Amelioration of the cardiovascular effects of cocaine in rhesus monkeys by a long-acting mutant form of cocaine esterase.
Amelioration of the cardiovascular effects of cocaine in rhesus monkeys by a long-acting mutant form of cocaine esterase.
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DOI：
10.1038/npp.2010.242
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发表时间：
2011-04
期刊：
影响因子：
--
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中科院分区：
文献类型：
--
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天然细菌可卡因酯酶（T172R/G173Q CocE；DM CocE）的长效突变体此前已被证明可以拮抗可卡因对啮齿类动物的增强、惊厥和致命作用。然而，在更临床相关的背景下，DM CocE 在非人灵长类动物中的有效性和治疗特征尚不清楚。目前的研究旨在 1) 表征可卡因对自由活动的恒河猴的心血管影响，2) 评估在可卡因后 10 分钟给药时 DM CocE 改善可卡因诱发的心血管影响的能力，以及 3) 评估重复给药后猴子对 DM CocE 的免疫反应。静脉注射可卡因会导致平均动脉压 (MAP) 和心率 (HR) 呈剂量依赖性增加，这种增加在 3.2 mg/kg 可卡因剂量后的两小时观察期内持续存在。可卡因未能对心电图参数、体温和运动活动产生可靠的变化。 DM CocE 对心血管效应产生快速且剂量依赖性的改善，在 DM CocE 给药后 5 至 10 分钟内恢复类似盐水的 MAP 测量，并且在 20 至 40 分钟内恢复类似盐水的 HR 测量。尽管给予 DM CocE 会增加抗 CocE 抗体，但它们似乎对 DM CocE 逆转可卡因心血管作用的能力没有中和作用。总之，这些在猴子身上的发现提供了强有力的证据，表明高效的可卡因酯酶，例如 DM CocE，可以为治疗人类急性可卡因中毒提供潜在的治疗选择。
A long-acting mutant form of a naturally occurring bacterial cocaine esterase (T172R/G173Q CocE; DM CocE) has previously been shown to antagonize the reinforcing, convulsant, and lethal effects of cocaine in rodents. However, the effectiveness and therapeutic characteristics of DM CocE in nonhuman primates, in a more clinically relevant context, are unknown. The current studies were aimed at 1) characterizing the cardiovascular effects of cocaine in freely moving rhesus monkeys, 2) evaluating the capacity of DM CocE to ameliorate these cocaine-induced cardiovascular effects when administered 10 minutes after cocaine, and 3) assessing the monkeys’ immunologic responses to DM CocE following repeated administration. Intravenous administration of cocaine produced dose-dependent increases in mean arterial pressure (MAP) and heart rate (HR) that persisted throughout the two-hour observation period following a dose of 3.2 mg/kg cocaine. Cocaine failed to produce reliable changes in ECG parameters, body temperature, and locomotor activity. DM CocE produced a rapid and dose-dependent amelioration of the cardiovascular effects, with saline-like MAP measures restored within 5 to 10 minutes, and saline-like HR measures restored within 20 to 40 minutes of DM CocE administration. Although administration of DM CocE produced increases in anti-CocE antibodies, they did not appear to have a neutralizing effect on the capacity of DM CocE to reverse the cardiovascular effects of cocaine. In conclusion, these findings in monkeys provide strong evidence to suggest that highly efficient cocaine esterases, such as DM CocE, can provide a potential therapeutic option for treatment of acute cocaine intoxication in humans.
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影响因子：
10.6
作者：
Haney, Margaret;Gunderson, Erik W.;Jiang, Huiping;Collins, Eric D.;Foltin, Richard W.
通讯作者：
Foltin, Richard W.
影响因子：
2.9
作者：
Fareed, Fareed N.;Chan, Gar M.;Hoffman, Robert S.
通讯作者：
Hoffman, Robert S.
影响因子：
3.6
作者：
Cooper, Ziva D.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.
DOI：
10.1038/nsb742
发表时间：
2002-01-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Larsen, NA;Turner, JM;Wilson, IA
通讯作者：
Wilson, IA
影响因子：
7.6
作者：
Brimijoin, Stephen;Gao, Yang;Carroll, Marilyn E.
通讯作者：
Carroll, Marilyn E.