Ishizaka Tomomichi, Yoshimatsu Yu, Ozawa Minori, Kimotsuki Tomofumi, Takasaki Wataru, Manabe Sunao, Yasuda Mitsuya
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., 717 Horikoshi, Fukuroi, Shizuoka 437-0065, Japan.
J Pharmacol Toxicol Methods. 2009 Mar-Apr;59(2):86-93. doi: 10.1016/j.vascn.2009.01.002.
Cynomolgus monkeys are used in in vivo models of safety pharmacological studies to evaluate the effects of drug candidates on the cardiovascular system. Models using halothane-anesthetized animals have been used for the detection of drug-induced QT interval prolongation, but few studies with anesthetized monkeys have been reported.
The electrophysiological changes induced by dl-sotalol, a representative class III antiarrhythmic drug, were assessed in halothane-anesthetized monkeys (n = 4) or conscious and unrestrained monkeys (n = 4).
In terms of basal characteristics, the QT interval was longer and the heart rate (HR) was lower under anesthesia than those under conscious conditions. Intravenous administration of 0.1 to 3 mg/kg dl-sotalol to anesthetized monkeys decreased the HR and prolonged the QT interval, monophasic action potential (MAP) duration and ventricular effective refractory period in a dose-dependent manner. In addition, reverse use-dependent prolongation of MAP duration was detected by electrical pacing, whereas the terminal repolarization period was hardly affected at any dose. Oral administration of 3 to 30 mg/kg dl-sotalol to conscious monkeys also decreased the HR and prolonged the QT interval in a dose-dependent manner. When compared at similar plasma concentrations of sotalol, the extent of QT interval prolongation under halothane anesthesia was equal to or greater than that under conscious conditions.
The sensitivity for detection of drug-induced QT prolongation under halothane anesthesia may be satisfactory compared with that under conscious conditions. The present examinations indicated the usefulness of a model using halothane-anesthetized monkeys for evaluation of drug-induced QT interval prolongation.
食蟹猴被用于安全药理学研究的体内模型，以评估候选药物对心血管系统的影响。使用氟烷麻醉动物的模型已被用于检测药物诱导的QT间期延长，但关于麻醉猴的研究报道较少。
在氟烷麻醉的猴子（n = 4）或清醒且不受约束的猴子（n = 4）中评估了代表性Ⅲ类抗心律失常药物dl-索他洛尔诱导的电生理变化。
就基础特征而言，麻醉状态下的QT间期比清醒状态下更长，心率（HR）更低。向麻醉猴静脉注射0.1至3 mg/kg的dl-索他洛尔会使HR降低，并使QT间期、单相动作电位（MAP）持续时间和心室有效不应期呈剂量依赖性延长。此外，通过电起搏检测到MAP持续时间存在反向使用依赖性延长，而在任何剂量下终末复极期几乎不受影响。向清醒猴口服3至30 mg/kg的dl-索他洛尔也会使HR降低，并使QT间期呈剂量依赖性延长。当在索他洛尔相似血浆浓度下进行比较时，氟烷麻醉下QT间期延长的程度等于或大于清醒状态下的程度。
与清醒状态相比，氟烷麻醉下检测药物诱导的QT延长的敏感性可能令人满意。本研究表明，使用氟烷麻醉猴的模型对于评估药物诱导的QT间期延长是有用的。
