Hayase T, Yamamoto Y, Yamamoto K
Department of Legal Medicine, Kyoto University Faculty Medicine, Japan.
J Toxicol Sci. 1996 May;21(2):143-56. doi: 10.2131/jts.21.2_143.
The lethal effects of combining cocaine and ethanol administration in mice and the protective effects of buprenorphine, a mixed opioid agonist-antagonist, were examined with consideration to the involvement of cocaethylene. In Experiment 1, buprenorphine (0.25 or 0.5 mg/kg, i.p.) protected against a dose of cocaine exceeding the LD50 value (75 mg/kg, i.p.) combined with ethanol (3 g/kg, i.p.), although this attenuated lethality was not lower than the non-ethanol group (acute administration experiment). In Experiment 2, daily administrations of non-lethal doses of cocaine (40 mg/kg, i.p.) were combined with ethanol (1.5 g/kg, i.p.) for up to 5 days (repeated administration experiment). In Experiment 3, one dose of cocaine (75 mg/kg, i.p.) was administered after the ad libitum ingestion of an ethanol liquid diet, created by replacing 35% of the total calories with ethanol, for five days (ethanol liquid diet experiment). In all three experiments, 2 lethal groups could be discerned: an immediate lethal group (IL group) and a delayed lethal group (DL group). These groups were differentiated based on their survival times after the cocaine administrations, observed respiratory and locomotive disorders, and drug concentrations. The number of the DL group animals were elevated only in the combined cocaine-ethanol groups of Experiment 1. Buprenorphine (0.25 mg/kg, i.p.) administered before each cocaine injection attenuated the total percent lethality to levels not higher than the total percent lethality of the non-ethanol groups in the latter two experiments. This supports the validity of the protective effects of buprenorphine on cocaine toxicity amplified by non-lethal doses of ethanol. Quantitative postmortem drug analyses of mice from the IL groups, in which the drug levels were high enough to be determined, suggested that buprenorphine had a protective effect against combined cocaine-ethanol lethality without significantly decreasing the drug distributions, except for the concentration of cocaethylene in the brain.
考虑到可卡因乙烯醚的参与，研究了可卡因与乙醇联合给药对小鼠的致死作用以及混合阿片类激动剂-拮抗剂丁丙诺啡的保护作用。在实验1中，丁丙诺啡（0.25或0.5毫克/千克，腹腔注射）对超过半数致死量（75毫克/千克，腹腔注射）的可卡因与乙醇（3克/千克，腹腔注射）联合给药具有保护作用，尽管这种致死率的降低并不低于非乙醇组（急性给药实验）。在实验2中，将非致死剂量的可卡因（40毫克/千克，腹腔注射）与乙醇（1.5克/千克，腹腔注射）每日联合给药，持续5天（重复给药实验）。在实验3中，在自由摄取由用乙醇替代总热量的35%制成的乙醇液体饲料5天后，给予一剂可卡因（75毫克/千克，腹腔注射）（乙醇液体饲料实验）。在所有三个实验中，可区分出2个致死组：即时致死组（IL组）和延迟致死组（DL组）。这些组根据可卡因给药后的存活时间、观察到的呼吸和运动障碍以及药物浓度进行区分。仅在实验1的可卡因-乙醇联合给药组中，DL组动物的数量有所增加。在后面两个实验中，每次注射可卡因前给予丁丙诺啡（0.25毫克/千克，腹腔注射）可将总致死率降低至不高于非乙醇组的总致死率水平。这支持了丁丙诺啡对由非致死剂量乙醇放大的可卡因毒性具有保护作用的有效性。对IL组小鼠进行的定量死后药物分析表明，丁丙诺啡对可卡因-乙醇联合致死具有保护作用，除了脑中可卡因乙烯醚的浓度外，不会显著降低药物分布。
