title: Pharmacokinetics and Safety Assessment of l-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study.
abstract: 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 AUC0→∞was 211.5 and 261.4 h·ng/mL, and the Cmaxwas 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.|Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
authors.forename: Hazem E
authors.initials: HE
authors.lastname: Hassan
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Deanna
authors.initials: D
authors.lastname: Kelly
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Honick
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ibrahim
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Gorelick
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Glassman
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: McMahon
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Heidi J
authors.initials: HJ
authors.lastname: Wehring
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Kearns
authors.affiliation: Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Feldman
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Mingming
authors.initials: M
authors.lastname: Yu
authors.affiliation: Lake Erie College of Osteopathic Medicine, Bradenton, FL, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Bauer
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Jia Bei
authors.initials: JB
authors.lastname: Wang
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D001600:Berberine Alkaloids / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D013050:Spectrometry, Fluorescence
chemical_list: D001600:Berberine Alkaloids; D018492:Dopamine Antagonists; C014215:tetrahydropalmatine; D003042:Cocaine
keywords: addiction medicine; central nervous system; clinical pharmacology; clinical trials; drug metabolism; drug-drug interactions; pharmacokinetics