MECHANISMS OF INCREASED RISK OF TORSADES DE POINTES ASSOCIATED WITH POTASSIUM

与钾相关的尖端扭转型室速风险增加的机制

• 批准号: 7717513
• 负责人: James E. Tisdale
• 金额: --
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7717513
• 关键词: Age; Amiodarone; Arrhythmia; Atrial Fibrillation; Computer Retrieval of Information on Scientific Projects Database; Control Groups; Drug Kinetics; Electric Countershock; Enrollment; Funding; Grant; Half-Life; Heart failure; Hour; Infusion procedures; Institution; Left Ventricular Dysfunction; Life; Measures; Methods; Myocardial; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Potassium; Potassium Channel; Research; Research Personnel; Resources; Risk; Serum; Source; Time; Torsades de Pointes; United States National Institutes of Health; Venous blood sampling; drug development; ibutilide; sex

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. More than 50 drugs with the potential to cause the life threatening arrhythmia torsades de pointes (TdP) are available in the U.S. Patients with heart failure (HF) due to left ventricular (LV) dysfunction are at increased risk for drug-induced TdP, due to undetermined mechanisms. We hypothesize that the increased risk of drug-induced TdP in patients with HF is due to 1) Increased myocardial responsiveness to potassium channel blockade, manifested by altered QT interval pharmacodynamics, and/or 2) Alterations in pharmacokinetics of hepatically metabolized potassium channel blocking agents. Patients with HF and atrial fibrillation (AF) undergoing DC cardioversion will be enrolled, as will a control group of AF patients without HF matched for age, sex, and B-Blocker or amiodarone use. Patients will receive ibutilide 1.0 mg intravenously over 10 minutes. ECGs and venous blood samples will be taken before ibutilide administration and at specific times for 48 hours following the end of infusion. QT intervals will be measured and corrected using several methods and serum ibutilide concentrations will be determined. Expected outcomes: 1) Patients with HF will have: Lower QT interval Ec50; Higher AUQCT; Greater QT interval Emax, 2) Patients with LV dysfunction will have: Higher ibutilide Cmax; Reduced CL; Smaller Vd; Greater AUC; Longer half-life. This research will show that patients with HF have increased myocardial responsiveness to potassium channel inhibition and impaired ability to eliminate a heptically metabolized potassium channel blocking drug, and will have important implications regarding use of potassium channel blocking agents and for drug development.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 美国有超过 50 种药物可能导致危及生命的尖端扭转型室速 (TdP) 心律失常。由于左心室 (LV) 功能障碍而导致心力衰竭 (HF) 的患者发生药物性 TdP 的风险增加，因为至未确定的机制。 我们假设心力衰竭患者药物诱发 TdP 的风险增加是由于 1) 心肌对钾通道阻断剂的反应性增加，表现为 QT 间期药效学改变，和/或 2) 肝代谢钾通道阻断剂的药代动力学改变。 将纳入接受 DC 电复律的心力衰竭和心房颤动 (AF) 患者，以及年龄、性别和 B 阻滞剂或胺碘酮使用情况相匹配的无心力衰竭的 AF 患者对照组。 患者将在 10 分钟内静脉注射 1.0 mg 伊布利特。 在伊布利特给药前以及输注结束后 48 小时内的特定时间采集心电图和静脉血样本。 将使用多种方法测量和校正 QT 间期，并确定血清伊布利特浓度。 预期结果： 1) 心力衰竭患者将： QT 间期 Ec50 较低；更高的 AUQCT；更大的 QT 间期 Emax，2) 左心室功能不全的患者将： 更高的伊布利特 Cmax；降低 CL； Vd 较小；更大的 AUC；半衰期更长。 这项研究将表明，心力衰竭患者的心肌对钾通道抑制的反应性增加，并且消除肝脏代谢的钾通道阻断药物的能力受损，并且将对钾通道阻断剂的使用和药物开发产生重要影响。