An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel
An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel
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DOI：
10.1016/j.vascn.2016.03.009
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发表时间：
2016-09-01
影响因子：
1.9
通讯作者：
Strauss, David G.
中科院分区：
文献类型：
--
作者：
Crumb, William J., Jr.;Vicente, Jose;Strauss, David G.
简介：综合性体外致心律失常试验（CiPA）旨在解决仅基于hERG和QT数据的药物相关尖端扭转型室性心动过速风险的错误识别。这种新的范例将由四个相互关联的组件组成，其中之一是由六个离子通道组成的面板，其电流在心脏动作电位的去极化和复极化中都很重要。方法：采用全细胞膜片钳技术，检测了30种临床常用药物对这些离子通道的影响。电流引起使用心室动作电位波形或步进斜坡电压protocols.Results：研究的七个离子电流，hERG是最常见的阻断电流，其次是Nav1.5晚，Cav1.2。使用电流幅度降低20%作为任意标记，在游离血浆C-max浓度下，没有测试的药物以该量阻断Nav1.5峰、KvLQT 1/貂、Kir2.1和Kv4.3。在3x游离血浆C-max下，除Kir2.1外的每种电流都有至少一种药物使电流幅度降低至少20%。讨论：这是同类研究中首次研究30种临床药物对目前提出的组成CiPA离子通道面板的7种离子电流的影响。结果表明在临床相关浓度下药物诱导的hERG、Nav1.5-late和Cav1.2阻滞的重要性，低风险扭转型室性心动过速药物的Nav1.5-late或Cav1.2阻滞与hERG阻滞相等或更大。此外，本研究的结果提供了可用于测试各种计算机模型预测药物诱导的心律失常的能力的数据。(C)2016 Elsevier Inc. All rights reserved.
Introduction: The Comprehensive in vitro Proarrhythmia Assay (CiPA) is intended to address the misidentification of drug-associated torsade de pointes risk based solely on hERG and QT data. This new paradigm will consist of four interrelated components, one of which is a panel consisting of six ion channels whose currents are important in both depolarization and repolarization of the cardiac action potential. This study examined the effects of 30 clinical drugs on these ion channels.Methods: Ion currents were evaluated in expression systems using the manual whole cell patch clamp technique. Currents were elicited using either a ventricular action potential waveform or step-ramp voltage protocols.Results: Of the seven ion currents studied, hERG was the most often blocked current followed by Nav1.5-late, and Cav1.2. Using a 20% reduction in current amplitude as an arbitrary maker, at a free plasma C-max concentration, no drug tested blocked Nav1.5-peak, KvLQT1/ mink, Kir2.1 and Kv4.3 by that amount. At a 3x free plasma C-max, every current except Kir2.1 had at least one drug reduce current amplitude by at least 20%.Discussion: This is the first study of its kind to examine the effects of 30 clinical drugs against the seven ion currents currently proposed to makeup the CiPA ion channel panel. The results indicate the importance of drug-induced block of hERG, Nav1.5-late and Cav1.2 at clinically relevant concentrations, with low risk torsade drugs having equal or greater Nav1.5-late or Cav1.2 block compared to hERG block. In addition, the results of this study provide data which can be used to test the ability of various in silico models to predict drug-induced arrhythmias. (C) 2016 Elsevier Inc. All rights reserved.