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PubMed1992

Lack of bioequivalence between disulfiram formulations. Exemplified by a tablet/effervescent tablet study.

A comparison of the bioavailability of disulfiram (DSF) after administration of non-effervescent Antabuse tablets (CP Pharmaceuticals, UK) and Antabuse effervescent tablets Antabuse (A/S Dumex, DK) has been made in two cross-over studies. The first study included 6 volunteers who were given 400 mg DSF after an overnight fast. The bioavailability of DSF after administration of non-effervescent was found to be only 27% of that achieved with effervescent tablets. The second study included 24 volunteers who were given 800 mg DSF after a light standardized meal. The relative bioavailability of DSF after administration of non-effervescent compared with effervescent tablets was found to be only 34%. In addition to the difference in bioavailability of DSF after administration of the two preparations, a considerable difference was seen between the two studies. A light meal seems both to increase the bioavailability of DSF and to reduce the interindividual variation. A two to threefold increase in the bioavailability of DSF was found. Thus, the bioavailability of DSF appears to depend on both the formulation (preparation) and the mode of administration. A lack of bioequivalence between the two investigated DSF preparations was found.

Administration, Oral↗
PubMed1984

Neurotoxic effects of disulfiram on autonomic nervous system in rat.

Two groups of male Wistar rats weighing about 140 (WI) and 200 g (WII) and a group of Sprague-Dawley (S.D.) rats (140 g) received oral disulfiram 220-580 mg/kg (DSF) daily for one or three weeks. Isolated ilea of both control and treated rats showed similar responses to acetylcholine, but the responses to 5-hydroxytryptamine (5-HT) were decreased after one and three weeks' treatment in the WI and SD rats. Pretreatment with reserpine intensified this effect in treated WI rats. A distinct decrease in the histochemical reactivity for the acetylcholinesterase and the non-specific cholinesterase was observed in the nerve plexuses of the gut wall indicating a DSF-induced nerve damage. Autonomic (cholinergic) nerves seemed thus to be affected by DSF. The two rats strains studied did not differ in their responses to 5-HT.

Acetylcholine↗
PubMed1991

Drug interaction effects on antitumour drugs (VIII): prevention of ifosfamide-induced urotoxicity by disulfiram and its effect on antitumour activity and acute toxicity of alkylating agents in mice.

To reduce the side-effects and to enhance the antitumour activities of antitumour agents, we have been investigating their combined use with routine drugs. In the present study, we examined the effects of disulfiram (DSF) in combination with ifosfamide (IFX). DSF prevented IFX-induced bladder damage in a dose-dependent manner in tumour-free ddY mice when orally administered simultaneously with antitumour agent, but failed to diminish the acute lethal toxicity or leukocytotoxicity of IFX. Diethyldithiocarbamate (DDTC) prevented IFX-induced bladder damage when administered simultaneously with IFX or 1 to 5 hr afterwards. The antitumour activity of IFX in ddY-mice inoculated with Sarcoma 180 or in C57BL/6J mice inoculated with EL-4 leukaemia was not impaired when it was given simultaneously with DSF or 3 hr before DDTC. Thus, neither DSF nor DDTC impaired the antitumour effect of IFX and both diminished its adverse effects. The bladder protection of DSF and DDTC appeared resulted from adduct formation with acrolein and not from inhibition of the metabolic activation of IFX.

Animals↗
PubMed1991

Dose-effect relationship of disulfiram in human volunteers. I: Clinical studies.

The aim of this study was to investigate the relation between Antabus dosage and the disulfiram-alcohol reaction (DAR) after ethanol challenge. Fifty-two healthy volunteers, 29 men and 23 women, aged 20-61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.

Adult↗
PubMed1982

Disulfiram-like effect of diethyl maleate on barbiturate-induced hypnosis and 5-hydroxytryptamine metabolism.

Diethyl maleate (DEM, 600 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis and lowered plasma hexobarbitone level on awakening. Sleeping time following intracerebroventricular (i.c.v.) injection of phenobarbitone was also prolonged by DEM treatment. When administered to DEM-treated rats, L-tryptophan (50 mg kg-1 i.p.) significantly potentiated hexobarbitone hypnosis, although alone it had no effect in control rats. DEM markedly diminished the activity of brain low-Km aldehyde dehydrogenase (A1DH) and the formation of 5-hydroxyindoleacetic acid from 5-hydroxytryptamine (5-HT) without affecting MAO activity in various areas of the brain. Conversely, the protein-bound radioactivity derived from i.c.v. [14C]-5-HT was increased by DEM treatment. These results showed that DEM is comparable with disulfiram, a brain A1DH inhibitor, in terms of its effect on 5-HT metabolism and barbiturate hypnosis.

Aldehyde Dehydrogenase↗
PubMed1982

Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram.

Disulfiram labeled with carbon-14 reacts specifically with human liver aldehyde dehydrogenase E1 with loss of catalytic activity and no incorporation of label. Carbon-14-labeled diethyldithiocarbamate is formed and the number of enzyme sulfhydryl groups decreases from 34 to 30 during this process. Activity is recovered by-mercaptoethanol but not by glutathione, the physiological reducing agent.

Aldehyde Dehydrogenase↗
PubMed1983

Probation linked supervised disulfiram in the treatment of habitual drunken offenders: results of a pilot study.

Sixteen habitual drunken offenders agreed to take disulfiram in liquid form under supervision as a condition of a probation order. They knew that failure to take medication, as with failure to observe any other condition of probation, could result in their being returned to court. Three defaulted but only two of the remainder committed further offences. Nine were entirely successful. At the end of the study the average period of abstinence for the whole group was 30 weeks compared with six weeks during the previous two years. Nine risked drinking alcohol but none suffered any serious consequences or side effects. This technique may be a judicially acceptable and more hopeful alternative to prison for these offenders.

Adult↗
PubMed1985

A comparative study of the inhibition of hepatic aldehyde dehydrogenases in the rat by methyltetrazolethiol, calcium carbimide, and disulfiram.

Methyltetrazolethiol (1-methyl-5-mercapto-1,2,3,4-tetrazole, MTT) is a heterocyclic substituent of the cephalosporin antibiotics, cefamandole, cefoperazone, and moxalactam. Pretreatment of rats with MTT has been reported to increase blood acetaldehyde concentration after ethanol administration. The time course of MTT-induced inhibition of hepatic aldehyde dehydrogenases (ALDH) was determined in adult, male Sprague-Dawley rats in comparison with the hepatic ALDH inhibition induced by calcium carbimide (calcium cyanamide, CC) and disulfiram (D). The apparent onset of maximal inhibition of hepatic low Km ALDH occurred at 2 h for 50 mg/kg MTT (subcutaneous, s.c.) and 7 mg/kg CC (oral) and at 24 h for 300 mg/kg D (oral). The relative magnitude of maximal inhibition of low Km ALDH was CC greater than D greater than MTT. The relative duration of enzyme inhibition was D greater than MTT greater than CC. High Km ALDH was only inhibited by CC. Hepatic low Km ALDH was selectively inhibited by s.c. and oral administration of 125 mg/kg MTT. For s.c. administration of 125 mg/kg MTT, the magnitude of maximal enzyme inhibition and the duration of inhibition were greater than for the 50 mg/kg dose. Oral administration of 125 mg/kg MTT produced similar inhibition of hepatic low Km ALDH compared with s.c. administration of the same dose. The time course of blood ethanol and acetaldehyde concentrations was determined for the intravenous infusion of two 0.3-g/kg doses of ethanol to rats that were pretreated orally with saline (1 h), MTT (125 mg/kg, 2 h), or CC (7 mg/kg, 1 h). The relative increase in blood acetaldehyde concentration compared with saline pretreatment was CC greater than MTT. The elimination of ethanol from blood was slower in the MTT- and CC-pretreated animals, and this effect was more pronounced for CC pretreatment. Overall, the data demonstrate that the characteristics of hepatic ALDH inhibition for MTT are different from those of the known ALDH inhibitors, CC and D.

Acetaldehyde↗
PubMed2006

Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity.

Disulfiram (DSF), a member of the dithiocarbamate family capable of binding copper and an inhibitor of aldehyde dehydrogenase, is currently being used clinically for the treatment of alcoholism. Recent studies have suggested that DSF may have antitumor and chemosensitizing activities, although the detailed molecular mechanisms remain unclear. Copper has been shown to be essential for tumor angiogenesis processes. Consistently, high serum and tissue levels of copper have been found in many types of human cancers, including breast, prostate, and brain, supporting the idea that copper could be used as a potential tumor-specific target. Here we report that the DSF-copper complex potently inhibits the proteasomal activity in cultured breast cancer MDA-MB-231 and MCF10DCIS.com cells, but not normal, immortalized MCF-10A cells, before induction of apoptotic cancer cell death. Furthermore, MDA-MB-231 cells that contain copper at concentrations similar to those found in patients, when treated with just DSF, undergo proteasome inhibition and apoptosis. In addition, when administered to mice bearing MDA-MB-231 tumor xenografts, DSF significantly inhibited the tumor growth (by 74%), associated with in vivo proteasome inhibition (as measured by decreased levels of tumor tissue proteasome activity and accumulation of ubiquitinated proteins and natural proteasome substrates p27 and Bax) and apoptosis induction (as shown by caspase activation and apoptotic nuclei formation). Our study shows that inhibition of the proteasomal activity can be achieved by targeting tumor cellular copper with the nontoxic compound DSF, resulting in selective apoptosis induction within tumor cells.

Animals↗
PubMed1987

Development of a subacute tetraparesis after disulfiram intoxication. Case report.

A chronic alcoholic was intoxicated with the excessive dose of 25 g of disulfiram and developed a subacute flaccid tetraparesis and an associated encephalopathy. The severity of the clinical picture is partly explained by malnourishment including folate and vitamin B12 deficiency. The clinical, electrophysiological and pathological examinations are in accordance with the concept of a central-peripheral distal axonopathy.

Alcoholism↗
PubMed1981

Effect of disulfiram on acetoxymethyl-methyl-nitrosamine-induced tumors in rats.

Male Sprague-Dawley rats were given 10 weekly intravenous injections of acetoxymethyl-methylnitrosamine (AMMN = N-nitroso-acetoxymethyl-methylamine). One group was also treated with disulfiram (DSF) by gavage twice daily five times per week. DSF markedly reduced the rate of heart and lung tumors but not of tumors at other organ sites. In animals treated with the combination of DSF and AMMN a significant incidence of neurogenic tumors was observed. No neurogenic neoplasms occurred in animals treated with AMMN alone. During the observation period DSF showed no carcinogenic potential.

Adenocarcinoma↗
PubMed1997

Induction of cystine transport and other stress proteins by disulfiram: effects on glutathione levels in cultured cells.

Disulfiram (Antabuse) (DSF) has been reported to protect rats and other animals from the effects of hyperbaric hyperoxia at 4 to 6 ATA (atmospheres). In contrast, DSF and diethyldithiocarbamate (DDC), its metabolite, accelerate the toxic effects in rats of 100% oxygen at 1 to 2 ATA. We have examined the effects of DSF and DDC on glutathione (GSH) levels in bovine pulmonary artery endothelial cells and Chinese hamster ovary cells. Increases in intracellular GSH occurred 8 to 24 h after addition of DSF to the culture media. These increases in intracellular GSH were associated with increases in the rate of uptake of cystine into the cells. DDC was a less effective inducer of cystine uptake and increased intracellular GSH levels than was DSF. At the concentrations used, neither DDC nor DSF caused significant decreases in intracellular superoxide dismutase levels. Exogenous sulfhydryl compounds including GSH and cysteine partially blocked the induction of cystine transport by DSF or DDC, suggesting that the induction might be mediated through a sulfhydryl reaction between DSF and some cellular components. The increases in GSH in the cultured cells were not significant by 4 h of exposure. In contrast, other stress proteins including heme oxygenase are induced by 2 to 4 h after DSF addition. In previously reported in vivo studies, DSF treatment protected against hyperbaric oxygen damage after as little as 1 to 4 h pre-exposure. This suggests that effects of DSF exposure other than GSH augmentation may be responsible for the protective effects seen in vivo.

Animals↗
PubMed1993

Long-term, high-dose disulfiram in the treatment of alcohol abuse.

A patient who had experienced most of the standard methods of managing alcohol abuse found that during 11 years of treatment, the most consistently effective intervention has been the taking of disulfiram under family supervision. He has received 600 mg daily almost continuously for over six years without side-effects. Smaller doses do not have an adequate deterrent effect.

Adult↗
PubMed1981

Disulfiram neuropathy.

In four patients, sensorimotor polyneuropathy developed during treatment with disulfiram. Each patient began to improve with the cessation of treatment. Clinical, electrophysiologic, and pathologic observations point to a potentially reversible and probably dose-related axonal polyneuropathy.

Adult↗
PubMed2000

Effects of lipid composition on the transcorneal penetration of liposomes containing disulfiram, a potential anti-cataract agent, in the rabbit.

We previously demonstrated that topical treatment with disulfiram (DSF) prevented the development of cataracts in sodium selenite-injected rat pups. In biological systems, DSF is rapidly reduced to diethyldithiocarbamate (DDC), a potent antioxidant. In this study, we investigated the effect of altering the lipid composition of liposomes containing DSF on the transcorneal transit of DDC. Liposomes containing DSF were prepared with various molar ratios of dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC) and cetylpyridinum chloride (CPC) by reverse-phase evaporation. Liposomes with a DMPC to DPPC molar ratio of 5:5, examined by differential scanning calorimetry, had the highest enthalpy of transition and the presence of one molar ratio of CPC further enhanced the enthalpy value. The addition of bovine serum albumin or a homogenate of rabbit cornea to the incubation buffer resulted in the release of DDC, but not DSF from the liposomes. The amount of DDC present in the aqueous humor of rabbit eyes following topical administration increased with increase in DMPC to DPPC ratios and was also enhanced by the addition of CPC to the liposomes. The results of this study suggest that liposome formulations are effective for transcorneal drug delivery of anticataract agents such as DSF. DSF in liposomes consisting of DMPC, DPPC, and CPC with a molar ratio of 8:2:1 may be a potential drug formulation for the prevention and/or treatment of cataracts.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1985

Effects of diethyldithiocarbamate, a metabolite of disulfiram, on the pharmacokinetics of alcohol and acetaldehyde in the rat.

The effects of diethyldithiocarbamate (DDC), a metabolite of disulfiram which is known as Antabuse, on the blood concentrations of alcohol and acetaldehyde were determined simultaneously by head space gas chromatography in rats. After an intravenous injection of alcohol, the blood concentration of acetaldehyde was much lower than that of the alcohol. A pharmacokinetic model featuring the liver compartment for acetaldehyde was used to estimate pharmacokinetic parameters on the assumption that the distribution volumes of the central compartments were same for alcohol and acetaldehyde, and that the elimination rate of acetaldehyde from liver was large enough to isolate the liver compartment from the central compartment. The results showed that the clearance of alcohol was 0.0226 l/min/kg and the elimination rate constant of acetaldehyde from the liver compartment was very large and 35 min-1. The administration of DDC decreased the above significantly to 0.0132 l/min/kg and 20 min-1, respectively. After intravenous infusion of acetaldehyde, the time course of the blood concentration of acetaldehyde was analyzed by the one compartment model. The estimated elimination rate constants from blood and the distribution volume were in good agreement with those calculated from alcohol injection, indicating the appropriateness of the method used in this study. DDC had no effect on the elimination of infused acetaldehyde from blood indicating that the elimination may be due to the loss from lungs into breath, from skin surfaces and/or from the kidney but not by metabolism in the liver.

Acetaldehyde↗