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: 10220133
• 负责人: James E. Tisdale
• 金额: $ 48.95万
• 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/10220133
• 关键词: Age; Age-Years; 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; Placebos; Postmenopause; Prevention; Prevention strategy; Preventive; Progesterone; Publishing; Randomized; Research; Research Personnel; Risk; Risk Factors; 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; 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/摘要 尖端扭转性室性心动过速（TdP）是一种与校正QT（QTc）延长相关的室性心动过速 间隔，可能由> 150种广泛使用的药物引起。TdP会导致灾难性的后果， 包括心脏猝死年龄较大是药物诱导的TdP的一个危险因素，可能是由于 绝经后女性和男性的血清孕酮和睾酮浓度。的 ECG生物标志物J-Tpeak和Tpeak-Tend分别代表早期和晚期复极，以及 复极化离散度（T峰-T末）。我们小组的临床前证据和初步数据表明， 孕酮和睾酮对药物引起的心室延长具有保护作用 复极化降低高血压患者药物性QTc间期延长和TdP风险的有效方法 尚未确定需要QTc延长药物治疗的风险人群， 激素对早期与晚期心室复极和复极离散度的影响尚不清楚。的 本研究的目的是评价新的治疗方法，以减轻药物诱导的QTc 延长。我们的中心假设是，药物诱导的QTc延长通过给予 口服黄体酮和透皮睾酮。具体目标1：确定口服孕酮的疗效， 一种预防绝经后妇女药物性QTc间期延长的方法。具体 目的2：确定口服孕酮对药物诱导的早、晚心室延长的影响 绝经后妇女的复极。具体目标3：确定经皮睾酮的疗效 作为一种预防性方法，以减弱≥ 65岁男性中药物诱导的QTc间期延长。具体 目的4：确定睾酮透皮给药对药物诱导的早期和晚期延长的影响。 ≥ 65岁男性的心室复极。具体目标1和2将通过前瞻性， 在年龄≥ 50岁的绝经后女性中进行的随机、双盲、安慰剂对照双向交叉研究 年（n=48）。每例受试者将每天口服黄体酮400 mg或匹配的安慰剂7天（≥ 14天 阶段之间的洗脱期）。第7天，每例受试者将接受单次QTc延长给药 药物伊布利特0.003 mg/kg。具体目标3和4将通过一项前瞻性、随机、双盲、 在≥ 65岁男性中进行的安慰剂对照双向交叉研究（n=35）。每个主题将适用于 经皮睾酮1% 100 mg或经皮安慰剂，每日一次，持续3天（≥ 7天洗脱期 阶段之间）。第7天，每例受试者将接受伊布利特0.003 mg/kg。在两项研究中，伊布利特后QT、J-T峰值 和Tpeak-Tend间期和血清伊布利特浓度将连续测定。主要结局 测量：1）伊布利特给药后最大QTc间期，2）伊布利特给药后QTc间期的最大%变化，3） QTc间期-时间曲线下面积，以及4）J-T峰和T峰-T末间期。这项研究将确定 降低高风险患者中药物诱导的QTc间期延长风险的有效方法。