Hayase T, Yamamoto Y, Yamamoto K
Department of Legal Medicine, Kyoto University Graduate School of Medicine, Faculty of Medicine, Japan.
J Toxicol Sci. 1999 Aug;24(3):227-35. doi: 10.2131/jts.24.3_227.
The present study investigated the toxicity of repeated subcutaneous cocaine administrations combined with oral doses of ethanol, and discussed the role of the toxic metabolite cocaethylene. Subcutaneous cocaine (70 mg/kg) was given to male ICR mice at 45 min after an oral administration of either ethanol (maximum 3 g/kg) (cocaine-ethanol group; n = 50) or saline control (cocaine group; n = 30), once per day, for up to 5 days. In the combined cocaine-ethanol group, the total frequency of death was significantly increased (86%) as compared to the cocaine group (40%). In both administration groups, regardless of the day of death, "late" deaths characterized by the late and unexpected onset of fatal symptoms could be differentiated from "early" deaths on the basis of the survival time after the last cocaine injection, the drug concentrations in the tissues at the time of death, and/or the observed physical disorders. In the combined cocaine-ethanol group, a late death group with survival times exceeding 12 hr and two early death groups could be differentiated, based on the presence or absence of cocaethylene and the different types of clinical symptoms. In the early death group in which cocaethylene could be detected, the volume of ethanol ingested was not significantly different from the late death group with large ethanol consumption and slow exacerbation of the respiratory and locomotive symptoms. Furthermore, the severity of the cocaine-induced seizures was also similarly decreased by ethanol. In the other early death group in which cocaethylene could not be detected, the volume of ethanol ingested was significantly lower than in the late death group, and seizures as severe as in the cocaine-only group were observed.
本研究调查了重复皮下注射可卡因并口服乙醇的毒性，并探讨了有毒代谢物可卡乙碱的作用。在口服乙醇（最大剂量3 g/kg）（可卡因 - 乙醇组；n = 50）或生理盐水对照（可卡因组；n = 30）45分钟后，给雄性ICR小鼠皮下注射可卡因（70 mg/kg），每天一次，持续5天。与可卡因组（40%）相比，可卡因 - 乙醇联合组的总死亡频率显著增加（86%）。在两个给药组中，无论死亡日期如何，根据最后一次注射可卡因后的存活时间、死亡时组织中的药物浓度和/或观察到的身体紊乱情况，可将以致命症状延迟和意外发作特征的“晚期”死亡与“早期”死亡区分开来。在可卡因 - 乙醇联合组中，根据可卡乙碱的存在与否和不同类型的临床症状，可区分出存活时间超过12小时的晚期死亡组和两个早期死亡组。在可检测到可卡乙碱的早期死亡组中，摄入的乙醇量与乙醇摄入量高且呼吸和运动症状加重缓慢的晚期死亡组无显著差异。此外，乙醇对可卡因诱发的癫痫发作严重程度的降低作用也相似。在另一个未检测到可卡乙碱的早期死亡组中，摄入的乙醇量显著低于晚期死亡组，且观察到与仅使用可卡因组一样严重的癫痫发作。
