Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

最小化药物引起的 QT 间期延长的新方法

• 批准号: 10699983
• 负责人: James E. Tisdale
• 金额: $ 50.21万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699983
• 关键词: Age; Age Years; Anti-Arrhythmia Agents; Antibiotics; Antidepressive Agents; Antipsychotic Agents; Area; Arrhythmia; Attenuated; Biological Markers; Blood; Cardiac; Cardiac Electrophysiologic Techniques; Clinical; Clinical Trials; Cross-Over Studies; Data; Dose; Double-Blind Method; Drug usage; Electrocardiogram; Fluoroquinolones; Goals; Gonadal Steroid Hormones; Heart Rate; Hormones; Macrolides; Measurement; Methadone; Methods; Oral; Oral Administration; Outcome; Outcome Measure; Patients; Pharmaceutical Preparations; Pharmacists; Pharmacodynamics; Phase; Placebo Control; Placebos; Postmenopause; Prevention; Prevention strategy; Preventive; Progesterone; Publishing; Randomized; Research; Research Personnel; Risk; Risk Factors; Risk Reduction; Scientist; Serum; Testing; Testosterone; Torsades de Pointes; Ventricular; Ventricular Arrhythmia; Ventricular Tachycardia; Woman; Work; antimicrobial; attenuation; cardiovascular pharmacology; effective therapy; efficacy evaluation; experience; high risk; high risk population; human old age (65+); ibutilide; improved; medication safety; men; multidisciplinary; novel; novel strategies; novel therapeutic intervention; older men; older patient; older women; pre-clinical; primary outcome; prospective; protective effect; response; sudden cardiac death; time interval

PROJECT SUMMARY/ABSTRACT Torsades de pointes (TdP) is a ventricular tachycardia associated with prolongation of the corrected QT (QTc) interval, and which may be caused by > 150 widely used drugs. TdP results in catastrophic outcomes, including sudden cardiac death. Older age is a risk factor for drug-induced TdP, possibly due to declining serum progesterone and testosterone concentrations in postmenopausal women and men, respectively. The ECG biomarkers J-Tpeak and Tpeak-Tend, represent early and late repolarization, respectively, as well as dispersion of repolarization (Tpeak-Tend). Preclinical evidence and preliminary data from our group indicate that progesterone and testosterone exert protective effects against drug-induced prolongation of ventricular repolarization. Effective means of reducing the risk of drug-induced QTc interval prolongation and TdP in high risk populations requiring therapy with QTc-prolonging drugs have not been identified, and the effects of sex hormones on early vs late ventricular repolarization and dispersion of repolarization are unknown. The objectives of this research are to evaluate novel therapeutic approaches to attenuate drug-induced QTc lengthening. Our central hypothesis is that drug-induced QTc lengthening is attenuated by administration of oral progesterone and transdermal testosterone. Specific Aim 1: Determine the efficacy of oral progesterone as a preventive method to attenuate drug-induced QTc interval lengthening in postmenopausal women. Specific Aim 2: Determine the influence of oral progesterone on drug-induced lengthening of early and late ventricular repolarization in postmenopausal women. Specific Aim 3: Determine the efficacy of transdermal testosterone as a preventive method to attenuate drug-induced QTc interval lengthening in men ≥ 65 years of age. Specific Aim 4: Determine the influence of transdermal testosterone on drug-induced lengthening of early and late ventricular repolarization in men ≥ 65 years of age. Specific Aims 1&2 will be achieved via a prospective, randomized, double-blind, placebo-controlled two-way crossover study in postmenopausal women age ≥ 50 years (n=48). Each subject will take oral progesterone 400 mg or matching placebo daily for 7 days (≥ 14-day washout period between phases). On day 7, each subject will receive a single dose of the QTc-lengthening drug ibutilide 0.003 mg/kg. Specific Aims 3&4 will be achieved via a prospective, randomized, double-blind, placebo-controlled two-way crossover study in men ≥ 65 years of age (n=35). Each subject will apply transdermal testosterone 1% 100 mg or transdermal placebo once daily for 3 days (≥ 7-day washout period between phases). On day 7, each subject will ibutilide 0.003 mg/kg. In both studies, post-ibutilide QT, J-Tpeak and Tpeak-Tend intervals and serum ibutilide concentrations will be determined serially. Primary outcome measures: 1) Maximum post-ibutilide QTc intervals, 2) Maximum post-ibutilide % change in QTc intervals, 3) Area under the QTc interval-time curves, and 4) J-Tpeak and Tpeak-Tend intervals. This research will identify effective approaches for reducing the risk of drug-induced QTc interval prolongation in high-risk patients.

项目总结/文摘