Pharmacokinetics and Safety Assessment of l-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study

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• 作者：Hazem E. Hassan ; Deanna Kelly ; Moshe Honick ; Sagar Shukla ; Ahmed Ibrahim ; David A. Gorelick ; Matthew Glassman ; Robert P. McMahon ; Heidi J. Wehring ; Ann Marie Kearns ; Stephanie Feldman ; Mingming Yu ; Ken Bauer and Jia Bei Wang
• 刊名：The Journal of Clinical Pharmacology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：57
• 期：2
• 页码：151-160
• 全文大小：405K
• ISSN：1552-4604

文摘

Cocaine use disorder (CUD) remains a significant public health challenge. l-Tetrahydropalmatine (l-THP), a well-tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive l-THP (30 mg twice a day orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for l-THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of l-THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC_0→∞ was 211.5 and 261.4 h·ng/mL, and the C_max was 83.3 and 104.5 ng/mL for the l-THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l-THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD.