Molecular mechanism and clinical trial center for the drug-induced QT prolongation syndrome

众所周知，服用普通药物会意外地导致心电图QT延长和致死性心律失常。由于常见药物引起的死亡，这种药物引起的心室复极延迟(QT延长)引起了全球的关注。迫切需要阐明这种药物所致QT延长的机制，以防止医源性事故的发生。本研究试图阐明药物引起QT延长的机制。此外，还建立了临床试验中心，建设药物安全数据库。在两年的项目中，我们获得了新的发现，并成功地启动了临床试验中心。(1)药物引起的长QT综合征的分子分析：确定了结构不同的药物如苯丙地尔、硝苯卡兰、胺碘酮、屈诺酮等的结合部位。药物与通道结合的亲和力与通道腔内的药物捕获无关。这些数据发表在2006年的Mol Phrmacol杂志上。临床试验中心：与我所生物信息学教研室合作开发了符合ICH指南E14的QT间期精确分析系统。为2006年成立的临床试验中心提供技术支持。

It is well known that administration of common drugs unexpectedly induce QT prolongation in ECG and lethal arrhythmias. This drug-induced delay in ventricular repolarization (QT prolongation) attracts global attention because of the death caused by common drugs. It is an urgent need to clarify the mechanism of this drug-induced QT prolongation to prevent iatrogenic accidents. In this study, we try to clarify the mechanisms of drug-induced QT prolongation. In addition, clinical trial center was founded to construct drug data base for safety. During two years of the project, we could get novel findings and start clinical trial center successfully.(1)Molecular analysis of drug-induced long QT syndrome : Binding sites were determined in structurally diverse drugs such as bepridil, nifekalant, amiodarone, dronedarone and so on. Affinity of drug binding to channel was revealed not to correlate with drug trapping within the channel cavity. These data were published in Mol Phrmacol 2006. And also drug action to IKs channel was demonstrated to be modulated by expression of KCNE1, be-ta subunit.(2)Clinical trial center : System of precise analysis of QT interval compatible with ICH guideline E14 was developed with the collaboration of Department of Bioinformatics of our research institute. Technical support was delivered to clinical trial center founded in 2006.