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PubMed1988

Ethanol decreases plasma sulphydryls in man: effect of disulfiram.

Based on animal experiments, interactions of ethanol and its metabolites with sulphydryls have been implicated in the toxicity of ethanol, but acute effects of ethanol on sulphydryls have not been documented in man. Plasma free glutathione and cysteine were therefore measured following the administration of 0.2 g kg-1 ethanol to normal healthy volunteers and chronic alcoholics on disulfiram, where the effects of high concentrations of acetaldehyde can be observed. In both groups, plasma glutathione decreased shortly following ethanol, and a sustained decreased in glutathione was seen in the subjects on disulfiram. In patients on disulfiram, but not the healthy controls, plasma cysteine decreased significantly. The decrease in plasma cysteine was correlated to the rise in acetaldehyde, suggesting that cysteine, but not glutathione, forms an adduct with acetaldehyde in man. We conclude that even moderate doses of ethanol may disturb the sulphydryl homeostasis and could interfere with biologically important processes that depend on sulphydryl groups.

Acetaldehyde↗
PubMed1994

Factors influencing commitment to abstinence from alcohol: a model grounded from client perceptions of disulfiram therapy.

This paper describes the findings of a qualitative research study aimed at eliciting the perspectives of problem drinkers concerning the drug disulfiram (Antabuse). A grounded theory model of Commitment to Abstinence, which was generated from the study data, is presented. The influence of disulfiram upon this model is examined via the perspectives of disulfiram users. It is suggested that the drug could be used in a flexible way with some clients to their advantage. The significance of the study and the derived model for mental health nursing is discussed, the value of the model as an assessment tool is explored and other more generic applications are suggested.

Alcohol Deterrents↗
PubMedDate not supplied

Pathology of disulfiram neuropathy.

The pathological changes in a sural nerve biopsy from a 42-year-old woman with disulfiram-induced peripheral neuropathy were assessed by quantitative light microscopy, electron microscopy, and the study of teased nerve fibres. The nerve had a marked loss of myelinated fibres; of the remaining myelinated fibres some were undergoing Wallerian-type axonal degeneration. Large myelinated fibres were preferentially involved. Primary demyelination, remyelination, and evidence of regeneration were not present. Because of the marked differences between the pathological findings in disulfiram neuropathy and carbon disulfide neuropathy, it is concluded that carbon disulfide is not responsible for the neurotoxic effect of disulfiram.

Adult↗
PubMed1972

Selective inhibition of angiotensin pressor responses in the pithed rat by tetraethylthiuram disulphide (disulfiram) and sodium diethyldithiocarbamate (DDC).

1. Pressor responses to sympathetic outflow stimulation, noradrenaline and angiotensin have been recorded in pithed rats.2. Disulfiram (50 mg/kg) and sodium diethyldithiocarbamate (DDC) (5-100 mg/kg) both caused an initial increase in the pressor response to all three procedures followed by a selective inhibition of the angiotensin responses.3. Penicillamine (1-100 mg/kg) and ascorbic acid (1-500 mg/kg) increased the pressor responses to all three procedures without any subsequent blocking action.4. Reserpine (5 mg/kg daily for 3 days) abolished responses to sympathetic outflow stimulation but did not impair angiotensin or noradrenaline responses.5. In reserpinized rats, the initial enhancement of angiotensin responses after disulfiram and sodium diethyldithiocarbamate was absent or reduced and the onset of the subsequent block was accelerated.6. Possible mechanisms for the angiotensin-blocking action of disulfiram and sodium diethyldithiocarbamate are discussed.

Angiotensin II↗
PubMedDate not supplied

Erythrocyte aldehyde dehydrogenase and disulfiram-like side effects of hypoglycemics and antianginals.

Disulfiram-like responses to various drug therapies are caused by elevated ethnol-derived blood acetaldehyde concentrations resulting from drug-induced inhibition of aldehyde dehydrogenase enzymes. We have found that the nitrate ester antianginal drugs, isosorbide dinitrate and nitroglycerin, are potent inhibitors of human erythrocyte aldehyde dehydrogenase. To further characterize this drug-induced enzyme inhibition, erythrocyte aldehyde dehydrogenase activities were measured in patients undergoing therapy with nitrate ester antianginals (isosorbide dinitrate and nitroglycerin) and sulfonylurea hypoglycemics (chlorpropamide and tolazamide). The erythrocyte enzyme was decreased by approximately 25% in sulfonylurea-treated patients, whereas in the nitrate ester-treated patients, an 88% inhibition was observed. The minimal enzyme inhibition in the sulfonylurea-treated group was unexpected because these therapies have well-documented disulfiram-like side effects. This weak inhibition contrasted with the severe inhibition observed in the nitrate ester-treated group where the disulfiram-like side effects are not considered a serious clinical problem. This apparent anomaly was attributed to differences in inhibition of the erythrocyte and liver aldehyde dehydrogenase by the parent drugs and their hepatic metabolites.

Aldehyde Dehydrogenase↗
PubMed1987

Liver toxicity encountered in the Veterans Administration trial of disulfiram in alcoholics.

Alcoholic subjects (453) were randomly assigned to disulfiram or placebo therapy and followed for up to 12 months for drinking. Drinking status was determined from interviews of the subject and a household contact each 2 months and from the analysis of eight blood samples or 39 urines submitted at intervals during the year. Liver status was monitored each 2 months by obtaining serum alkaline phosphatase, bilirubin, and AST. Sensitive criteria were arbitrarily selected to identify about 1/5 of the patients with episodic elevations of liver tests. There was no relationship of liver test elevations to disulfiram treatment. However, the elevated AST related significantly to drinking status (p = 0.004) as did elevated bilirubin (p = 0.044), but not elevated alkaline phosphatase (p = 0.146). Two hundred one patients had liver test elevations at least one time and were continued on drug, four were dropped. One hundred seventy-nine of these patients were drinking, 22 were abstinent, and four were indeterminant. It is concluded that patients on disulfiram with minor liver test abnormalities are usually drinking.

Alcoholism↗
PubMed1988

Effect of disulfiram on canine liver aldehyde dehydrogenase activity: in vivo inactivation in a nonrodent animal model.

Dogs were used as nonrodent animal models to study the in vivo effects of disulfiram on hepatic aldehyde dehydrogenase (ALDH) activity. Dogs were treated with disulfiram either intraperitoneally or orally (100 mg/kg/day for 2 days followed by 40 mg/kg/day for 3 days). Liver biopsies from control and treated animals were fractionated by differential centrifugation and the subcellular fractions were analyzed for ALDH activity. Significantly less activity was observed in cell homogenates from treated animals (20-50% of control activity per gram of liver). The majority of loss in activity was accounted for by a decrease in ALDH activity in the soluble fraction of the cell (12-30% of control activity) and in the mitochondrial fraction (23-30% of control activity). Activities at both high (5 mM) and low (50 microM) acetaldehyde concentrations were affected. The subcellular distribution of ALDH activity and in vivo inhibition by disulfiram in dogs is different from that reported for rats.

Aldehyde Dehydrogenase↗
PubMed1992

Techniques to enhance compliance with disulfiram.

Pharmacodynamic benefits of disulfiram in the treatment of alcoholism have yet to be clearly demonstrated. Nevertheless, research does suggest that disulfiram may well have positive effects on drinking if medicational compliance procedures are employed. This paper reviews research on four strategies for enhancing disulfiram compliance: implants, incentives, contracts, and patient information. Generalizations about the strategies are drawn and needs for future research are briefly addressed.

Alcoholism↗
PubMed1998

Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.

Acamprosate↗
PubMed1978

A comparative study on the effects of disulfiram, cyanamide and 1-aminocyclopropanol on the acetaldehyde metabolism in rats.

1-aminocyclopropanol (ACP) is a potent inhibitor of aldehyde dehydrogenase (ALDH) in vivo and in vitro. Like cyanamide it has a rapid onset of action in vivo with the highest inhibition occurring after 2--24 hrs. and a long duration of action like disulfiram with measurable inhibition after 144 hrs. All the three inhibitors decreased the activity of the mitochondrial low-Km ALDH strongly in vivo, however, in markedly different doses. Cyanamide inhibited the high-Km ALDH only in vivo, whereas in vitro, the hihgh-Km ALDH was unaffected by cyanamide but significantly inhibited by disulfiram and ACP. The inhibition produced by the inhibitors appeared to be irreversible. Acetaldehyde protected the low-Km enzyme at different extents depending on the inhibitor used. The inhibition of ALDH in intoxicated and control rats and its relation to acetaldehyde oxidation and the disulfiram-ethanol reaction are discussed.

Acetaldehyde↗
PubMed1980

Concentration of serotonin metabolites in the cerebrospinal fluid from alcoholics before and during disulfiram therapy.

The levels of 5-hydroxytryptophol and 5-hydroxyindoleacetic acid were measured in the cerebrospinal fluid before and after one week of disulfiram treatment (400 mg/day) from ten male hospitalized alcoholic patients. The disulfiram treatment induced elevated (P less than 0.001) levels of 5-hydroxytryptophol. The levels were higher than in a control group, both before (P less than 0.01) and after (P less than 0.001) the treatment. No effects on the levels of 5-hydroxyindoleacetic acid were noted. The results indicate an altered serotonin metabolism in alcoholics, which is further potentiated by disulfiram treatment.

Alcoholism↗
PubMed1995

Changes in serotonin metabolism during treatment with the aldehyde dehydrogenase inhibitors disulfiram and cyanamide.

The effect of the aldehyde dehydrogenase inhibitors disulfiram (Antabuse) and cyanamide (calcium carbimide, Dipsan) on the metabolism of serotonin measured as relative amounts of the metabolites 5-hydroxyindole-3-acetic acid and 5-hydroxytryptophol in urine were studied in alcoholic patients. Sixteen out of 23 patients receiving drug therapy showed elevated excretion of 5-hydroxytryptophol. However, there was a marked, 15-fold, variability in 5-hydroxytryptophol excretion rate between patients. A high degree of variability was also seen in another group of patients studied before and after introduction of drug therapy. When patients were followed during the dose interval, a time-dependent response after each single dose could be observed. The disulfiram response lasted over the course of several days whereas the response to cyanamide lasted for less than 12 hr. It is concluded that treatment with disulfiram and cyanamide affects serotonin metabolism leading to increased production of 5-hydroxytryptophol, but there is a marked inter-individual variability in degree of response.

Adult↗
PubMed1999

Differential regulation of peptide alpha-amidation by dexamethasone and disulfiram.

alpha-Amidation is essential for the function of many peptides in intercellular communication. This C-terminal modification is mediated in a two-step process by the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The first step, catalyzed by peptidylglycine-alpha-hydroxylating monooxygenase (PHM; EC 1.14.17. 3), is rate limiting in the process, and therefore subject to regulation. Dexamethasone and disulfiram (tetraethylthiuram disulfide; Antabuse) were used as in vivo treatments to study the regulation of PHM expression and activity in cardiac atrium. Our findings show that both dexamethasone and disulfiram treatment increase the activity of PHM in atrial tissue but that they do so by distinctly different mechanisms. Dexamethasone elevated tissue levels of PAM mRNA and protein concurrently, suggesting that glucocorticoids regulate PAM expression at the level of gene transcription. In contrast, disulfiram treatment, which depletes stores of alpha-amidated peptides, increased the specific activity of PHM without affecting the level of PAM expression. The catalytic efficiency of PHM was enhanced by raising the Vmax of the enzyme. Importantly, this increase in Vmax was retained through purification to homogeneity, indicating that either a covalent modification or a stable conformational change had occurred in the protein. These novel findings demonstrate that the rate-limiting enzyme in the bioactivation of peptide messengers is differentially regulated by transcriptional and post-transcriptional mechanisms in vivo. It is proposed that regulation of PHM's expression and catalytic efficiency serve as coordinated physiologic mechanisms for maintaining appropriate levels of alpha-amidating activity under changing conditions in vivo.

Animals↗
PubMed1978

Disulfiram enhances pharmacological activity of barbital and impairs its urinary elimination.

Disulfiram or diethyldithiocarbamate significantly enhanced the sleeping time induced by barbital in rats. At identical time intervals after rats were injected with barbital the concentration of barbital in the blood or brain of animals that had previously received disulfiram was significantly higher than the concentrations in the corresponding tissues of control animals. Urinary excretion of barbital was significantly reduced in disulfiram-treated animals.

Animals↗
PubMed1987

Cefotetan-induced disulfiram-type reactions and hypoprothrombinemia.

A double-blind, placebo-controlled study in eight healthy male volunteers was conducted to study possible disulfiram-type reactions and hypoprothrombinemia associated with cefotetan administration. Three doses of cefotetan (2 g) or of placebo were administered at 12-h intervals. Ethanol (0.5 g/kg of total body weight) was ingested 1 h after the third dose. Blood ethanol, serum acetaldehyde, and prothrombin times were measured throughout the study. Heart rate, blood pressure, and clinical signs as well as symptoms suggestive of a disulfiram-type reaction were also noted. Five of eight volunteers that received cefotetan showed significant flushing. A significant increase in heart rate also was noted. No change in mean arterial pressure was observed during the cefotetan phase, and no one experienced nausea or vomiting. No statistical differences were observed between phases with respect to ethanol area under the time-concentration curve, elimination rate, or serum acetaldehyde concentrations. A slight but statistically significant increase in prothrombin time also was observed with cefotetan. This study suggests that patients receiving cefotetan might be at risk to develop disulfiram-type reactions and hypoprothrombinemia.

Acetaldehyde↗
PubMed1980

Effect of long-term disulfiram administration on rat liver.

No hepatotoxicity was demonstrated after 90 days in rats treated with two dose levels of disulfiram. A reversible inhibition of microsomal p-nitroanisole demethylase activity was found. In phenobarbital-treated rats disulfiram 100 mg/kg did not alter the induction response as indicated by the cytochrome P-450 content, but inhibited the p-nitroanisole activity to control levels. As no sign of histological liver damage was found, we conclude that the rare cases of disulfiram hepatotoxicity in man may be due to an allergic reaction.

Animals↗
PubMed1984

Fulminant polyneuritis after overdose of disulfiram and ethanol.

A 39-year-old woman developed a severe sensorimotor polyneuritis after simultaneous ingestion of ethanol and disulfiram in high doses. The disorder was similar to other cases of disulfiram neuropathy, but was acute and more severe. Disulfiram can cause a fulminant polyneuropathy that is not always benign and reversible.

Adult↗