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PubMed1983

Can disulfiram use precipitate urges to drink alcohol?

Although pharmacological data suggest that patients taking disulfiram should have a reduced desire to drink alcohol, voluntary compliance with disulfiram treatment is quite poor. As a possible explanation for why so many patients discontinue taking disulfiram and return to excessive drinking, it was hypothesized that daily disulfiram administration might serve as a cognitive stimulus precipitating urges to drink alcohol and/or inadvertently exposing patients to additional drinking-related cues. If this is the case, then patients taking disulfiram should report more thoughts about or urges to drink alcohol. In an exploratory, uncontrolled clinical study, alcohol abusers who were taking disulfiram tended to self-record more cravings for alcohol over a two week period than did abstinent patients who were not taking disulfiram. Controlled research is needed to investigate whether disulfiram use may serve as a cue antecedent to relapse to drinking.

Alcohol Drinking↗
PubMed2001

Oxidative stress and c-Jun-amino-terminal kinase activation involved in apoptosis of primary astrocytes induced by disulfiram-Cu(2+) complex.

Disulfiram is frequently used in the treatment of alcoholism. In this study, we found that CuCl(2) (1-10 microM), but not other metal ions (Fe(2+), Zn(2+), Pb(2+)), markedly potentiated disulfiram-induced cytotoxicity by 440-fold in primary astrocytes. Thus, the molecular mechanisms of the cytotoxic effects induced by the disulfiram-Cu(2+) complex were explored. The changes in morphology (nuclear condensation and apoptotic body formation) and hypodiploidy of DNA suggested that the disulfiram-Cu(2+) complex induced an apoptotic process. Our studies of the death-signaling pathway reveal that decreased mitochondrial membrane potential, increased free radical production, and depletion of non-protein-thiols (glutathione) were involved. The disulfiram-Cu(2+) complex activated c-Jun-amino-terminal kinase (JNK) and caspase-3 followed by poly (ADP-ribose) polymerase degradation in a time-dependent manner. Moreover, the cellular Cu content was markedly increased and the copper chelator bathocuproine disulfonate abolished all of these cellular events, suggesting that Cu(2+) is essential for death signaling. The antioxidants N-acetylcysteine and vitamin C also inhibited the cytotoxic effect. Thus, we conclude that the disulfiram-Cu(2+) complex induces apoptosis and perhaps necrosis at a late stage mediated by oxidative stress followed by sequential activation of JNK, caspase-3 and poly (ADP-ribose) polymerase degradation. These findings imply that the axonal degeneration and neurotoxicity observed after the chronic administration of disulfiram are perhaps, at least in part, due to the cytotoxic effect of the disulfiram-Cu(2+) complex formed endogenously.

Animals↗
PubMed1989

Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics.

The influence of disulfiram on theophylline metabolism was studied in 20 recovering alcoholics. Ten of the patients, who were selected at random, received 250 mg of disulfiram daily. The other 10 patients received 500 mg of disulfiram daily. Two single-dose studies of theophylline kinetics were performed--one as a baseline control and the other after 1 week of treatment with disulfiram. With disulfiram pretreatment, the plasma clearance of theophylline was decreased from 105.7 +/- 10.2 (mean +/- SEM) to 83.1 +/- 8.1 ml/kg per hour (p less than 0.001) in the 250 mg group and from 94.3 +/- 13.3 to 65.4 +/- 10.7 ml/mg per hour (p less than 0.001) in the 500 mg group. The elimination half-life was prolonged significantly in both groups. The percent reduction in theophylline clearance was greater in the 500 mg group (32.5 +/- 3.1; range, 21.6 to 49.6) than it was in the 250 mg group (21.2 +/- 1.7; range, 14.6 to 29.6; p less than 0.01). Disulfiram decreased the formation of all theophylline metabolites in smokers in both treatment groups. In each group, the hydroxylation pathway was affected more than the demethylation pathway. These data indicate that at therapeutic doses disulfiram exerts a dose-dependent inhibitory effect on theophylline metabolism. Depending on the dose of disulfiram, a dose reduction of theophylline by as much as 50% may be necessary to minimize the risk of toxicity.

Adult↗
PubMed1993

Single-dose disulfiram inhibition of chlorzoxazone metabolism: a clinical probe for P450 2E1.

Disulfiram and its reduced metabolite diethyldithiocarbamate have been identified previously as selective mechanism-based inhibitors of human liver microsomal cytochrome P450 2E1 in vitro. In animals, a single oral dose of disulfiram has been shown to produce a rapid and selective inactivation of hepatic P450 2E1 content and catalytic activity in vivo. This investigation explored the efficacy of single dose disulfiram as an inhibitor of human P450 2E1 activity in vivo. Clinical P450 2E1 activity was assessed by the 6-hydroxylation of chlorzoxazone, a metabolic pathway catalyzed selectively by P450 2E1. Six healthy volunteers received 750 mg oral chlorzoxazone on two occasions in a crossover design, 10 hours after 500 mg oral disulfiram, or after no pretreatment (control subjects). Disulfiram pretreatment markedly decreased chlorzoxazone elimination clearance to 15% of control values (from 3.28 +/- 1.40 to 0.49 +/- 0.07 ml/kg/min, p < 0.005), prolonged the elimination half-life (from 0.92 +/- 0.32 to 5.1 +/- 0.9 hours, p < 0.001), and caused a twofold increase in peak plasma chlorzoxazone concentrations (20.6 +/- 9.9 versus 38.7 +/- 10.3 micrograms/ml, p < 0.001). Disulfiram also profoundly decreased the formation clearance of 6-hydroxychlorzoxazone, from 2.30 +/- 0.93 to 0.17 +/- 0.05 ml/kg/min (p < 0.005). These findings show that a single dose of disulfiram significantly diminishes the activity of human P450 2E1 in vivo. The efficacy of single-dose disulfiram as an inhibitor of human P450 2E1 suggests that this modality for manipulating clinical P450 2E1 activity may provide a useful probe for delineating P450 2E1 participation in human drug biotransformation or for the treatment of poisoning by P450 2E1-activated toxins.

Adult↗
PubMed1982

Further studies of the action of disulfiram and 2,2'-dithiodipyridine on the dehydrogenase and esterase activities of sheep liver cytoplasmic aldehyde dehydrogenase.

1. Pre-modification of cytoplasmic aldehyde dehydrogenase by disulfiram results in the same extent of inactivation when the enzyme is subsequently assayed as a dehydrogenase or as an esterase. 2. 4-Nitrophenyl acetate protects the enzyme against inactivation by disulfiram, particularly well in the absence of NAD+. Some protection is also provided by chloral hydrate and indol-3-ylacetaldehyde (in the absence of NAD+). 3. When disulfiram is prevented from reacting at its usual site by the presence of 4-nitrophenyl acetate, it reacts elsewhere on the enzyme molecule without causing inactivation. 4. Enzyme in the presence of aldehyde and NAD+ is not at all protected against disulfiram. It is proposed that, under these circumstances, disulfiram reacts with the enzyme-NADH complex formed in the enzyme-catalysed reaction. 5. Modification by disulfiram results in a decrease in the amplitude of the burst of NADH formation during the dehydrogenase reaction, as well as a decrease in the steady-state rate. 6. 2,2'-Dithiodipyridine reacts with the enzyme both in the absence and presence of NAD+. Under the former circumstances the activity of the enzyme is little affected, but when the reaction is conducted in the presence of NAD+ the enzyme is activated by approximately 2-fold and is then relatively insensitive to the inactivatory effect of disulfiram. 7. Enzyme activated by 2,2'-dithiodipyridine loses most of its activity when stored over a period of a few days at 4 degrees C, or within 30 min when treated with sodium diethyldithiocarbamate. 8. Points for and against the proposal that the disulfiram-sensitive groups are catalytically essential are discussed.

2,2'-Dipyridyl↗
PubMed2003

Comparison of disulfiram and placebo in treatment of alcohol dependence of adolescents.

About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that disulfiram may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term disulfiram treatment in alcohol dependence of adolescents. In this double-blind, placebo-controlled study we recruited 26 adolescents, aged 16-19 years, with chronic or episodic alcohol dependence. Patients were allocated treatment randomly with disulfiram (200 mg daily) or placebo for 90 days. Patients were assessed on the day treatment started and on days 30 and 90 by interview, self-report, questionnaire and laboratory screening. Patients were classified as abstinent, relapsing or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. The disulfiram (n=13) and placebo (n=13) groups were well matched in terms of baseline demographic and alcohol-related variables. Thirteen disulfiram-treated and 13 placebo-treated patients completed the treatment phase; seven (1 vs. 6) relapsed, five (3 vs. 2) refused to continue treatment, three (1 vs. 2) had concurrent illness and two (1 vs. 1) had adverse side effects. At the end of treatment, seven disulfiram-treated and two placebo-treated patients had been abstinent continuously (p=0.0063). Mean cumulative abstinence duration was significantly greater in the disulfiram group than in the placebo group [68.5 (SD 37.5) vs. 29.7 (19.0) days; p=0.012]. Apart from occasional diarrhoea, there was no difference in side effects between groups. In some cases, disulfiram may be an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of adolescent alcohol-dependent patients.

Adolescent↗
PubMed2004

Liver transplantation for disulfiram-induced fulminant hepatic failure.

Disulfiram has been used as a popular adjunct in programs for alcohol rehabilitation. However, in rare cases, disulfiram has been reported to cause fulminant hepatitis. Disulfiram use and its associated complications in adolescents have received minimal attention in the literature. We report the first pediatric case of successful orthotopic liver transplantation for disulfiram-induced fulminant hepatic failure in a 16-year-old girl, who developed an idiosyncratic reaction associated with short-term, low-dose disulfiram use, as evidenced by her liver biopsy and explanted liver. This case report indicates that a high index of suspicion, and aggressive therapeutic interventions are necessary to recognize and manage disulfiram-induced fulminant hepatic failure in adolescents. Success of this case suggests that transplant centers should consider liver transplantation of an adolescent alcoholic patient with fulminant hepatic failure due to non-alcohol-related causes such as disulfiram. Orthotopic liver transplantation should be considered early in the management of disulfiram-induced fulminant hepatic failure.

Adolescent↗
PubMed1993

Screening for disulfiram-induced liver test dysfunction in an inpatient alcoholism program.

The objective of this study was to report the frequency of disulfiram-related elevations of four commonly used hepatic screening chemistries using a retrospective record review design. An inpatient alcoholism program was selected for the setting. Patients who had initial laboratory values within the normal range started daily supervised doses of disulfiram, then underwent follow-up testing after 2 and 4 weeks on the drug. The study population consisted of 108 patients receiving disulfiram and 27 patients who did not receive disulfiram (controls). The four screening serum chemistries performed were aspartate aminotransferase (SGOT), alanine aminotransferase (SGPT), alkaline phosphatase, and gamma-glutamyl transferase. Twenty-seven (25%) of the 108 patients who were taking 250 mg of disulfiram a day for 2 to 4 weeks had disulfiram-related elevations in alanine aminotransferase above the upper limit of normal, as opposed to one elevation in 27 patients (4%) for whom disulfiram was not prescribed. In the 108 patients (with initially normal serum chemistries) who were prescribed disulfiram, 32 were discontinued from the drug at 2 weeks and an additional 11 were discontinued from the drug at 4 weeks because of one or more abnormal serum chemistries. Alanine aminotransferase was the most specific and sensitive indicator of the four screening chemistries performed.

Adult↗
PubMed1975

Anomalous results of studies on drug interaction in man. III. Disulfiram and antipyrine.

Disulfiram inhibited antipyrine metabolism reproducibly in three experiments utilizing three different groups of normal human volunteers. In these experiments disulfiram in a dose of 3.5 mg/kg body weight was given orally twice daily for 4 consecutive days and in two subsequent experiments for 10 consecutive days. In each experiment the mean antipyrine half-life was prolonged and the mean metabolic clearance rate of antipyrine was shortened by disulfiram. Large interindividual variations occurred; one volunteer with a very short initial plasma antipyrine half-life shortened, rather than prolonged, his antipyrine half-life after 10 days of disulfiram. In the first 10-day study the apparent volume of distribution of antipyrine was significantly increased in each volunteer after disulfiram administration, whereas in the second 10-day study, disulfiram failed to alter this value. Another anomalous result concerned attempts to determine whether a correlation existed between the initial antipyrine half-life and the percent change in this value produced by disulfiram administration. A significant correlation occurred in the initial 10-day study (4 = 0.71, p less than 0.05), whereas neither in the second 10-day study (r = 0.20, p greater than 0.05) nor in the 4-day study (r = 0.57, p greater than 0.05) was a significant correlation observed. Each of the three studies revealed no significant correlation between the initial metabolic clearance rate of antipyrine and the percent change in this value produced by disulfiram administration.

Administration, Oral↗
PubMed1992

Disulfiram treatment of alcoholism.

To assess the efficacy of supervised disulfiram as an adjunct to out-patient treatment of alcoholics, a randomised, partially blind, six-month follow-up study was conducted in which 126 patients received 200 mg disulfiram or 100 mg vitamin C under the supervision of a nominated informant. In the opinion of the (blinded) independent assessor, patients on disulfiram increased average total abstinent days by 100 and patients on vitamin C by 69, thus enhancing by one-third this measure of treatment outcome. Mean weekly alcohol consumption was reduced by 162 units with disulfiram, compared with 105 units with vitamin C, and the disulfiram patients reduced their total six-month alcohol consumption by 2572 units compared with an average reduction of 1448 units in the vitamin C group. Serum gamma-GT showed a mean fall of 21 IU/I in patients on disulfiram but rose by a mean of 13 IU/I with vitamin C. Unwanted effects in the disulfiram group led to a dose reduction in seven patients and to treatment withdrawal in four (and in one vitamin C patient). Two-thirds of the disulfiram group asked to continue the treatment at the end of the study. There were no medically serious adverse reactions.

Adolescent↗
PubMed1998

Disulfiram use in patients with abnormal liver function test results.

BACKGROUND: Concern about the precipitation of severe hepatitis by disulfiram often causes clinicians to avoid using this effective treatment in patients who have elevated baseline transaminase levels, even though no empirical evidence has so far shown severe hepatotoxicity to be related to such laboratory abnormalities. This study examines the effects of disulfiram in alcohol-dependent patients with elevated liver function test results and/or serologic evidence of hepatitis C virus (HCV) infection. METHOD: Hepatitis serologies and baseline transaminase levels were obtained for 57 male alcoholics starting treatment with disulfiram. Sequential liver function test results were obtained for up to 12 weeks while subjects took disulfiram. RESULTS: Although subjects with elevated baseline transaminase levels and serologic evidence of HCV infection were the most likely to evidence marked elevations in transaminase levels while taking disulfiram, most subjects took disulfiram without other adverse consequences. In only 1 subject did elevations appear directly related to disulfiram. CONCLUSION: Monitoring of liver function test results is warranted for patients taking disulfiram and permits most patients with moderately elevated transaminase levels to take it safely.

Adult↗
PubMed2000

Comparison of cyanamide and disulfiram in effects on liver function.

BACKGROUND: Cyanamide, an aversive drug widely used in Japan, develops ground-glass inclusion bodies in the hepatocytes at high incidences, which may be associated with portal inflammation and fibrosis. When cyanamide-treated alcoholics relapse drinking, the combined effect of cyanamide and alcohol produce more severe portal inflammation along with the emergence of ground-glass inclusions. Disulfiram also causes hepatitis, but there have been no comparative studies of effects of cyanamide and disulfiram on liver function. METHODS: We reviewed the laboratory data of 408 alcoholics admitted for a 3 month course of alcohol detoxification and rehabilitation. Patients tested negative for hepatitis virus markers and were diagnosed as not having cirrhosis. Among the subjects, 222 patients received cyanamide treatment (a daily dose of 70 mg) without a history of disulfiram treatment, and 186 received disulfiram (a daily dose of 200 mg) without a history of cyanamide treatment. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels obtained at 0, 4, 8, and 12 weeks of administration of each aversive drug were compared between the two alcoholic groups. RESULTS: Elevation of serum transaminases (AST > ALT) probably due to alcoholic liver disease quickly fell after abstinence. In patients who took cyanamide, the ALT levels were significantly higher at 4 and 12 weeks than in those who took disulfiram. Re-elevations of ALT after alcohol detoxification were more frequently observed in those who took cyanamide than in those who took disulfiram (19.4% vs. 5.9%, p < 0.001). The re-elevations of ALT were slight to moderate, being more than 3-fold in three (1.4%) patients who took cyanamide and four (2.2%) who took disulfiram. The re-elevations occurred more frequently in those with a history of cyanamide treatment before the present treatment than in those who took cyanamide for the first time (31.1% vs. 16.4%, p < 0.05). CONCLUSIONS: Cyanamide, compared with disulfiram, was more frequently associated with elevations of ALT that persisted after abstinence.

Adult↗
PubMed2004

Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease.

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.

Animals↗
PubMed1986

Disulfiram treatment of alcoholism. A Veterans Administration cooperative study.

We conducted a controlled, blinded, multicenter study of disulfiram treatment of alcoholism in 605 men randomly assigned to 250 mg of disulfiram (202 men); 1 mg of disulfiram (204 men), a control for the threat of the disulfiram-ethanol reaction; or no disulfiram (199 men), a control for the counseling that all received. Bimonthly treatment assessments were done for one year. Relative/friend interviews and blood and urine ethanol analyses were used to corroborate patients' reports. There were no significant differences among the groups in total abstinence, time to first drink, employment, or social stability. Among the patients who drank and had a complete set of assessment interviews, those in the 250-mg disulfiram group reported significantly fewer drinking days (49.0 +/- 8.4) than those in the 1-mg (75.4 +/- 11.9) or the no-disulfiram (86.5 +/- 13.6) groups. There was a significant relationship between adherence to drug regimen and complete abstinence in all groups. We conclude that disulfiram may help reduce drinking frequency after relapse, but does not enhance counseling in aiding alcoholic patients to sustain continuous abstinence or delay the resumption of drinking.

Actuarial Analysis↗
PubMed1998

Differential mechanisms in the effects of disulfiram and diethyldithiocarbamate intoxication on striatal release and vesicular transport of glutamate.

Intoxication with the alcohol-aversive drug disulfiram (Antabuse) and related dithiocarbamates may provoke neuropathies and, in some cases, damage the basal ganglia. Rats received a single administration of disulfiram (7 and 500 mg kg-1 i.p.) and equimolar doses (4 and 290 mg kg-1 i.p.) of its metabolite diethyldithiocarbamate (DDC), roughly corresponding to the daily maximum dose in alcohol abusers or to an estimated nonlethal overdose, respectively. The striatal, extracellular levels of glutamate in freely moving rats previously implanted with a microdialysis probe increased after low and intoxicating doses of disulfiram (126 +/- 3% and 154 +/- 10% of basal values, respectively) and DDC as well (135 +/- 10% and 215 +/- 14%, respectively), a partially Ca++-dependent effect. The prolonged (>7 hr) disulfiram-induced increase in glutamate observed in vivo may reflect the in vitro disulfiram-evoked release of glutamate from striato-cortical synaptic vesicles, where the drug nonspecifically inhibited (Ki approximately 4 microM) the uptake function and abolished the transmembrane proton gradient (DeltapH). In contrast, DDC did not seem to affect DeltapH. The prompt DDC-provoked increase in extracellular levels of glutamate was prevented by 7-nitroindazole, an in vivo specific inhibitor of neuronal nitric oxide synthase, which suggests that the thiol metabolite also acts via the nitric oxide synthesis. At variance, the short-acting 7-nitroindazole did not prevent the sustained in vivo effects of disulfiram and of DDC putatively formed with time. These findings provide new evidence for differential mechanisms underlying disulfiram- and DDC-induced increases in striatal glutamate release. Present glutamatergic changes, although not appearing dramatic enough to represent the only cause for neuronal damage from disulfiram overdose, might contribute to the drug neurotoxicity.

Alcohol Deterrents↗
PubMed2002

Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy.

Disulfiram is widely used in the treatment of chronic alcoholism. Adverse drug reactions with fatal outcome following disulfiram therapy are infrequent, and hepatic failure accounts for most of them. Since disulfiram is a cytochrome P450 (CYP450) enzyme system inhibitor, numerous interactions with several drugs metabolized in the liver have been reported. Like disulfiram, clarithromycin inhibits a CYP450 isoenzyme, but, despite its widespread use for the treatment of respiratory tract infections, no interactions with disulfiram have been described as yet. We report a case of fatal toxic epidermal necrolysis (Lyell disease) and fulminant hepatitis shortly after starting treatment with clarithromycin in a patient who was receiving disulfiram. This is the first case of such a severe dermatosis in a patient receiving either disulfiram or clarithromycin therapy. The temporal relationship between drug administration and clinical symptoms in this case suggests a probable interaction between the 2 drugs.

Alcohol Deterrents↗
PubMed1985

The effects of disulfiram on the experimental C3H mouse embryo.

Disulfiram, in 1 mg and 10 mg oral doses, was given to inbred C3H mice prior to and for the duration of pregnancy. The effects on the fetus have been assessed at 18 days gestation by means of fetal and placental weights, number of resorptions, skeletal preparations and Wilson's sections. Disulfiram dissolved in diethyl ether was administered to 8- and 9-day embryos in vitro in concentrations of 0.1, 10 and 100 micrograms ml-1 of culture medium, and the effects of ether alone and ether plus disulfiram assessed by evaluation of morphological development over a 28-h period, and inhibition of DNA synthesis using tritiated thymidine labelling over a 4-h period. Disulfiram (1 mg) in vivo caused no adverse effects on the fetus, but disulfiram (10 mg) was toxic, in that it caused a significant increase in early resorptions. Disulfiram in vitro, in the 10 and 100 micrograms ml-1 concentrations, proved to be very toxic to the embryos, affecting both morphological development and DNA synthesis in 9-day embryos and morphological development in 8-day embryos. DNA synthesis was only inhibited at the 100 micrograms ml-1 concentration in 8-day embryos. The 0.1 micrograms ml-1 concentration of disulfiram caused abnormal central nervous system development in 8-day embryos, but was otherwise non-toxic to 8- and 9-day embryos. Apart from a reduction in somite counts, ether in concentrations of 0.285 mg ml-1 and 2.85 mg ml-1 caused no adverse effects on morphological development in 8- or 9-day embryos. DNA synthesis was inhibited by ether in a concentration of 2.85 mg ml-1 in 9-day embryos.

Abnormalities, Drug-Induced↗
PubMed1989

Inhibition of erythrocyte aldehyde dehydrogenase activity and elimination kinetics of diethyldithiocarbamic acid methyl ester and its monothio analogue after administration of single and repeated doses of disulfiram to man.

The elimination kinetics of the methyl esters of diethyldithiocarbamic acid (Me-DDC) and its monothio analogue (Me-DTC) has been compared in ten alcoholic patients after a single oral dose of 400 mg disulfiram (Antabuse). Erythrocyte aldehyde dehydrogenase (ALDH) activity was continuously followed in the subjects until complete inactivation. The relation between individual steady-state concentrations of Me-DTC in plasma, blood acetaldehyde concentration and the dose of disulfiram sufficient to give the disulfiram alcohol reaction was investigated in 12 healthy volunteers treated with increasing doses of disulfiram and then challenged with ethanol. The mean peak plasma concentration of Me-DDC occurred at 1.8 h and its plasma half-life was 6.3 h. The corresponding values for Me-DTC were 3.3 h and 11.2 h, respectively. This suggests oxidative formation of Me-DTC from Me-DDC. In alcoholics with a rapid decrease in erythrocyte ALDH activity (in less than 5 days), the mean peak plasma concentration of Me-DTC was 278 nmol.l-1, whereas the peak concentration was below the detection limit in subjects with a prolonged inactivation time (7-20 days). The healthy volunteers were divided into three groups of four subjects, with clinically valid disulfiram alcohol reactions at 100, 200, and 300 mg doses of disulfiram, respectively. The mean plasma concentrations of Me-DTC at steady-state were proportional to the disulfiram doses given, compared within groups at different doses, and between groups at equal and different optimal doses of the drug. The concentrations of Me-DTC were significantly increased, as compared above, whereas the blood concentrations of acetaldehyde were not significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗