GENDER AND RISK OF DRUG INDUCED CARDIAC ARRHYTHMIAS

性别和药物引起的心律失常的风险

• 批准号: 6389723
• 负责人: Steven N. Ebert
• 金额: $ 22.45万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389723
• 关键词: arrhythmia; arrhythmic agent; disease /disorder proneness /risk; drug adverse effect; electrocardiography; female; gender difference; laboratory rabbit; long QT syndrome; organ culture; pharmacogenetics; potassium channel; quinidine; voltage /patch clamp

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.

描述：（改编自申请人的摘要）一个明显的基于性别的 对药物反应的差异是女性发展的风险更大 危及生命的心律失常尖端扭转型室性心动过速药物具有 在女性中引起扭转型室性心动过速的倾向通常会阻断钾通道， 从而延长心脏复极。主要研究者 进行了一项临床研究，比较了QT间期对奎尼丁的反应， 证实女性的QT反应比男性更大。这 申请书提出了研究，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PI已经在隔离的 兔心脏，以研究复极的性别差异， 发生扭转型室性心动过速，发现基线和药物诱导（奎尼丁 和索他洛尔）改变女性心脏的QT间期， 延迟整流钾电流和内向整流钾电流， 女性心脏会出现扭转型室性心动过速本申请建议使用 家兔模型，以确定与性别相关的电生理学差异 （基线时和奎尼丁时的动作电位和膜片钳记录， 索他洛尔），以确定性别差异的离子基础。的潜在 性类固醇激素在调节特定离子通道中的作用将 也要加以研究。该申请提出，这些结果将提供 关于电生理学和 女性药物性心律失常的风险更大，并可能导致 筛选有药物诱发心律失常风险的个体， 降低诱发心律失常风险的药物。

项目成果

Nicotine induces a long QT phenotype in Kcnq1-deficient mouse hearts.

尼古丁在 Kcnq1 缺陷小鼠心脏中诱导长 QT 表型。

• DOI: 10.1124/jpet.103.053017
• 发表时间: 2003
• 期刊: The Journal of pharmacology and experimental therapeutics.
• 作者: Tosaka,Toshimasa;Casimiro,MathewC;Rong,Qi;Tella,Srihari;Oh,Michelle;Katchman,AlexanderN;Pezzullo,JohnC;Pfeifer,Karl;Ebert,StevenN
• 通讯作者: Ebert,StevenN