长效突变型细菌可卡因酯酶对大鼠急性可卡因毒性的影响。
Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats.
机构信息
Department of Pharmacology, 1301 MSRB III, 1150 W. Medical Center Drive, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
出版信息
Drug Alcohol Depend. 2011 Nov 1;118(2-3):158-65. doi: 10.1016/j.drugalcdep.2011.03.015. Epub 2011 Apr 11.
BACKGROUND
A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine's cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine's cardiovascular, convulsant, and lethal effects in male and female rats.
METHODS
Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats.
RESULTS
Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4h, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity.
CONCLUSIONS
Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity.
背景
一种长效、双突变细菌可卡因酯酶（CocE T172R/G173Q；DM CocE）已被证明可保护小鼠免受可卡因致死毒性的影响，抑制可卡因在大鼠中的强化作用，并逆转恒河猴体内可卡因的心血管作用。目前的研究评估了 DM CocE 预防和逆转可卡因对雄性和雌性大鼠心血管、惊厥和致死作用的有效性。
方法
预处理研究用于确定 DM CocE 预防大鼠发生与急性可卡因毒性相关的心血管变化、惊厥和致死作用的有效性和体内作用持续时间。治疗后研究用于评估 DM CocE 从大剂量可卡因的心血管和致死作用中拯救大鼠的能力。此外，研究了雄性和雌性大鼠，以确定 DM CocE 预防或逆转急性可卡因毒性的能力是否存在任何潜在的性别影响。
结果
DM CocE 的预处理剂量依赖性地保护大鼠免受可卡因引起的心血管变化、惊厥和致死作用，较高剂量的作用可持续长达 4 小时，将可卡因引起的致死作用至少向右移动 10 倍。除了剂量依赖性地使大鼠从可卡因的致命剂量中恢复过来外，DM CocE 的治疗后处理还逆转了可卡因的心血管作用。DM CocE 预防或逆转急性可卡因毒性的效果在性别方面没有差异。
结论
综上所述，这些结果支持开发 DM CocE 用于治疗急性可卡因毒性。
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