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    • Proof of concept studies with disulfiram

    2020-03-17

    Proof-of-concept studies with disulfiram suggest the potential utility of DβH inhibitors for treatment of cocaine use disorder. In a study of 74 subjects stabilized on methadone and randomized into disulfiram and placebo groups for 10weeks, disulfiram treatment reduced cocaine-positive urines, and disulfiram efficacy differed by DβH genotype (Kosten et al., 2013). These outcomes were similar to a recent report in 177 buprenorphine-treated participants that received 12weeks of treatment with disulfiram or placebo, and participants treated with disulfiram reported significantly less frequent cocaine use (Schottenfeld et al., 2014). The lack of selectivity of disulfiram for DβH over other enzymes and its extensive metabolism into additional enzyme inhibitors (e.g., diethylthiocarbamate) (Lipsky et al., 2001) contributes to a wide range of severe adverse side effects (e.g., respiratory depression, peripheral neuropathy, cardiovascular complications, compromised liver function) (Chick, 1999, Wright et al., 1993). Disulfiram also inhibits plasma esterases to slow the elimination of cocaine, resulting in elevated peak plasma cocaine levels and, therefore, the potential for cocaine toxicity (Baker et al., 2007, McCance-Katz et al., 1998a, McCance-Katz et al., 1998b). Additionally, intravenous (IV) administration of alcohol in cocaine-dependent participants during disulfiram treatment produced adverse electrocardiogram (ECG) changes and a pronounced disulfiram ethanol reaction (Roache et al., 2011). Taken together, the practicality of employing disulfiram pharmacotherapy for cocaine use disorder is limited by its overall lack of specificity of action. Nepicastat (SYN117; RS-25560-197) demonstrates significantly higher potency as a DβH inhibitor (IC50=9nM) as compared to disulfiram (IC50≅1000nM) and greater selectivity over other enzymes (Stanley et al., 1997) (K. Walker, Roche Biosciences, personal communication). In line with its actions as a DβH inhibitor, nepicastat effectively reduces NE and enhances levels of DA in the SB203580 (Bourdelat-Parks et al., 2005). A recent microdialysis study in rats revealed that nepicastat differentially affects DA and NE release in the corticostriatal circuit (Devoto et al., 2014), reducing NE release both in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc), and increasing DA release in the mPFC but not in the NAc. In addition, the authors reported that nepicastat markedly potentiated cocaine- and amphetamine-induced extracellular DA accumulation in the mPFC, but not in the NAc (Devoto et al., 2014). Like disulfiram, nepicastat blocks cocaine-primed reinstatement of cocaine-seeking in rats at a dose that significantly reduced brain NE levels (Schroeder et al., 2010). In a more recent study, nepicastat significantly lowered the breakpoint for cocaine in rats, and attenuated cue-, footshock-, or yohimbine-induced reinstatement (Schroeder et al., 2013). These data indicate that nepicastat reduces the reinforcing properties of cocaine under a stringent schedule and attenuates relapse-like behavior produced by cocaine, formerly cocaine-paired cues, and physiological and pharmacological stressors. In a drug discrimination study, pretreatment with either disulfiram or nepicastat produced leftward shifts in the cocaine dose–response function and also conferred cocaine-like stimulus effects to the selective NE transporter inhibitor reboxetine. These results suggest that pharmacological inhibition of DβH functionally enhances the interoceptive stimulus effects of cocaine possibly due to facilitated increases in DA released from noradrenergic terminals (Manvich et al., 2013). Nepicastat is well tolerated in healthy adults and in patients with congestive heart failure (Hegde and Friday, 1998) (Roche Biosciences, unpublished observations) and may represent a better tolerated, more efficacious treatment for cocaine use disorder than disulfiram. As such, the present study was initiated to evaluate the safety of administration of oral nepicastat in combination with IV cocaine to participants who metcriteria for cocaine use disorder in an inpatient, hospital-based setting. We hypothesized that nepicastat would have minimal effects on the pharmacokinetic and cardiovascular properties of cocaine and would reduce the positive subjective effects produced by cocaine.