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Studies on an alternative in vitro method for assessment of physical dependence potential of opioid substances

评估阿片类物质身体依赖性潜力的替代体外方法的研究

基本信息

批准号：
01480503
负责人：
YANAGITA Tomoji
金额：
$ 2.18万
依托单位：
Central Institute for Experimental Animals
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

In assessment of the physical dependence potential of drugs, withdrawal signs are usually observed in whole animals, but establishment of alternative in vitro methods are needed since whole animal experiments may entail sow withdrawal discomfort if physical dependence develops. For this reason, an in vitro method of assessing the physical dependence potential of some opioid substances was sought by using isolated animal organs, and the following results were obtained.1)A longitudinal muscle preparation of guinea pig ileum was suspended in Magnus bath and electrically stimulated. Morphine, pethidine, codeine, pentazocine, and ethyl-keto-cyclazocine(EKC)inhibited the contraction and IC50 values were obtained with these drugs. The effects of these drugs were antagonized by naloxone.2)When the preparations were incubated with a test drug solution for 24 hrs, then suspended in the bath and naloxone was applied, the baseline of the contraction was elevated. The extent of this elevation paral … More leled the incubation time. When the preparations were not incubated but were pretreated with the drugs for 30 min in the bath, the elevation was obvious with morphine or codeine but unclear with the other drugs.3)In deferent duct preparations of the rabbit none of the drugs, except EKC, inhibited the contraction, and with EKC no elevation of the baseline was observed with naloxone application, following 24 hr incubation.4)In an in vivo experiment in rats, EKC was intravenously infused every hour for 72 hrs, then nalox one was subcutaneously administered and withdrawal signs were observed for lhr. The animals manifested appearent withdrawal signs such as hyperirritability, diarhea, and body weight loss, but the signs were weaker than those of pentazocine. The results were in agreement with those of the in vitro experiments.Thus, the method of using isolated guinea pig ileum was found to have practical value for the assessment of physical dependence potential of opioid substances if applied in a stepwise fashion ; first to observe IC50, then to incubate the preparation with a test drug for 24 hrs at 1 to 5 multiple concentrations of IC50, and if the baseline elevation is observed to then pretreat the preparation with the test drug for 30 min in a bath prior to naloxone application. Less

在评估药物的身体依赖潜力时，通常在整个动物中观察到戒断症状，但需要建立替代的体外方法，因为如果出现身体依赖，整个动物实验可能会导致母猪戒断不适。为此，我们利用分离的动物器官，探索了一种评估某些阿片类物质的身体依赖潜力的体外方法，并获得了以下结果：1)豚鼠回肠的纵向肌肉制剂悬浮在Magnus浴中，并受到电刺激。吗啡、度冷丁、可待因、五氮唑碱和乙基酮-环佐辛(EKC)对收缩有抑制作用，并获得IC50值。这些药物的作用可被纳洛酮所拮抗。2)用受试药物溶液孵育24小时后，悬液中加入纳洛酮，可使收缩基线升高。与…平行的高程范围更多的是延长了孵化时间。3)在兔输精管标本中，除EKC外，其余药物均不能抑制其收缩。4)在大鼠体内实验中，除EKC外，其他药物均不能抑制LHR的收缩。4)在大鼠体内实验中，EKC每小时静脉滴注一次，持续72小时，然后皮下注射纳洛酮，观察到LHR的戒断征象。这些动物表现出明显的戒断体征，如过敏、腹泻和体重减轻，但这些体征弱于戊唑西林。实验结果与体外实验结果一致。因此，采用豚鼠离体回肠法对阿片类物质的身体依赖潜力进行分级应用，首先观察IC50，然后以1~5倍的IC50浓度与受试药物孵育24小时，如果观察基线升高，则在纳洛酮应用前用受试药物在浴缸中预处理30分钟。较少