title: Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.
abstract: In the present study, we tested the hypothesis that the potent and selective dopamine-β-hydroxylase (DβH) inhibitor nepicastat would have minimal effects on cardiovascular and pharmacokinetic parameters associated with cocaine administration and would reduce the positive subjective effects produced by cocaine. We conducted a double-blind, placebo-controlled, inpatient study of oral nepicastat (0, 80 and 160mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40mg) in non-treatment seeking participants who metcriteria for cocaine use disorder. Safety analyses revealed that nepicastat was well-tolerated and there were no differences in adverse events observed after nepicastat plus cocaine vs. cocaine alone. In addition, the pharmacokinetic properties of cocaine administration were not altered by nepicastat treatment. Cocaine-induced cardiovascular and subjective effects were evaluated for completers in the cohort randomized to nepicastat (n=13) using a within-subjects statistical analysis strategy. Specifically, the cardiovascular and subjective effects of cocaine were assessed in the presence of placebo (0mg), 80mg of nepicastat or 160mg of nepicastat on study Days 4, 8 and 12, respectively. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects. Taken together, these data indicate that nepicastat is safe when co-administered with cocaine and may suppress its positive subjective effects, and may be viable as a pharmacotherapy for treatment of cocaine use disorder.
authors.affiliation: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States. Electronic address: rg12@bcm.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: De La Garza
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Marcy J
authors.initials: MJ
authors.lastname: Bubar
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Carbone
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Institute for Drug and Alcohol Studies, Addiction Medicine, Virginia Commonwealth University, Richmond, VA, United States.
authors.forename: F Gerard
authors.initials: FG
authors.lastname: Moeller
authors.affiliation: Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Newton
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Noelle C
authors.initials: NC
authors.lastname: Anastasio
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Tod A
authors.initials: TA
authors.lastname: Harper
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: David L
authors.initials: DL
authors.lastname: Ware
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fuller
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Gaylyn J
authors.initials: GJ
authors.lastname: Holstein
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Jayroe
authors.affiliation: Biotie Therapies, Inc. (formerly Synosia Therapeutics), South San Francisco, CA, United States.
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Bandak
authors.affiliation: Biotie Therapies, Inc. (formerly Synosia Therapeutics), South San Francisco, CA, United States.
authors.forename: Kirsten Z
authors.initials: KZ
authors.lastname: Reiman
authors.affiliation: Biotie Therapies, Inc. (formerly Synosia Therapeutics), South San Francisco, CA, United States.
authors.forename: Ann C
authors.initials: AC
authors.lastname: Neale
authors.affiliation: Biotie Therapies, Inc. (formerly Synosia Therapeutics), South San Francisco, CA, United States.
authors.forename: Lesley B
authors.initials: LB
authors.lastname: Pickford
authors.affiliation: Center for Addiction Research, University of Texas Medical Branch, Galveston, TX, United States; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Cunningham
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002319:Cardiovascular System / Q000187:drug effects; D019970:Cocaine-Related Disorders / Q000097:blood / Q000188:drug therapy*; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D010147:Pain Measurement; D011569:Psychiatric Status Rating Scales; D012054:Reinforcement, Psychology; D013871:Thiones / Q000097:blood / Q000627:therapeutic use*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004299:Dopamine beta-Hydroxylase; C109487:nepicastat
keywords: Cocaine; Dopamine-β-hydroxylase; Nepicastat; SYN117