Prevention and reversal by cocaine esterase of cocaine-induced cardiovascular effects in rats.
Prevention and reversal by cocaine esterase of cocaine-induced cardiovascular effects in rats.
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DOI：
10.1016/j.drugalcdep.2009.09.001
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发表时间：
2010-01-15
影响因子：
4.2
通讯作者：
Woods JH
中科院分区：
文献类型：
--
作者：
Wood SK;Narasimhan D;Cooper Z;Sunahara RK;Woods JH
本研究首次利用细菌可卡因酯酶（CocE）来增加致死剂量可卡因的消除并评估其心脏保护作用。大鼠接受5种治疗之一：生理盐水后1分钟的CocE;致死剂量的可卡因腹膜内注射后1分钟的CocE;致死剂量的可卡因腹膜内注射后1分钟的生理盐水;观察到可卡因诱导的惊厥后立即的CocE;以及观察到可卡因诱导的惊厥后1分钟的CocE。测量心电图、血压和心肌肌钙蛋白I（cTnI）。CocE对可卡因的特异性通过评价其对可卡因类似物WIN-35，065 -2的作用来确定，WIN-35，065 -2缺乏CocE的酯攻击点。此外，还将CocE的效果与咪达唑仑（一种常用于治疗可卡因过量的苯二氮卓类药物）的效果进行了比较。尽管单独使用CocE对心血管的影响可以忽略不计，但它可以阻断或逆转可卡因诱导的QRS波群增宽、QTc间期延长、ST段抬高、心动过缓和高血压。可卡因给药后1分钟，CocE抑制心肌损伤;然而，可卡因诱导惊厥后1分钟（可卡因诱导死亡前约40 s），CocE不阻断cTnI释放，但恢复心脏功能。咪达唑仑阻断惊厥，但对可卡因诱导的心脏毒性的保护不足。大多数给予可卡因和咪达唑仑的大鼠死亡。CocE不能预防WIN-35，065 -2的致死性心血管效应。很可能，CocE迅速而特异性地降低了可卡因的身体负担，并抑制或逆转了高剂量可卡因的心血管后果。这些结果支持CocE作为可卡因过量的潜在治疗途径。
The present study is the first to utilize bacterial cocaine esterase (CocE) to increase elimination of a lethal dose of cocaine and evaluate its cardioprotective effects. Rats received one of 5 treatments: CocE 1 min after saline; CocE 1 min after a lethal i.p. dose of cocaine; saline 1 min after a lethal i.p. dose of cocaine; CocE immediately after observing a cocaine-induced convulsion; and CocE 1 min after observing a cocaine-induced convulsion. Measures were taken of ECG, blood pressure, and cardiac troponin I (cTnI). The specificity of CocE against cocaine was determined by evaluating its actions against the cocaine analogue, WIN-35,065-2, which lacks an ester attack point for CocE. In addition, CocE’s effects were compared with those of midazolam, a benzodiazepine often used to manage cocaine overdose. Whereas CocE alone had negligible cardiovascular effects, it blocked or reversed cocaine-induced QRS complex widening, increased QTc interval, ST elevation, bradycardia, and hypertension. When administered 1 min after cocaine, CocE inhibited myocardial damage; however, administered 1 min after a cocaine-induced convulsion (approximately 40 s before cocaine-induced death), CocE did not block cTnI release, but did restore cardiac function. Midazolam blocked convulsions, but exhibited inadequate protection against cocaine-induced cardiotoxicity. The majority of rats given cocaine plus midazolam died. CocE did not prevent the lethal cardiovascular effects of WIN-35,065-2. In all likelihood, CocE rapidly and specifically reduced the body burden of cocaine and inhibited or reversed the cardiovascular consequences of high-dose cocaine. These results support CocE as a potential therapeutic avenue in cocaine overdose.
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DOI：
10.1124/jpet.104.068122
发表时间：
2004-09-01
影响因子：
3.5
作者：
Gao, Y;Brimijoin, S
通讯作者：
Brimijoin, S
影响因子：
9.9
作者：
Woodruff, BK;Britton, JW;Jaffe, AS
通讯作者：
Jaffe, AS
影响因子：
3.6
作者：
Cooper, Ziva D.;Narasimhan, Diwahar;Woods, James H.
通讯作者：
Woods, James H.
影响因子：
37.8
作者：
Hsue, PY;Salinas, CL;Waters, DD
通讯作者：
Waters, DD
影响因子：
8.8
作者：
Zimmerman, JL
通讯作者：
Zimmerman, JL