Joshi Ajay, Dimino Tara, Vohra Yogesh, Cui Changcong, Yan Gan-Xin
Main Line Health Heart Center, Wynnewood, PA 19096, USA.
J Electrocardiol. 2004;37 Suppl:7-14. doi: 10.1016/j.jelectrocard.2004.08.003.
The recognition of QT prolongation and torsade de pointes (TdP) in humans has resulted in the re-labeling of some drugs and the removal of others from the market in the past decade. Recent regulatory guidelines have recommended a battery of preclinical tests to assess a new drug for the QT liability in humans. The assessment includes the effect of a drug on: 1) the ionic current in stable cell lines expressing hERG channel; 2) action potential duration (APD) measured in isolated ventricular tissues; 3) the QTc interval and TdP in animals in vivo; and 4) APD, the QT interval, transmural dispersion of repolarization (TDR) and TdP potential in the isolated arterially-perfused ventricular wedge preparation. Because a noncardiac drug with an incidence of TdP even less than 0.1% can be potentially removed from the market, the experimental models used for preclinical testing have to be high sensitive and specific to the signals related to TdP. Among available experimental models, the rabbit left ventricle wedge preparation exhibits a high sensitivity and a high specificity in the identification of compounds positive and negative for QT prolongation and TdP. This is attributed to the fact that the preparation demonstrates strong signals related to QT prolongation in response to even a weaker QT prolonging agent. Signals specifically pertinent to the development of TdP, ie, early afterdepolarization (EAD) and an increase in TDR can be detected as well. The preclinical data obtained from the wedge preparation correlate well with clinical outcomes.
在过去十年中，人类对QT间期延长和尖端扭转型室速（TdP）的认识导致了一些药物重新标注以及其他一些药物退出市场。最近的监管指南推荐了一系列临床前试验，以评估一种新药在人体中的QT相关风险。评估内容包括药物对以下方面的影响：1）表达人乙醚-a- go -相关基因（hERG）通道的稳定细胞系中的离子电流；2）在离体心室组织中测量的动作电位时程（APD）；3）动物体内的QTc间期和TdP；4）在离体动脉灌注心室楔形标本中的APD、QT间期、复极跨壁离散度（TDR）和TdP发生可能性。由于一种TdP发生率甚至低于0.1%的非心脏药物都可能被撤出市场，因此用于临床前测试的实验模型必须对与TdP相关的信号具有高敏感性和特异性。在现有的实验模型中，兔左心室楔形标本在识别QT间期延长和TdP阳性及阴性化合物方面表现出高敏感性和高特异性。这归因于该标本即使对较弱的QT间期延长剂也能显示出与QT间期延长相关的强烈信号。与TdP发生相关的特异性信号，即早期后除极（EAD）和TDR增加也能够被检测到。从楔形标本获得的临床前数据与临床结果具有良好的相关性。
