Elinore F. McCance-Katz

Concurrent cocaine-ethanol ingestion in humans: pharmacology, physiology, behavior, and the role of cocaethylene.

Simultaneous abuse of cocaine and ethanol is a common occurrence. Cocaethylene, the ethyl ester of benzoylecgonine, has been detected in the urine of patients reporting concurrent use of cocaine and ethanol, and high levels have been found in the blood of victims of fatal drug overdose. This placebo-controlled, double-blind study examined the pharmacokinetic, physiologic, and behavioral effects of dual cocaine and ethanol administration in humans (n=6). Cocaethylene was found in the plasma only after administration of both cocaine and ethanol, and appeared to be eliminated more slowly than cocaine. Plasma cocaine concentrations were significantly higher during cocaine/ethanol administration. Euphorigenic effects were both enhanced and prolonged, and heart rate was significantly increased, following cocaine/ethanol administration as compared to administration of cocaine or ethanol alone.

A haplotype at the DBH locus, associated with low plasma dopamine β-hydroxylase activity, also associates with cocaine-induced paranoia

Low levels of dopamine β-hydroxylase (DβH) protein in the plasma or cerebrospinal fluid (CSF) are associated with greater vulnerability to positive psychotic symptoms in several psychiatric disorders. DβH level is a stable, genetically controlled trait. DBH, the locus encoding DβH protein, is the major quantitative trait locus controlling plasma and CSF DβH levels. We therefore hypothesized that DBH variants or haplotypes, associated with low levels of DβH in the plasma, would also associate with greater vulnerability to cocaine-induced paranoia. To test this hypothesis, we first showed that a di-allelic variant, DBH*5′-ins/del, located approximately 3 kb 5′ to the DBH transcriptional start site, significantly associates with plasma DβH activity in European-Americans (n = 66). Linkage disequilibrium analysis of that polymorphism and DBH*444g/a, another di-allelic variant associated with DβH levels, demonstrated that alleles of similar association to DβH levels are in positive disequilibrium. We then estimated DBH haplotype frequencies in cocaine-dependent European Americans rated for cocaine-induced paranoia (n = 45). As predicted, the low-DβH-associated haplotype, Del-a, was significantly more frequent (P = 0.0003) in subjects endorsing cocaine-induced paranoia (n = 29) than in those denying it (n = 16). Comparison to control haplotype frequencies (n = 145 healthy European-Americans) showed that the association predominantly reflected under-representation of Del-a haplotypes in those denying cocaine-induced paranoia. We conclude that: (a) the two DBH polymorphisms we studied are associated with plasma DBH levels; (b) those two polymorphisms are in significant linkage disequilibrium in European Americans, with alleles of similar association to DβH levels in positive disequilibrium; and (c) the haplotype associated with low DBH activity is also associated with cocaine-induced paranoia.

Concurrent use of cocaine and alcohol is more potent and potentially more toxic than use of either alone : A multiple-dose study

BACKGROUND Simultaneous abuse of cocaine and alcohol is widespread and increasingly detected in patients seeking emergent care. This double-blind, randomized, within-subjects study used a paradigm more closely approximating practices of drug abusers to better understand the pathogenesis of cocaine-alcohol abuse. METHODS Subjects meeting DSM-IV criteria for cocaine dependence and alcohol abuse participated in three drug administration sessions: four doses of intranasal cocaine (1 mg/kg every 30 min) with oral alcohol (1 g/kg) administered following the initial cocaine dose and a second dose (120 mg/kg) at 60 min calculated to maintain plasma alcohol concentration at approximately 100 mg/dL during cocaine administration; four doses of cocaine/placebo alcohol; four doses of cocaine placebo/alcohol. Pharmacokinetic, physiological, and behavioral effects were followed over 8 hours. RESULTS Cocaine-alcohol produced greater euphoria and increased perception of well-being relative to cocaine. Heart rate significantly increased following cocaine-alcohol administration relative to either drug alone. Cocaine concentrations were greater following cocaine-alcohol administration. Cocaethylene had a longer halflife with increasing concentrations relative to cocaine at later time points. CONCLUSIONS Enhanced psychological effects during cocaine-alcohol abuse may encourage ingestion of larger amounts of these substances over time placing users at heightened risk for greater toxicity than with either drug alone.

Drug interactions of clinical importance among the opioids, methadone and buprenorphine, and other frequently prescribed medications: a review.

Drug interactions are a leading cause of morbidity and mortality. Methadone and buprenorphine are frequently prescribed for the treatment of opioid addiction. Patients needing treatment with these medications often have co-occurring medical and mental illnesses that require medication treatment. The abuse of illicit substances is also common in opioid-addicted individuals. These clinical realities place patients being treated with methadone and buprenorphine at risk for potentially toxic drug interactions. A substantial literature has accumulated on drug interactions between either methadone or buprenorphine with other medications when ingested concomitantly by humans. This review summarizes current literature in this area.

The Protease Inhibitor Lopinavir-Ritonavir May Produce Opiate Withdrawal in Methadone-Maintained Patients

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

Gender Differences in Treatment-Seeking Cocaine Abusers - Implications for Treatment and Prognosis

This study examined gender differences in demographics, psychosocial functioning, substance abuse severity, psychopathology, and 1-year outcome in cocaine-dependent patients with the goal of identifying factors important to improving treatment and identifying prognostic indicators. The sample included 298 cocaine-dependent adults (92 women). Ninety-four patients (29 women) provided 1-year follow-up assessments. Compared to men, women consumed similar quantities of cocaine by more addictive routes and experienced more rapid progression of drug dependence, thus highlighting the need to facilitate treatment entry. The substantial rates of positive treatment outcomes emphasizes the effectiveness of treatment for cocaine-dependent individuals.

Methadone effects on zidovudine disposition (AIDS Clinical Trials Group 262)

Large numbers of injection drug users (IDUs) are infected with HIV and receive both methadone and zidovudine (ZDV) therapy. Pharmacokinetic interactions between these agents may effect drug efficacy, toxicity, and compliance. To confirm and expand previous studies that identified a potential interaction between ZDV and methadone, we performed a within-subject study to determine oral and intravenous ZDV pharmacokinetics in 8 recently detoxified, heroin-addicted patients with HIV disease before and after initiation of methadone treatment. Acute methadone treatment increased oral ZDV in the area under the curve (AUC) by 41% (p = .03) and intravenous ZDV AUC by 19% (p = .06). Clearance was reduced by 21% (p = .007) and 19% (p = .04), respectively. Chronic methadone treatment increased oral ZDV AUC by 29% (p = .15) and intravenous ZDV AUC by 41% (p = .05). Clearance was decreased by 26% for both routes (p = .02). Methadone levels remained in the therapeutic range during ZDV treatment. These effects resulted primarily from inhibition of ZDV glucuronidation, but also from decreased renal clearance of ZDV. This study confirms that methadone-maintained patients receiving standard ZDV doses experience greater ZDV exposure and may be at increased risk for ZDV side effects and toxicity. Increased toxicity surveillance and possibly reduction in ZDV dose are indicated when these two agents are given concomitantly.

A Pilot Study Assessing the Safety and Latency-Reversing Activity of Disulfiram in HIV-1–Infected Adults on Antiretroviral Therapy

BACKGROUND Transcriptionally silent human immunodeficiency virus type 1 (HIV-1) DNA persists in resting memory CD4(+) T cells despite antiretroviral therapy. In a primary cell model, the antialcoholism drug disulfiram has been shown to induce HIV-1 transcription in latently infected resting memory CD4(+) T cells at concentrations achieved in vivo. METHODS We conducted a single-arm pilot study to evaluate whether 500 mg of disulfiram administered daily for 14 days to HIV-1-infected individuals on stable suppressive antiretroviral therapy would result in reversal of HIV-1 latency with a concomitant transient increase in residual viremia or depletion of the latent reservoir in resting memory CD4(+) T cells. RESULTS Disulfiram was safe and well tolerated. There was a high level of subject-to-subject variability in plasma disulfiram levels. The latent reservoir did not change significantly (1.16-fold change; 95% confidence interval [CI], .70- to 1.92-fold; P = .56). During disulfiram administration, residual viremia did not change significantly compared to baseline (1.53-fold; 95% CI, .88- to 2.69-fold; P = .13), although residual viremia was estimated to increase by 1.88-fold compared to baseline during the postdosing period (95% CI, 1.03- to 3.43-fold; P = .04). In a post hoc analysis, a rapid and transient increase in viremia was noted in a subset of individuals (n = 6) with immediate postdose sampling (HIV-1 RNA increase, 2.96-fold; 95% CI, 1.29- to 6.81-fold; P = .01). CONCLUSIONS Administration of disulfiram to patients on antiretroviral therapy does not reduce the size of the latent reservoir. A possible dose-related effect on residual viremia supports future studies assessing the impact of higher doses on HIV-1 production. Disulfiram affects relevant signaling pathways and can be safely administered, supporting future studies of this drug.

Disulfiram effects on acute cocaine administration

Disulfiram (Antabuse) is being used in outpatient clinical trials to determine its efficacy as a treatment for cocaine dependence. This inpatient randomized, double-blind, placebo-controlled, within-subjects study was conducted to determine whether disulfiram (placebo, 250 or 500 mg/day) alters responses to acute intranasal cocaine (placebo, 1 or 2 mg/kg) administration. Effects of disulfiram on cocaine pharmacokinetics, physiological, and behavioral responses were determined. Disulfiram treatment increased plasma cocaine concentrations three to six times and significantly increased cocaine-associated cardiovascular responses, but did not significantly alter behavioral responses to cocaine. These interactions should be considered in the decision regarding disulfiram treatment in cocaine dependent patients.

Desipramine and contingency management for cocaine and opiate dependence in buprenorphine maintained patients

Co-dependence on opiates and cocaine occurs in about 60% of patients entering methadone treatment and has a poor prognosis. However, we recently found that desipramine (DMI) could be combined with buprenorphine to significantly reduce combined opiate and cocaine use among these dually dependent patients. Furthermore, contingency management (CM) has been quite potent in reducing cocaine abuse during methadone maintenance. To test the efficacy of combining CM with these medications we designed a 12-week, randomized, double blind, four cell trial evaluating DMI (150 mg/day) or placebo plus CM or a non-contingent voucher control in 160 cocaine abusers maintained on buprenorphine (median 16 mg daily). Cocaine-free and combined opiate and cocaine-free urines increased more rapidly over time in those treated with either DMI or CM, and those receiving both interventions had more drug-free urines (50%) than the other three treatment groups (25-29%). Self reported opiate and cocaine use and depressive and opioid withdrawal symptoms showed no differences among the groups and symptom levels did not correlate with urine toxicology results. Lower DMI plasma levels (average 125 ng/ml) were associated with greater cocaine-free urines. DMI and CM had independent and additive effects in facilitating cocaine-free urines in buprenorphine maintained patients. The antidepressant appeared to enhance responsiveness to CM reinforcement.