Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys.
Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys.
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DOI：
10.1111/j.1369-1600.2011.00424.x
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发表时间：
2013-01
影响因子：
3.4
通讯作者：
Goldberg SR
中科院分区：
文献类型：
--
作者：
Schindler CW;Justinova Z;Lafleur D;Woods D;Roschke V;Hallak H;Sklair-Tavron L;Redhi GH;Yasar S;Bergman J;Goldberg SR
虽然大量的研究工作集中在开发可卡因滥用的药物治疗上，但尚未开发出有效的药物。最近的研究表明，在外周代谢可卡因的酶，阻止其进入大脑，可以防止可卡因毒性及其对啮齿动物行为的影响。在这里，我们报告一个这样的酶（Albu-CocH）对松鼠猴可卡因的药代动力学和行为效应的影响。Albu-CocH是从人丁酰胆碱酯酶（BChE）的连续突变中开发出来的，对可卡因的催化活性比天然存在的BChE高1000倍。药代动力学研究表明，Albu-CocH（5 mg/kg）在松鼠猴中的半衰期为56.6小时。在这些研究中，静脉注射1 mg/kg可卡因后的可卡因血浆水平在给予Albu-CocH后两小时降低，而可卡因代谢物爱贡碱甲酯的血浆水平升高。这些作用在Albu-CocH给药后72小时仍然明显。在猴的行为实验中，用5 mg/kg Albu-CocH预处理显著减少了持续24小时以上的静脉注射加强剂量可卡因（30 μg/kg/注射）的自我给药。用5 mg/kg Albu-CocH预处理还减弱了通过静脉内启动注射可卡因（0.1或0.3 mg/kg）而消退的可卡因自我给药的恢复，并且在单独的研究中，减弱了可卡因的辨别性刺激作用。Albu-CocH减弱松鼠猴中可卡因滥用相关效应的能力表明，有必要进一步研究BChE突变体作为可卡因滥用和毒性的潜在治疗方法。
Although substantial research effort has focused on developing pharmacological treatments for cocaine abuse, no effective medications have been developed. Recent studies show that enzymes that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine (0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine abuse and toxicity is warranted.
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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：
3.6
作者：
Cooper, Ziva D.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.
DOI：
10.1073/pnas.0507332102
发表时间：
2005-11-15
影响因子：
11.1
作者：
Pan, YM;Gao, DQ;Zhan, CG
通讯作者：
Zhan, CG
影响因子：
4.2
作者：
Wood SK;Narasimhan D;Cooper Z;Sunahara RK;Woods JH
通讯作者：
Woods JH
影响因子：
3.6
作者：
Brim, Remy L.;Nance, Mark R.;Woods, James H.
通讯作者：
Woods, James H.