对服用莫西沙星和胺碘酮的非临床物种进行优化的 J 峰至 T 峰和 T 峰至 T 端测量。

IF 1.3 4区 医学 Q4 PHARMACOLOGY & PHARMACY Journal of pharmacological and toxicological methods Pub Date : 2024-06-08 DOI:10.1016/j.vascn.2024.107527
Theresa M. Bartko , Stephen M. Lutgen , Rebecca A. Ross , Jacqueline A. Walisser , Eric P. Garske , Kerry R. Kopelke , Kelly Ashcroft-Hawley , Hai-Ming Tang , John J. Kremer , Gregory S. Friedrichs , Jill V. Nichols
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引用次数: 0

摘要

简介:长期以来,心血管安全性和可能致命的室性快速心律失常--Torsades de Pointes(TdP)--的发病风险一直是药物研发的主要关注点。TdP 与心电图(ECG)中以 QT 间期延长为代表的心室复极化延迟有关,通常是由于人类醚-a-go-go 相关基因(hERG)编码的钾通道受阻所致。但重要的是,并不是所有能延长 QT 间期的药物都有致扭转作用,也不是所有 hERG 阻滞剂都能延长 QT 间期。最近的临床报告表明,将 QT 间期分为早期(J 到 T 峰;JTp)和晚期复极化(T 峰到 T 端;TpTe)两部分可能对区分低风险混合离子通道阻滞剂(hERG 加钙和/或晚期钠离子电流)和高风险纯 hERG 通道阻滞剂很有价值。如果这一策略适用于非临床动物模型,则可用于在药物开发过程的早期阶段降低 QT 延长化合物的风险:为了探讨这一问题,我们研究了从遥测犬和/或猴身上收集的心电图数据中的 JTp 和 TpTe,这些数据是以相关临床暴露剂量为目标给药莫西沙星或胺碘酮的。对 Tpeak 标志的位置进行了优化,并对所有时间间隔进行了心率校正(QTc、JTpc、TpTec):结果:正如预期的那样,在使用纯 hERG 阻滞剂莫西沙星时检测到 QTc 和 JTpc 间期延长,而在使用混合离子通道阻滞剂胺碘酮时检测到 QTc 和 JTpc 间期先缩短后延长,这与临床数据一致。然而,两种标准药物均未检测到预期的 TpTec 增加:讨论:由于无法检测到 TpTec 的变化,因此利用从自由活动的狗和猴子身上采集的连续单导联心电图预测心律失常时,这些子区间的实用性降低了。
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Optimized J to T peak and T peak to T end measurements in nonclinical species administered moxifloxacin and amiodarone

Introduction

Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process.

Methods

To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec).

Results

Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected.

Discussion

The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single‑lead ECGs collected from freely moving dogs and monkeys.

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来源期刊
Journal of pharmacological and toxicological methods
Journal of pharmacological and toxicological methods PHARMACOLOGY & PHARMACY-TOXICOLOGY
CiteScore
3.60
自引率
10.50%
发文量
56
审稿时长
26 days
期刊介绍: Journal of Pharmacological and Toxicological Methods publishes original articles on current methods of investigation used in pharmacology and toxicology. Pharmacology and toxicology are defined in the broadest sense, referring to actions of drugs and chemicals on all living systems. With its international editorial board and noted contributors, Journal of Pharmacological and Toxicological Methods is the leading journal devoted exclusively to experimental procedures used by pharmacologists and toxicologists.
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