Cavero Icilio, Holzgrefe Henry
54 Rue de la Glacière, 75013 Paris, France.
13765 Seabiscuit Drive, Reno, NV, USA.
J Pharmacol Toxicol Methods. 2015 Nov-Dec;76:27-37. doi: 10.1016/j.vascn.2015.06.004. Epub 2015 Jul 6.
The comprehensive in vitro proarrhythmia assay (CiPA) is a nonclinical, mechanism-based paradigm for assessing drug proarrhythmic liability.
The first CiPA assay determines effects on cloned human cardiac ion channels. The second investigates whether the latter study-generated metrics engender proarrhythmic markers on a computationally reconstructed human ventricular action potential. The third evaluates conclusions from, and searches possibly missed effects by in silico analysis, in human stem cell-derived cardiomyocytes (hSC-CMs). CiPA ad hoc Expert-Working Groups have proposed patch clamp protocols for seven cardiac ion channels, a modified O'Hara-Rudy model for in silico analysis, detailed procedures for field (MEA) and action potential (VSD) measurements in hSC-CMs, and 29 reference drugs for CiPA assay testing and validation.
CiPA adoption as drug development tool for identifying electrophysiological mechanisms conferring proarrhythmic liability to candidate drugs is a complex, multi-functional task requiring significant time, reflection, and efforts to be fully achieved.
全面体外致心律失常试验（CiPA）是一种基于机制的非临床范式，用于评估药物的致心律失常风险。
首个CiPA试验确定对克隆的人类心脏离子通道的影响。第二个试验研究前者研究生成的指标是否会在计算机重建的人类心室动作电位上产生致心律失常标志物。第三个试验评估来自人类干细胞衍生心肌细胞（hSC-CMs）的计算机分析得出的结论，并搜索可能遗漏的效应。CiPA特设专家工作组已经提出了针对七种心脏离子通道的膜片钳方案、用于计算机分析的改良O'Hara-Rudy模型、hSC-CMs中电场（MEA）和动作电位（VSD）测量的详细程序，以及用于CiPA试验测试和验证的29种参考药物。
采用CiPA作为药物开发工具来识别赋予候选药物致心律失常风险的电生理机制是一项复杂的多功能任务，需要大量时间、思考和努力才能完全实现。
