Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends
Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends
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DOI：
10.1016/j.vascn.2005.07.003
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发表时间：
2006-03-01
影响因子：
1.9
通讯作者：
Warner, Barbara
中科院分区：
文献类型：
--
作者：
Hoffmann, Peter;Warner, Barbara
当代临床前体外和体内方法在预测药物诱导的尖端扭转型室性心动过速（TdP）方面并不完善。更好地了解药物诱导的TdP的起源的其他相关因素是必要的。新的复杂的体外技术，如动脉灌注心室楔准备或离体灌注心脏，可能提供更好地了解扭转型室性心动过速的机制和完善的药物测试。特别感兴趣的是跨心室壁的不同细胞类型的复极和不应性的分散、动作电位的三角测量、反向使用依赖性和动作电位持续时间的不稳定性。体内模型目前通过建立参数来完善，例如从体外致心律失常指数导出的心跳间变异性和T波形态。迄今为止，不推荐将致心律失常动物模型用于常规评价。与致室性心动过速化合物联合用药的药效学相互作用是另一个需要考虑的领域。尽管有大量证据表明心脏G蛋白偶联受体可以调节hERG通道功能，但对通道/受体串扰知之甚少。有必要进行更多的研究，以进一步评估基因表达改变，突变和多态性在药物诱导的TdP中的作用。药物诱导的室性心动过速发生的一种新机制是由于运输缺陷导致质膜上hERG通道蛋白的表达减少。药代动力学和代谢数据对于计算人的潜在性室性心动过速风险是至关重要的。考虑心内蓄积有助于描述药代动力学-药效学关系。用新的化学实体来预测hERG阻滞的计算机虚拟筛选程序可能会发展成为一种有前途的工具。UP心律失常的计算机建模对于组织和整合大量生成的数据可能变得越来越重要。目前。然而，计算机模拟方法不能取代现有的临床前体外和体内模型。(c)2005年爱思唯尔公司All rights reserved.
Contemporary preclinical in vitro and in vivo methods have been imperfect in predicting drug-induced Torsades de Pointes (TdP) in humans. A better understanding of additional relevant factors in the genesis of drug-induced TdP is necessary. New sophisticated in vitro techniques, such as arterially perfused ventricular wedge preparations or isolated perfused hearts, potentially offer a better understanding of torsadogenic mechanisms and a refinement of drug testing. Of particular interest are the dispersion of repolarization and the refractoriness of different cell types across the ventricular wall, triangulation of the action potential, reverse use dependence and instability of the action potential duration. In vivo models are currently refined by establishing parameters such as beat-to-beat variability and T-wave morphology as derived from the in vitro proarrhythmia indices. Animal models of proarrhythmia are to date not recommended for routine evaluation. A pharmacodynamic interaction with combinations of torsadogenic compounds is another area to be considered. Little is known about channel/receptor cross talk, although considerable evidence exists that cardiac G protein-coupled receptors can modulate hERG channel function. More investigations are necessary to further evaluate the role of altered gene expression, mutations, and polymorphisms in drug-induced TdP. A novel mechanism of drug-induced torsadogenesis is the reduced expression of hERG channel protein on the plasma membrane due to a trafficking defect. Pharmacokinetic and metabolism data are crucial for calculating the risk of a torsadogenic potential in man. Consideration of intracardiac accumulation can help in delineating pharmacokinetic-pharmacodyamic relationships. In silico virtual screening procedures with new chemical entities to predict hERG block may develop as a promising tool. The role of in silico modeling of UP arrhythmia is likely to become increasingly important for organizing and integrating the vast amount of generated data. At present.. however, in silico methods cannot replace existing preclinical in vitro and in vivo models. (c) 2005 Elsevier Inc. All rights reserved.