), 69.3 (55.3-86.8), 54.2 (43.2-68.0), 4.7 (3.8-5.8), 19.9 (15.9-25.0), 8.1 (6.5-10.1), 3.2 (2.5-4.1), 7.1 (5.5-9.2), and 254.8 (168.5-385.4), respectively. The medians and quartiles of time-to-onset for aprindine (oral) and bepridil were 20.0 (11.0-35.8) and 18.0 (6.0-43.0) days, respectively. The lower 95% confidence interval of the shape parameter ß of bepridil was over 1 and the hazard was considered to increase over time.Our study indicated that the pattern of LQTS onset might differ among drugs. Based on these results, careful long-term observation is recommended, especially for specific drugs such as bepridil and aprindine. This information may be useful for the prevention of sudden death following LQTS and for efficient therapeutic planning.
[Mh] Termos MeSH primário: Aprindina/efeitos adversos
Bepridil/efeitos adversos
Bases de Dados Factuais
Síndrome do QT Longo
[Mh] Termos MeSH secundário: Administração Oral
Aprindina/administração & dosagem
Bepridil/administração & dosagem
Feminino
Seres Humanos
Síndrome do QT Longo/induzido quimicamente
Síndrome do QT Longo/epidemiologia
Síndrome do QT Longo/fisiopatologia
Masculino
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
5Y48085P9Q (Aprindine); 755BO701MA (Bepridil)
[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:161011
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0164309


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[PMID]:27032905
[Au] Autor:Chiba T; Kondo N; Takahara A
[Ad] Endereço:Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan; Department of R&D, Fukushima Research Laboratories, TOA EIYO Ltd., Iizaka, Fukushima 960-0211, Japan.
[Ti] Título:Influences of rapid pacing-induced electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits.
[So] Source:J Pharmacol Sci;130(3):170-6, 2016 Mar.
[Is] ISSN:1347-8648
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Electrical remodeling plays a pivotal role in maintaining the reentry during atrial fibrillation. In this study, we assessed influence of electrical remodeling on pharmacological manipulation of the atrial refractoriness in rabbits. We used an atrial electrical remodeling model of the rabbit, subjected to rapid atrial pacing (RAP; 600 beats/min) for 2-4 weeks, leading to shortening of atrial effective refractory period (AERP). Intravenous administration of dl-sotalol (6 mg/kg), bepridil (1 mg/kg), amiodarone (10 mg/kg) or vernakalant (3 mg/kg) significantly prolonged the AERP both in the control and RAP rabbits. The extents in the RAP rabbits were similar to those in the control animals. On the other hand, prolonging effects of intravenously administered ranolazine (10 mg/kg) or tertiapin-Q (0.03 mg/kg) on the AERP in the RAP rabbits were more potent than those in the control animals. These results suggest that rapid pacing-induced electrical remodeling effectively modified the prolonging effects of ranolazine and tertiapin-Q on the AERP in contrast to those of clinically available antiarrhythmic drugs, dl-sotalol, bepridil amiodarone and vernakalant.
[Mh] Termos MeSH primário: Amiodarona/farmacologia
Anisóis/farmacologia
Antiarrítmicos/farmacologia
Fibrilação Atrial/tratamento farmacológico
Fibrilação Atrial/fisiopatologia
Remodelamento Atrial/efeitos dos fármacos
Remodelamento Atrial/fisiologia
Bepridil/farmacologia
Pirrolidinas/farmacologia
Sotalol/farmacologia
[Mh] Termos MeSH secundário: Amiodarona/administração & dosagem
Animais
Anisóis/administração & dosagem
Antiarrítmicos/administração & dosagem
Bepridil/administração & dosagem
Estimulação Cardíaca Artificial
Modelos Animais de Doenças
Infusões Intravenosas
Masculino
Pirrolidinas/administração & dosagem
Coelhos
Sotalol/administração & dosagem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anisoles); 0 (Anti-Arrhythmia Agents); 0 (Pyrrolidines); 755BO701MA (Bepridil); 9G468C8B13 (vernakalant); A6D97U294I (Sotalol); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160402
[St] Status:MEDLINE


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[PMID]:26654806
[Au] Autor:Kondo T; Miake J; Kato M; Ogura K; Iitsuka K; Yamamoto K
[Ad] Endereço:Division of Cardiovascular Medicine, Department of Molecular Medicine and Therapeutics, Faculty of Medicine, Tottori University, Yonago, Japan. Electronic address: med1626@yahoo.co.jp.
[Ti] Título:Impact of postprocedural antiarrhythmic drug therapy with bepridil on maintaining sinus rhythm after catheter ablation for persistent atrial fibrillation.
[So] Source:J Cardiol;68(3):229-35, 2016 09.
[Is] ISSN:1876-4738
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Although several studies have assessed the predictors of recurrent atrial fibrillation (AF) after catheter ablation for persistent AF, the impact of antiarrhythmic drug (AAD) therapy on maintaining sinus rhythm after catheter ablation for persistent AF has not been fully evaluated. This case-control study aimed to evaluate the effect of bepridil on maintaining sinus rhythm after catheter ablation for persistent AF. METHODS AND RESULTS: We enrolled 122 consecutive patients (87 men; mean age: 62.3 years) who underwent catheter ablation for persistent AF and were administered AAD therapy after the initial procedure. Restoration of sinus rhythm was achieved in all of the patients by catheter ablation and cardioversion after the initial procedure. After a median 12-month follow up, 51 of 122 (41.8%) patients had recurrence of AF. In Cox proportional hazard regression analysis, postprocedural AAD therapy with bepridil was a significantly correlated factor with freedom from recurrent AF after the initial ablation procedure (hazard ratio 0.446, 95% confidence interval 0.236-0.842, p=0.012). In Kaplan-Meier analysis, AF-free survival was significantly better with bepridil compared with amiodarone (AMD) and sodium channel blocker (SCB) (log-rank test, bepridil vs AMD, p=0.012; bepridil vs SCB, p=0.018). CONCLUSIONS: Bepridil reduced the recurrence of AF compared with AMD and SCB in patients who underwent catheter ablation for persistent AF.
[Mh] Termos MeSH primário: Antiarrítmicos/uso terapêutico
Fibrilação Atrial/terapia
Bepridil/uso terapêutico
Ablação por Cateter
[Mh] Termos MeSH secundário: Amiodarona/uso terapêutico
Estudos de Casos e Controles
Feminino
Seguimentos
Seres Humanos
Masculino
Meia-Idade
Recidiva
Bloqueadores dos Canais de Sódio/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Sodium Channel Blockers); 755BO701MA (Bepridil); N3RQ532IUT (Amiodarone)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE


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[PMID]:26498939
[Au] Autor:Ma F; Takanari H; Masuda K; Morishima M; Ono K
[Ad] Endereço:Department of Pathophysiology, Oita University School of Medicine, Yufu, 879-5593, Oita, Japan.
[Ti] Título:Short- and long-term inhibition of cardiac inward-rectifier potassium channel current by an antiarrhythmic drug bepridil.
[So] Source:Heart Vessels;31(7):1176-84, 2016 Jul.
[Is] ISSN:1615-2573
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Bepridil is an effective antiarrhythmic drug on supraventricular and ventricular arrhythmias, and inhibitor of calmodulin. Recent investigations have been elucidating that bepridil exerts antiarrhythmic effects through its acute and chronic application for patients. The aim of this study was to identify the efficacy and the potential mechanism of bepridil on the inward-rectifier potassium channel in neonatal rat cardiomyocytes in acute- and long-term conditions. Bepridil inhibited inward-rectifier potassium current (I K1) as a short-term effect with IC50 of 17 µM. Bepridil also reduced I K1 of neonatal cardiomyocytes when applied for 24 h in the culture medium with IC50 of 2.7 µM. Both a calmodulin inhibitor (W-7) and an inhibitor of calmodulin-kinase II (KN93) reduced I K1 when applied for 24 h as a long-term effect in the same fashion, suggesting that the long-term application of bepridil inhibits I K1 more potently than that of the short-term application through the inhibition of calmodulin kinase II pathway in cardiomyocytes.
[Mh] Termos MeSH primário: Antiarrítmicos/farmacologia
Bepridil/farmacologia
Miócitos Cardíacos/efeitos dos fármacos
Bloqueadores dos Canais de Potássio/farmacologia
Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores
[Mh] Termos MeSH secundário: Animais
Animais Recém-Nascidos
Benzilaminas/farmacologia
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo
Calmodulina/antagonistas & inibidores
Calmodulina/metabolismo
Células Cultivadas
Potenciais da Membrana
Miócitos Cardíacos/metabolismo
Canais de Potássio Corretores do Fluxo de Internalização/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Ratos Wistar
Sulfonamidas/farmacologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (Benzylamines); 0 (Calmodulin); 0 (Potassium Channel Blockers); 0 (Potassium Channels, Inwardly Rectifying); 0 (Protein Kinase Inhibitors); 0 (Sulfonamides); 139298-40-1 (KN 93); 65595-90-6 (W 7); 755BO701MA (Bepridil); EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:171014
[Lr] Data última revisão:
171014
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151027
[St] Status:MEDLINE
[do] DOI:10.1007/s00380-015-0762-1


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[PMID]:26459984
[Au] Autor:Pérez L; Vílchez MC; Gallego V; Morini M; Peñaranda DS; Asturiano JF
[Ad] Endereço:Grupo de Acuicultura y Biodiversidad, Instituto de Ciencia y Tecnología Animal, Universitat Politècnica de València, Camino de Vera s/n. Edificio 7G, 46022 Valencia, Spain. Electronic address: mlpereig@dca.upv.es.
[Ti] Título:Role of calcium on the initiation of sperm motility in the European eel.
[So] Source:Comp Biochem Physiol A Mol Integr Physiol;191:98-106, 2016 Jan.
[Is] ISSN:1531-4332
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sperm from European eel males treated with hCGrec was washed in a calcium free extender, and sperm motility was activated both in the presence (seawater, SW) and in the absence of calcium (NaCl+EDTA), and treated with calcium inhibitors or modulators. The sperm motility parameters were evaluated by a computer-assisted sperm analysis (CASA) system, and changes in the [Ca(2+)]i fluorescence (and in [Na(+)]i in some cases) were evaluated by flow cytometry. After sperm motility was activated in a medium containing Ca(2+) (seawater, SW) the intracellular fluorescence emitted by Ca(2+) increased 4-6-fold compared to the levels in quiescent sperm. However, while sperm activation in a Ca-free media (NaCl+EDTA) resulted in a percentage of motility similar to seawater, the [Ca(2+)]i levels did not increase at all. This result strongly suggests that increasing [Ca(2+)]i is not a pre-requisite for the induction of sperm motility in European eel sperm. Several sperm velocities (VCL, VSL, VAP) decreased when sperm was activated in the Ca-free activator, thus supporting the theory that Ca(2+) has a modulatory effect on sperm motility. The results indicate that a calcium/sodium exchanger (NCX) which is inhibited by bepridil and a calcium calmodulin kinase (inhibited by W-7), are involved in the sperm motility of the European eel. Our results indicate that the increase in [Ca(2+)]i concentrations during sperm activation is due to an influx from the external medium, but, unlike in most other species, it does not appear to be necessary for the activation of motility in European eel sperm.
[Mh] Termos MeSH primário: Anguilla/fisiologia
Cálcio/farmacologia
Motilidade Espermática/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Bepridil/farmacologia
Calcimicina/farmacologia
Ionóforos/farmacologia
Cinética
Masculino
Água do Mar
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ionophores); 0 (Sulfonamides); 37H9VM9WZL (Calcimycin); 65595-90-6 (W 7); 755BO701MA (Bepridil); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151014
[St] Status:MEDLINE


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[PMID]:26375298
[Au] Autor:Schlecht W; Li KL; Hu D; Dong W
[Ad] Endereço:The Gene and Linda Voiland School of Chemical Engineering and Bioengineering, PO Box 646515, Washington State University, Pullman, WA 99164-6515, USA.
[Ti] Título:Fluorescence Based Characterization of Calcium Sensitizer Action on the Troponin Complex.
[So] Source:Chem Biol Drug Des;87(2):171-81, 2016 Feb.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Calcium sensitizers enhance the transduction of the Ca(2+) signal into force within the heart and have found use in treating heart failure. However the mechanisms of action for most Ca(2+) sensitizers remain unclear. To address this issue an efficient fluorescence based approach to Ca(2+) sensitizer screening was developed which monitors cardiac troponin C's (cTnC's) hydrophobic cleft. This approach was tested on four common Ca(2+) -sensitizers, EMD 57033, levosimendan, bepridil and pimobendan with the aim of elucidating the mechanisms of action for each as well as proving the efficacy of the new screening method. Ca(2+) -titration experiments were employed to determine the effect on Ca(2+) sensitivity and cooperativity of cTnC opening, while stopped flow experiments were used to investigate the impact on cTnC relaxation kinetics. Bepridil was shown to increase the sensitivity of cTnC for Ca(2+) under all reconstitution conditions, sensitization by the other drugs was context dependent. Levosimendan and pimobendan reduced the rate of cTnC closing consistent with a stabilization of cTnC's open conformation while bepridil increased the rate of relaxation. Experiments were also run on samples containing cTnT(T204E), a known Ca(2+) -desensitizing phosphorylation mimic. Levosimendan, bepridil, and pimobendan were found to elevate the Ca(2+) -sensitivity of cTnT(T204E) containing samples in this context.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Cardiotônicos/metabolismo
Miocárdio/metabolismo
Troponina/metabolismo
[Mh] Termos MeSH secundário: Animais
Bepridil/química
Bepridil/metabolismo
Cardiotônicos/química
Hidrazonas/química
Hidrazonas/metabolismo
Cinética
Mutagênese Sítio-Dirigida
Fosforilação
Ligação Proteica
Piridazinas/química
Piridazinas/metabolismo
Ratos
Espectrometria de Fluorescência
Troponina/química
Troponina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cardiotonic Agents); 0 (Hydrazones); 0 (Pyridazines); 0 (Troponin); 349552KRHK (simendan); 34AP3BBP9T (pimobendan); 755BO701MA (Bepridil); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170201
[Lr] Data última revisão:
170201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150917
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12651


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[PMID]:26616666
[Au] Autor:Obejero-Paz CA; Bruening-Wright A; Kramer J; Hawryluk P; Tatalovic M; Dittrich HC; Brown AM
[Ad] Endereço:ChanTest Corporation, a Charles River Company, Discovery Services, 14656 Neo Parkway, Cleveland, OH 44128, USA.
[Ti] Título:Quantitative Profiling of the Effects of Vanoxerine on Human Cardiac Ion Channels and its Application to Cardiac Risk.
[So] Source:Sci Rep;5:17623, 2015 Nov 30.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Although a potent blocker of hERG, it produced no serious adverse events. We attributed the unexpected result to offsetting Multiple Ion Channel Effects (MICE). Vanoxerine's effects were strongly frequency-dependent and we repositioned it for treatment of atrial fibrillation and flutter. Vanoxerine terminated AF/AFL in an animal model and a dose-ranging clinical trial. Reversion to normal rhythm was associated with QT prolongation yet absent proarrhythmia markers for Torsade de Pointes (TdP). To understand the QT/TdP discordance, we used quantitative profiling and compared vanoxerine with dofetilide, a selective hERG-blocking torsadogen used for intractable AF, verapamil, a non-torsadogenic MICE comparator and bepridil, a torsadogenic MICE comparator. At clinically relevant concentrations, verapamil blocked hCav1.2 and hERG, as did vanoxerine and bepridil both of which also blocked hNav1.5. In acute experiments and simulations, dofetilide produced early after depolarizations (EADs) and arrhythmias, whereas verapamil, vanoxerine and bepridil produced no proarrhythmia markers. Of the MICE drugs only bepridil inhibited hERG trafficking following overnight exposure. The results are consistent with the emphasis on MICE of the CiPA assay. Additionally we propose that trafficking inhibition of hERG be added to CiPA.
[Mh] Termos MeSH primário: Coração/efeitos dos fármacos
Canais Iônicos/metabolismo
Miocárdio/metabolismo
Piperazinas/farmacologia
[Mh] Termos MeSH secundário: Potenciais de Ação/efeitos dos fármacos
Animais
Bepridil/farmacologia
Células CHO
Simulação por Computador
Cricetulus
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores
Canais de Potássio Éter-A-Go-Go/metabolismo
Células HEK293
Seres Humanos
Concentração Inibidora 50
Potenciais da Membrana/efeitos dos fármacos
Modelos Biológicos
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/fisiologia
Técnicas de Patch-Clamp
Fenetilaminas/farmacologia
Sulfonamidas/farmacologia
Verapamil/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Ether-A-Go-Go Potassium Channels); 0 (Ion Channels); 0 (Phenethylamines); 0 (Piperazines); 0 (Sulfonamides); 755BO701MA (Bepridil); 90X28IKH43 (vanoxerine); CJ0O37KU29 (Verapamil); R4Z9X1N2ND (dofetilide)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:170103
[Lr] Data última revisão:
170103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151201
[St] Status:MEDLINE
[do] DOI:10.1038/srep17623


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[PMID]:26195225
[Au] Autor:Doki K; Sekiguchi Y; Kuga K; Aonuma K; Homma M
[Ad] Endereço:Department of Pharmaceutical Sciences, Faculty of Medicine, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan. Electronic address: k-doki@mail.hosp.tsukuba.ac.jp.
[Ti] Título:Serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity.
[So] Source:Drug Metab Pharmacokinet;30(4):257-62, 2015 Aug.
[Is] ISSN:1880-0920
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aims of this study were to clarify whether the ratio of S- to R-flecainide (S/R ratio) in the serum flecainide concentration was associated with the stereoselectivity of flecainide metabolism, and to investigate the effects of the cytochrome P450 (CYP) 2D6 (CYP2D6) genotype and CYP2D6 inhibitor on the serum flecainide S/R ratio. In vitro studies using human liver microsomes and cDNA-expressed CYP isoforms suggested that variability in the serum flecainide S/R ratio was associated with the stereoselectivity of CYP2D6-mediated flecainide metabolism. We examined the serum flecainide S/R ratio in 143 patients with supraventricular tachyarrhythmia. The S/R ratio was significantly lower in intermediate metabolizers and poor metabolizers (IMs/PMs) than in extensive metabolizers (EMs) identified by the CYP2D6 genotype. The cut-off value for the S/R ratio to allow the discrimination between CYP2D6 EMs and IMs/PMs was 0.99. The S/R ratio in patients with co-administration of bepridil, a potent CYP2D6 inhibitor, was lower than 0.99, regardless of the CYP2D6 genotype status. Other factors, including age, sex, body weight, and renal function, did not affect the serum flecainide S/R ratio. This study suggests that the serum flecainide S/R ratio reflects the CYP2D6 genotype and changes in CYP2D6 activity on co-administration of a CYP2D6 inhibitor.
[Mh] Termos MeSH primário: Citocromo P-450 CYP2D6/genética
Flecainida/sangue
[Mh] Termos MeSH secundário: Antiarrítmicos/uso terapêutico
Bepridil
Bignoniaceae/genética
DNA Complementar/genética
Feminino
Genótipo
Seres Humanos
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Meia-Idade
Farmacogenética/métodos
Taquicardia/sangue
Taquicardia/tratamento farmacológico
Taquicardia/genética
Taquicardia Supraventricular/sangue
Taquicardia Supraventricular/tratamento farmacológico
Taquicardia Supraventricular/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 0 (DNA, Complementary); 755BO701MA (Bepridil); EC 1.14.14.1 (Cytochrome P-450 CYP2D6); K94FTS1806 (Flecainide)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:150808
[Lr] Data última revisão:
150808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150722
[St] Status:MEDLINE


  9 / 719 MEDLINE  
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[PMID]:26162947
[Au] Autor:Nakatani Y; Sakamoto T; Nishida K; Kataoka N; Yamaguchi Y; Sakabe M; Fujiki A; Mizumaki K; Inoue H
[Ad] Endereço:Second Department of Internal Medicine, University of Toyama, Toyama, Japan.
[Ti] Título:Bepridil enhances aprindine-induced prolongation of atrial effective refractory period in a canine atrial rapid pacing model.
[So] Source:J Cardiol;66(5):445-50, 2015 Nov.
[Is] ISSN:1876-4738
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Bepridil in combination with aprindine could restore sinus rhythm in patients with persistent atrial fibrillation (AF). The present study aimed to investigate the electrophysiological mechanisms of the combined effects of bepridil and aprindine. METHODS: Subjects consisted of 6 dogs without and 6 dogs with atrial rapid pacing (ARP) carried out at 400 bpm for 2 weeks. Bepridil was administered for 1 week in both groups (ARP dogs were administered bepridil in the second week). The electrophysiological effects of the intravenous administration of aprindine (1mg/kg) were evaluated before and after the administration of bepridil. RESULTS: In non-paced dogs, the atrial effective refractory period (AERP) became longer after the administration of bepridil (from 151±10 ms to 170±7 ms, p<0.05); however, no additional AERP prolongation was observed after the acute administration of aprindine. In ARP dogs, the AERP shortened with ARP for a week, and tended to lengthen after the administration of bepridil (from 93±5 ms to 118±9 ms, p=0.08). In these dogs, the acute aprindine administration did not prolong the AERP before the administration of bepridil, although it did after the administration of bepridil (from 118±9 ms to 142±8 ms, p<0.01). AF duration did not change after the administration of bepridil, although it shortened significantly after the additional administration of aprindine (from 2.2±0.3s to 1.4±0.8s, p<0.05). CONCLUSIONS: Bepridil enhances the effect of aprindine for the prevention of AF by reversing atrial electrical remodeling.
[Mh] Termos MeSH primário: Antiarrítmicos/administração & dosagem
Aprindina/administração & dosagem
Fibrilação Atrial/tratamento farmacológico
Função Atrial/efeitos dos fármacos
Bepridil/administração & dosagem
[Mh] Termos MeSH secundário: Animais
Fibrilação Atrial/veterinária
Remodelamento Atrial/efeitos dos fármacos
Cães
Quimioterapia Combinada/métodos
Átrios do Coração/efeitos dos fármacos
Átrios do Coração/fisiopatologia
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Arrhythmia Agents); 5Y48085P9Q (Aprindine); 755BO701MA (Bepridil)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:151013
[Lr] Data última revisão:
151013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150712
[St] Status:MEDLINE


  10 / 719 MEDLINE  
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[PMID]:26109583
[Au] Autor:Papadaki M; Vikhorev PG; Marston SB; Messer AE
[Ad] Endereço:National Heart and Lung Institute, Imperial College London, London W12 0NN, UK.
[Ti] Título:Uncoupling of myofilament Ca2+ sensitivity from troponin I phosphorylation by mutations can be reversed by epigallocatechin-3-gallate.
[So] Source:Cardiovasc Res;108(1):99-110, 2015 Oct 01.
[Is] ISSN:1755-3245
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:AIMS: Heart muscle contraction is regulated via the ß-adrenergic response that leads to phosphorylation of Troponin I (TnI) at Ser22/23, which changes the Ca(2+) sensitivity of the cardiac myofilament. Mutations in thin filament proteins that cause dilated cardiomyopathy (DCM) and some mutations that cause hypertrophic cardiomyopathy (HCM) abolish the relationship between TnI phosphorylation and Ca(2+) sensitivity (uncoupling). Small molecule Ca(2+) sensitizers and Ca(2+) desensitizers that act upon troponin alter the Ca(2+) sensitivity of the thin filament, but their relationship with TnI phosphorylation has never been studied before. METHODS AND RESULTS: Quantitative in vitro motility assay showed that 30 µM EMD57033 and 100 µM Bepridil increase Ca(2+) sensitivity of phosphorylated cardiac thin filaments by 3.1- and 2.8-fold, respectively. Additionally they uncoupled Ca(2+) sensitivity from TnI phosphorylation, mimicking the effect of HCM mutations. Epigallocatechin-3-gallate (EGCG) decreased Ca(2+) sensitivity of phosphorylated and unphosphorylated wild-type thin filaments equally (by 2.15 ± 0.45- and 2.80 ± 0.48-fold, respectively), retaining the coupling. Moreover, EGCG also reduced Ca(2+) sensitivity of phosphorylated but not unphosphorylated thin filaments containing DCM and HCM-causing mutations; thus, the dependence of Ca(2+) sensitivity upon TnI phosphorylation of uncoupled mutant thin filaments was restored in every case. In single mouse heart myofibrils, EGCG reduced Ca(2+) sensitivity of force and kACT and also preserved coupling. Myofibrils from the ACTC E361G (DCM) mouse were uncoupled; EGCG reduced Ca(2+) sensitivity more for phosphorylated than for unphosphorylated myofibrils, thus restoring coupling. CONCLUSION: We conclude that it is possible to both mimic and reverse the pathological defects in troponin caused by cardiomyopathy mutations pharmacologically. Re-coupling by EGCG may be of potential therapeutic significance for treating cardiomyopathies.
[Mh] Termos MeSH primário: Cálcio/metabolismo
Catequina/análogos & derivados
Miofibrilas/metabolismo
Troponina I/metabolismo
[Mh] Termos MeSH secundário: Animais
Bepridil/farmacologia
Catequina/farmacologia
Seres Humanos
Camundongos
Contração Muscular/efeitos dos fármacos
Mutação
Fosforilação
Quinolinas/farmacologia
Coelhos
Tiadiazinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Quinolines); 0 (Thiadiazines); 0 (Troponin I); 120223-04-3 (EMD 53998); 755BO701MA (Bepridil); 8R1V1STN48 (Catechin); BQM438CTEL (epigallocatechin gallate); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150626
[St] Status:MEDLINE
[do] DOI:10.1093/cvr/cvv181



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