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

基本信息

批准号：
10462808
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
项目类别：
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/10462808
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 Placebo Control 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

项目摘要

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.

项目概要/摘要尖端扭转型室速 (TdP) 是一种与校正 QT (QTc) 延长相关的室性心动过速间隔，这可能是由> 150种广泛使用的药物引起的，导致灾难性的结果，包括心源性猝死是药物引起的 TdP 的一个危险因素，可能是由于年龄下降。分别测定绝经后女性和男性的血清孕酮和睾酮浓度。心电图生物标志物 J-Tpeak 和 Tpeak-Tend 分别代表早期和晚期复极，以及复极化分散度（Tpeak-Tend）。临床前证据和我们小组的初步数据表明：黄体酮和睾酮对药物引起的心室延长发挥保护作用复极是降低高危人群药物引起的 QTc 间期延长和 TdP 风险的有效方法。尚未确定需要使用延长 QTc 的药物治疗的危险人群，并且性别的影响激素对早期心室复极与晚期心室复极以及复极离散度的影响尚不清楚。本研究的目的是评估减轻药物引起的 QTc 的新治疗方法我们的中心假设是药物引起的 QTc 延长会因服用药物而减弱。口服黄体酮和透皮睾酮具体目标 1：确定口服黄体酮的功效。一种减轻绝经后妇女药物引起的 QTc 间期延长的预防方法。目标 2：确定口服黄体酮对药物引起的早期和晚期心室延长的影响具体目标 3：确定透皮睾酮的功效。作为减轻 65 岁以上男性药物引起的 QTc 间期延长的预防方法。目标 4：确定透皮睾酮对药物诱导的早期和晚期延长的影响 ≥ 65 岁男性的心室复极将通过前瞻性实现。针对 50 岁以上绝经后女性的随机、双盲、安慰剂对照双向交叉研究年 (n=48)。每位受试者每天口服 400 毫克黄体酮或匹配的安慰剂，持续 7 天（≥ 14 天）在第 7 天，每个受试者将接受单剂量的 QTc 延长。药物伊布利特 0.003 mg/kg 将通过前瞻性、随机、双盲、安慰剂对照双向交叉研究，对象为 ≥ 65 岁的男性（n=35）。透皮睾酮 1% 100 mg 或透皮安慰剂，每天一次，持续 3 天（≥ 7 天的冲洗期在第 7 天，每个受试者服用伊布利特 0.003 mg/kg，伊布利特后 QT、J-Tpeak。 Tpeak-Tend 间隔和血清伊布利特浓度将连续确定主要结果。测量：1) 伊布利特治疗后最大 QTc 间期，2) 伊布利特治疗后 QTc 间期最大变化百分比，3) QTc 间期曲线下的面积，以及 4) J-Tpeak 和 Tpeak-Tend 间期本研究将确定。降低高危患者药物引起的 QTc 间期延长风险的有效方法。