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PubMed1989

[Fulminant hepatitis induced by disulfiram in a patient with alcoholic cirrhosis. Survival after liver transplantation].

Fulminant hepatitis was observed in a 44-year-old patient with cirrhosis, 38 days after the beginning of a treatment by disulfiram. Hepatitis was associated with fever and hypereosinophilia. Liver transplantation was performed with success. We reviewed 15 previously published cases of disulfiram-induced hepatitis. They occurred from 10 to 180 days after the beginning of the treatment by disulfiram, aminotransferases were increased whereas alkaline phosphatases were not markedly changed; there was either focal or widespread necrosis. Fulminant hepatitis was observed mainly in patients with alcoholic chronic liver disease or in patients who continued to ingest disulfiram while jaundice was already present. An immunoallergic mechanism is thought to be responsible for disulfiram-induced hepatitis.

Adult↗
PubMed1979

The effect of dietary disulfiram upon the tissue distribution and excretion of 14C-1,2-dibromoethane in the rat.

Dietary disulfiram enhances the toxicity of inhaled 1,2-dibromoethane in rats. This study was undertaken to determine whether the differential toxicity noted was associated with alterations in the levels of the compound and/or its metabolites in the target organs. A comparison of the levels of 14C in selected tissues of male rats, with and without dietary disulfiram, following the oral administration of 14C-1,2-dibromoethane was made. The results indicated that levels of radioactivity in the target organs of animals in the disulfiram group were significantly elevated both at 24 and 48 hours following compound administration. The data indicate a direct correlation between tissue levels and the enhancement of toxicity noted in the disulfiram-treated rats in the inhalation study. A significant elevation in the levels of radioactivity in washed liver nuclei obtained from animals receiving dietary disulfiram was also noted, suggesting a relationship between nuclear uptake and the increased incidence of liver tumors appearing in the disulfiran group in the inhalation study.

Animals↗
PubMed1979

Inhibition of N-n-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder cancer in rats by administration of disulfiram in the diet.

The objective of this study was to determine if disulfiram would influence the induction of urinary bladder cancer in rats given N-n-butyl-N(4-hydroxybuty)nitrosamine (BHBN). Adult male Wistar rats were divided into: Group 1, control diet, 30 rats; Group 2, control diet plus 0.025% BHBN in the drinking water, 60 rats; Group 3, control diet containing 0.5% disulfiram, 30 rats; and Group 4, control diet containing 0.5% disulfiram plus 0.025% BHBN in the drinking water, 60 rats. The animals were kept on these regimens for 15 weeks and then were transferred to and maintained on control diet. The average total intake of BHBN was 1.21 g/rat for Group 2 and 1.23 g/rat for Group 4. The cumulative incidences of bladder cancer at 25 weeks after initial exposure to BHBN were: Group 1, 0 of 9; Group 2, 27 of 27; Group 3, 0 of 9; and Group 4, 0 of 27. At termination of the experiment (32 to 42 weeks), the final bladder cancer incidences were: Group 1, 0 of 30 (0%); Group 2, 57 of 57 ()00%); Group 3, 0 of 24 (0%); and Group 4, 7 of 55 (13%). Except for a carcinoma of the renal pelvis in one rat in Group 2 and the bladder tumors in Groups 2 and 4, tumors were not detected in other organs of any of these rats. It was concluded that disulfiram significantly inhibited the induction of bladder cancer in rats exposed to BHBN. The mechanism of action of disulfiram in this process is under investigation.

Animals↗
PubMed1977

Cerebrospinal fluid homovanillic acid in male alcoholics: effects of disulfiram.

It is well know that if an individual maintained on disulfiram (Antabuse) ingests alcohol, excess acetaldehyde is formed, resulting in a toxic reaction. In addition to this toxic interaction with alcohol (the basis of its use as a deterrent), there are both behavioral and biochemical observations to suggest that disulfiram alone has a direct effect on the CNS. The possibility that some of disulfiram's effects are related to alterations in biogenic amine metabolism led to the present study of cerebrospinal fluid amine metabolites in a group of male alcoholics. In this group, disulfiram treatment was associated with a significant reduction in homovanillic acid, the major metabolite of dopamine, while no change was noted in 5-hydroxyindoleacetic acid, the major metabolite of serotonin. Prior to disulfiram, patients with withdrawal symptoms had significantly lower homovanillic acid than those without such symptoms.

Adult↗
PubMed1978

Catatonia associated with disulfiram therapy.

This is the first report of a catatonic syndrome occurring in a patient receiving disulfiram treatment. A causal relationship is strongly suggested by the mode of onset, the absence of a previous history of catatonia, and the rapid resolution of the syndrome within 72 hours of discontinuance of the disulfiram therapy. Neurophysiological mechanisms which aid in elucidating the role of disulfiram in the etiology of catatonia are discussed. It is important that physicians be alerted to this serious, potentially lethal, complication, as it is readily reversible if the disulfiram is discontinued and appropriate supportive measures are taken. Also, it appears that these patients may be more susceptible to complications with future disulfiram usage and should be strongly counseled to seek alternative therapies for their alcohol problems in the future.

Alcoholism↗
PubMed1982

Mechanism of alcohol sensitivity and disulfiram-ethanol reaction.

Human aldehyde dehydrogenase (ALDH) consists of two main isozymes with low and high Km for aldehyde. ALDH isozymes in hair sheats were tested from 40 Japanese using isoelectric focusing and blood acetaldehyde determination with gas chromatography. About 43% of Japanese, who lacked the low Km enzyme (ALDH I) showed an elevated acetaldehyde concentration due to their inability to metabolize acetaldehyde quickly and effectively. Studies regarding the inhibitory reaction of disulfiram and its metabolites have been performed. Among the metabolites, diethylamine inhibited the low Km enzyme strongly. It is presumed that vasomotor symptoms and high acetaldehyde concentration in blood after alcohol intake in patients who are treated with disulfiram might be mainly due to a decrease in activity of the low Km enzyme caused by diethylamine which is produced in vivo as one of the metabolites from disulfiram, rather than to an inhibitory reaction of disulfiram only. Thus, alcohol sensitivity in Mongoloids and disulfiram-ethanol reaction may have a common mechanism.

Acetaldehyde↗
PubMedDate not supplied

The effect of prolonged administration of disulfiram alone or in combination with ethanol on some indices of lipid metabolism in the blood serum and hepatic tissue of the rat.

Disulfiram alone or in combination with ethanol was administered orally for six weeks. Disulfiram significantly elevated the triglyceride level in the blood serum and hepatic tissue and cholesterol level in the blood serum, and depressed the content of free fatty acids in the hepatic tissue. Given together with ethanol, disulfiram increased the concentration of triglycerides and cholesterol in the blood serum and depressed the cholesterol level in the hepatic tissue. Given separately or in combination with ethanol, disulfiram disturbed the lipid metabolism. The results may indicate that chronically given disulfiram may produce in man similar disturbance and owing to that may aggravate hepatic steatosis present in 60--90% of alcoholics, in this way intensifying the damage of this organ.

Administration, Oral↗
PubMed1995

Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the bioactivation of disulfiram.

Disulfiram is bioactivated through a series of intermediates, ultimately forming S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the metabolite proposed to be responsible for the in vivo inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase (ALDH2). Diethyldithiocarbamate methyl ester sulfine (DDTC-Me sulfine) also has been recently identified as a possible metabolite of disulfiram (Madan and Faiman, 1994). In the present studies, DDTC-Me sulfine was characterized and was found to inhibit ALDH2 in vivo (ID50 = 57 mumol/kg) but not in vitro. Maximum inhibition of ALDH2 in rats was observed 1 hr after the i.p. administration of DDTC-Me sulfine. Pretreatment of rats with 1-benzylimidazole, a cytochrome P450 inhibitor, blocked the DDTC-Me sulfine-mediated inhibition of ALDH2. This suggested that DDTC-Me sulfine was further bioactivated by a cytochrome P450-dependent mechanism. DDTC-Me sulfine could not be detected in rat plasma after the i.p. administration of disulfiram (75 mg/kg), DDTC-Me (122 mg/kg) or DDTC-Me sulfine (22.6 mg/kg). However, S-methyl N,N-diethylthiolcarbamate (DETC-Me), the desulfurated form of DDTC-Me, was detected as a major metabolite of DDTC-Me sulfine in rat plasma after DDTC-Me sulfine administration. Also, a disulfiram-like-ethanol reaction was observed in rats treated with DDTC-Me sulfine and challenged with ethanol. These data provided additional support for the idea that DDTC-Me sulfine is an intermediate formed after DDTC-Me metabolism and is probably a precursor to DETC-Me in the overall bioactivation of disulfiram to DETC-Me sulfoxide.

Aldehyde Dehydrogenase↗
PubMedDate not supplied

[Collateral effects of disulfiram on the central nervous system in alcoholics that have become totally abstemious. Description of 8 cases].

Disulfiram is used in alcohol rehabilitation because it inhibits aldehyde dehydrogenase and consequently causes the disulfiram-ethanol reaction (vomiting, vertigo, anxiety, cardiovascular effects) after ingestion of alcoholic beverages. However, adverse effects on the central nervous system (for the most part psychotic reactions, acute organic brain syndrome, catatonia) may appear as a direct result of the drug itself. Disulfiram and its metabolite carbon disulfide inhibit dopamine beta-hydroxylase, increasing the levels of dopamine and reducing those of norepinephrine in the central nervous system. We observed direct disulfiram-induced toxicity on the central nervous system in 8 abstinent patients in whom a disulfiram-ethanol reaction had been excluded. Risk is increased when 1) excessive amounts of the drug are ingested; 2) the patient is already suffering from a major psychiatric illness; 3) the patient has anatomical brain lesions. In all cases observed, the toxic effects appeared in the first weeks and were reversed after suspension of the drug (except in one patient who died from severe bronchopulmonary infection). We thus suggest the following protocol: 1) physical examination and interview 3-4 weeks after initiation of treatment; 2) as a general rule, in abstinent patients, the lowest possible maintenance dosage should be administered. This strategy, despite the risk of underdosage, meets the goals inherent in an integrated medical and psychosocial approach to the treatment of alcoholism with which these patients seem better able to comply.

Adult↗
PubMed1997

Studies on the metabolic activation of disulfiram in rat. Evidence for electrophilic S-oxygenated metabolites as inhibitors of aldehyde dehydrogenase and precursors of urinary N-acetylcysteine conjugates.

Recent studies on the mechanism by which disulfiram inhibits aldehyde dehydrogenase have provided evidence for the formation of reactive intermediates that are thought to carbamoylate, and thereby inactivate the enzyme. In our study, rats were dosed with either disulfiram (0.25 mmol kg-1 i.p.) or its reduced metabolite diethyldithiocarbamate (DDTC; 0.5 mmol kg-1 i.p.) and urine was collected for the analysis of metabolites derived from putative reactive intermediates. By means of ionspray LC-MS/MS, two novel N-acetylcysteine (NAC) conjugates, i.e., N-acetyl-S-(N, N-diethylcarbamoyl)cysteine and N-acetyl-S-(N, N-diethylthiocarbamoyl)cysteine, were identified in urine specimens. Quantitative analyses indicated that, over the 0- to 24-hr period after drug administration, urinary excretion of N-acetyl-S-(N, N-diethylcarbamoyl)cysteine accounted for 7.5 +/- 4.0 and 6.2 +/- 1.0%, respectively, of the dose of disulfiram and diethyldithiocarbamate, while the corresponding thiocarbamoyl conjugate, N-acetyl-S-(N, N-diethylthiocarbamoyl)cysteine, accounted for a further 0.5 +/- 0.3 and 0.3 +/- 0.1%, respectively, of the dose. These conjugates are believed to derive from reactive sulfoxide and sulfone metabolites of disulfiram, namely S-methyl-N, N-diethylthiocarbamate sulfoxide (DETC-MeSO), S-methyl-N, N-diethylthiocarbamate sulfone (DETC-MeSO2), S-methyl-N, N-diethyldithiocarbamate sulfoxide (DDTC-MeSO) and S-methyl-N, N-diethyldithiocarbamate sulfone (DDTC-MeSO2), which were found to carbamoylate N-acetylcysteine in vitro with the following rank order of reactivity: DDTC-MeSO2 > DETC-MeSO2 > DDTC-MeSO > DETC-MeSO. In vitro experiments with aldehyde dehydrogenase showed that all four S-oxygenated metabolites inhibited the enzyme effectively. Furthermore, inclusion of NAC in incubation media attenuated significantly the inhibition by DDTC-MeSO2, DETC-MeSO2 and DDTC-MeSO, but had little effect on that by DETC-MeSO. Our results are consistent with the hypothesis that disulfiram and diethyldithiocarbamate undergo activation by a sequence of metabolic reactions leading to the formation of electrophilic S-methyl sulfoxides and sulfones that carbamoylate, and thereby inhibit, aldehyde dehydrogenase and possibly other enzymes.

Acetylcysteine↗
PubMed1997

The efficacy of disulfiram: a review of outcome studies.

Twenty-four studies of outcome following oral disulfiram and 14 following implanted disulfiram were identified for review from MEDLINE and PsycINFO databases and by manual searching for the period 1967-95. The methodological rigour of these studies was generally poor, albeit not as poor as that of earlier studies (not reviewed here). An overall assessment of the results of research in this field is hampered by the diversity of both the methods used and the subject populations studied. However, it is clear that support for the general use of oral disulfiram is equivocal, mostly being found in the form of reduced quantity of alcohol consumed and a reduced number of drinking days. Evidence for an effect in increasing the proportion of patients who achieve abstinence is surprisingly lacking. Where it is prescribed, disulfiram use should be supervised and it should be employed as one part of a comprehensive treatment programme. There is no good evidence in favour of implanting disulfiram tablets, but the possibility of a depot injection is intriguing.

Administration, Oral↗
PubMed1983

Use of disulfiram for alcoholics in methadone maintenance programs. A Veterans Administration Cooperative Study.

A multicentered clinical trial studied the efficacy and safety of disulfiram in controlling heavy alcohol consumption by patients on methadone maintenance regimens. The trial was stopped when sample size targets were not achieved. Efficacy comparisons were based on 82 patients who started the study; safety comparisons were based on 35 patients who completed 12 weeks of study. Patients received either disulfiram and methadone or placebo and methadone. Disulfiram was administered at a dosage of 125 mg/day for seven days and 250 mg/day thereafter for 36 weeks. No significant differences between the disulfiram and placebo groups were observed in either the retention in study or any other important end point. Both groups showed improvement in control of drinking during the study. There were no serious adverse reactions that could be attributed to the combined use of the two drugs.

Adult↗
PubMed2006

Inhibition of proteasome activity, nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram.

The proteasome pathway is an important target for anticancer drug development. Here, we identify the antialcoholism drug disulfiram and its analogue pyrrolidine dithiocarbamate (PDTC) as inhibitors of the 26S proteasome activity in a cell-based screening assay. As expected for proteasome inhibitors, these compounds also inhibited TNF-alpha-induced nuclear factor-KappaB (NF-KappaB) translocation and were cytotoxic. Disulfiram was more cytotoxic against chronic lymphocytic leukemia cells compared to peripheral blood mononuclear cells (PBMC) at clinically achievable concentrations. Proteasome and NF-KappaB inhibition were achieved with a potency in the same range as that of the clinically used proteasome inhibitor bortezomib. Disulfiram was also able to induce accumulation of p27(Kip1) and to prolong the half-life of c-Myc, both targets for proteasome-dependent degradation. It is concluded that the previously observed antitumoral and NF-KappaB inhibiting activity of disulfiram and PDTC could be attributed to their inhibition of the 26S proteasome.

Alcohol Deterrents↗
PubMedDate not supplied

Effects of disulfiram on serum dopamine-beta-hydroxylase and blood carbon disulphide concentrations in alcoholics.

The aim of this study was to investigate the effects of single and repeated disulfiram doses on serum dopamine-beta-hydroxylase activity and blood carbon disulphide concentrations in a group of abstinent alcoholics. The increase in the blood concentration of carbon disulphide was dose dependent after the oral administration of 100-400 mg of disulfiram. Free carbon disulphide peaked at 12 h while the protein-bound fraction increased at least up to 24 h. Both single (100-400 mg p.o.) and repeated (200 mg daily p.o. for ca. 1 month) administrations failed to inhibit the activity of serum dopamine-beta-hydroxylase. The repeated daily administration of 200 mg of disulfiram also had no influence on copper-activated serum dopamine-beta-hydroxylase, which was the same before and after 1-month treatment period. Contrary to the disulfiram group, the activity of the copper-activated enzyme in the serum of abstinent alcoholics declined significantly during the same 30 days.

Administration, Oral↗
PubMed1990

Lack of interaction between disulfiram and alprazolam in alcoholic patients.

Certain interactions between disulfiram and benzodiazepines, especially diazepam and chlordiazepoxide, have previously been reported. The influence of disulfiram on the pharmacokinetics of alprazolam, a triazolobenzodiazepine, metabolized by hepatic microsomal oxidation, has been evaluated in 11 chronic alcoholic patients (6 males, 5 females) undergoing treatment for the alcohol withdrawal syndrome. Each patient received alprazolam 2 mg on the first day (control) followed by two weeks of treatment with disulfiram 0.5 g/d, and then further oral dose of alprazolam 2 mg. No significant change was found in any of the kinetic parameters. Thus, a therapeutic dose of disulfiram did not significantly alter the clearance or half-life of alprazolam in chronic alcoholic patients.

Adult↗
PubMed1992

Effect of disulfiram (DS) on mitochondria from rat hippocampus: metabolic compartmentation of DS neurotoxicity.

This experiment was designed to study the acute effects of disulfiram on mitochondrial enzymes in nonsynaptic and synaptic mitochondria from rat hippocampus. Cytochrome c oxidase, monoamine oxidase-B, glycerolphosphate acyltransferase and beta-hydroxybutyrate dehydrogenase were studied. Differences in enzyme activity were seen in controls. Cytochrome c oxidase activity was higher in synaptic mitochondria whereas glycerolphosphate acyltransferase activity was higher in nonsynaptic mitochondria. Mitochondria from disulfiram treated rats, particularly synaptic mitochondria, exhibited lower specific activities of cytochrome c oxidase and monoamine oxidase-B. These alterations were not limited to either the inner or outer mitochondrial membrane. Transmission electron microscopy revealed that mitochondria from disulfiram treated rats were severely altered in isolated preparations as well as in those from whole tissue. This study shows that disulfiram exerts a differential effect on mitochondrial subpopulations.

Animals↗
PubMed1983

Studies in vitro on the inactivation of mitochondrial rat-liver aldehyde dehydrogenase by the alcohol-sensitizing compounds cyanamide, 1-aminocyclopropanol and disulfiram.

The inhibition of the low-Km, rat-liver mitochondrial aldehyde dehydrogenase (ALDH) by the alcohol-sensitizing agents cyanamide, 1-aminocyclopropanol (ACP) and disulfiram was studied in vitro. All three compounds caused a progressive decline in the enzyme activity. Restoration of activity could not be achieved by gel-filtration, dilution or by the addition of excess thiol. High concentrations of acetaldehyde partly restored the activity of the cyanamide-inactivated enzyme but had no effects on the disulfiram- or ACP-inactivated enzyme. In the presence of saturating concentrations of the coenzyme (NAD+), the inactivation process followed first-order kinetics at fixed concentrations of the inhibitors. Plots of the apparent first-order rate constants against inhibitor concentration were curved, suggesting the formation of saturable, reversible holoenzyme-inhibitor complexes prior to the covalent reactions. In the absence of NAD+, the rate of inactivation by disulfiram was biphasic and considerably higher than that in the presence of NAD+. In contrast, no inactivation was obtained with cyanamide in the absence of NAD+. Likewise, the presence of NAD+ greatly promoted the inactivation by ACP. The esterase activity of the enzyme was also affected by the inhibitors, although to a lesser extent than was the dehydrogenase activity. The results obtained suggest that all three inhibitors inactivate the enzyme through covalent reactions with the thiol groups at the active site. It is proposed that binding of NAD+ limits access of disulfiram to the thiols at the active site but provides a situation that favours an electrophilic attack of cyanamide and ACP on the thiol groups.

Aldehyde Oxidoreductases↗
PubMed1992

In vitro and in vivo inhibition of rat liver aldehyde dehydrogenase by S-methyl N,N-diethylthiolcarbamate sulfoxide, a new metabolite of disulfiram.

In summary, these data provide the first evidence that DETC-MeSO is a natural metabolite of disulfiram, and a potent inhibitor of rat liver mitochondrial low Km ALDH both in vitro and in vivo. It is therefore proposed that, based upon evidence to date, DETC-MeSO appears to be the chemical species to which disulfiram must be bioactivated, and is the metabolite most likely responsible for disulfiram's inhibition of rat liver mitochondrial low Km ALDH in vivo. Characterization of the properties of DETC-MeSO as the metabolite responsible for disulfiram's action as an ALDH inhibitor is presently in the process of being completed.

Aldehyde Dehydrogenase↗