摘要
心脏毒性是导致药物研发中断或撤市的主要原因之一。目前,临床前药物心脏安全性评价主要检测药物对h ERG(Human ether-a-go-go)单一钾离子通道的阻断作用和药物对动物心电图QT间期的影响。这些检测假阳性率高,已经影响了新药研发的进程。人诱导多功能干细胞分化的心肌细胞(Human induced pluripotent stem cell-derived cardiomyocytes,hi PSC-CMs)具有人心肌细胞相似的结构与性质,为临床前药物心脏安全性评价提供了新的细胞模型,已经成为了未来心律失常检测方法--体外综合性心律失常检测(Comprehensive in vitro proarrhythmia assay,Ci PA)的组成内容之一。此外这种技术也促进了非心律失常心脏毒性(包括药物导致的结构性心脏毒性与收缩性心脏毒性)检测方法的发展。文章介绍hi PSC-CMs的基本特性、在临床前药物心脏安全性评价中的研究进展以及局限性。
Cardiotoxicity is a major cause of attrition in preclinical and clinical drug development,and drug withdrawal from market.Current preclinical cardiac safety assessment requires new drugs to be assessed for their inhibition effects on the human ether-a-gogo( hERG) potassium channel,and their ability to cause QT interval prolongation in animal electrocardiogram studies. These approaches have high false positive rates and lead to attrition of potentially useful drugs. Human induced pluripotent stem cell-derived cardiomyocytes( hiPSC-CMs) have similar characters with human cardiomyocytes,providing a promising cell model for preclinical cardiac safety assessment,and have been included in the comprehensive in vitro proarrhythmia assay( CiPA) paradigm. hi PSC-CMs also improve the detection of drug-induced non-proarrhythmic cardiotoxicity( contractile and structural cardiotoxicity). This review summarizes the main properties of hi PSC-CMs,its progress in preclinical cardiac safety assessment and its limitations.
作者
裴俊杰
王旻
董海恒
PEI Jun-jie;WANG Min;DONG Hai-heng(School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China;Biology Unit,Research Service Division, Wuxi App Tec (Shanghai) Co. ,Ltd. ,Shanghai 200131 ,China)
出处
《药物生物技术》
CAS
2019年第3期278-282,共5页
Pharmaceutical Biotechnology
