Disulfiram Treatment Research Articles

Long-term Antabuse treatment: tolerance and reasons for withdrawal.

We studied 210 alcoholics, who were re-admitted to a disulfiram treatment programme after having voluntarily discontinued disulfiram therapy, primarily to ascertain whether illness, hospitalization, or serious adverse effects were the cause of the withdrawal. A simple 9-item questionnaire was used. About 70% of the patients gave either "a wish to drink again" or "no need for further treatment" as the reason. Withdrawal in the remaining patients was in no case related to adverse effects of disulfiram. The low incidence of adverse effects was confirmed in another group comprising 93 patients treated under supervision with disulfiram 600-800 mg twice a week for at least a year (i.e. total dose at least 70 g disulfiram). They were monitored by standard laboratory blood and urine tests. There were no clinically significant changes in the measures used. Indeed, many of the patients improved during the year of abstinence. These two studies add weight to the evidence that disulfiram is not a drug with a high incidence of adverse effects.

Disulfiram Treatment of Alcoholism

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

Disulfiram treatment of alcoholism: past, present and future: Richard J. Fuller. National Institute on Alcohol Abuse and Alcoholism, Rockville, MD

Disulfiram treatment of alcoholism: past, present and future: Richard J. Fuller. National Institute on Alcohol Abuse and Alcoholism, Rockville, MD

Induction of thermotolerance by chemical agents in enucleate erythrocytes.

Erythrocytes treated with various chemical agents for 1 h at 37 degrees C showed resistance to a subsequent 1 h heat treatment at 53 degrees C. Maximal thermotolerance was observed 6 h after 3 mM DNP and 0.03 mM disulfiram treatment and 4 h after diamide exposure at 0.3 mM. Our results suggest that chemically induced thermotolerance to heat treatment in erythrocytes was similar to heat-induced thermotolerance.

Consecutive Treatment of Disulfiram Inhibits Ovarian Carbonyl Reductase Activity in Rats

We investigated the effects of disulfiram (DS) on ovarian carbonyl reductase activity in rats to determine the influence of DS on female reproductive function. Three consecutive treatments with DS significantly inhibited ovarian carbonyl reductase activity as well as ovulation, dose-dependently. Single treatment with DS had no effect on ovarian carbonyl reductase activity. Our observations indicate that consecutive treatment with DS has an inhibitory action on female reproductive function, although DS is well-known to inhibit aldehyde dehydrogenase and dopamine β-hydroxylase.

Consecutive treatment of disulfiram inhibits ovarian carbonyl reductase activity in rats.

We investigated the effects of disulfiram (DS) on ovarian carbonyl reductase activity in rats to determine the influence of DS on female reproductive function. Three consecutive treatments with DS significantly inhibited ovarian carbonyl reductase activity as well as ovulation, dose-dependently. Single treatment with DS had no effect on ovarian carbonyl reductase activity. Our observations indicate that consecutive treatment with DS has an inhibitory action on female reproductive function, although DS is well-known to inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase.

Disulfiram treatment of patients with both alcohol dependence and other psychiatric disorders: a review.

In treatment of alcohol dependence, disulfiram is most useful in conjunction with a structured, supervised, aftercare program. However, it has been reported to cause psychiatric side effects and to interact with various psychiatric medications. Many patients with alcohol dependence suffer from other psychiatric disorders and are treated with such psychiatric medications. This paper reviews the pertinent clinical pharmacology of disulfiram and the literature on potential psychiatric complications and drug interactions of disulfiram. At the usual dosage, about 250 mg/day, disulfiram does not appear to increase significantly the risk of psychiatric complications or of psychiatric drug interactions. Therefore, it can be considered a treatment option for patients with alcohol dependence and other psychiatric disorders.

Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats

Disulfiram, widely used in avoidance therapy for alcohol abuse, has been shown to have protective effects against chemically induced toxicity and carcinogenesis. The purpose of this work was to elucidate the biochemical mechanisms of this protective action by examining its effects on cytochrome P450IIE1 and other related microsomal enzyme activities. When a dose of disulfiram was given intragastrically to rats, a very rapid decrease of N-nitrosodimethylamine (NDMA) demethylase activity, possibly due to the inactivation of P450IIE1, was seen. The loss of P450IIE1 protein from the microsomal membrane was observed at 18 hr after receiving disulfiram, but not within the first 5 hr after the treatment. P450IIB1, on the other hand, was induced markedly between 15 and 72 hr after the disulfiram treatment. The treatment, however, caused only moderate changes in some other P450 isozymes. Carbon disulfide, a putative metabolite of disulfiram, produced similar effects on P450IIE1, but with shorter duration. Carbon disulfide, however, did not induce P450IIB1. Diethyldithiocarbamate, a reductive product of disulfiram, was an inhibitor of P450IIE1 activity in vitro, and upon preincubation with microsomes, it produced an NADPH-dependent inactivation of NDMA demethylase activity. The results suggest that this or other metabolites of disulfiram are inhibitors of P450IIE1 and are responsible for the inactivation of P450IIE1 in vivo. Hepatotoxicity of NDMA or CCl 4 in rats was blocked by pretreatment with disulfiram. The present work demonstrates that P450IIE1 was inhibited and inactivated by disulfiram, and this mechanism can account for many of the reported inhibitory actions of disulfiram against chemically induced toxicity and carcinogenesis.

The influence of disulfiram on acetaminophen metabolism in man

1. Acetaminophen clearance and its partial clearance to its major metabolites has been determined before and after 5 days treatment with the anti-alcohol abuse agent disulfiram (200 mg daily). The study was conducted in 10 subjects, five without liver disease and five with alcoholic cirrhosis of the liver. Acetaminophen was given i.v. at a dose of 500 mg. Plasma samples were obtained up to 8 h after injection and urine collected for 24 h. 2. Across all subjects acetaminophen plasma clearance was reduced from 0.249 +/- 0.061 to 0.217 +/- 0.066 l/min after disulfiram treatment (mean +/- SD, P less than 0.05). Thus no change in acetaminophen dosage would be required in patients treated with disulfiram. 3. The partial clearance of acetaminophen to its glucuronide, sulphate and glutathione derivatives (i.e. cysteine and N-acetyl cysteine) was not significantly changed by disulfiram treatment. Thus it seems unlikely that the previously observed protective effects of disulfiram against acetaminophen-induced hepatotoxicity in animals due to inhibition of metabolism will be seen in man.

Combined lead acetate and disulfiram treatment-induced alterations of glial fibrillary acidic protein (GFA) immunoreactive astrocytes in brain smears

Dithiocabamates are known to form lipid-soluble complexes with lead and greatly increase brain lead levels. The present study was undertaken to investigate whether lead acetate, when administered together with disulfiram (Antabuse®, metabolite of dithiocarbamate) during development, would induce morphological changes in brain astrocytes. Female Sprague-Dawley rats were given 0.25% lead acetate in the drinking water from day one of pregnancy and this treatment was continued after birth until the litters were 4 weeks old. In addition, some dams received disulfiram in a dose of 0.1 mmol/ kg p.o. twice weekly and after parturition this dose was given s.c. directly to the offspring twice a week. Lead acetate and disulfiram treatments were discontinued at weaning and animals sacrificed 3 weeks later. Samples of partietal cortex, hippocampal formation and cerebellar cortex were dissected out and smeared onto glass-slides and astrocytes were visualized in toto using immunohistochemistry with antibodies against glial fibrillary acid protein (GFA), enabling morphometric analysis with a computerized image analyser. Animals treated with lead acetate showed a minor increase in the size of the GFA-immunoreactive astrocytes in parietal cortex smears, while animals treated with disulfiram showed no difference in size or form compared to controls. However, in combined lead acetate and disulfiram-treated animals a profound increase in astrocyte size and an increase in the number of processes of the individual GFA-immunoreactive astrocytes could be demonstrated in parietal cortex. No significant changes were noted in GFA-immunoreactive astrocytes of hippocampal smears following the different treatments, while GFA-immunoreactive astrocytes in cerebellar cortex smears were significantly smaller and had reduced number or processes following the combined lead acetate and disulfiram treatment compared to lead acetate treatment or controls. It is concluded that combined exposure to lead acetate and disulfiram during development induces regionally specific changes in GFA-immunoreactive astrocyte morphology. Furthermore, the present study demonstrates the usefulness of smear preparations combined with computerized image analysis to study the morphology of GFA-immunoreactive astrocytes as an index of toxic effects in CNS.

Use of Leukocyte Aldehyde Dehydrogenase Activity to Monitor Inhibitory Effect of Disulfiram Treatment

Aldehyde dehydrogenase (ALDH; EC 1.2.1.3) activity was determined in leukocytes and erythrocytes from alcoholic patients during different stages of disulfiram (Antabuse) treatment. Assays were performed by incubating intact isolated blood cells in phosphate-buffered saline (pH 7.4, 37 degrees C), using 3,4-dihydroxyphenylacetaldehyde (DOPAL), the biogenic aldehyde derived from dopamine, as substrate. The ALDH activity was assessed from the amount of 3,4-dihydroxyphenylacetic acid (DOPAC) formed, as analysed by high-performance liquid chromatography with electrochemical detection. The leukocyte ALDH, which is similar to the liver "mitochondrial" low-Km ALDH isozyme, was maximally inhibited (about 40-60%) within 2 to 3 days after the initial disulfiram administration (dosage 200 or 400 mg/day orally). The time to reach maximum inhibition (about 95%) of the erythrocyte ALDH, which closely resembles the liver "cytosolic" high-Km isozyme, varied from 3 to more than 6 days. When medication was completed, the leukocyte ALDH activity remained unaltered for the first 2 days, and did not revert to normal levels until about 6 to 7 days after terminating treatment. The erythrocyte ALDH was still inhibited by about 90% 1 week after the last disulfiram administration. These results suggest that the leukocyte ALDH activity might provide an easily accessible marker for monitoring effect and time course of ALDH inhibition during disulfiram treatment.

Ethylene dichloride: The influence of disulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats

Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiolabeled EDC was affected. The urinary excretion of 14C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiramtreated rats, only 35 to 36% of the administered 14C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulforxide, and chloroacetic acid.

Loss of viability after disulfiram treatment without preceding depletion of intracellular GSH.

Effects of disulfiram (DSF) on freshly isolated hepatocytes were examined. Its effects on the cellular reduced form of glutathione (GSH) were triphasic; GSH decreased instantly after the addition of DSF, returned to subnormal levels within 30 min, and then declined gradually. The initial decrease in GSH after DSF treatment and the subsequent recovery of GSH were accompanied by an increase and decrease in the oxidized form of glutathione (GSSG), respectively. Decreases in cell viability brought about by 0.4 mM of DSF were correlated with the later gradual decrease in GSH. The loss of viability by DSF treatment seemed to appear when the initial GSH levels became lower than approximately 5 nmole/10(6) cells. Hepatocyte toxicity of DSF was potentiated by diethylmaleate (GSH depletor) and inhibited by N-acetylcysteine (GSH biosynthesis precursor). 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of GSH reductase, inhibited the GSH recovery and potentiated the toxicity. Respiration of hepatocytes was also inhibited by DSF. Free sulfhydryl groups other than GSH showed similar changes to those of GSH. From these results, it seemed that DSF reacted with cellular GSH and other free sulfhydryl groups to form diethyldithiocarbamate and GSSG, GSSG was reduced back to GSH by glutathione reductase, and the decrease in the viability was dependent on the initial loss of GSH.

Giving ethanol to alcoholics in a research setting: its effect on compliance with disulfiram treatment

In order to evaluate the effect of experimental ethanol administration on disulfiram compliance, a 6-month follow-up study was conducted with inpatient alcoholics. Two groups of patients were studied. Though not randomly assigned, the groups were matched on a variety of demographic and alcoholic-related variables. One group (N = 15) received ethanol in a laboratory-based study while the other group (N = 21) underwent treatment as usual. Days of disulfiram use did not differ between groups at follow-up. Studies concerning compliance with disulfiram support the validity of this measure as an indicator of treatment outcome. Our findings are consistent with other studies of the effect of experimental administration of ethanol to alcoholics, in that there were no immediate adverse effects and treatment outcome did not appear to suffer as a consequence of ethanol exposure.

Ethylene Dichloride: The Influence of Disulfiram or Ethanol on Oncogenicity, Metabolism, and DNA Covalent Binding in Rats

Ethylene Dichloride: The Influence of Disulfiram or Ethanol on Oncogenicity, Metabolism, and DNA Covalent Binding in Rats. CHEEVER, K. L., CHOLAKJS, J. M., EL-HAWARI, A. M., KOVATCH, R. M., AND WEISBURGER, E. K. (1990) Fundam. Appl. Toxicol14, 243–261. Male and female Sprague-Dawley rats were exposed to 50 ppm ethylene dichloride (EDC) for 7 hr/ day, 5 days/week, for 2 years by inhalation. Additional rats were exposed to 50 ppm EDC either with 0.05% disulfiram in the diet or with 5% ethanol in the drinking water. Histopathologic lesions related to the combination of inhaled EDC and dietary disulfiram were observed in the liver, mammary, and testicular tissues of rats. This combined exposure resulted in a significant increase in the incidence of intrahepatic bile duct cholangiomas in both male and female rats. Male rats exposed to both EDC and disulfiram also had an increased incidence of subcutaneous fibromas, neoplastic nodules, and interstitial cell tumors in the testes. The female rats exposed to EDC and disulfiram also had a higher incidence of mammary adenocarcinomas. No significant increase in the number of any tumor type was observed in rats exposed to only EDC, disulfiram, or ethanol. Similarly, no significant increase in the number of tumors was observed in rats exposed to inhaled EDC and ethanol in water. At the end of the 2-year period animals from each group were evaluated for EDC metabolism and DNA binding. Blood levels of EDC at the end of a 7-hr exposure period were significantly higher for rats exposed to both EDC and disulfiram than for rats exposed to EDC alone. In addition, the elimination of a single oral dose of radiola-beled EDC was affected. The urinary excretion of I4C from control rats was 47 to 55% of the administered dose with 28 to 30% detected as unchanged EDC in the breath. In disulfiram-treated rats, only 35 to 36% of the administered I4C was eliminated in the urine with 41 to 55% as unchanged EDC in the breath. The urinary metabolite HPLC profile was qualitatively unchanged by long-term EDC, disulfiram, or ethanol treatment, either alone or in combination, and consisted primarily of thiodiglycolic acid, thiodiglycolic acid sulfoxide, and chloroacetic acid.

Disulfiram administration affects substance P-like immunoreactive and monoaminergic neural systems in rodent brain.

The biosynthetic enzyme peptidylglycine alpha-amidating monooxygenase catalyzes the formation of a variety of biologically active alpha-amidated peptides from respective COOH-terminal glycine-extended peptide precursors. Peptidylglycine alpha-amidating monooxygenase activity is dependent on copper, ascorbate, and molecular oxygen and is inhibited by the relatively selective copper chelator N,N-diethyldithiocarbamate or its disulfide dimer disulfiram (Antabuse). In the present study, chronic disulfiram treatment (100 mg/kg/day, for 12-25 days) resulted in significant changes in several neurochemical parameters in the mouse central nervous system, including levels of substance P-like, unamidated substance P-Gly-like, and protease-generated substance P-Gly-Lys-like immunoreactivities (SP-LI, SP-G-LI, and SP-G-K-LI, respectively). Combined high performance liquid chromatography/radioimmunoassay analyses of the extracted SP-LI, SP-G-LI, and SP-G-K-LI species indicated very similar chromatographic and immunochemical behavior as demonstrated for chemically authentic peptide standards. Additionally, changes in levels of monoamines and their metabolites were observed after drug administration. Complementary immunohistochemical analyses using affinity-purified anti-SP-G sera localized these drug-induced changes in levels of immunoreactive unamidated precursor to neural elements that normally express SP. As a functional corollary to alterations in neurochemical parameters, we observed significant disulfiram-induced increases in pain thresholds, potentiated by capsaicin treatment. Overall, our results indicate that the observed changes in steady state levels of immunoreactive SP and of the immature COOH-terminal extended forms of SP may reflect compensatory biosynthetic and posttranslational processing events in SP-containing neural systems after pharmacological challenge.

Disulfiram treatment for alcoholism.

Disulfiram treatment for alcoholism.

Inhibition of acute CNS-tolerance to hexobarbital and prolongation of hexobarbital anaesthesia by disulfiram treatment in rats.

In many studies disulfiram treatment has been found to prolong hexobarbital anaesthesia, but the underlying mechanisms have not been clarified. In the present study, the effect of disulfiram on the development of acute tolerance to hexobarbital was studied in 2 age groups of rats (80 and 130 days old). Acute tolerance was measured as the increase in the brain concentration of hexobarbital (in 4 brain regions) needed to keep the rats on a constant EEG-monitored anaesthetic level for 1 hr. The effects of disulfiram on the metabolism in vitro and elimination in vivo of hexobarbital were also measured. The results suggest that the prolonged hexobarbital anaesthesia found after disulfiram treatment was the result of an inhibition of at least two different mechanisms: (1) the ability of the brain to develop acute tolerance to hexobarbital, and (2) the metabolism of hexobarbital by the liver, the latter resulting in a decreased elimination of the anaesthetic from the brain. The impaired development of acute tolerance was apparent only in the older rats. The inhibition of hexobarbital metabolism was most obvious in the younger ones.

The metabolism of acetaldehyde and not acetaldehyde itself is responsible for in vivo ethanol-induced lipid peroxidation in rats

A single oral administration of ethanol (5 g/kg) to rats induced a marked increase in lipid peroxidation, in the liver and kidney within 9 hr, as assessed by malondialdehyde accumulation. The pretreatment with alcohol dehydrogenase (ADH) inhibitor, 4-methylpyrazole (1mmol/kg) caused approximately 50% inhibition of the hepatic ADH activity and abolished this ethanol-induced lipid peroxidation. The disulfiram treatment (100mg/kg) significantly inhibited 63% of the hepatic low K m aldehyde dehydrogenase (ALDH) but not the high K m ALDH. The cyanamide treatment (15mg/kg) effectively decreased 83% of the low K m and 70% of the high K m ALDH in the liver. Although there was more than a 20-fold elevation of acetaldehyde levels by the inhibition of acetaldehyde metabolism with disulfiram or cyanamide, the ethanol-induced lipid peroxidation was significantly suppressed by pretreatment with these drugs. More than 90% inhibition of xanthine oxidase and dehydrogenase by the pretreatment with allopurinol (100 mg/kg), with no effect on the hepatic ADH and ALDH activities, did not alter the enhancement of lipid peroxidation following ethanol administration. We propose that the metabolism of acetaldehyde (probably via the low K m ALDH) and not acetaldehyde itself is responsible for the ethanol-induced lipid peroxidation in vivo and that the contribution of xanthine oxidase, as an initiator of lipid peroxidation through acetaldehyde oxidation is minute during acute intoxication.

Validity of self-report in alcoholism research: results of a Veterans Administration Cooperative Study.

The validity of self-report in alcoholism treatment research is controversial. Our recently completed Veterans Administration Cooperative Study evaluating the efficacy of disulfiram treatment for alcoholism provided an opportunity to assess the validity of self-report. To assess treatment response, patients and household contacts were interviewed at seven scheduled points during the 1 year of follow-up. Blood specimens also were obtained from the patients at these times and were analyzed for ethanol. Eighty-eight percent of the patient and/or collateral interviews were obtained at 6 months and 90% at 1 year. The mean number of blood and urine specimens collected per patient was 4.3 and 14.4, respectively. Outcome criteria included continuous abstinence during the year and total number of drinking days. Continuous abstinence: If we had had only the patients' self reports, we would have significantly underestimated the percentage of men who drank. By self-report 58.7% (355/605) relapsed whereas the combination of self report, collaterals' reports, and laboratory tests indicated that 72.4% (438/605) drank (p less than 0.001). Using Bayes' theorem, the conditional probability that a patient is continuously abstinent for 1 year when he so claims is 65%. Total drinking days: Of the 213 patient-collateral pairs each of whom provided all seven scheduled interviews, 46.9% (100/213) agreed on the total number of drinking days during the year.(ABSTRACT TRUNCATED AT 250 WORDS)