Dataset Information

Evaluation of the dopamine ?-hydroxylase (D?H) 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-?-hydroxylase (D?H) 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.

SUBMITTER: De La Garza R

PROVIDER: S-EPMC4777897 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

De La Garza Richard R Bubar Marcy J MJ Carbone Crystal L CL Moeller F Gerard FG Newton Thomas F TF Anastasio Noelle C NC Harper Tod A TA Ware David L DL Fuller Michael A MA Holstein Gaylyn J GJ Jayroe Jason B JB Bandak Stephen I SI Reiman Kirsten Z KZ Neale Ann C AC Pickford Lesley B LB Cunningham Kathryn A KA

Progress in neuro-psychopharmacology & biological psychiatry 20150117

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 ...[more]

PMID: 25602710

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Project description:Atomoxetine is the most widely used nonstimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). It selectively acts on the norepinephrine (NE) system. Dopamine beta hydroxylase (DBH) regulates the synthesis of NE. This study aimed to investigate whether variants in the DBH gene have an effect on the differential response to atomoxetine.Children and adolescents with ADHD were enrolled in a prospective, open-label study of atomoxetine for 8-12 weeks. The dose was titrated to 1.2-1.4?mg/kg per day and maintained for at least 4 weeks. The primary efficacy measure was the investigator-rated ADHD Rating Scale-IV (ADHD-RS-IV). Three categorical evaluations of treatment effects (defined as response, robust response, and remission) were used. We used a candidate gene approach. Eight single nucleotide polymorphisms (SNPs) in DBH were selected and genotyped based on the functional annotation in literature. Their association with response or remission status was analyzed.Four SNPs were found nominally associated with response status (rs1076150, p?=?0.0484; rs2873804, p?=?0.0348; rs1548364, p?=?0.0383; and rs2519154, p?=?0.0097), two were associated with robust response (rs1076150, p?=?0.0349; and rs2519154, p?=?0.0047), and one was associated with remission (rs2519154, p?=?0.0479). The association between rs2519154 and robust response was significant after correction of multiple comparison (p?=?0.0384). Two haplotypes of linkage disequilibrium (LD) block1 (constituted by rs1108580, rs2873804, rs1548364, and rs2519154) were nominally associated with response and robust response status (CTAC: p?=?0.0301 for response, p?=?0.0374 for robust response; TCGT: p?=?0.0317 for response, p?=?0.021 for robust response), whereas one haplotype (GC) of LD block2 (constituted by rs2073837 and rs129882) was associated with robust response and remission status (p?=?0.0377 for robust response; p?=?0.0321 for remission), although none achieved significant threshold after multiple comparison.Variants in DBH genes were associated with atomoxetine response in the treatment of ADHD. Further replication in larger samples would be warranted.

Dataset Information

Evaluation of the dopamine ?-hydroxylase (D?H) inhibitor nepicastat in participants who meet criteria for cocaine use disorder.

Publications

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

Similar Datasets

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