Recanatini Maurizio, Poluzzi Elisabetta, Masetti Matteo, Cavalli Andrea, De Ponti Fabrizio
Department of Pharmaceutical Sciences, Via Belmeloro 6, University of Bologna, I-40126 Bologna, Italy.
Med Res Rev. 2005 Mar;25(2):133-66. doi: 10.1002/med.20019.
Prolongation of the QT interval of the electrocardiogram is a typical effect of Class III antiarrhythmic drugs, achieved through blockade of potassium channels. In the past decade, evidence has accrued that several classes of drugs used for non-cardiovascular indications may prolong the QT interval with the same mechanism (namely, human ether-a-go-go-related gene (hERG) K(+) channel blockade). The great interest in QT prolongation is because of several reasons. First, drug-induced QT prolongation increases the likelihood of a polymorphous ventricular arrhythmia (namely, torsades de pointes, TdP), which may cause syncope and degenerate into ventricular fibrillation and sudden death. Second, the fact that several classes of drugs, such as antihistamines, fluoroquinolones, macrolides, and neuroleptics may cause the long QT syndrome (LQTS) raises the question whether this is a class effect (e.g., shared by all agents of a given pharmacological class) or a specific effect of single agents within a class. There is now consensus that, in most cases, only a few agents within a therapeutic class share the ability to significantly affect hERG K(+) channels. These compounds should be identified as early as possible during drug development. Third, QT prolongation and interaction with hERG K(+) channels have become surrogate markers of cardiotoxicity and have received increasing regulatory attention. This review briefly outlines the mechanisms leading to QT prolongation and the different strategies that can be followed to predict this unwanted effect. In particular, it will focus on the approaches recently proposed for the in silico screening of new compounds.
心电图QT间期延长是Ⅲ类抗心律失常药物的典型效应，是通过阻断钾通道实现的。在过去十年中，有证据表明，几类用于非心血管适应症的药物可能通过相同机制（即人醚 - 去极化相关基因（hERG）钾通道阻断）延长QT间期。对QT间期延长的高度关注有几个原因。首先，药物诱导的QT间期延长增加了多形性室性心律失常（即尖端扭转型室速，TdP）的可能性，这可能导致晕厥并恶化为心室颤动和猝死。其次，几类药物，如抗组胺药、氟喹诺酮类、大环内酯类和抗精神病药可能导致长QT综合征（LQTS），这一事实引发了一个问题，即这是一种类效应（例如，给定药理学类别的所有药物共享）还是该类别中单一药物的特定效应。现在人们达成共识，在大多数情况下，治疗类别中只有少数药物具有显著影响hERG钾通道的能力。这些化合物应在药物研发过程中尽早识别。第三，QT间期延长以及与hERG钾通道的相互作用已成为心脏毒性的替代标志物，并受到越来越多的监管关注。本综述简要概述了导致QT间期延长的机制以及预测这种不良效应可采用的不同策略。特别是，它将重点关注最近提出的用于新化合物计算机筛选的方法。
