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PubMed1984

A comparison of disulfiram acceptors and refusers on selected demographic and clinical characteristics.

Male problem drinkers who accepted a treatment recommendation to take disulfiram were compared to those who refused the drug therapy. Subjects were drawn from a clinical population presenting to an outpatient alcoholism assessment service over a 3-year period. Both univariate and multivariate analyses were employed to investigate which client variables were associated with compliance to the disulfiram recommendation. The most important variable that distinguished the two groups was the percentage of other treatment recommendations adhered to by the client with the disulfiram acceptors being more likely to accept the other treatment recommendations. In addition, clients agreeing to take disulfiram were slightly younger and had higher scores on the Michigan Alcoholism Screening Test (MAST). Variables such as socio-economic status, previous treatment history, other drug use and drinking pattern were not associated with agreement to take disulfiram. The implications of these findings are discussed, particularly their relevance to research on the therapeutic effectiveness of disulfiram.

Adult↗
PubMed1998

Inhibition of recombinant human mitochondrial aldehyde dehydrogenase by two intermediate metabolites of disulfiram.

Disulfiram is used in aversion therapy for alcoholism. S-Methyl-N,N-diethylthiocarbamate (MeDTC) sulfoxide, a potent inhibitor of the target enzyme mitochondrial aldehyde dehydrogenase (ALDH2), is thought to be the principal active metabolite of disulfiram in vivo. We examined the effects on recombinant human ALDH2 of two intermediate metabolites of disulfiram, S-methyl-N,N-diethyldithiocarbamate (MeDDC) sulfoxide and MeDDC sulfine. MeDDC sulfoxide was a potent inhibitor of ALDH2 with an IC50 of 2.2 +/- 0.5 microM (mean +/- SD, N = 4) after preincubation with enzyme for 30 min. MeDDC sulfine was a relatively weak inhibitor of ALDH2 under the same conditions with an IC50 value of 62 +/- 14 microM. The inhibition of ALDH2 by both compounds was irreversible and did not require the cofactor NAD. The latter finding demonstrates that inactivation of ALDH2 is independent of the dehydrogenase activity of the enzyme. GSH blocked almost completely the inhibition by 20 microM of MeDDC sulfoxide and greatly diminished the inhibition by 200 microM of MeDDC sulfine. Inactivation by MeDDC sulfoxide was time dependent. MeDTC sulfoxide was a more potent inhibitor of recombinant human ALDH2 (IC50 = 1.4 +/- 0.3 microM after preincubation for 15 min) than either of the intermediate metabolites, and its inhibition was unaffected by GSH. Our results suggest that these newer intermediate metabolites of disulfiram, especially the more potent MeDTC sulfoxide, have the potential to inhibit the target enzyme ALDH2 in patients receiving disulfiram. However, until the significance of the interactions of the inhibitors with GSH is more fully understood, the contribution of MeDDC sulfine and MeDDC sulfoxide to the pharmacological effects of disulfiram in vivo is uncertain.

Alcohol Deterrents↗
PubMed2006

[Optic neuropathy while taking disulfiram].

INTRODUCTION: Disulfiram has been used since the late 1940s to treat chronic alcoholism. This drug interferes with alcohol metabolism resulting in an acetaldehyde increase. This causes painful symptoms, encouraging abstinence. Side effects include rare cases of bilateral optic neuropathies. Visual recovery occurs frequently upon cessation of therapy. METHOD AND OBSERVATION: We retrospectively studied patients referred for visual loss while treated with disulfiram between 1987 and 2005. Fourteen patients (three females, 11 males; aged 35-62 years) complained of visual loss, but a toxic, disulfiram-related, optic neuropathy was diagnosed in only five patients. Following cessation of disulfiram therapy, visual acuity and field improved in all five patients. DISCUSSION: and conclusion: When disulfiram toxicity is suspected with optic neuropathy, cessation of treatment is mandatory. Visual prognosis is good in the majority of cases, as illustrated by our series. Disulfiram toxicity can be diagnosed only after excluding all other possible causes of visual loss.

Adult↗
PubMed2004

Cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients.

Converging evidence suggests that disulfiram is a promising treatment for cocaine dependence. We study the cost-effectiveness of providing disulfiram to methadone-maintained opioid addicts in a randomized clinical trial setting. Our economic evaluation is based on a double blind clinical trial in which 67 cocaine-dependent methadone-maintained opioid-dependent subjects were randomized to get the additional treatment of disulfiram or placebo in a 12-week trial. Outcome measures used are the number of days of cocaine use and grams of cocaine per week. Cost measures used are the cost of providing standard methadone treatment and the incremental cost of adding disulfiram to the standard treatment. Cost measures of standard and disulfiram-enhanced treatment were collected retrospectively from the provider. Results from this cost-effectiveness analysis imply that, even though disulfiram increases slightly the cost of methadone treatment, its increase in effectiveness may be important enough to warrant its addition for treating cocaine dependence in methadone-maintained opiate addicts.

Adult↗
PubMed1997

The effects of disulfiram and related compounds on equine hepatic alcohol dehydrogenase.

The reversible inhibition and the irreversible inactivation of equine hepatic alcohol dehydrogenase by disulfiram have been investigated. Disulfiram was found to be a potent competitive reversible inhibitor with KEO,I values at pH 7.0 and 10.0 of 50 microM and 30 microM, respectively. Reversible monodentate binding to the active site zinc is indicated by comparison with related compounds. Disulfiram was also found to chemically modify and inactivate the enzyme in an irreversible reaction, which proceeds via the formation of a reversible enzyme-disulfiram binary complex with a dissociation constant at pH 7.0 of 30 microM. The inactivation reaction has been studied over the pH 6.0 to 10.0 range. The dissociation constants for binding to the enzyme and the apparent first-order rate constants for inactivation have been determined as a function of pH. A pKa of 8.3 for the free enzyme has been assigned to the zinc-water ionization. Similar inhibition and affinity labelling kinetics are exhibited by diethyldithiocarbamate and by 2,2'- and 4,4'-dipyridyl disulphide, which have similar enzyme "on" velocity pKa values of 8.3 and 8.2, respectively. The enzyme is competitively protected from inactivation with disulfiram by 2,2'-dipyridyl, 1,7'-phenanthroline, acetone, and ethanol, all of which combine with the active site zinc to form binary complexes. Acetate gave mixed protection against inactivation due to an additional interaction with the anion binding site of the enzyme. In view of the effect of disulfiram on ethanol metabolism and the polyol pathway, its importance as an aversive drug are considered.

Affinity Labels↗
PubMedDate not supplied

Effects on endogenous acetaldehyde production by disulfiram and ethanol feeding on rat pancreas.

Exogenous acetaldehyde infusion can induce pancreatitis-like injury of the pancreas in some isolated pancreas models, whereas in vivo such treatment has failed to induce pancreatitis. In vivo exogenous acetaldehyde may not be effective because it is rapidly metabolized. The aim of this study was to investigate whether endogenous acetaldehyde accumulates in the pancreas after ethanol feeding when acetaldehyde metabolism is blocked by disulfiram, and whether this treatment can induce pancreatitis-like injury in the rat. The liver was studied for comparison. In part I of the experiment, adult male Wistar rats were given water (n = 24), ethanol (n = 24), disulfiram (n = 24), and ethanol plus disulfiram for 1 week (n = 24) or 3 weeks (n = 24) and for 3 weeks with (n = 6) and without (n = 6) hypovolemia. In part II of the experiment, rats were given water (n = 6), ethanol (n = 6), and high-dose disulfiram (n = 6) and ethanol plus high-dose disulfiram (n = 6). Ethanol and acetaldehyde concentrations in blood, liver, and pancreas were measured. Animal behavior was monitored, and weight changes, plasma amylase activity, water content, and histomorphology of the pancreas and liver were studied without knowing the group. No increases in plasma amylase activity and no histomorphologic changes in the pancreas were observed under light or electron microscopy in part I of the experiment. In part II, treatment with ethanol induced acetaldehyde accumulation in the liver (33.6 +/- 2.6 micromol/L), but to a lesser degree in the blood (9.6 +/- micromol/L) and pancreas (5.0 +/-.2 micromol/L). Ethanol plus disulfiram induced marked accumulation of acetaldehyde in the liver (83.2 +/- 15.9 micromol/L), blood (280.0 +/- 47.4 micromol/L), and pancreas (43.6 +/- 4.7 micromol/L). When tissue acetaldehyde levels reached 30 to 40 micromol/L, we found a decrease in zymogen granules along with formation of small intracytoplasmic vacuolizations in the acinar cells and accumulation of lipid droplets in the hepatocytes, whereas physiologic signs of pancreatitis (hyperamylasemia, edema) or increases in liver enzymes did not develop. High levels of acetaldehyde accumulate in the liver and pancreas with the treatment described. Although this was accompanied by lipid degeneration of the hepatocytes and some subcellular changes in the acinar cells, physiologic signs of pancreatitis did not develop. Thus acetaldehyde accumulation alone, or in combination with hypovolemia, is not responsible for the induction of acute pancreatitis.

Acetaldehyde↗
PubMed1981

Dynamic interaction between disulfiram and separated enantiomorphs of racemic warfarin.

To evaluate the interaction of disulfiram with the separated enantiomorphs of racemic warfarin, seven normal subjects received single doses of R-warfarin (1.5 mg/kg body weight) and S-warfarin (0.75 mg/kg body weight) with and without a daily dose of disulfiram 250 mg, beginning 3 days before the warfarin dose and continuing for the duration of the hypoprothrombinemia. Disulfiram augmented the S-warfarin hypoprothrombinemia (p less than 0.001) but not that of R-warfarin (p less than 0.10). Disulfiram did not alter plasma concentrations of either R-warfarin (p greater than 0.10) or S-warfarin (p greater than 0.40). Disulfiram augments the hypoprothrombinemia of racemic warfarin stereoselectively by interacting primarily with S-warfarin. As disulfiram did not change the plasma concentrations of either enantiomorph, it may augment the anticoagulant effect of racemic warfarin by directly affecting the hepatic mechanism responsible for the hypoprothrombinemia.

Adult↗
PubMed1993

First trimester disulfiram exposure: report of two cases.

Disulfiram has been used effectively to deter alcohol consumption in patients with a history of alcohol abuse. Its use in reproductive age women has become increasingly common in recent years, intensifying the risk of fetal exposure. Nonspecific but significant abnormalities have been described in the infants of women treated with disulfiram in the first trimester of their pregnancies. Based on these data, authors have previously exposure is confirmed despite a lack of any pattern to the defects reported. We report the outcomes of two pregnancies with first trimester disulfiram exposure. In both cases, the timing and dose of disulfiram was known. In one case, disulfiram was the only potential teratogen exposed to the fetus. Both neonates were normal at birth and have shown subsequent normal development. This report suggests that the poor prognosis previously given to fetuses exposed to disulfiram in the first trimester may not be warranted.

Abnormalities, Drug-Induced↗
PubMed1989

The effect of dietary cholecalciferol, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol on the development of tibial dyschondroplasia in broiler chickens in the absence and presence of disulfiram.

Four experiments were conducted to determine the effect of dietary cholecalciferol (vitamin D3), 25-hydroxycholecalciferol (25-OHD3) and 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on the changes in growth, feed efficiency and bone ash, and the incidence, severity and number of #3 scores of tibial dyschondroplasia caused by the addition of disulfiram to the diet. The basal diet used was low in calcium and high in phosphorus and chlorine and known to promote a high incidence of tibial dyschondroplasia in broiler chickens. The chickens in all experiments received enough ultraviolet radiation from fluorescent lights in the pens to nearly satisfy their need for vitamin D. The addition of disulfiram to the diet caused an increase in most of the measurements indicating development of tibial dyschondroplasia in all of the experiments, and caused a decrease in bone ash in two of the experiments and a decrease in growth and gain:feed in one experiment. The addition of D3 to a diet containing no D3 caused higher bone ash and lower incidence of tibial dyschondroplasia in the absence or presence of disulfiram. The effects of the addition of 25-OHD3 to diets containing approximately five times the requirement of D3 in the absence and presence of disulfiram caused variable results. The addition of 1,25-(OH)2D3 to the D3-supplemented diet in the absence or presence of disulfiram caused dramatic increases in bone ash and a decrease in most of the criteria used to measure development of tibial dyschondroplasia. There was no indication of interaction of the effects of D3, 25-OHD3 and 1,25-(OH)2D3 with the action of disulfiram.

Animals↗
PubMed2004

Patterns of dispensed disulfiram and naltrexone for alcoholism treatment in a veteran patient population.

BACKGROUND: Short-term treatment trials indicate that two Food and Drug Administration-approved agents, disulfiram and naltrexone, may each curtail alcohol consumption, but two large 1-year Veterans Administration cooperative studies showed no long-term benefits for these agents over placebo. To assess whether these agents are being prescribed for extended periods, as an indicator of long-term use in nonexperimental settings, we compared dispensing patterns in a veteran patient population. METHODS: The New England Veterans Integrated Service Network outpatient pharmacy files between January 1, 1998, and June 30, 2001, were analyzed; only patients with prescriptions on or after March 1, 1998, were included. Measurements for each patient included data on new and refilled prescriptions of disulfiram, naltrexone, and control medications. Prescription survival curves with right censoring were constructed. Distinct treatment episodes were defined by having six or more months between the end date of a prior prescription and the start date of a new prescription. RESULTS: From eight New England Veterans Integrated Service Network centers, 754 patients were dispensed disulfiram, and 971 were dispensed naltrexone, encompassing 873 and 1075 treatment episodes, respectively. Treatment episode durations were virtually identical for both drugs: more than 35% of episodes were 1 month or shorter, more than 50% were 2 months or shorter, and 75% were 5 months or shorter. Concurrently prescribed neuroleptic or statin medications predicted longer disulfiram and naltrexone treatment episodes. However, for patients newly prescribed common neuroleptic, antidepressant, or statin agents, the risks for discontinuing disulfiram or naltrexone were 1.4 to 2.3 times greater than for discontinuing these other agents. CONCLUSIONS: In clinical settings, veteran patients were likely to be dispensed either disulfiram or naltrexone for only several months or less. The contexts and reasons for these predominantly short-term treatment episodes or the benefits derived were not known and merit further study.

Adult↗
PubMed1987

Chemical monitoring of disulfiram compliance: a study of alcoholic outpatients.

Poor compliance with disulfiram (Antabuse) therapy may reduce its efficacy in the treatment of alcoholism. This study was designed to examine two questions: (a) Could use of a chemical test for disulfiram ingestion be used clinically to improve disulfiram compliance and if so, (b) could improved disulfiram compliance contribute to improved compliance with other aspects of treatment? The results suggest that disulfiram compliance rates can be increased by clinical use of chemical monitoring data; however in this sample increased compliance with disulfiram did not correlate with improvements in other aspects of treatment compliance.

Adult↗
PubMed1993

In vivo effects of disulfiram and cyanamide on canine liver aldehyde dehydrogenase isoenzymes as detected by high-performance (pressure) liquid chromatography.

Methods for analysis of aldehyde dehydrogenase isoenzymes using high-performance (pressure) liquid chromatography (HPLC) were used to determine in vivo effects of disulfiram and cyanamide on canine liver aldehyde dehydrogenase (ALDH) isoenzymes. Liver ALDH isoenzymes from control and disulfiram- or cyanamide-treated dogs were separated by ion-exchange HPLC, and enzyme activity was detected using a postcolumn reactor. Two major peaks of ALDH activity (peaks I and II) were detected. Varying the composition of the reaction column reagents resulted in alterations in the elution profiles consistent with the kinetic properties of individual isoenzymes (i.e., ALDH IB in peak I and ALDH IIB in peak II), including estimates of the Km for acetaldehyde and the effects of magnesium ions on ALDH activity. Disulfiram treatment decreased both peaks depending on disulfiram dose and length of treatment, with peak I being more sensitive to inactivation than peak II. Reagents containing MgCl2 (1 mM) decreased peak I and increased peak II compared with EDTA (1 mM) for samples from both control and disulfiram-treated animals. These data are consistent with the assignment of the disulfiram-sensitive isoenzyme (ALDH IB) to peak I and the isoenzyme stimulated by magnesium ions (ALDH IIB) to peak II. In vivo cyanamide treatment produced similar decreases in both peaks to a maximum decrease of approximately 30% of control depending on cyanamide dose. Peak I, however, was more sensitive than peak II to in vitro inactivation by cyanamide, which suggests that cytosolic ALDH in the dog (in contrast to other mammals) is more sensitive to inactivation than mitochondrial ALDH.

Aldehyde Dehydrogenase↗
PubMed1996

S-methyl-N,N-diethylthiocarbamate sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone, two candidates for the active metabolite of disulfiram.

The mechanism of action of disulfiram involves inhibition of hepatic aldehyde dehydrogenase (ALDH). Although disulfiram inhibits ALDH in vitro, it is believed that the drug is too short-lived in vivo to inhibit the enzyme directly. The ultimate inhibitor is thought to be a metabolite of disulfiram. In this study, we examined the effects of S-methyl-N,N-diethylthiocarbamate (MeDTC) sulfoxide and S-methyl-N,N-diethylthiocarbamate sulfone (confirmed and proposed metabolites of disulfiram, respectively) on rat liver mitochondrial low K(m) ALDH. MeDTC sulfoxide and MeDTC sulfone, in 10-min incubations with detergent-solubilized mitochondria, inhibited ALDH activity with an IC50 (mean +/- SD) of 0.93 +/- 0.04 and 0.53 +/- 0.11 microM, respectively, compared with 7.4 +/- 1.0 microM for the parent drug disulfiram. Inhibition by MeDTC sulfone and MeDTC sulfoxide, both at 0.6 microM, was time-dependent, following apparent pseudo-first-order kinetics with a t1/2 of inactivation of 3.5 and 8.8 min, respectively. Dilution of ALDH inhibited by either sulfoxide or sulfone did not restore activity, an indication of irreversible inhibition. Addition of glutathione (50 to 1000 microM) to ALDH before the inhibitors did not alter the inhibition by MeDTC sulfoxide. In contrast, the inhibition by MeDTC sulfone was decreased > 10-fold (IC50 = 6.3 microM) by 50 microM of glutathione and almost completely abolished by 500 microM of glutathione. The cofactor NAD, in a concentration-dependent manner, protected ALDH from inhibition by MeDTC sulfoxide and MeDTC sulfone. In incubations with intact mitochondria, the potency of the two compounds was reversed (IC50 of 9.2 +/- 3.6 and 0.95 +/- 0.30 microM for the MeDTC sulfone and sulfoxide, respectively). Our results suggest that MeDTC sulfone is highly reactive with normal cellular constituents (e.g., glutathione), which may protect ALDH from inhibition, unless this inhibitor is formed very near the target enzyme. In contrast, MeDTC sulfoxide is a better candidate for the ultimate active metabolite of disulfiram, because it is more likely to be sufficiently stable to diffuse from a distant site of formation, such as the endoplasmic reticulum, penetrate the mitochondria, and react with ALDH located in the mitochondrial matrix.

Alcohol Deterrents↗
PubMed1979

Blood pressure response to ethanol in relation to acetaldehyde levels and dopamine-beta-hydroxylase activity in rats pretreated with disulfiram, cyanamide and coprine.

The blood pressure response after ethanol administration was studied in relation to blood acetaldehyde levels, aldehyde-dehydrogenase (ALDH)--and dopamine-beta-hydroxylase (DBH) activities in rats pretreated with the ethanol-sensitizing compounds disulfiram, cyanamide and coprine and the DBH-inhibitor FLA-57. Disulfiram, cyanamide and coprine, but not FLA-57, inhibited the low-Km ALDH in the liver and caused an increased acetaldehyde level in blood. Disulfiram and FLA-57, but not cyanamide and coprine, decreased the DBH-activity in the heart and the levels of norepinephrine in the heart and the brain. In disulfiram-treated rats with a low DBH-activity, a fall in blood pressure was observed at acetaldehyde levels being slightly higher than those found in control rats. In disulfiram-treated rats with a DBH-activity close to control activity and in rats pretreated with cyanamide or coprine, a fall in blood pressure were observed in rats pretreated with FLA-57. In rats pretreated with coprine + FLA-57, the fall in blood pressure was similar, or even lower, than in rats pretreated with coprine alone. The results suggest that acetaldehyde is the main determinant of the hypotension elicited by ethanol in rats pretreated with ALDH-inhibitors, and that the role of DBH in the disulfiram-ethanol reaction has been over-estimated in previous studies.

Acetaldehyde↗
PubMed1988

Disulfiram prevents acetaminophen hepatotoxicity in rats.

Hepatic necrosis due to an oral acetaminophen overdose (4.25 g/kg b.wt.) was prevented by pretreatment with disulfiram 100 mg/kg, given for 3 weeks or as a single dose. Twenty-four hours after acetaminophen the impairment of hepatic function, measured as prothrombin index, and the depletion of hepatic glutathione were prevented. Hepatic cytochrome P-450 levels were unchanged but cytochrome P-450 mediated p-nitroanisole demethylation was reduced by disulfiram pretreatment. Disulfiram pretreatment reduced 24 hour urinary excretion of acetaminophen-mercapturate and- cysteine while excretion of -sulfate and -glucuronide was unchanged. After 72 hours acetaminophen induced hepatic necrosis were prevented. Identical observations were made in animals pretreated with disulfiram for 3 weeks. Five hours after acetaminophen overdose its irreversible binding to hepatic proteins was not changed. After 24 hours, however, it was increased in animals pretreated with a single disulfiram dose and unchanged in animals pretreated for 3 weeks. The protective mechanism of disulfiram after acetaminophen overdose is not mediated via a change in overall irreversible binding of acetaminophen to hepatic protein.

Acetaminophen↗
PubMed1981

Acute effects of disulfiram on anxiety levels of chronic alcoholics.

30 male alcoholics, who were anxious by clinical research standards, received either disulfiram (250 mg) or placebo daily for 1 week. There are claims that disulfiram has a sedative effect and that this has some useful antianxiety action, but this had not been tested in a controlled manner. There were no significant differences in the mean changes between the disulfiram and placebo groups as determined by any of the tests used. Both the Zung self-rating anxiety scale and the anxiety scale of the profile of mood states indicated ( p less than 0.05) that those receiving disulfiram were extreme reactors as compared to the placebo group; those receiving disulfiram either became more anxious or experienced the most improvement. The study suggests that disulfiram may selectively relieve or increase the anxiety level of subgroups of subjects, but does not delineate a predictor response.

Adult↗
PubMed1979

Patient management in disulfiram implant therapy.

Data from 100 disulfiram implant, placebo, and no-implant control patients demonstrate the effectiveness of the disulfiram implant in keeping the alcoholic dry. However, the superiority of the disulfiram implant group over the placebo group is interpreted as evidence of a pharmacological component to the procedure operating independent of the disulfiram-ethanol reaction (DER). Hypotheses involving inhibition of aldehyde dehydrogenase or inhibition of dopamine-beta-hydroxylase are offered as mechanisms by which the pharmacological effect may be mediated. Finally, in view of the low (approximately 0.5) probability with which a DER follows ingestion of alcohol by a disulfiram implant patient, it is suggested that the approach to patient management should be changed to maximize the effectiveness of the disulfiram implant procedure. Guidelines are given.

Acetaldehyde↗
PubMed1976

Disulfiram implantation: placebo, psychological deterrent, and pharmacological deterrent effects.

In an effort to examine the placebo, psychological deterrent, and pharmacological deterrent effects associated with implanted disulfiram, subjects were given either disulfiram implants or sham operations. Ethanol challenges elicited no disulfiram-ethanol reactions (DERs), indicating that at the time of the challenge neither a pharmacological deterrent nor a placebo effect was operating. Of the patients who resumed drinking, only those with disulfiram implants experienced DERs. Sham operation subjects continued to drink after their first post-challenge drink; four of five disulfiram implant recidivists remained abstinent following their experience of a DER. It is concluded that the pharmacological deterrent effect of the disulfiram implant may have been underestimated in previous reports.

Alcohol Drinking↗