Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.
Cocaine cardiovascular effects and pharmacokinetics after treatment with the acetylcholinesterase inhibitor donepezil.
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DOI：
10.1111/ajad.12402
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Sturgill M
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文献类型：
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作者：
Grasing K;Mathur D;DeSouza C;Newton TF;Moody DE;Sturgill M
在啮齿类动物中，胆碱酯酶抑制剂可导致可卡因的强化作用持续下降。然而，可卡因是通过丁酰胆碱酯酶（BuChE）代谢的，这引起了人们的关注，即胆碱酯酶抑制可能会增加其外周浓度，也许会增加毒性。尽管多奈哌齐被批准用于患者，并且对抑制乙酰胆碱酯酶的选择性超过BuChE，但没有研究报告接受多奈哌齐的人类受试者中的可卡因生物利用度。12名可卡因依赖的退伍军人接受了为期3天的口服安慰剂或每天5毫克多奈哌齐治疗，然后交叉到相反的治疗。在两种经口给药期间，在实验室环境中以0.0、0.18、0.36 mg/kg剂量双盲静脉注射可卡因，随后测定心率、血压和可卡因及主要代谢物的血浆浓度。静脉注射可卡因产生剂量相关的收缩压升高，在治疗后的最初30分钟内最明显。口服多奈哌齐减弱低剂量可卡因（0.18 mg/kg）后药物诱导的收缩压升高。高剂量可卡因（0.36 mg/kg）后，安慰剂或多奈哌齐治疗后血压无显著差异。血压和心率的峰值不受多奈哌齐的影响。可卡因和代谢物的血浆浓度在多奈哌齐和安慰剂治疗的参与者中没有差异。我们的结论是，多奈哌齐可以减弱低剂量可卡因后药物引起的收缩压升高，但不会改变静脉注射可卡因的心血管效应。可卡因生物利用度和心血管效应的临床显著变化在该剂量的多奈哌齐后不会发生。
In rodents, cholinesterase inhibitors can cause sustained decreases in the reinforcing effects of cocaine. Nonetheless, cocaine is metabolized by butyrylcholinesterase (BuChE), raising concerns that cholinesterase inhibition could increase its peripheral concentrations, perhaps augmenting toxicity. Although donepezil is approved for use in patients and selective for inhibiting acetylcholinesterase over BuChE, no studies have reported cocaine bioavailability in human subjects receiving donepezil. Twelve cocaine-dependent veterans received three days of treatment with either oral placebo or 5 mg daily of donepezil, followed by cross-over to the opposite treatment. During both oral treatments, double-blind intravenous cocaine was administered at 0.0, 0.18, 0.36 mg/kg in a laboratory setting, followed by determinations of heart rate, blood pressure, and plasma concentrations of cocaine and major metabolites. Intravenous cocaine produced dose-related increases in systolic blood pressure that were most pronounced over the initial 30 minutes after treatment. Oral donepezil attenuated drug-induced elevations of systolic blood pressure following low-dose cocaine (0.18 mg/kg). No significant difference in blood pressure following treatment with placebo or donepezil after high-dose cocaine (0.36 mg/kg). Peak values of blood pressure and heart rate were unaffected by donepezil. Plasma concentrations of cocaine and metabolites did not differ in donepezil- and placebo- treated participants. We conclude that donepezil can attenuate drug-induced increases in systolic blood pressure following low-dose cocaine, but does not otherwise modify the cardiovascular effects of intravenous cocaine. Clinically significant changes in cocaine bioavailability and cardiovascular effects do not occur following this dose of donepezil.