Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death
Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death
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DOI：
10.1093/eurheartj/ehi092
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发表时间：
2005-03-01
影响因子：
39.3
通讯作者：
Leufkens, HGM
中科院分区：
文献类型：
--
作者：
De Bruin, ML;Pettersson, M;Leufkens, HGM
目的抑制HERG钾通道导致的药物性qtc延长可导致严重的室性心律失常和猝死。我们在日常实践中研究了促心律失常药物的定量抗herg活性作为这一结果的危险因素。方法与结果采用世界卫生组织国际药物监测规划（WHO-UMC）截至2003年第一季度收到的28426例已知抗herg活性药物疑似不良反应报告，计算报告优势比（RORs）。病例定义为心脏骤停、猝死、点扭转、心室颤动和室性心动过速报告（n = 5591），并与非病例比较抗HERG活性，定义为有效治疗血浆浓度（ETCPunbound）除以可疑药物的HERG IC50值。我们发现，以log(10) （ETCPunbound/IC50）测量的药物抗herg活性与向WHO-UMC数据库报告的严重室性心律失常和猝死之间存在1.93 （95% CI: 1.89-1.98）的显著相关性。结论抗herg活性与WHO-UMC数据库中报告的严重室性心律失常和猝死的风险相关。这些发现支持临床前HERG测试对预测药物的促心律失常作用的价值。
Aims Drug-induced QTC-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricutar arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice.Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n = 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89-1.98) between the anti-HERG activity of drugs, measured as log(10) (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database.Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.