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PubMed1978

Interaction of disulfiram with benzodiazepines.

The disposition of chlordiazepoxide (50 mg, intravenously), diazepam (0.143 mg/kg, orally), and oxazepam (0.429 mg/kg, orally) were studied in normal and alcoholic men before and after chronic disulfiram administration. Decreases in the plasma clearance of chlordiazepoxide (54%, p less than 0.05), diazepam (41%, p less than 0.05), and their active N-desmethyl metabolites were observed. Oxazepam has no important active metabolites and its net disposition is minimally altered by disulfiram. Oxazepam disposition is unaffected by age and liver disease. These considerations together with that of the short half-life of oxazepam (median, 6.1 hr) suggest that oxazepam may be the drug of choice if benzodiazepine therapy is used for patients taking disulfiram.

Adult↗
PubMed1982

Modulation of synthesis of specific proteins in endothelial cells by copper, cadmium, and disulfiram: an early response to an angiogenic inducer of cell migration.

Copper, cadmium, and disulfiram (an ionophore for copper) modulate the synthesis of several polypeptides in two clonal lines of bovine aortal endothelial cells. After treatment of Type 1 endothelial cells with 10(-3) M CuSO4 or 10(-5) M CdCl2 four cell-associated polypeptides (Mr = 28,000, 32,000, 73,000, and 83,000 daltons) were induced. In contrast, in Type 2 endothelial cells, which have cultural characteristics distinct from Type 1, only one new cell-associated protein (Mr = 32,000 daltons) was induced by CuSO4 or CdCl2. The same four polypeptides, described above, were induced by disulfiram (10(-7) M) in Type 1 endothelial cells. In contrast when Type 2 endothelial cells were treated with disulfiram the synthesis of only two new cell-associated proteins (Mr = 32,000 and 40,000 daltons) was induced. Other differences are revealed by analyses of proteins secreted into the growth medium. In particular low levels of only CuSO4 (10(-6) M) enhanced the synthesis in Type 2 cells of a protein (Mr = 220,000 daltons) identified as fibronectin. Since only copper ions induced fibronectin, we propose that the mechanism of induction of fibronectin synthesis, in contrast to the induction of cell-associated polypeptides, does not involve a sulphydryl-containing receptor molecule. It is suggested that the specific enhancement of fibronectin synthesis by copper ions may be a controlling event in the stimulation by copper ions of endothelial cell migration and angiogenesis.

Animals↗
PubMed1991

Dystonia and akinesia due to pallidoputaminal lesions after disulfiram intoxication.

A case with segmental cranial plus crural dystonia of delayed onset and akinesia after acute intoxication with disulfiram is presented. Computed tomography showed bilateral pallidal lesions, whereas on magnetic resonance imaging additional small lesions of the putamen could be detected. Long-term observation with progression and a change of symptoms over a period of 10 years after the intoxication is demonstrated on videotape. Although other central side effects after intoxication with disulfiram are well known, movement disorders are uncommon. Carbon disulfide, a disulfiram metabolite, may be important in the etiopathogenesis.

Adult↗
PubMedDate not supplied

Peripheral neuropathy associated with disulfiram administration.

Very few cases of peripheral neuropathy as a complication of disulfiram therapy have been described. The clinical and electrodiagnostic features of two patients who developed a severe peripheral neuropathy during disulfiram administration are reported. Evidence is presented which suggests that disulfiram causes a dying-back axonal neuropathy.

Action Potentials↗
PubMed1980

On the interaction of human liver aldehyde dehydrogenase E1 isoenzyme with disulfiram and iodoacetamide.

The E1 isoenzyme of human liver aldehyde dehydrogenase (Km acetaldehyde = 30uM, pH 7.0), when incubated with disulfiram at a stoichiometry of four moles disulfiram/tetrameric E1, is immediately inhibited to within 10% of control activity. The inhibition is reversed by 0.1% (v/v) mercaptoethanol, indicating disulfide bridge formation. An indirect attempt to locate, on maps, a peptide binding disulfiram has yielded inconsistent results. Iodoacetamide inhibits E1 slowly; inhibition is facilitated in the presence of NAD, resulting in loss of ca. 90% of control activity. Incubation with 14C iodoacetamide labels a 16,000 dalton CNBr peptide, and a ca. 4,000 dalton tryptic cleavage product. These fragments can be equated with those which have been suggested by disulfiram.

Aldehyde Oxidoreductases↗
PubMed1989

Extensive Ca2+ release from energized mitochondria induced by disulfiram.

The effect of the alcohol-deterrent drug, disulfiram, on mitochondrial Ca2+ content was studied. Addition of this drug (20 microM) to mitochondria induces a complete loss of accumulated Ca2+. The calcium release is accompanied by a collapse of the transmembrane potential, mitochondrial swelling, and a diminution of the NAD(P)H/NAD(P) radio. These effects of disulfiram depend on Ca2+ accumulation; thus, ruthenium red reestablished the membrane delta psi and prevents the oxidation of pyridine nucleotides. The binding of disulfiram to the membrane sulfhydryls appeared to depend on the metabolic state of mitochondria, as well as on the mitochondrial configuration. In addition, it is shown that modification of 9 nmol -SH groups per mg protein suffices to induce the release of accumulated Ca2+.

Adenosine Diphosphate↗
PubMed1995

Comparative effects of two dithiocarbamates disulfiram and thiram, on adrenal catecholamine content and on plasma dopamine-beta-hydroxylase activity.

Both disulfiram (tetraethylthiuram disulfide), an alcohol aversive drug, and thiram (tetramethyl-thiuram disulfide), a widely used pesticide, significantly increased the dopamine pool in the adrenal glands of dosed rats. The dopamine increase was detectable within 4 h of oral dosing with 100 mg/kg of either dithiocarbamate and peaked 24 h later at 10 times control values. In control rats the dopamine turnover was 0.51 h-1 as calculated by the assumed first order decline of dopamine after a single injection of alpha-methyl-p-tyrosine (alpha-MT, 400 mg/kg i.p.) resulting in a dopamine-beta-hydroxylase (DBH) activity of 0.73 nmol/h per pair of adrenals. In the adrenals of rats pretreated with thiram and then injected with alpha-MT, the adrenal dopamine content did not significantly decline, indicating that thiram reduced the conversion of dopamine to noradrenaline, eventually leading to the observed dopamine increase. Plasma DBH activity was significantly reduced 4 h and 24 h after dosing with thiram, but was unchanged after treatment with disulfiram. The determination of plasma DBH activity could be a marker to monitor the effect of thiram on catecholamine metabolism in occupationally exposed workers but not that of disulfiram in abstinent alcoholics.

Administration, Oral↗
PubMed1980

Disulfiram inhibits DNA breakage by hydroxyradical-producing agents.

Disulfiram (Antabuse, tetraethylthiuram) inhibits DNA cleavage by 1,2-dimethylhydrazine, ascorbate and cysteine. DNA cleavage by these agents is thought to be caused by hydroxyradicals which are formed during auto-oxidation in the presence of transition metals. H2O2 is an intermediate of these auto-oxidation reactions. The inhibitory action of disulfiram is at the level of hydroxyradical formation from H2O2 or at a later step of the reaction, since DNA cleavage by Fenton's reagent (H2O2/FeCl2) is also inhibited. DNA methylation by N-methyl-N'-nitro-N-nitrosoguanidine or methylazoxymethanolacetate is not affected by disulfiram.

Ascorbic Acid↗
PubMed1985

Endogenous acetaldehyde in rats. Effects of exogenous ethanol, pyrazole, cyanamide and disulfiram.

Male Long-Evans rats consumed the alcohol and aldehyde dehydrogenase inhibitors pyrazole, cyanamide or disulfiram, for 6 days. No endogenous blood acetaldehyde could be detected in controls and pyrazole treated rats, endogenous blood concentrations up to 2-5 nmoles/ml were, however, measured in the cyanamide and disulfiram-treated animals. Other rats received daily ethanol gastric intubations in addition to the consumption of the inhibitors. Little or no acetaldehyde was detected in the controls and pyrazole treated animals during acute ethanol intoxication or on the subsequent days. High blood levels (200-500 nmoles/ml) were observed in the rats consuming cyanamide and disulfiram, and concentrations up to 10-12 nmoles/ml were still found on the following day after all the ethanol had been eliminated. This acetaldehyde and the endogenous acetaldehyde could only be observed with the hemolyzation method in which blood hemolyzates were directly heated prior to headspace GC analysis; none was detected if blood proteins were first precipitated and removed with perchloric acid. It is suggested that aldehyde dehydrogenase inhibitors elevate endogenous concentrations of bound acetaldehyde and that exogenous ethanol increases this form of acetaldehyde.

Acetaldehyde↗
PubMed1987

Effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes in isolated human blood cells and platelets.

The effects of ethanol, acetaldehyde and disulfiram on the metabolism of biogenic aldehydes were measured in different human blood fractions. Intact erythrocytes, leukocytes and platelets were incubated in phosphate-buffered saline with 3,4-dihydroxyphenylacetaldehyde (DOPAL) or 5-hydroxy-indole-3-acetaldehyde (5-HIAL), the aldehydes derived from dopamine and serotonin, respectively. The disappearance of the aldehyde and the formation of acid and alcohol metabolites were analysed in the presence of different concentrations of ethanol, acetaldehyde or disulfiram using high-performance liquid chromatography with electrochemical detection. Ethanol at a concentration of 20 mM did not affect the biogenic aldehyde metabolism. High concentrations of acetaldehyde caused a dose-dependent inhibition of the disappearance rate of the biogenic aldehydes and of the formation rate of acid metabolites. In incubations with leukocytes or platelets, the inhibition of the acid formation was associated with a slight increase in the formation of the alcohol metabolites. Disulfiram at a concentration of 50 microM totally inhibited the metabolism of DOPAL and 5-HIAL in incubations with erythrocytes or platelets, whereas much less inhibition was observed in incubations with leukocytes.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. II. D-Glucuronic acid pathway.

Hepatic enzymes connected with the formation and metabolism of free D-glucuronic acid were affected in rats after treatment with disulfiram or diethyldithiocarbamate (300 mg/kg, intragastrically, per day, 4 X). The activities of UDPglucose dehydrogenase, UDPglucuronic acid pyrophosphatase, UDPglucuronosyltransferase and L-gulonate dehydrogenase were enhanced, while those of glucose-6-phosphate dehydrogenase, beta-glucuronidase and D-glucuronolactone dehydrogenase were inhibited. These changes were more pronounced with disulfiram than diethyldithiocarbamate. Treatment with phenobarbital (80 mg/kg, i.p., per day, 4 X) enhanced UDP glucuronosyl-transferase, but brought about different effects on the other enzymes. Concurrent administration of phenobarbital with disulfiram or diethyldithiocarbamate led to potentiation or antagonism of the primary effects of each compound when given alone. The results suggest that activation of the D-glucuronic acid pathway may proceed in various ways, and that it is not necessarily followed by a simultaneous induction of the microsomal mixed-function oxygenase activity.

Alcohol Oxidoreductases↗
PubMed1980

Changes in the serotonin and 5-hydroxyindoleacetic acid contents in rat brain after ethanol and disulfiram treatments.

Disulfiram (700 mg/kg, p.o.) significantly increased the brain levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in rats. Ethanol (1 g/kg and 2 x 1.5 g/kg, i.p.) did not affect the 5-HT level, but at the higher dose it significantly increased the 5-HIAA level. When disulfiram was given in combination with ethanol, the brain level of 5-HT was significantly higher and, conversely, the 5-HIAA level was significantly lower, as compared to the results with disulfiram alone. These results suggest that the biogenic aldehyde derived from 5-HT may influence 5-HT metabolism and the elimination of 5-HIAA from the brain.

Aldehyde Oxidoreductases↗
PubMed1985

Therapeutic effects of disulfiram in spinal cord contusion of rabbits.

The purpose of the present investigation was to evaluate methods to prevent the development of the immediate and delayed tissue damage in the injured spinal cord by early drug (disulfiram) interference with the molecular mechanism of tissue injury. The edematous inflammation as well as change in the levels and distribution of metallic ions like calcium following spinal cord contusion is known to contribute to the destructive process. A contusion model was applied in the spinal cord of rabbits using a pneumatic impactor. The effect of the systemically administered drug, disulfiram, in the traumatized spinal cord was determined by assaying the tissue water and Ca2+ contents at different locations of the spinal cord. A significant increase in the levels of the assayed parameters at the injured site of the spinal cord is markedly reduced by the pretreatment with disulfiram.

Animals↗
PubMed1985

Human mitochondrial aldehyde dehydrogenase inhibition by diethyldithiocarbamic acid methanethiol mixed disulfide: a derivative of disulfiram.

A derivative and possible physiological metabolite of disulfiram, diethyldithiocarbamic acid methanethiol mixed disulfide, is shown here for the first time to inactivate the mitochondrial low-Km isozyme of human aldehyde dehydrogenase (EC 1.2.1.3). By comparing inactivating effects of diethyldithiocarbamic acid mixed disulfides with thiols of increasing chain length evidence is provided that steric hindrance is the reason for lack of inhibition of the mitochondrial enzyme by disulfiram in vitro. Since methanethiol is a normal metabolite [(1983) Annu. Rev. Biochem. 52, 187-222] the results also suggest a mechanism by which aldehyde dehydrogenase is inhibited by disulfiram and diethyldithiocarbamic acid in vivo.

Aldehyde Dehydrogenase↗
PubMed1981

Disulfiram neuropathy. A morphometric study of sural nerve.

This report describes peripheral nerve morphology in 3 patients whose acute polyneuropathy followed disulfiram therapy. In all patients a combination of axonal degeneration with segmental demyelination and remyelination was seen, suggesting a varying degree of toxicity to both cytons and Schwann cells. The observed randomness of abnormal internodes argued against primary axonal atrophy and secondary demyelination. While large myelinated fibres were preferentially lost, ultrastructural studies also suggested degeneration of unmyelinated fibres. Because of high chloral consumption at the onset of peripheral nerve disease in 2 patients, the possibility of disulfiram-chloral interaction was considered. Present evidence suggests that the combined use of chloral or its derivatives with disulfiram is best avoided.

Adult↗
PubMed1991

Role of glutathione reductase system in disulfiram conversion to diethyldithiocarbamate.

Experiments were carried out to establish the role of glutathione reductase (GR), if any, in the metabolic conversion of disulfiram (DS) to diethyldithiocarbamate (DDC). It was observed that, under standard assay conditions, whereas DS was incorporated as a substrate instead of oxidised glutathione (GSSG), the enzymes from both human liver extract and yeast sources failed to reduce the parent compound, implying that glutathione reductase perse do not reduce disulfiram. However, the incorporation of disulfiram into an assay system comprising of GSSG, NADPH and reductase resulted in DS reduction to DDC. Further, the observation, that the GR assay system devoid of either GSSG or NADPH was found to lack DS reducing ability, implies that GSH as a reaction product of GR system is responsible for the reduction of DS to DDC. The results of in-vitro experiments indicated that GSH perse could reduce DS to DDC nonenzymatically, with a stoichiometric relationship of 2:1. Thus it is inferred that GR perse do not reduce DS, whereas GSH, as an intermediary metabolite of GR system, brings about non-enzymatic reduction of DS via a sulfhydral group exchange reaction.

Disulfiram↗
PubMed1983

Aldehyde dehydrogenase in blood: a sensitive assay and inhibition by disulfiram.

The characteristics of human blood aldehyde dehydrogenase with indole-3-acetaldehyde as the substrate were investigated. Blood volumes of less than 25 microliter could be assayed. The Km-value was below 10 microM for indole-3-acetaldehyde and 100 microM for NAD+. The ALDH-activity appeared to be located exclusively in the intracellular fraction of the erythrocytes. Acetaldehyde or ethanol at concentrations up to 1 and 40 mM respectively did not affect the activity. Disulfiram caused a pronounced inhibition of the enzyme both in vitro and in vivo. The blood ALDH-activity in disulfiram-treated patients was not fully restored until 6 weeks after discontinuation of the treatment. The inhibition observed in vitro was reversed completely by 2-mercaptoethanol but only partially by glutathione. No restoration of activity in blood from disulfiram-treated patients was obtained with these two reagents. The inhibition found in vitro and in vivo was more pronounced when the assays were performed with indole-3-acetaldehyde than with acetaldehyde. The results suggest that different isozymes of ALDH are involved in the assay with these two substrates.

Adolescent↗
PubMed1990

Lack of immunomodulating effect of disulfiram on HIV positive patients.

Disulfiram (Antabuse (R)) is metabolized to two molecules of diethyldithiocarbamate, which has been reported to be an immunomodulating agent. In a double blind trial, 15 HIV antibody positive homosexual men were given daily doses of 100 mg or 400 mg of disulfiram or placebo, for 4 weeks. All had a CD4-count below 500 X 10(6)/l and/or a pokeweed mitogen response in a lymphocyte proliferation assay less than 50% of normal controls. None suffered from opportunistic infections. No significant effect of disulfiram on immunological, haematological, biochemical or clinical variables was observed in this short-term trial.

Adjuvants, Immunologic↗