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PubMed1989

Alcohol-induced bone marrow damage: status before and after a 4-week period of abstinence from alcohol with or without disulfiram. A randomized bone marrow study in alcohol-dependent individuals.

The investigation described in this paper has confirmed the existence of alcohol-induced bone marrow damage as a nosological entity in alcohol-dependent individuals. In our patients total abstinence from alcohol without disulfiram or similar drugs led to reversal of the pathological findings in peripheral blood and in bone marrow. In patients undergoing detoxification while taking disulfiram, on the other hand, the pathological bone marrow findings, especially erythropoiesis associated with impaired iron utilization, persisted. The metabolic pathway of disulfiram is discussed. It is probably justifiable to assume that the toxin responsible for alcohol-induced bone marrow damage is the ethanol metabolite acetaldehyde. The persistence of erythropoiesis with impaired iron utilization during abstinence from alcohol and treatment with disulfiram is also of importance in differential diagnosis from the myelodysplastic syndrome (MDS), and especially from refractory anaemia with ring sideroblasts (RARS). For this reason, where the situation is unclear, it is essential that a diagnosis of MDS be supported by specific investigations such as cell cultures, cytogenetic analyses, etc. It is the first time that the toxic, alcohol-like-effect of disulfiram on haematopoiesis is discussed.

Alcoholism↗
PubMed1982

Effect of disulfiram in combination with L-tryptophan and lithium on pentylenetetrazol-induced seizure.

Disulfiram prolonged the latency to clonic seizure caused by pentylenetetrazol (PTZ, 100 mg/kg SC). The effect of disulfiram was augmented by combination with tryptophan plus lithium, although neither tryptophan or lithium prolonged the latency to clonic seizure. The latency to tonic seizure was also prolonged in disulfiram-treated animals in parallel with the prolongation of the latency to clonic seizure. Lithium treatment completely prevented the incidence of tonic seizure, while this effect was cancelled in disulfiram-treated animals. Disulfiram acts on the clonic and tonic seizures in different ways.

Animals↗
PubMed1989

Effects of disulfiram and coprine on rat brain tryptophan hydroxylation in vivo.

The effects of disulfiram and coprine on brain tryptophan hydroxylation, and on the brain-levels of serotonin and 5-hydroxyindole-3-acetic acid, were studied in 45 and 235 days old rats. Both drugs were found to affect the parameters measured. Disulfiram increased the rate of tryptophan hydroxylation and the serotonin level in young rats, while these parameters appeared to be unaffected in old disulfiram-treated rats. In contrast, coprine increased the rate of tryptophan hydroxylation and possibly also the serotonin level in old rats while no significant effects were seen in young coprine-treated rats. Regarding the 5-hydroxyindole-3-acetic acid concentration, this appeared to be increased by disulfiram in both age-groups, while no significant effects were found with coprine. The lack of similarity in the action of disulfiram and coprine, which are both potent aldehyde dehydrogenase inhibitors, suggests that the effects found were not caused by an impaired metabolism of monoamine-derived biogenic aldehydes.

5-Hydroxytryptophan↗
PubMed1982

Alcoholism treatment by disulfiram and community reinforcement therapy.

Traditional disulfiram treatment has often been ineffective because of a failure to maintain usage. The present study with 43 alcoholics compared: (1) a traditional disulfiram treatment, (2) a socially motivated Disulfiram Assurance program and (3) a Disulfiram Assurance program combined with reinforcement therapy. About five sessions were given for each program. At the 6-month follow-up, the traditional treatment clients were drinking on most days and no longer taking the medication. The Disulfiram Assurance treatment resulted in almost total sobriety for married or (cohabitating) clients but had little benefit for the single ones. The combined program produced near-total sobriety for the single and married clients. These results indicate a promising integration of chemical, psychological and social treatment of alcoholism.

Adult↗
PubMed1985

Effects of disulfiram on the oxidation of benzaldehyde and acetaldehyde in rat liver.

The in vitro oxidation of benzaldehyde and acetaldehyde was studied in liver samples from disulfiram-treated and control rats. With 25 microM substrate, both cytosol and mitochondria appeared to make a nearly equal contribution to the oxidation of benzaldehyde, whereas ca. 90% of acetaldehyde oxidation occurred in mitochondria. When the Km values for benzaldehyde with aldehyde dehydrogenase (ALDH) were determined, two Km values (3 and 120 microM) were obtained with mitochondria, but only a single Km value (25 microM) was obtained with the cytosolic fraction. The relatively high Km (2.9 mM) found with microsomes makes it unlikely that microsomes are important in the oxidation of benzaldehyde. In intact mitochondria, with 200 microM acetaldehyde or benzaldehyde the matrix space enzyme accounted for 77 and 62%, respectively, of the total ALDH activity. When the activity was determined in a mixture containing both substrates, the activity was found not to be additive, indicating that both substrates are oxidized by the same matrix space enzyme. With subcellular fractions, from livers of disulfiram-treated and control rats, a greater degree of inhibition of ALDH was obtained when acetaldehyde was a substrate compared to that with benzaldehyde in cytosol and mitochondria. Microsomal ALDH was not inhibited by disulfiram. In liver slices from rats given disulfiram, a statistically significant inhibition was found when either 25 or 250 microM acetaldehyde was used (46 and 33%). With benzaldehyde, a significant inhibition (24%) was observed only with the lower substrate concentration. Finding that both mitochondrial fractions and slices were less inhibited at the higher substrate concentration implies that the high Km enzyme is not inhibited. It can be concluded that, in rat, disulfiram inhibiting liver ALDH not only affects oxidation of acetaldehyde, but also that of benzaldehyde.

Acetaldehyde↗
PubMed1989

Inhibition of human erythrocyte and leukocyte aldehyde dehydrogenase activities by diethylthiocarbamic acid methyl ester. An in vivo metabolite of disulfiram.

The inhibitory effects of diethylthiocarbamic acid methyl ester (DTC-Me), an in vivo metabolite of disulfiram (Antabuse), on the aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activities in human erythrocytes and leukocytes were studied. ALDH assays were performed by incubating intact isolated blood cells in the presence of different concentrations of DTC-Me, using 3,4-dihydroxy-phenylacetaldehyde, the aldehyde derived from dopamine, as the substrate. DTC-Me was more selective as inhibitor of the leukocyte ALDH activity (which resembles the liver "mitochondrial" low Km ALDH), whereas both disulfiram and diethyldithiocarbamic acid, the reduced monomer of disulfiram, were more selective for the erythrocyte ALDH (which is similar to the "cytosolic" high-Km ALDH). Diethylthiocarbamic acid, the free acid of DTC-Me, was less potent than DTC-Me, and caused similar inactivation of the erythrocyte and leukocyte ALDH activities. The inhibition of ALDH by DTC-Me could not be completely restored by extensive dilution of intact or sonicated blood cell samples, which indicated that ALDH was irreversibly inhibited. Since the inhibition patterns with DTC-Me agrees with the previously reported patterns of inhibition of the high-Km and low-Km isozymes after the administration of disulfiram, the results suggest that DTC-Me might be the active in vivo inhibitory metabolite of disulfiram.

Aldehyde Dehydrogenase↗
PubMed1995

S-methyl N,N-diethylthiocarbamate sulfone, a potential metabolite of disulfiram and potent inhibitor of low Km mitochondrial aldehyde dehydrogenase.

Disulfiram inhibits hepatic aldehyde dehydrogenase (ALDH) causing an accumulation of acetaldehyde after ethanol ingestion. It is thought that disulfiram is too short-lived in vivo to directly inhibit ALDH, but instead is biotransformed to reactive metabolites that inhibit the enzyme. S-Methyl N,N-diethylthiocarbamate (MeDTC) sulfoxide has been identified in the blood of animals given disulfiram and is a potent inhibitor of ALDH (Hart and Faiman, Biochem Pharmacol 46: 2285-2290, 1993). MeDTC sulfone is a logical metabolite of MeDTC sulfoxide. Therefore, we investigated the effects of MeDTC sulfone on the activity of rat hepatic low Km mitochondrial ALDH, the major enzyme in the metabolism of acetaldehyde. MeDTC sulfone inhibited the low Km mitochondrial ALDH in vitro with an IC50 of 0.42 +/- 0.04 microM (mean +/- SD, N = 5) compared with disulfiram, which had an IC50 of 7.5 +/- 1.2 microM under the same conditions. The inhibition of ALDH by MeDTC sulfone was time dependent. The decline in ALDH activity followed pseudo first-order kinetics with an apparent half-life of 2.1 min at 0.6 microM MeDTC sulfone. Inhibition of ALDH by MeDTC sulfone was apparently irreversible; dilution of the inhibited enzyme did not restore lost activity. The substrate (acetaldehyde, 80 microM) and cofactor (NAD, 0.5 mM) together completely protected ALDH from inhibition by MeDTC sulfone; substrate alone partially protected the enzyme. Addition of either thiol-containing compound glutathione (GSH) or dithiothreitol (DTT) to MeDTC sulfone before incubation with the enzyme increased the IC50 of MeDTC sulfone by 7- to 14-fold. Neither GSH nor DTT could restore lost ALDH activity after exposure of the enzyme to MeDTC sulfone. Results of these studies indicate that MeDTC sulfone, a potential metabolite of disulfiram, is a potent, irreversible inhibitor of low Km mitochondrial ALDH.

Aldehyde Dehydrogenase↗
PubMed1983

Compliance with disulfiram treatment of alcoholism.

One hundred twenty-four men were randomly assigned to receive disulfiram with a riboflavin marker or riboflavin alone. During a one year follow-up urine specimens were collected at each visit and analyzed for riboflavin. There was a strong relationship between excellent attendance and infrequent drinking. For subjects taking disulfiram there was a high correlation between a subject submitting 15 or more positive urines during follow-up and infrequent drinking. For the disulfiram patients there was also a strong relationship between continuous usage of disulfiram and infrequent drinking. However, the correlation between percentage of urine specimens positive for the riboflavin marker and infrequent drinking was slight. This occurred because a person who was drinking tended to return for follow-up only when he was not drinking and thus submitted only a few specimens of which the majority were positive. We conclude that (1) excellent attendance, (2) submission of a large number of positive urines and (3) a period of continuous compliance to the disulfiram regimen were highly associated with infrequent drinking.

Adult↗
PubMed1982

Effect of disulfiram and its reduced metabolite, diethyl-dithiocarbamate on aldehyde dehydrogenase of human erythrocytes.

Inhibition of human erythrocyte aldehyde dehydrogenase (ALDH) activity was studied using disulfiram and its reduced metabolite, diethyldithiocarbamate (DDC). The enzyme was rapidly inactivated by disulfiram and the inhibition was protected by reduced glutathione (GSH), in a concentration dependent manner when the enzyme premixed with GSH was reacted with disulfiram. Higher reactivity of the thiol group of the enzyme than that of GSH to disulfiram was suggested from the observation that half of the enzyme activity was inhibited when the ratio of disulfiram to GSH was 1:10. Although DDC alone showed no inhibitory effect on the enzyme, inactivation was mediated by a low concentration of heme-containing peroxidases, but not by methemoglobin. Under this condition, the inhibition potential was not protected, even with a high concentration of GSH. The constant reoxidation system of DDC is probably directly related to the enzyme inactivation.

Aldehyde Dehydrogenase↗
PubMed1984

Hypotensive response of ethanol in rats pretreated with disulfiram or nitrefazole.

The effect of disulfiram or nitrefazole pretreatment on ethanol induced hypotension was examined in urethane anesthetized rats. A relatively low dose of ethanol (150 mg/kg; i.p.) produced a characteristic hypotensive response in rats pretreated for various periods with disulfiram or nitrefazole. This hypotensive episode started 5-10 minutes following ethanol administration and lasted 40-60 minutes. The hypotensive response was not seen unless disulfiram or nitrefazole treatment preceded ethanol administration by a least 6-8 hours. The low dose of ethanol produced a plasma ethanol concentration of 10mg/100ml or less. One treatment with nitrefazole (200 mg/kg) rendered rats vulnerable to ethanol-induced hypotension for 6 but not 8 days. One treatment with disulfiram (200 mg/kg) lasted 4 but not 6 days. In addition, the hypotensive response was greater in rats treated with nitrefazole than in rats treated with an equal dose (200 mg/kg) of disulfiram.

Animals↗
PubMed1991

Comparative effects of disulfiram and N-methyltetrazolethiol on spermatogenic development in young CD rats.

N-Methyltetrazolethiol (NMTT) and NMTT-containing cephalosporin antibiotics cause characteristic testicular lesions in young but not adult rats. In addition, NMTT-containing cephalosporins inhibit aldehyde dehydrogenase and have been associated with a disulfiram-like reaction in humans and animals. Therefore, the potential testicular toxicity of disulfiram (10, 30, or 100 mg/kg) was evaluated in 37-day-old rats given oral doses on Postpartum Days 6 through 36, and was compared to the toxicity induced by NMTT (100 mg/kg). NMTT and each dose of disulfiram caused a decrease in testes weight. By DNA flow cytometry, testicular cell suspensions from rats given 100 mg/kg of NMTT had a 40% reduction in spermatids while those from rats given 10, 30, or 100 mg/kg of disulfiram had reductions of 52, 61, or 89%, respectively. Microscopically, the testes of rats given either NMTT or disulfiram had qualitatively similar changes, characterized by delayed maturity of the leading waves of germinal cells which had reached early maturation phase in control animals. Moderate to severe reduction occurred in the total number of spermatids with complete absence of acrosome phase and maturation phase spermatids. There was also a prominent reduction in the number of spermatocytes. Reduction in number of spermatogonia was minimal. While the mechanism of toxicity is not known for either compound, it is possible that the toxicity was related to the enzyme-inhibitory effects which both compounds possess. By defining the mechanism of testicular toxicity for compounds which cause a NMTT-like testicular toxicity in rats, biological differences in the spermatogenic process between the young and adult rat may be further understood. Direct extrapolation of the testicular effects in neonatal rats to man is not possible because of the substantial differences in initiation of spermatogenesis between rodents and humans.

Aldehyde Dehydrogenase↗
PubMed1982

Acute effects of ethanol and acetaldehyde on blood pressure and heart rate in disulfiram-treated and control rats.

The cardiovascular effects of ethanol and acetaldehyde were studied in control rats and rats pretreated with disulfiram. Ethanol administration to control rats decreased mean blood pressure and increased heart rate significantly. Injection of ethanol to disulfiram-treated rats decreased mean blood pressure, increases pulse pressure and increased heart rate and respiratory rate. The blood acetaldehyde levels were 10-15 times higher than those found in controls. The effects evoked by ethanol in disulfiram-treated rats were prevented or abolished in rats given 4-methylpyrazole before or after ethanol. Heart rate increased with increasing concentrations of acetaldehyde in control rats given acetaldehyde intravenously. Only a slight decrease in mean blood pressure was seen at high acetaldehyde levels (150-250 microM), whereas pulse pressure increased markedly as well as respiratory rate. At acetaldehyde levels lower than 50 microM, no effects on blood pressure were seen. The effects of acetaldehyde infusion in disulfiram-treated rats were similar to those observed in controls having comparable acetaldehyde levels. The results suggest that the disulfiram-ethanol reaction in rats is caused by the combined action of ethanol and acetaldehyde on the cardiovascular system.

Acetaldehyde↗
PubMed1995

[Disulfiram (Esperal) toxicity. Apropos of 3 original cases].

Prescribed since 1948 to control chronic alcoholism, disulfiram may cause severe toxicity as report in three cases of acute motive axonal polyneuritis. Disulfiram toxicity may present different clinical aspects: 1) Cytolytic hepatitis with fatal evolution in 30% of cases (fulminant hepatitis), and full recovery for the other 70%. The onset of the symptoms usually occurs as early as 15 days to a maximum of 6 months (most within 2 months) after initiation of treatment. 2) Severe optic neuritis with full recovery in 2 months. 3) Peripheral neuropathy usually dose dependent, with different clinical presentations: polyneuritis with sensory, motor, or both deficits, and few cases of tetraplegia. 4) Encephalopathy frequently associated with one of the precedent symptoms, having a favorable outcome (probably resulting in inhibition of dopamine-beta-hydroxylase by disulfiram). The mechanism of toxicity (direct or idiosyncractic) remain unclear. Disulfiram has been used safely in millions of people since 1948, and we have only few cases reports of severe toxicity. From a practical point of view, treated patients should benefit by a neurological examination once a month, ophtalmological examination every 2 months, and hepatic enzymes monitored twice a month during the 2 first months. This is the price to prevent and to detect side effects of disulfiram therapy.

Adult↗
PubMedDate not supplied

Peripheral neuropathy after disulfiram administration: reversibility despite continued therapy.

The clinical history of an abstinent alcoholic developing paresthesias after one year's treatment with disulfiram (250 mg daily) is presented. Despite continued disulfiram in decreased dosage (125 mg daily), associated with multivitamin supplementation, marked improvement in symptoms and signs was noted, contrary to previous case reports. The peripheral sensorimotor neuropathy associated with disulfiram administration has been well described [1 - 8]. From those reports, it appears that symptoms may appear from several weeks to several months after the drug has been administered. Although the etiology of this neuropathy remains speculative, the usual treatment is to discontinue disulfiram once the toxicity develops. Presented here is the clinical course of a subject, whose neuropathic symptoms resolved with continued disulfiram administration at a lower daily dosage in conjunction with multivitamin therapy.

Adult↗
PubMed1987

Effect of disulfiram on milk transfer and tissue distribution of lead in the neonatal rat.

The effect of disulfiram (tetraethylthiuram disulphide) on uptake and tissue distribution of 203Pb was studied in neonatal rats exposed to lead via dams' milk. In the dams, treatment with disulfiram greatly increased the 203Pb concentration in brain and liver and decreased 203Pb concentration in plasma and erythrocytes, as compared to controls given only 203Pb. However, in the pups of disulfiram-treated dams total uptake of 203Pb was reduced by 50% and the concentration of 203Pb in brain and liver was significantly reduced. Consistent with these findings, the level of 203Pb in the maternal milk was lower in the disulfiram-treated dams compared to controls. It is suggested, that the lower lactational transfer and uptake of lead in the neonatal rat after treatment of the dams with disulfiram is due to retention and strong binding of lead to tissue components in the dams after formation of a lead-dithiocarbamate complex.

Animals↗
PubMedDate not supplied

Effect of diet and disulfiram on acetaldehyde blood levels after ethanol in UChA and UChB rats.

Acetaldehyde (AcH) levels in blood samples taken from different zones of the vascular system 2 h after a p.o. dose of ethanol (2.76 g/kg) were studied in UChA (low ethanol consumer) and UChB (high ethanol consumer) rats fed a diet devoid of animal products, diet 1 (D1), and a diet containing fish meal, diet 2 (D2), and in rats pretreated with disulfiram (600 mg/kg p.o.). The results showed that, while there is no significant difference between UChA and UChB rats fed D1 with respect to blood AcH levels and the basal activity of the hepatic mitochondrial high-affinity aldehyde dehydrogenase (AIDH), a significant strain difference was observed in rats fed D2, which induced high blood AcH levels in UChA rats but not in UChB ones. No strain differences were observed in blood ethanol levels in the two groups of rats. When rats fed D1 were pretreated with disulfiram, the raising of AcH blood levels induced by ethanol after disulfiram was significantly higher in UChA than in UChB rats in suprahepatic vein, femoral vein, and tail blood. This difference was concomitant with a greater inhibition of the hepatic mitochondrial high-affinity ADH activity in UChA rats than in UChB ones, whether disulfiram was administered in vivo or in vitro, which excluded the possibility that the strain difference would be caused by a different bioavailability of disulfiram.

Acetaldehyde↗
PubMed2004

Sex differences in cocaine-dependent individuals' response to disulfiram treatment.

The objective of this study is to evaluate differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Significant sex by treatment interactions were found, where men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment have important clinical and theoretical implications. Reasons for this apparent sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram.

Adult↗
PubMed2004

Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans.

To find novel drugs for effective antifungal therapy in candidiasis, we examined disulfiram, a drug used for the treatment of alcoholism, for its role as a potential modulator of Candida multidrug transporter Cdr1p. We show that disulfiram inhibits the oligomycin-sensitive ATPase activity of Cdr1p and 2.5mM dithiothreitol reverses this inhibition. Disulfiram inhibited the binding of photoaffinity analogs of both ATP ([alpha-(32)P]8-azidoATP; IC(50)=0.76 microM) and drug-substrates ([(3)H]azidopine and [(125)I]iodoarylazidoprazosin; IC(50) approximately 12 microM) to Cdr1p in a concentration-dependent manner, suggesting that it can interact with both ATP and substrate-binding site(s) of Cdr1p. Furthermore, a non-toxic concentration of disulfiram (1 microM) increased the sensitivity of Cdr1p expressing Saccharomyces cerevisiae cells to antifungal agents (fluconazole, miconazole, nystatin, and cycloheximide). Collectively these results demonstrate that disulfiram reverses Cdr1p-mediated drug resistance by interaction with both ATP and substrate-binding sites of the transporter and may be useful for antifungal therapy.

Adenosine Triphosphate↗