药物诱导的心室复极变化中的性别差异。
Sex differences in drug-induced changes in ventricular repolarization.
作者信息
Vicente Jose, Johannesen Lars, Mason Jay W, Pueyo Esther, Stockbridge Norman, Strauss David G
机构信息
Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD, USA; Division of Cardiovascular and Renal Products, Office of New Drugs, CDER, US FDA, Silver Spring, MD, USA; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
Office of Science and Engineering Laboratories, CDRH, US FDA, Silver Spring, MD, USA; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
出版信息
J Electrocardiol. 2015 Nov-Dec;48(6):1081-7. doi: 10.1016/j.jelectrocard.2015.08.004. Epub 2015 Aug 4.
INTRODUCTION
Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs.
METHODS AND RESULTS
Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men.
CONCLUSIONS
There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation.
引言
心率校正QT（QTc）间期延长是药物诱发尖端扭转型室速的一个预测指标，尖端扭转型室速是一种潜在致命的室性心律失常，对女性的影响尤为严重。本研究评估了四种不同的人乙醚相关基因（hERG）钾通道阻断药物所诱发的心电图变化是否存在性别差异。
方法与结果
在一项双盲五周期交叉研究中，22名健康受试者（11名女性）接受了单次口服剂量的多非利特、奎尼丁、雷诺嗪、维拉帕米和安慰剂。在给药前及给药后的15个时间点采集心电图和血浆药物浓度。多非利特、奎尼丁和雷诺嗪可延长QTc。在考虑暴露差异后，任何药物的QTc延长均无性别差异。仅在多非利特用药时观察到任何心电图生物标志物存在性别差异，与男性相比，多非利特使女性的J-Tpeakc延长幅度更大（p = 0.045），但Tpeak-Tend延长幅度更小（p = 0.006），T波振幅降低幅度更小（p = 0.003）。
结论
所研究的任何药物在QTc延长方面均无性别差异。此外，本研究未观察到其他药物诱发的心电图生物标志物变化存在系统性性别差异。该研究表明，女性与男性相比更高的尖端扭转型室速风险并非由于浓度依赖性QTc延长幅度更大所致。
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