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PubMed1979

Disulfiram for the treatment of alcoholism. An evaluation in 128 men.

One hundred twenty-eight alcoholic men were assigned randomly to receive either a regular dose of disulfiram (250 mg), a pharmacologically inactive dose (1 mg), or no disulfiram. There were no statistically significant differences among the three treatment groups in total abstinence, percentage of drinking days, days worked, family stability (living with same relative), or percent of scheduled appointments kept. However, 21% of those who received the regular dose of disulfiram and 25% who received the pharmacologically inactive dose remained abstinent, whereas only 12% of those who received no disulfiram did so. These results indicate that disulfiram may be of limited value in the treatment of alcoholism, fear of the disulfiram-ethanol reaction is important in preventing drinking, and patients willing to take disulfiram are more likely to be abstinent if given the drug. We also found that complete abstinence correlated significantly with compliance and obtaining employment.

Adult↗

PubMed2002

Lack of toxicity from concomitant directly observed disulfiram and isoniazid-containing therapy for active tuberculosis.

We retrospectively evaluated the use of disulfiram among alcoholic patients being treated for active tuberculosis. There were 13 alcoholics treated with disulfiram, 105 alcoholics not on disulfiram, and 249 non-alcoholics. Rates of toxicity were higher among alcoholics than among non-alcoholics (58% vs. 32%), but there was no difference between alcoholics taking and those not taking disulfiram (61% vs. 57%). There were no neurological side effects in the disulfiram group. Disulfiram appeared to be safe when added to intermittent, directly observed isoniazid-containing tuberculosis treatment, and was useful in managing complications of alcohol abuse. However, the small number of patients on disulfiram limits the strength of this negative finding.

Alcohol Deterrents↗

PubMed2002

[Disulfiram neuropathy. Report of 3 cases].

Disulfiram is widely used for aversive treatment of alcoholism. Although it is well tolerated in most patients, one in 15,000 patients will develop peripheral neuropathy every year, which is frequently misdiagnosed as alcoholic neuropathy. Disulfiram neuropathy can be mild or severe, depending on diverse factors such as time of exposure and the dosage. Most patients will present with a motor-sensory neuropathy of the lower limbs, which tends to improve as disulfiram administration ceases, however some cases may remain with permanent sequelae. We report the clinical, laboratory and electrophysiological features of three patients who developed disulfiram neuropathy during treatment of alcoholism. Recovery was incomplete at 8 weeks after treatment cessation in all of them. No other findings justified the clinical features described in these patients. Considering the incidence of alcoholism and the wide use of disulfiram treatment in Chile, we suggest that disulfiram neuropathy is being underdiagnosed. We also stress the fact that disulfiram neuropathy could be avoided by using lower doses.

Adult↗

PubMedDate not supplied

Disulfiram treatment for alcoholism in severe mental illness.

Controlled research has shown that supervised disulfiram is an effective treatment for alcoholism. Despite this, little is known about the effects of disulfiram in persons with alcoholism and severe mental illness. We conducted comprehensive chart reviews on 33 patients with alcoholism and severe mental illness (70% schizophrenia or schizoaffective disorder) who had been prescribed disulfiram. Twenty-one percent reported side effects from disulfiram, whereas significant psychiatric complications were not reported. Although 76% of patients reported drinking while on disulfiram, only 28% experienced negative reactions to alcohol. Sixty-four percent of the patients saw a remission of alcoholism for at least one year during a three-year follow-up, and 30% experienced a two-year remission. Disulfiram treatment was associated with decreases in days hospitalized but not with changes in work status. The results suggest disulfiram may be a useful adjunctive treatment for alcoholism in patients with severe mental illness and that controlled research is needed to evaluate its effects in this population.

Absenteeism↗

PubMed1988

Disulfiram-induced fulminating hepatitis: guidelines for liver-panel monitoring.

Although psychiatrists have medical responsibility for many alcoholic patients, the psychiatric literature, in contrast with the general medical literature, contains few reports of disulfiram-induced hepatotoxicity. For that reason, the authors review the literature on disulfiram hepatitis and report a case of severe fulminating hepatitis associated with disulfiram use, despite careful and currently accepted standard-of-care clinical and biochemical monitoring. All but two of the 17 disulfiram-associated hepatotoxic cases reviewed developed symptoms after 2 weeks to 2 months of use. Six patients died. This article discusses strategies for avoiding that rare but life-threatening side effect. The strategies include more frequent initial measurements of liver enzymes than is now accepted. Currently, only two reports recommend liver-function studies on a regular schedule for patients taking disulfiram. The authors believe that liver-function tests should be administered before treatment, at 2-week intervals for 2 months, and at 3- to 6-month intervals thereafter. The authors emphasize that the hepatotoxicity reaction is rare and do not discourage the use of disulfiram in appropriate patients; rather, they wish to heighten the index of suspicion to disulfiram-induced hepatotoxicity.

Adult↗

PubMed1987

Increased nickel concentrations in body fluids of patients with chronic alcoholism during disulfiram therapy.

Nickel concentrations were measured by electrothermal atomic absorption spectrophotometry in body fluids of 61 patients with chronic alcoholism during disulfiram treatment (tetraethylthiuram disulfide, 250 mg/day, po). Nickel concentrations in serum, whole blood, and urine were significantly increased at 12 hours after the initial dose of disulfiram. In serum and whole blood, the Ni concentrations reached a plateau after two weeks of treatment; in urine, the Ni concentrations increased progressively during the initial four months of treatment. During the interval from four months to three years of disulfiram treatment, the median concentrations of nickel in serum, whole blood, and urine were elevated 17-, 15-, and 39-fold, respectively, compared to pretreatment values. The effects of disulfiram on nickel metabolism evidently involve chelation of dietary nickel by diethyldithiocarbamate (DDC), a disulfiram metabolite, and gastrointestinal absorption of the Ni-DDC complex. Since animal studies have demonstrated cerebral uptake of the lipophilic Ni-DDC complex, nickel may possibly accumulate in brain cells of disulfiram-treated patients; physicians should therefore be cautious in administering disulfiram to persons with nickel-containing orthopedic prostheses or occupational exposures to nickel.

Adult↗

PubMedDate not supplied

Behavioral and neurochemical effects after combined perinatal treatment of rats with lead and disulfiram.

Lead exposure during pregnancy and lactation is known to result in various neurochemical and behavioral disturbances. Dithiocarbamates are known to markedly increase lead levels in the brain. However, the neurotoxicity due to combined treatment with lead and dithiocarbamates is not known. Behavioral and neurochemical effects of lead and disulfiram (tetraethylthiuram disulfide) given singly or in combination, were studied in rats. Pregnant rats were treated with lead (0.25% Pb in the drinking water), with disulfiram (0.1 mmol/kg PO twice a week) or with both lead and disulfiram from day 1 of pregnancy until parturition. After parturition the offspring were exposed to lead via the milk of the dams while the disulfiram (0.1 mmol/kg SC twice a week) was given directly to the offspring. At weaning, 26 days after parturition, the treatment was discontinued and after 2 more weeks behavioral and neurochemical studies were started. Neither lead alone nor disulfiram alone caused any significant effects in the behavior activity measurements. However, in combination the two compounds caused an increase in home cage activity and an increased behavioral reactivity as measured in a holeboard apparatus. Extracellular levels of some neurotransmitters and amino acids were measured in the caudate nucleus using the intracerebral dialysis technique. The levels of dopamine were significantly increased in both the lead-treated and the lead plus disulfiram-treated groups. The levels of the metabolites of dopamine (DOPAC and HVA) and serotonin (5-HIAA) were increased in the group treated with lead plus disulfiram.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1981

Interaction of lithium and disulfiram in hexobarbital hypnosis: possible role of the 5-HT system.

The effects of lithium and disulfiram on the 5-hydroxytryptamine (5-HT) system and hexobarbital (HX)-induced hypnosis were studied. Treatment with lithium significantly prolonged HX hypnosis. Disulfiram, a potent inhibitor of brain aldehyde dehydrogenase, also produced a prolongation of HX hypnosis. A combination of lithium treatment for 3 days with disulfiram synergistically potentiated the HX hypnosis and reduced the brain HX levels on awakening. Furthermore, L-tryptophan loading significantly increased the HX sleeping time and reduced the brain HX level on awakening in lithium-pretreated rats, whereas it had not effect on HX hypnosis in controls rats. L-Tryptophan also potentiated HX hypnosis in disulfiram-treated rats. The combination of L-tryptophan, lithium and disulfiram caused the greatest prolongation of HX hypnosis. However, no synergism between lithium and disulfiram was observed in animals treated with lithium for 5 days. after 3 days of lithium treatment, the rate of synthesis of 5-HT was elevated, whereas it had returned to the control level after 5 days of lithium treatment. Tryptophan loading increased the rate of synthesis of 5-HT more than 2-fold in control animals. The increase in the rate of 5-HT synthesis caused by lithium was further potentiated by tryptophan loading. These results suggest that lithium and disulfiram exert their synergistic effect on HX hypnosis by acting on the 5-HT system and that an accumulation of 5-hydroxyindoleacetaldehyde, an active metabolite of 5-HT, may be responsible for the increase in the brain sensitivity to barbiturates caused by these drugs.

Animals↗

PubMed1981

Stability of aqueous suspensions of disulfiram.

The stability of disulfiram in aqueous suspension is reported. Aqueous suspensions of disulfiram were prepared from bulk powder and from disulfiram tablets. Acacia and sodium benzoate were present in the suspension, the final concentration of which was 25 mg/ml disulfiram. Suspensions were stored in amber bottles under fluorescent light at 24 degrees C for 178 days (tablets) and 295 days (bulk powder). Samples were taken at various intervals during storage and assayed by high-pressure liquid chromatography (HPLC) and a modified NF method. Both types of suspension were stable. Potency remained constant, and no new peaks appeared in the chromatograph. Physical integrity of the suspensions was maintained. The suspension made from tablets contained less foam and air than the one made from bulk powder; both types were easily dispersible. A degradation product of disulfiram, diethyldithiocarbamic acid, did not interfere with the assay. The HPLC assay method was more reproducible than the modified NF method. Aqueous suspensions of disulfiram are stable at room temperature for the indicated time periods, and the HPLC assay method for disulfiram is reproducible and accurate.

Chromatography, High Pressure Liquid↗

PubMed1998

Monitoring relapse drinking during disulfiram therapy by assay of urinary 5-hydroxytryptophol.

Screening for recent alcohol use by testing urine for the ratio of 5-hydroxytryptophol (5HTOL) to 5-hydroxyindole-3-acetic acid (5HIAA) was performed in 10 methadone patients on disulfiram (Antabuse) maintenance therapy in an outpatient setting. Apart from alcohol ingestion, treatment with aldehyde dehydrogenase inhibitors such as disulfiram is the only known cause of an abnormally high 5HTOL/5HIAA ratio. After introduction of drug therapy, increased ratios were observed in all patients. The new higher level reached was relatively stable over time within the same patient but variable between patients. Four patients continued to consume alcohol, as evidenced by 5HTOL/5HIAA ratios well above the new individual plateau, while still taking 400 mg disulfiram 3 times per week under strict supervision. To try to achieve sobriety in two patients who drank frequently while on therapy, the disulfiram dose was doubled. Continued testing demonstrated this to increase the 5HTOL/5HIAA steady-state level further, and the absence of extreme values above this new baseline level indicated adherence to abstinence with possibly one single relapse. When disulfiram administration was discontinued, as planned, by five of the patients, four of them returned to drinking very soon. The present results show that during disulfiram maintenance the continuous inhibition of aldehyde dehydrogenase produces a new higher and dose-related 5HTOL to 5HIAA steady state level in urine, but relapse to drinking will still lead to further increased 5HTOL/5HIAA ratios. It is also suggested that an individual dose-titration regimen, whereby the disulfiram dose is raised gradually until 5HTOL/5HIAA testing indicates sobriety, will improve therapeutic effectiveness.

Adult↗

PubMed1991

Inhibition of membrane-bound succinate dehydrogenase by disulfiram.

The effect of disulfiram on succinate oxidase and succinate dehydrogenase activities of beef heart submitochondrial particles was studied. Results show that disulfiram inhibits both functions. Succinate and malonate suppress the inhibitory action of disulfiram when succinate dehydrogenase is stabilized in an active conformation. Disulfiram is not able to inhibit the enzyme when succinate dehydrogenase is inactivated by oxaloacetate. The inhibitory effect of disulfiram is reverted by the addition of dithiothreitol. From these results, it is proposed that disulfiram inhibits the utilization of succinate by a direct modification of an -SH group located in the catalytically active site of succinate dehydrogenase.

Animals↗

PubMed1975

Effect of tetraethyl thiuram disulfide (disulfiram) on the multiplication of enveloped viruses.

Disulfiram at concentrations between 0.1 and 0.3 mM inhibits the multiplication of Semliki Forest virus (SFV), fowl plague virus (FPV), Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), and pseudorabies virus (PRV), when administered 1 hour before and during adsorption. There is, however, no inhibition of virus multiplication, when the drug is added after adsorption onto chick embryo cells. Disulfiram interferes neither with the receptors of the virus nor of erythrocytes, and it does not prevent virus adsorption. Possibly an early step in virus multiplication is affected by disculfiram. Infected cells once treated with the drug recover after some time of incubation in an ingibitor-free medium. The inhibitory state can be maintained, however, if relatively low doses of disulfiram are present in the culture medium also after adsorption. Disulfiram has no effect on macromolecular synthesis of the host cells. It has, however, a marked affect on membrane function. While virus multiplication is readily inhibited by disulfiram when chick embryo or BHK cells were investigated, virus multiplication in HeLa cells is almost resestant against the action of disulfiram.

Adsorption↗

PubMed1995

Effects of ethanol on the pancreas of disulfiram-treated rats.

To study the effects of ethanol on disulfiram-treated rats, we administered ethanol orally at a does of 2000 mg/kg, twice daily for 5 days. The administration of ethanol or disulfiram alone produced no recognizable changes in pancreatic acinar cells. Ethanol administration, in disulfiram-treated rats resulted in a decrease in the content of zymogen granules in acinar cells, and the appearance of intraplasmic vacuolization. Electron microscopically, these vacuoles appeared on the basal side of nuclei. In addition, similar vacuoles appeared in liver cells, and these vacuolizations seemed to show lipid inclusions. However, ethanol administration to disulfiram-treated rats did not cause inflammatory changes or edema in the pancreas. A comparison of blood ethanol levels in rats receiving ethanol alone and disulfiram plus ethanol showed no significant difference, but acetaldehyde levels in rats receiving ethanol plus disulfiram rats were significantly higher than those in rats receiving ethanol alone. These findings suggested that acetaldehyde caused a decrease of zymogen granules and the presence of lipid inclusions in pancreatic acinar cells.

Acetaldehyde↗

PubMed2003

Effects of disulfiram on excitation-contraction coupling in rat soleus muscle.

The aim of this study was to analyze whether disulfiram could affect excitation-contraction coupling in rat slow-twitch ( soleus) muscle.In small bundles of intact fibers, the amplitude and the time constant of relaxation of twitch and potassium contractures were dose-dependently and reversibly reduced by disulfiram at concentrations up to 27 microM. At larger concentrations (up to 67.5 microM) these effects were still present but less pronounced. In the presence of disulfiram (27 microM), the relationship between the amplitude of potassium contractures and membrane potential was shifted to more positive potentials whereas, the steady state inactivation curve was unchanged. These observations suggest that disulfiram has no effect on voltage sensors. In saponin-skinned fibers, the amount of Ca(2+) taken up, estimated by using the amplitude of 10 mM of caffeine contracture, was increased by disulfiram (27 microM). By contrast no significant modification was observed in the sensitivity of the ryanodine receptors to caffeine (contractures generated at 5 mM of caffeine) and in the myofibrillar Ca(2+) sensitivity (Triton X-100 skinned fibers). These results indicate that disulfiram induces a dose-dependent reversible effect on the contractile responses of soleus mammalian skeletal muscle by acting mainly on the sarcoplasmic reticulum Ca(2+)-ATPase activity.

Alcohol Deterrents↗

PubMed2005

Effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice.

RATIONALE: Dopamine beta-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE), thus playing a critical role in catecholamine metabolism. OBJECTIVES/METHODS: We examined the effects of Dbh gene dosage and the DBH inhibitor disulfiram in mice with zero, one, or two null Dbh alleles (+/+, +/-, and-/- mice). RESULTS: DBH protein levels in adrenal and prefrontal cortex (PFC) and adrenal DBH activity were proportional to number of wild-type alleles. Adrenal DA was slightly increased in+/- mice and markedly increased (80-fold) in -/- mice compared to wild-type animals. While adrenal NE and epinephrine (EPI) were undetectable in -/- mice, adrenal concentrations of NE and EPI were similar in +/+ and +/- mice, suggesting that the increase in DA maintains the normal rate of beta-hydroxylation in Dbh +/- mice. Disulfiram had little effect on adrenal catecholamine levels, regardless of genotype or dose. NE was absent in the PFC of -/- mice, but only slightly reduced in +/- animals compared to wild-type animals. PFC DA was increased twofold in +/- mice and fivefold in -/- mice, and the NE to DA ratio was reduced ( approximately 35%) in +/- mice, compared to wild-type mice. Disulfiram significantly decreased PFC NE and increased DA in +/+ and +/- animals, with the disulfiram and genotype effects on the PFC NE to DA ratio apparently additive. CONCLUSIONS: The data reveal potentially important and apparently additive effects of Dbh genotype and disulfiram administration on PFC catecholamine metabolism. These effects may have implications for genetic control of DBH activity in humans and for understanding therapeutic effects of disulfiram.

Adrenal Cortex↗

PubMed1978

Effect of antabuse (disulfiram) on Rous sarcoma virus and on eukaryotic cells.

Antabuse (disulfiram) is widely used in the treatment of chronic alcoholism. We have examined the effect of this drug on malignant transformation by Rous sarcoma virus, on eukaryotic cell synthesis, and on nucleic acid binding. It was found that: (1) Disulfiram inhibits the activity of the RNA dependent DNA polymerase of Rous sarcoma virus and inactivates the ability of the virus to malignantly transform chick embryo cells. The monomer of disulfiram, diethyldithiocarbamate does not affect the virus. (2) Disulfiram induced the synthesis of four proteins in normal chick embryo and human foreskin cells. The monomer diethyldithiocarbamate, induced these proteins also. Cellular DNA synthesis is more sensitive to disulfiram than are RNA and protein synthesis. (3) Disulfiram binds to neither DNA or RNA in the presence or absence of copper. However, diethyldithiocarbamate in the presence of, but not in the absence of, copper binds to HeLa cell DNA and to Rous sarcoma virus 70 S genome RNA. These results indicate that this compound, which causes no symptoms in people who do not consume alcohol, may have significant effects on a cellular level.

Animals↗

PubMed1989

Pharmacological effects of diethylthiocarbamic acid methyl ester, the active metabolite of disulfiram?

A recently discovered metabolite, diethylthiocarbamic acid methyl ester (Me-DTC), has been found in the plasma of man and rats in much higher concentrations than any other described metabolite after therapeutic doses of disulfiram. Me-DTC, in contrast to other disulfiram metabolites, is a potent inhibitor of liver aldehyde dehydrogenase (ALDH) in vitro. Like disulfiram, Me-DTC had a pronounced hypothermic effect in rats. This hypothermic effect and the augmented blood pressure response to ethanol challenge in rats developed rapidly with Me-DTC but were somewhat delayed with disulfiram. The blood pressure response outlasted the presence of Me-DTC in plasma (less than 24 h); a significant effect was found 48 h after pretreatment but not 72 h after a single dose. No effect was observed when ethanol was given 15 min before Me-DTC or disulfiram. These latter two observations are consistent with a function of Me-DTC as a suicide inhibitor of ALDH. Since Me-DTC has been reported to inhibit ALDH in vitro, even under anaerobic conditions, Me-DTC may be the active metabolite of disulfiram.

Animals↗

PubMed1995

Peptide alpha-amidation: differential regulation by disulfiram and its metabolite, diethyldithiocarbamate.

The rate limiting step in the alpha-amidation of bioactive peptides is catalyzed by peptidylglycine-alpha-hydroxylating mono-oxygenase (PHM; EC 1.14.17.3). Sustained treatment with disulfiram (Antabuse), the disulfide dimer of diethyldithiocarbamate (DDC), inhibits PHM in vivo, causing tissue levels of alpha-amidated peptides to decrease. As a compensatory response, PHM protein is modified in such a way that its activity is increased when assayed under optimal conditions in a test tube. Because disulfiram is rapidly reduced to DDC in vivo, this investigation sought to determine if metabolic transformation plays a role in the effects of disulfiram treatment on alpha-amidation. While disulfiram treatment reduced concentrations of alpha-amidated peptides in the pituitary neurointermediate lobe and brain, DDC treatment did not, even at comparatively high doses. Both treatments increased the activity of PHM extracted from the neurointermediate pituitary and assayed under optimal copper conditions in vitro. Only disulfiram treatment elicited an increase in PHM activity extracted from cardiac atrium. It is concluded that the activity of PHM is regulated in a tissue specific fashion and that not all of the actions of disulfiram require its metabolism to DDC.

Animals↗