Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening

项目摘要/摘要 尖端扭转性室性心动过速是一种与校正的QT间期延长有关的室性心动过速。 间歇性，可能是由广泛使用的药物引起的。TDP会导致灾难性的后果， 包括心源性猝死。高龄是药物引起TDP的危险因素，可能是由于年龄下降所致。 绝经后女性和男性的血清孕酮和睾酮浓度。这个 心电生物标志物J-T峰和T峰-Tend分别代表早期复极和晚期复极以及 复极离散度(T峰-Tend)。来自我们小组的临床前证据和初步数据表明 孕酮和睾酮对药物所致的室性心动过速延长的保护作用 复极化。降低高血压病患者药物性QT间期延长和TDP的有效途径 需要QTC延长药物治疗的危险人群尚未确定，性行为的影响 激素对早期和晚期心室复极和复极离散度的影响尚不清楚。这个 本研究的目的是评估减轻药物引起的QTC的新的治疗方法。 加长。我们的中心假设是药物引起的QT间期延长可通过给予 口服黄体酮和透皮睾酮。具体目标1：测定口服黄体酮的疗效 一种预防药物引起的绝经后妇女QT间期延长的方法。特定的 目的2：观察口服黄体酮对药物引起的心室早、晚期延长的影响。 绝经后妇女的复极。具体目标3：确定睾酮透皮吸收的疗效 作为一种预防方法，在65岁的男性≥中减轻药物引起的QTc间期延长。特定的 目的4：测定透皮睾酮对药物引起的早、晚期血管延长的影响。 65岁男性≥的心室复极。具体目标1和2将通过前瞻性的、 年龄为≥50的绝经后妇女的随机、双盲、安慰剂对照的双向交叉研究 年龄：48岁。每个受试者每天口服黄体酮400毫克或匹配的安慰剂，连续7天(≥14天 阶段之间的冲洗期)。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。具体目标3和4将通过前瞻性、随机化、双盲、 65岁男性≥的安慰剂对照双向交叉研究(n=35)。每门课程都将适用 1%100毫克睾酮透皮贴剂或透皮安慰剂，每日1次，连续3天(≥7天洗脱期 阶段之间)。第7天，每个受试者将伊布利特0.003 mg/kg。在这两项研究中，伊布利特治疗后的QT、J-T峰 并将连续测定Tak-Tend间期和血清伊布利特浓度。主要结果 测量：1)伊布利特治疗后最大QT间期，2)伊布利特治疗后QT间期最大变化%，3) QT间期-时间曲线下面积；(4)J-T峰和T峰-T间期。这项研究将确定 降低高危患者药物所致QT间期延长风险的有效方法。

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.