Trenor Beatriz, Gomis-Tena Julio, Cardona Karen, Romero Lucia, Rajamani Sridharan, Belardinelli Luiz, Giles Wayne R, Saiz Javier
Channels (Austin). 2013 Jul-Aug;7(4):249-62. doi: 10.4161/chan.24905.
Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (I(NaL)) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K(+) current (I(Kr)). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of I(Kr)/I(NaL) ratio of steady-state block of drug candidates on "torsadogenic" biomarkers. The O'Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of I(NaL) and I(Kr) were evaluated. "Safety plots" were developed to illustrate the value of the specific biomarker for selected combinations of IC(50)s for I(Kr) and I(NaL) of potential drugs. The reference biomarkers at baseline changed depending on the "drug" specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of I(NaL)) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.
药物诱导的动作电位（AP）延长导致尖端扭转型室速是抗心律失常药物研发中的一个主要问题。然而，研发改进的抗心律失常药物仍然是一个重要机遇，其中一些药物可能会阻断不同的通道。晚钠电流（I(NaL)）的部分阻断已成为一种新的抗心律失常机制。在自由基攻击或缺氧情况下，它可能有效。此外，这种方法可以减弱阻断快速延迟整流钾电流（I(Kr)）所产生的促心律失常作用。我们计算工作的主要目标是开发一种计算机模拟工具，用于临床前抗心律失常药物安全性评估，通过说明候选药物稳态阻断的I(Kr)/I(NaL)比值对“致扭转型室速”生物标志物的影响。使用了奥哈拉等人的人心室肌细胞AP模型。心律失常风险的生物标志物，即动作电位时程、三角测量、反向频率依赖性、复极跨壁离散度和心电图QT间期，通过单个心肌细胞和一维肌束模拟进行计算。评估了I(NaL)和I(Kr)的预定阻断量。绘制了“安全性图”，以说明特定生物标志物对于潜在药物I(Kr)和I(NaL)的IC(50)选定组合的值。基线时的参考生物标志物根据这两个离子通道靶点的“药物”特异性而变化。雷诺嗪和GS967（一种新型强效I(NaL)抑制剂）产生了一个根据标准监管标准被认为安全的生物标志物数据集。这种新的计算机模拟方法有助于评估人心室中药物和候选药物的促心律失常潜力。
