GENDER AND RISK OF DRUG INDUCED CARDIAC ARRHYTHMIAS

描述：(改编自申请人的摘要)明显的基于性别的 对药物反应的不同是女性患上癌症的风险更大 危及生命的心律失常急转直下。这些药物具有 导致女性扭体的倾向通常阻断钾通道和 从而延长心脏复极。首席调查员已经 进行了一项临床研究，比较了奎尼丁和奎尼丁对QT间期的反应 证实了女性对QT的反应比男性更大。这 应用程序提出研究以检验基于性别的假设 心脏离子电流密度的差异是观察到的 QT间期长度的差异和女性对 导致QT延长的药物。国际和平研究所已经在孤立的 兔心复极性别差异的研究 出现扭动并发现更大的基线和药物诱导(奎尼丁 和索他洛尔)改变女性心脏的QT间期，降低心脏的密度。 延迟整流和内向整流钾电流，并增加 女性心脏有发生扭动的倾向。此应用程序建议使用 识别电生理学性别差异的兔模型 (动作电位和膜片钳记录在基线和奎尼丁和 索他洛尔)，以确定性别差异的离子基础。潜力 性类固醇激素在调节特定离子通道中的作用 也被调查。应用程序提出，这些结果将提供 关于电生理和性别差异的有价值的信息 女性发生药物引起的心律失常的风险更大，并可能导致采取措施 筛查有可能发生药物引起的心律失常或发生 降低引发心律失常风险的药物。

DESCRIPTION: (adapted from the applicant's abstract) A pronounced gender-based difference in response to drugs is the far greater risk for women to develop the life threatening arrhythmia torsades de pointes. Drugs that have the tendency to cause torsades in women commonly block potassium channels and thereby prolong cardiac repolarization. The Principal Investigator has performed a clinical study comparing the QT interval response to quinidine and confirmed the greater response of the QT in women compared to men. This application proposes studies to test the hypothesis that gender based differences in cardiac ion current densities are responsible for the observed differences in QT interval length and the greater sensitivity of females to drugs that cause QT lengthening. The PI has done initial studies in isolated rabbit hearts to investigate gender differences in repolarization and the development of torsades and found greater baseline and drug induced (quinidine and sotalol) changes of QT intervals in female hearts, and reduced densities of delayed rectifier and inward rectifier potassium currents, and an increased tendency to develop torsades in female hearts. This application proposes to use the rabbit model to identify gender-related differences in electrophysiology (action potential and patch clamp recordings at baseline and with quinidine and sotalol) to identify the ionic basis for the gender differences. The potential roles for sex steroid hormones in the regulation of specific ion channels will also be investigated. The application proposes that these results will provide valuable information regarding gender differences in electrophysiology and the greater risk of drug-induced arrhythmias in women, and might lead to methods of screening individuals at risk of drug-induced arrhythmias or the development of drugs with reduced risk of inducing arrhythmia.