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PubMed2006

Protein S-glutathionylation and platelet anti-aggregating activity of disulfiram.

Blood platelets are central to haemostasis, and reactions in platelets involving sulfhydryl groups play important roles in platelet function. Reduced glutathione (GSH) plays an important role in platelet aggregation and glutathione-depleting chemicals inhibit platelet aggregation. The lipophilic drug disulfiram, because of its affinity for sulfhydryl groups, is a highly thiol-reacting agent. As a consequence, GSH and sulfhydryl groups of protein cysteines in human platelets, in analogy to other components of human blood, are a potential target of disulfiram. In the present study, we have shown that exposure of human platelets to disulfiram causes the depletion of platelet GSH and augmentation of mixed disulfides between GSH and protein sulfhydryl groups to form protein-glutathione mixed disulfides (S-glutathionylated proteins). The depletion of platelet GSH and the increase in S-glutathionylated proteins occurred at concentrations of disulfiram that inhibited platelet aggregation, suggesting that protein S-glutathionylation is involved in the inhibition of platelet aggregation caused by disulfiram.

Blood Platelets↗

PubMed2006

Clinical characteristics and prognostic markers in disulfiram-induced liver injury.

BACKGROUND/AIMS: Limited systematic data exists on the incidence of drug-induced hepatotoxicity due to disulfiram and the most important prognostic markers. We aimed to determine the nature and frequency of suspected disulfiram hepatotoxicity in Sweden. METHODS: All reports of suspected hepatic adverse drug reactions (ADR) associated with disulfiram received by the Swedish Adverse Drug Reactions Advisory Committee (SADRAC) 1966-2002 were reviewed. Causality assessment was based on the International Consensus Criteria. RESULTS: A total of 82 reports of disulfiram suspected ADRs had at least a possible causal relationship. Eight patients died or underwent liver transplantation (Tx). Mortality or Tx was 16% in patients with jaundice. The median age of the patients (65% males) was 45 years with a median duration of treatment of 42 days. Bilirubin was higher (P<0.0001) in the deceased/transplanted patients compared to surviving patients. No difference was observed in age or duration of therapy between deceased and transplanted and those who recovered. Eosinophilic infiltration in liver biopsies was associated with a favourable outcome, hepatocyte drop-out with a poor outcome. CONCLUSIONS: Disulfiram associated hepatitis has a considerable mortality risk. Histological signs of immunoallergy seem to be common. Bilirubin and hepatocyte drop-out were the only predictors for death or transplantation.

Adult↗

PubMed1998

Chronic disulfiram treatment effects on intranasal cocaine administration: initial results.

BACKGROUND: Simultaneous abuse of cocaine and alcohol is common. Alcohol decreases negative stimulant effects and potentiates "high." Disulfiram (Antabuse) is being studied in outpatient trials as a cocaine pharmacotherapy with the rationale that inability to modulate cocaine effects with alcohol may decrease cocaine use. METHODS: We examined the interaction of disulfiram and cocaine in a randomized, double-blind, placebo-controlled study where subjects were chronically treated with disulfiram and then participated in intranasal cocaine administration studies. RESULTS: Disulfiram 250 mg/day treatment significantly increased plasma cocaine concentrations (p = .013), heart rate (cocaine 1 mg/kg, p = .046), and systolic (cocaine 2 mg/kg p = .003) and diastolic (cocaine 2 mg/kg, p = .022) blood pressure. "High" and "nervous" ratings were nonsignificantly increased. CONCLUSIONS: The combination of "high" with increased anxiety in the context of inability to lessen negative effects with alcohol may be an effective treatment in selected patients. The significant pharmacokinetic interaction must be considered in the decision regarding use of disulfiram.

Administration, Intranasal↗

PubMed1998

Expression of autoantibodies to specific cytochromes P450 in a case of disulfiram hepatitis.

BACKGROUND/AIMS: Immunological mechanisms are involved in many adverse drug reactions. In certain forms of drug-induced hepatitis, patients have been reported to express specific autoantibodies to hepatic drug-metabolising enzymes. The alcohol deterrent disulfiram is associated with a low frequency of severe liver toxicity, including hepatitis, but the mechanism of the toxicity is unknown. We investigated whether autoantibodies to cytochrome P450 enzymes were expressed in the serum of a 28-year-old male patient, who developed hepatitis after 7 weeks of disulfiram treatment and in whom possible causes of hepatitis other than disulfiram had been ruled out. METHODS: Patient serum IgG reactivity was analysed by immunoblotting or ELISA against test antigens consisting of recombinant/purified human or rat liver P450 enzymes, or isolated rat liver microsomes. RESULTS: A significant serum reactivity was found in immunoblotting against human cytochromes P450 1A2 and rat P450 3A1, using serum dilutions of up to 1:900 and 1:2400, respectively. In contrast, the reactivity against cytochromes P450 2E1, 2C9, 2D6, 3A4, and rat liver P450 reductase was either very low or undetectable. ELISA reactivity was low in general, indicating that the P450 epitopes were not surface exposed. Immunoblotting of rat liver microsomes revealed that autoantibodies recognised one major polypeptide corresponding to P450 3A. Autoantibody titres remained stable for at least 6 months after acute hepatitis. A similar reactivity was not found in any of ten control sera. CONCLUSIONS: The expression of autoantibodies directed against specific cytochromes P450 in a case of disulfiram hepatitis suggests that immunological mechanisms are involved in this adverse drug reaction, and that these P450 proteins should be evaluated as possible diagnostic test antigens in disulfiram hepatotoxicity.

Adult↗

PubMed1998

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.

Acute Disease↗

PubMed1997

Inhibition of recombinant human mitochondrial and cytosolic aldehyde dehydrogenases by two candidates for the active metabolites of disulfiram.

We expressed recombinant human cytosolic (ALDH1, high Km) and mitochondrial aldehyde dehydrogenase (ALDH2, low Km) in Escherichia coli and purified the enzymes to homogeneity to examine the nature of inhibition of human ALDH by disulfiram, its confirmed metabolite S-methyl N,N-diethylthiocarbamate (MeDTC) sulfoxide, and its proposed metabolite MeDTC sulfone. Disulfiram, MeDTC sulfoxide, and MeDTC sulfone, respectively, were potent inhibitors with IC50 values of 0.15 +/- 0.02 microM, 0.27 +/- 0.04 microM, and 0.12 +/- 0.02 microM for ALDH1, and 1.45 +/- 0.40 microM, 1.16 +/- 0.56, and 0.40 +/- 0.10 microM for ALDH2. Extensive dialysis did not restore the activity of the inactivated enzyme, indicating irreversible inhibition. Both the esterase and dehydrogenase activities of ALDH2 were inhibited to the same extent by MeDTC sulfone and sulfoxide, suggesting that both catalytic sites are closely linked. The time course of inhibition of ALDH appeared to be first-order for both MeDTC sulfone and MeDTC sulfoxide. Kitz and Wilson plots of the half-life of inactivation versus 1/[inhibitor] indicated that the reactions between ALDH and inhibitors were bimolecular. The pseudobimolecular rate constants (k3/KI) for the ALDH-inhibitor reactions were 1 x 10(5), 1 x 10(4), 3 x 10(3), and 1 x 10(3) s-1 M-1 ALDH1-sulfone, ALDH1-sulfoxide, ALDH2-sulfone, and ALDH2-sulfoxide, respectively. ALDH2 was not significantly protected from inactivation from either MeDTC sulfoxide or MeDTC sulfone by NAD alone, but high concentrations of NAD and acetaldehyde completely prevented inhibition. Since disulfiram is rapidly metabolized in vivo, it is believed that disulfiram is too short-lived to inhibit ALDH directly. The results of our study indicate that MeDTC sulfoxide and sulfone are potent inhibitors of human ALDH and are reasonable candidates for the proximal inhibitors of ALDH following disulfiram administration.

Aldehyde Dehydrogenase↗

PubMed1986

Plasma extracellular superoxide dismutase and erythrocyte Cu,Zn-containing superoxide dismutase in alcoholics treated with disulfiram.

Disulfiram has long been used in the treatment of chronic alcoholism. It is in vivo partially reduced to diethyldithiocarbamate, which is an efficient inhibitor of Cu,Zn-containing superoxide dismutase both in vitro and in vivo. The recently described extracellular superoxide dismutase is even more sensitive to diethyldithiocarbamate than Cu,Zn-superoxide dismutase. To test for the possibility that long term treatment with disulfiram leads to inhibiton of the superoxide dismutases, plasma extracellular superoxide dismutase and erythrocyte Cu,Zn-superoxide dismutase were determined in 12 disulfiram-treated alcoholics, and compared with 11 non-treated alcoholics and 19 healthy controls. Plasma extracellular superoxide dismutase was moderately reduced (about 20%) in the disulfiram-treated alcoholics as compared with the non-treated alcoholics and the healthy controls. No effect of disulfiram treatment on erythrocyte Cu,Zn-superoxide dismutase activity was demonstrated.

Adult↗

PubMedDate not supplied

Use of court-ordered supervised disulfiram therapy at DVA medical centers in the United States.

Having reported high adherence to court-mandated disulfiram treatment, we hypothesized that other Department of Veterans Affairs (DVA) medical centers would report frequent use of this modality. Telephone interviews with DVA substance abuse clinics in 48 of the 50 states matched the national DVA frequencies. Phone survey responders reported disulfiram prescription as never/rarely 63%, sometimes 32%, and often 5%, while court-ordered disulfiram was used never/rarely 95%, sometimes 3%, and often 2%. Nationally, disulfiram prescriptions covered only 0.07% of all veterans seen. These data suggest a need for a re-evaluation of disulfiram as an underused treatment for alcohol dependence.

Alcohol Deterrents↗

PubMed1999

Therapeutic review: do diethyldithiocarbamate and disulfiram have a role in acute nickel carbonyl poisoning?

INTRODUCTION: Sodium diethyldithiocarbamate and disulfiram have been proposed as effective nickel chelators. This paper examines the value of these compounds in the treatment of acute nickel carbonyl poisoning by reviewing published experimental and clinical data. REVIEW: In 2 studies, parenteral administration of diethyldithiocarbamate 50-100 mg/kg to rats immediately following nickel carbonyl exposure ensured the survival of all animals: Mortality fell from 73% to 8% when diethyldithiocarbamate was administered at 10 minutes in a third study. In the same study, there was no protection when diethyldithiocarbamate was administered at 6 hours, and the mortality was greater, though not significantly different, when diethyldithiocarbamate was administered at 24 hours. In another study in mice, total protection was afforded by diethyldithiocarbamate given at 8 hours but this protection was limited when diethyldithiocarbamate was administered at 24 hours, with diethyldithiocarbamate 100 mg/kg apparently being less protective than diethyldithiocarbamate 50 mg/kg. In 3 studies, oral diethyldithiocarbamate administration was less effective than parenteral administration. There are no adequately controlled clinical studies of the use of diethyldithiocarbamate in acute nickel carbonyl poisoning despite claims that this therapy has been effective in the treatment of several hundred such patients. Disulfiram, a metabolite of diethyldithiocarbamate, offered complete protection against nickel carbonyl-induced toxicity when administered in a dose of 1000 mg/kg to rats immediately following nickel carbonyl exposure. In contrast, disulfiram 500 mg/kg offered no protection and disulfiram 1500 mg/kg appeared to enhance mortality, possibly by increasing brain nickel accumulation. CONCLUSION: Animal studies demonstrate that diethyldithiocarbamate is an effective antidote in acute nickel carbonyl poisoning when it is administered parenterally soon after exposure. However, as no adequately controlled clinical studies have been performed, further clinical data are required before diethyldithiocarbamate can be recommended routinely in acute nickel carbonyl poisoning. If diethyldithiocarbamate is to be employed, it should be administered parenterally soon after exposure as delay in administration may increase nickel carbonyl toxicity. There are currently insufficient data to recommend disulfiram as an alternative to diethyldithiocarbamate even when diethyldithiocarbamate is not available.

Animals↗

PubMed1980

Ethylene dibromide and disulfiram: studies in vivo and in vitro on the mechanism of the observed synergistic carcinogenic response.

Two possible mechanisms for the reported carcinogenic synergism between ethylene dibromide (EDB) and disulfiram have been investigated in vivo and in vitro, the first involving increased production of an EDB-derived glutathione mustard and the second increased production of bromoacetaldehyde. Consistent with both of these suggested mechanisms, repeated administrations of disulfiram to rats inreased liver glutathione-S-transferase activity and decreased liver low Km aldehyde dehydrogenase activity. However, when added to a rat liver S-9 fraction in vitro, disulfiram decreased transferase activity and only depressed the dehydrogenase activity after a period of preincubation. Although the mutagenic potency of EDB to Salmonella typhimurium was slightly enhanced in vitro by the addition of a rat liver S-9 fraction, the further addition of disulfiram to the assay medium produced no additional change. Similarly, the addition of a range of S-9 and S-0.5 liver fractions derived from disulfiram-treated rats also failed to enhance significantly its mutagenic potency over the normal S-9 fraction. The general implications of these findings are discussed.

Acetaldehyde↗

PubMed1983

The effect of disulfiram on the carcinogenicity of N-butyl-N-(3-carboxypropyl)nitrosamine in the rat.

N-Butyl-N-(3-carboxypropyl)nitrosamine (BCPN) is a proximate carcinogenic metabolite of the bladder specific carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN). The objective of this study was to determine if disulfiram would inhibit the induction of bladder cancer in rats given BCPN, as reported for BHBN (Cancer Res., 39, 3040, 1979). Two groups of 30 male Wistar rats were given 1.5 mM BCPN (0.028%) in the drinking water for 12 weeks. The total dose of BCPN/rat was 5 mmol (0.95 g). During administration of the BCPN, one group of rats was fed a diet containing 0.5% disulfiram, while the other group was maintained on control diet. At the end of 12 weeks, the animals were maintained on control diet without BCPN for an additional 18 weeks, at which time the animals were sacrificed. It was found that 0.5% disulfiram significantly reduced the incidence of bladder cancer, decreasing from 30/30 (100%) in the group receiving BCPN alone to 3/30 (10%) in the group fed the disulfiram diet. The inhibition of BHBN-induced bladder cancer by disulfiram, previously reported, was also confirmed in these experiments.

Animals↗

PubMed1996

The effects of disulfiram on equine hepatic alcohol dehydrogenase and its efficiency against alcoholism: vinegar effect.

The effects of disulfiram, its metabolite diethyldithiocarbamate and dithiodipyridine on alcohol metabolism of equine hepatic alcohol dehydrogenase (EC.1.1.1.1.) have been investigated. They were found to form enzyme-NAD(+)-inhibitor complexes which were competitive inhibitors of alcohol metabolism with dissociation constants (KEO,I) at pH 7.0 of 50 microM, 1.3 mM, and 260 microM, respectively. Acetate and vinegar behaved similarly in forming an inhibitory enzyme-NAD(+)-acetate ternary complex competitive with ethanol, with at pH 7.0 essentially identical dissociation constants of 4.0 mM and 3.8 mM, respectively. Disulfiram, diethyldithiocarbamate and dithiodipyridine were also found to exhibit affinity-labelling kinetics with liver alcohol dehydrogenase. The liver enzyme is chemically modified and inactivated in a similar manner by all three reagents via binary enzyme complexes with dissociation constants of 30 microM, 200 microM and 50 microM, respectively. Used as a protector against enzyme inactivation by DL-alpha-bromo-beta-(5-imidazolyl)-propionic acid, disulfiram, diethyl-dithiocarbamate and dithiodipyridine were found to form competitive binary enzyme complexes by binding to the active zinc site with KE,I values of 30 microM, 170 microM and 50 microM, respectively. The disulfiram and acetate binding to zinc results in the formation of binary and ternary complexes which inhibit alcohol metabolism at the enzyme level. Due to many unwanted side-effect), and the easy removal of its anti-drinking effects by drinking vinegar (vinegar effect), disulfiram may still be questioned as an effective drug against alcoholism.

Acetates↗

PubMed2007

Refractive hypotension in a patient with disulfiram-ethanol reaction.

Disulfiram (Antabuse) is used for aversive treatment of alcohol dependence with good effects. Through inhibition of aldehyde dehydrogenase, disulfiram heightens serum aldehyde concentration after alcohol ingestion and causes aversive disulfiram-ethanol reaction. Typical symptoms of this reaction include flushing, nausea, dyspnea, tremor, and confusion, which are usually self-limiting. However, severe life-threatening arterial hypotension sometimes develops. We report here a patient with generalized flushing, tremor, and refractive hypotension after ingestion of alcohol 18 hours after disulfiram treatment. Initial volume resuscitation and dopamine infusion failed to restore the blood pressure. Noradrenaline was given and the blood pressure returned to normal range. This case illustrates the intensity of disulfiram-ethanol reaction and underscores the advantageous use of noradrenaline in patients in such a critical condition.

Adult↗

PubMed1994

Disulfiram for alcohol use disorders in adolescents.

Alcohol abuse and dependence in adolescents is a serious health concern with significant morbidity and mortality. Disulfiram has been used to treat alcoholism in adults since 1948, but there are no known reports of disulfiram treatment in minors. Case reports are presented on the use of disulfiram in two adolescent males with alcohol dependence and strong family histories of alcoholism. Prolonged abstinence from alcohol occurred in the first case, whereas poor pharmacological compliance resulted in an early relapse in the second case. The judicious use of disulfiram in adolescents is recommended for consideration in those with alcohol use disorders. A protocol is proposed that recommends a thorough medical and psychiatric evaluation, documentation of a serious alcohol use disorder, careful assessment for comorbid diagnoses, family involvement when possible, and obtainment of informed consent that encompasses education about the nature and effects of disulfiram along with its potential interactions with other medications.

Adolescent↗

PubMed1988

Evaluation of the hypothalamic-hypophysial, thyroid, and gonadal axes before and after disulfiram administration in patients with chronic alcoholism.

We studied 14 alcoholic men without evidence of liver damage. After two weeks of alcohol abstinence, the patients were divided into two groups of seven patients each. Hypothalamic-hypophysial, thyroid, and gonadal axis tests were done on group 1 patients before disulfiram administration, and the tests were later repeated while the patients were taking disulfiram. Group 2 patients had initial testing done while taking disulfiram and repeat testing after the drug was stopped. The following abnormalities were found and were not affected by disulfiram: lack of suppression of both growth hormone and glucagon with oral glucose intake, and lack of response of follicle-stimulating hormone after administration of synthetic gonadotropin-releasing hormone. After disulfiram administration, we noticed a blunted response of thyrotropin to thyrotropin-releasing hormone.

Adult↗

PubMed2006

Quantification of breath carbon disulphide and acetone following a single dose of disulfiram (Antabuse) using selected ion flow tube mass spectrometry (SIFT-MS).

Selected ion flow tube mass spectrometry (SIFT-MS) has been used to measure simultaneously the concentrations of both carbon disulphide and acetone in exhaled breath following the ingestion of a single dose of disulfiram (Antabuse). Carbon disulphide is a product of the metabolism of disulfiram and is excreted mainly through the lungs. Acetone is a product of normal metabolism and appears in the breath of all individuals. These breath analyses were performed in single exhalations and the results were available in real time. The levels of breath acetone and carbon disulphide were compared with levels obtained from a control subject who had not ingested disulfiram. Breath carbon disulphide was seen to increase from 15 p.p.b. to 618 p.p.b. over a 28-hour period, in the single individual tested, following ingestion of disulfiram, while acetone levels increased from 300 p.p.b. (normal) to over 4000 p.p.b. (greatly elevated). No such increases were seen in the breath of the control subject over the same period. An obvious positive correlation between breath carbon disulphide and acetone concentrations following disulfiram ingestion is seen and discussed.

Acetone↗

PubMed1994

Diethyldithiocarbamate methyl ester sulfoxide, an inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase and putative metabolite of disulfiram.

S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) is a potent inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2) both in vivo and in vitro, and has been proposed to be the metabolite responsible for ALDH2 inhibition by disulfiram. Diethyldithiocarbamate methyl ester (DDTC-Me), a key intermediate in the metabolism of disulfiram, has been shown to be bioactivated by microsomal monooxygenases to diethyldithiocarbamate methyl ester sulfoxide (DDTC-Me sulfoxide). Studies were conducted to determine if DDTC-Me sulfoxide was also an active metabolite of disulfiram and inhibitor of ALDH2. DDTC-Me sulfoxide inhibited ALDH2 in vitro with an IC50 of 10 microM, and in vivo with an ID50 of 31 mg/kg (170 mumol/kg). Maximal ALDH2 inhibition in vivo was observed 8 hr after the administration of 45.2 mg/kg DDTC-Me sulfoxide, with ALDH2 activity returning to control levels after 48 hr. Although DDTC-Me sulfoxide inhibited ALDH2 in vivo, DDTC-Me sulfoxide was not detected in plasma from rats treated with either disulfiram (75 mg/kg), DDTC-Me (122.25 mg/kg), or DDTC-Me sulfoxide (45.2 mg/kg). However, DDTC-Me and S-methyl N,N-diethylthiolcarbamate (DETC-Me) were detected in plasma from rats treated with DDTC-Me sulfoxide. In rats treated with DDTC-Me sulfoxide and challenged with ethanol, a small increase of approximately microM in blood acetaldhyde and an inconsistent drop in blood pressure was observed. In conclusion, DDTC-Me sulfoxide inhibited ALDH2 in vitro and in vivo, was less potent than DETC- MeSO, and was not detected after disulfiram administration.

Acetaldehyde↗

PubMed1996

Carbohydrate-deficient transferrin and gamma-glutamyl transferase levels during disulfiram therapy.

Serum samples for quantification of carbohydrate-deficient transferrin (CDT) and gamma-glutamyl transferase (GGT) were collected from alcohol-dependent men and women upon admission to the hospital for detoxification, and repeatedly over a 3- to 5-week period of supervised disulfiram administration as outpatients. On admission, 10 of 12 patients showed CDT concentrations above the conventional cutoff limits, whereas 6 had elevated GGT values. Normalization usually occurred within 1 to 3 weeks of disulfiram treatment, after which CDT and GGT leveled out at a relatively stable individual baseline level. However, in those patients with the highest values on admission, the decline continued during the entire observation period. The time for normalization of GGT was typically longer than for CDT. In four male patients who had taken disulfiram regularly (400-800 mg every second or third day) for at least 3 months before entering the study, the CDT and GGT concentrations were stable over time and all fell within normal limits. The present results indicate that disulfiram treatment does not influence the serum level of CDT. It is also suggested that consecutive CDT and GGT measurements during outpatient treatment with disulfiram after detoxification can be used to identify the individual baseline (i.e., abstinence) values for CDT and GGT, and, furthermore, for monitoring treatment outcome.

Adult↗