ILST-HESI cardiovascular safety subcommittee initiative: Evaluation of three non-clinical models of QT prolongation
ILST-HESI cardiovascular safety subcommittee initiative: Evaluation of three non-clinical models of QT prolongation
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DOI：
10.1016/j.vascn.2006.05.001
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发表时间：
2006-09-01
影响因子：
1.9
通讯作者：
Thomas, Karluss
中科院分区：
文献类型：
--
作者：
Hanson, Laurie A.;Bass, Alan S.;Thomas, Karluss
简介：由于QT间期延长与潜在致命性心律失常尖端扭转型室性心动过速（UP）之间的联系，延迟心脏复极的药物对患者构成潜在的安全性风险，并引起严重的监管问题。预测哪些药物会导致UP是一门不精确和困难的科学。非临床试验的效用尚未得到充分理解，部分原因是文献中报告的方法、种属和试验一致性存在差异。国际生命科学研究所的健康与环境科学研究所（ILSI/HESI）概述了一系列研究，以确定如何选择常用的非临床检测方法来识别已知引起UP和延长QT间期的化合物。研究方法：已知延长心室复极的化合物和多年临床使用认为安全的化合物在三种试验中进行了测试：HERG离子电流、浦肯野纤维复极和清醒遥测犬体内QT研究。结果如下：来自这些测定中的每一个的数据表明，可以将可能对患者造成致心律失常风险的化合物与被认为是安全的化合物区分开。讨论内容：总之，可以整合体外和体内临床前结果，以制定准确的临床前风险评估，从而支持临床安全性。(c)2006年由Elsevier Inc.出版
Introduction: Drugs that delay cardiac repolarization pose potential safety risks to patients and cause serious regulatory concern because of the link between QT interval prolongation and the potentially fatal arrhythmia torsades de pointes (UP). Predicting which drugs will cause UP is an inexact and difficult science. The utility of non-clinical assays was not well understood due in part to variability in methods, species, and consistency in the assays reported in the literature. The Health and Environmental Sciences Institute of the International Life Sciences Institute (ILSI/HESI) outlined a set of studies to determine how well selected commonly used non-clinical assays identified compounds known to cause UP and prolong QT interval in humans. Methods: Compounds known to prolong ventricular repolarization and compounds considered safe by years of clinical use were tested in three assays: HERG ionic current, Purkinje fiber repolarization, and in vivo QT studies in conscious telemeterized dogs. Results: The data from each of these assays demonstrate that compounds that may pose a proarrhythmia risk for patients can be distinguished from those that are considered safe. Discussion: Taken collectively, the in-vitro and in-vivo preclinical results can be integrated to develop an accurate preclinical risk assessment to support clinical safety. (c) 2006 Published by Elsevier Inc.