Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder

Richard De La Garza, Marcy J. Bubar, Crystal L. Carbone, F. Gerard Moeller, Thomas F. Newton, Noelle Anastasio, Tod A. Harper, David L. Ware, Michael Fuller, Gaylyn J. Holstein, Jason B. Jayroe, Stephen I. Bandak, Kirsten Z. Reiman, Ann C. Neale, Lesley B. Pickford, Kathryn Cunningham

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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 160. mg) concurrent with intravenous (IV) cocaine (0, 10, 20 and 40. mg) 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 (0. mg), 80. mg of nepicastat or 160. mg 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.

Original languageEnglish (US)
Pages (from-to)40-48
Number of pages9
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume59
DOIs
StatePublished - Jun 3 2015

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Keywords

  • Cocaine
  • Dopamine-β-hydroxylase
  • Nepicastat
  • SYN117

ASJC Scopus subject areas

  • Biological Psychiatry
  • Pharmacology

Cite this

De La Garza, R., Bubar, M. J., Carbone, C. L., Moeller, F. G., Newton, T. F., Anastasio, N., Harper, T. A., Ware, D. L., Fuller, M., Holstein, G. J., Jayroe, J. B., Bandak, S. I., Reiman, K. Z., Neale, A. C., Pickford, L. B., & Cunningham, K. (2015). Evaluation of the dopamine β-hydroxylase (DβH) inhibitor nepicastat in participants who meet criteria for cocaine use disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 59, 40-48. https://doi.org/10.1016/j.pnpbp.2015.01.009