br Methods br Results br Discussion Preclinical
Discussion Preclinical data indicate that nepicastat modulates sympathetic drive to the IDH-C35 with a mild pressor effect in various animal models of hypertension (Stanney et al., 1998). However in this clinical study, the doses of nepicastat employed did not significantly alter systolic or diastolic blood pressure or heart rate alone, and did not affect the anticipated transient increase in heart rate and blood pressure evoked by cocaine. Furthermore, unlike disulfiram, nepicastat did not change the kinetics, metabolism or clearance of cocaine or its metabolites. The lack of effects of nepicastat upon the cardiovascular and pharmacokinetic profile evoked by cocaine suggests that the selective targeting of nepicastat for the DβH enzyme improves the safety profile of this compound as compared to the nonselective DβH inhibitor disulfiram. Disulfiram treatment alone has been reported to significantly elevate heart rate and, when combined with cocaine, significantly enhanced the effects of cocaine to increase heart rate and blood pressure (McCance-Katz et al., 1998a, McCance-Katz et al., 1998b), although another group did not report these effects (Baker et al., 2007). Additionally, disulfiram consistently produces elevated plasma cocaine levels (Baker et al., 2007, Hameedi et al., 1995, McCance-Katz et al., 1998a, McCance-Katz et al., 1998b), likely due to its inhibition of plasma cholinesterases and plasma and microsomal carboxylesterases, which are critical for cocaine metabolism (Benowitz, 1993). These potentially dangerous cardiovascular and metabolic interactions of disulfiram with cocaine along with its medically significant interactions with alcohol (Roache et al., 2011) have limited the utility of disulfiram as a pharmacotherapy. The present findings suggest that nepicastat represents a safer alternative to disulfiram for evaluation in cocaine pharmacotherapy trials, as was recently completed (NCT01704196). A secondary goal of the present study was to gain insight into the potential efficacy of nepicastat as a treatment for cocaine use disorder. To this end, we evaluated the potential for nepicastat to alter the subjective effects produced by cocaine. As demonstrated previously (De La Garza et al., 2014, Hameedi et al., 1995, Newton et al., 2005, Verrico et al., 2014), acute cocaine exposure in this study increased several positive subjective effects. Analyses revealed a main effect of nepicastat to reduce several cocaine-induced positive subjective effects, though the cocaine by nepicastat interaction did not reach statistical significance. Although the attenuation of subjective effects of cocaine produced by nepicastat is encouraging, it is important to concede that these measures can produce false positives (Comer et al., 2008, Haney and Spealman, 2008). Previous studies have described variable effects of disulfiram upon the subjective effects produced by cocaine. Specifically, disulfiram decreased (Baker et al., 2007), had no effect (McCance-Katz et al., 1998a, McCance-Katz et al., 1998b), or evoked a non-significant trend to increase cocaine “high” (McCance-Katz et al., 1998a, McCance-Katz et al., 1998b). The exact nature of this variability across studies is unknown, but may be due to differences in drug dosing and/or route of cocaine administration (Baker et al., 2007). An additional factor that may have contributed to the variability observed when evaluating the effects of DβH inhibitors in humans is the existence of polymorphisms in the DβH gene that alter the function of the enzyme. For example, the single nucleotide polymorphism (SNP) C-1021T (-1021C>T) leads to decreased basal levels of DβH (Zabetian et al., 2001), and this SNP appears to control disulfiram response in cocaine-dependent subjects (Kosten et al., 2013, Schottenfeld et al., 2014). Thus, the specific allel expression and associated differences in DβH enzyme levels among individual subjects may produce varied responses to administration of the DβH inhibitor, thereby contributing to the variability in subjective effects reported in the current study. In the current study, DβH genotype appeared to influence responses to cocaine and also responses produced by nepicastat (data to be presented elsewhere). The current data add further credence to the theory that selective inhibition of DβH with nepicastat will be effective at reducing cocaine use in patients with cocaine use disorder. The observed effects for nepicastat to reduce (~25%) the positive subjective effects produced by cocaine are encouraging and support further evaluation of this drug as a pharmacotherapy for cocaine use disorder.