This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: This is a Phase I human laboratory clinical pharmacology study to assess potential interactions between intravenous cocaine and intravenous ethanol administration in cocaine-dependent subjects treated with oral disulfiram. The primary objective of this study is to determine safety of alcohol use in cocaine-dependent subjects that used cocaine after treatment with disulfiram. This will be achieved by measuring adverse events and changes in cardiovascular and psychiatric responses from baseline. RESEARCH PLAN: This is a double-blind, placebo-controlled inpatient Phase I clinical study to determine the cardiovascular and psychiatric safety of alcohol use in cocaine-dependent subjects who had used cocaine after treatment with disulfiram. The study will employ a gradual 'dose run-up' approach testing the safety and clinical tolerance of IV cocaine and ethanol alone, before and after treatment with disulfiram, before finally combining all three agents for the final test of safety. Study agent (disulfiram/placebo) will be administered double-blind, but the cocaine and ethanol doses will be single-blind and use double-dummy procedures. The study will be conducted under NIDA contract at two sites (San Antonio and UCLA). METHODS: Subjects who are cocaine dependent, but who are otherwise healthy and not seeking treatment, will be screened for eligibility and admitted for a 17-day stay on the residential research unit at University Hospital. On seven designated infusion days, subjects will be admitted to the GCRC for the conduct of experimental infusion sessions including demonstration of initial clinical tolerance (on day -3) to the infusion of cocaine, 30 mg IV. The next two infusion days will establish the baseline cardiovascular responses of subjects to IV cocaine and ethanol infusions (on days -2 and -1, respectively). Subsequently, subjects will be randomized into one of two treatment groups and initiate oral dosage treatment with 250 mg disulfiram or placebo once a day for 7 days. Three days after initiation of daily treatment with either disulfiram (N=8) or placebo (N=4), subjects will receive IV infusions as follows: (1) IV saline on day 4; (2) 30 mg IV cocaine on day 5; (3) IV dose of ethanol on day 6; (4) on day 7, 30 mg IV cocaine followed by IV ethanol 5 minutes later. Thereafter, the double-blind dose of disulfiram/placebo treatment will cease but subjects will remain at University Hospital until discharge one week later on day 14. Subjects will be requested to return for safety follow-up one and two weeks after discharge. CLINICAL
Many pharmaceutical agents have been tested for efficacy in the treatment of cocaine dependence, but none have been proven effective as yet. Recently, there have been three efficacy and three laboratory safety trials conducted evaluating the possible use of disulfiram to treat cocaine dependence. All of these have been positive and NIDA is eager to proceed with a major, Phase III cross-national clinical trial examining the efficacy of disulfiram in the treatment of primary cocaine dependence. However, the FDA will not approve such a study until a Phase I clinical trial has examined the safety of the 3-way drug interaction. The safety question raised by the FDA is a clinical characterization of the cardiac and cardiovascular risk in cocaine-dependent individuals when hypotension resulting from a disulfiram-ethanol reach into is induced in the presence of cardiac acceleration produced by cocaine. The proposed study is essential to the further development of disulfiram or any like agent for the treatment of cocaine dependence.
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