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PubMed1991

Action of a chronic disulfiram administration on memory decay and on central cholinergic and adrenergic systems.

The chronic administration (15 days) of disulfiram reduced the levels of noradrenaline (NA) in the olfactory system and in the subcortex at all the tested doses (50, 200 and 400 mg/kg/day). No modification of the density (Bmax) and of the dissociation constant (Kd) for alpha 1-adrenergic receptors was observed (radioligand [3H]prazosin). Only in the hippocampus the acetylcholine (ACh) levels and the Bmax for muscarinic receptors (radioligand [3H]QNB) were increased at all doses tested. Modifications of the cholinergic system were observed in the subcortex and in the cortex only at the higher doses of disulfiram. After 20 days interruption of the daily training in the staircase maze, 50, 100 and 200 mg/kg/day of disulfiram accelerated spontaneous decay of memory. It is hypothesized that the modifications of the hippocampal cholinergic system (increase of the ACh levels and of the density of the muscarinic receptors) may be the condition determining the acceleration of the decay of memory caused by disulfiram.

Acetylcholine↗
PubMed1988

Stabilization and quantitative determination of disulfiram in human plasma samples.

The rapid reduction of disulfiram at therapeutic plasma concentrations was inhibited by addition of the chelating agent, diethylenetriamine pentaacetic acid, and acidification in the presence of sodium chloride. The disulfiram recovery at concentrations ranging from 0.100-0.800 mumol/l was about 100% when preserved at 4 degrees C and analyzed immediately, and 95% and 75% after preservation for 1 h at 4 degrees C and for 24 h at -20 degrees C, respectively. The concentrations of disulfiram were determined in plasma from alcoholics receiving repeated therapeutic doses of disulfiram. Detectable concentrations in the range of 0.100-0.200 mumol/l could not be obtained until the second week of treatment.

Alcoholism↗
PubMed1989

Diethyldithiocarbamate and disulfiram inhibit MPP+ and dopamine uptake by striatal synaptosomes.

Diethyldithiocarbamate (DDC) was found to inhibit the uptake of both dopamine and 1-methyl-4-phenyl-pyridinium ion (MPP+, the putative toxic metabolite of the neurotoxicant MPTP) by striatal synaptosomes. Disulfiram, the corresponding disulfide of DDC, was effective at concentrations 1,000 times lower (10(-6) vs. 10(-3) M). Disulfiram, but not DDC, reacted very efficiently with synaptosomal protein thiols; both DDC- and disulfiram-induced uptake inhibition could be reversed by the thiol-reducing agent dithiothreitol. Two other thiol-reactive compounds, N-ethylmaleimide (NEM) and p-hydroxymercuribenzoate (PMB), also impaired the uptake of MPP+ by striatal synaptosomes. PMB, which does not cross membranes, was even more potent than the lipophilic NEM in blocking MPP+ uptake. These results suggest that (1) the effect of DDC may be mediated by disulfiram, (2) the uptake of MPP+ and dopamine by striatal synaptosomes is dependent on the redox state of protein thiols, and (3) these protein thiols are located at the outer surface of synaptosomal membranes.

1-Methyl-4-phenylpyridinium↗
PubMed1993

Deleterious effects of disulfiram on the respiratory electron transport system of liver mitochondria.

1. The mechanism of action of disulfiram on the respiratory electron transport system of the liver mitochondria was studied in vitro. 2. Disulfiram inhibited the respiration supported by malate-glutamate as well as succinate. 3. Mitochondrial respiration inhibition was dependent upon alteration of -SH groups. 4. The inhibitory action of disulfiram might be related to the crosslinking of several proteins of the inner mitochondrial membrane. 5. The effects described above could be attributed to disulfiram per se and not to the main metabolite diethyldithiocarbamate.

Cytochrome b Group↗
PubMed1983

Does consumption of alcohol in the presence of disulfiram cause brain damage?

After blocking aldehyde dehydrogenase activity with disulfiram in rats, a single injection of ethanol or a single day of inhaling ethanol vapor resulted in neuronal degeneration in the cerebral cortex and elsewhere that was detected by a specific silver stain and by electron microscopy. Treatment of rats with alcohol alone and with disulfiram alone did not cause neuronal degeneration. The minimum blood alcohol levels and disulfiram doses administered to the rats which caused neural degeneration are not distant from those values described in a clinical case of abuse of disulfiram.

Acetaldehyde↗
PubMed1979

Ethanol, disulfiram, and pyrazole: effects on interferon production in mice.

The effects of ethanol alone or combined with pyrazole or disulfiram were studied in reference to interferon production. Saline, ethanol (2 g/kg), pyrazole (2 mg/kg), or disulfiram (2 mg/kg) were injected, intraperitoneally, 3 hr after poly I:C, an interferon inducer. Drugs were administered either by a single injection, or twice daily for 7 days, and the mice were sacrificed 6 hr after poly I:C. Sera from mice were pooled, dialyzed, and assayed for interferon by the microplaque reduction method. Administration of ethanol alone reduced interferon production 76% and 66% after the single and the multiple injections, respectively. A similar inhibition of interferon occurred after either pyrazole or disulfiram, with a greater potency for pyrazole. Treatment with pyrazole prior to ethanol reduced interferon production further, but only after the 7-day schedule. All drugs tested affected cellular immunity as measured by interferon production. Moreover, reduced interferon production by these agents was associated with a loss of splenic lymphoid tissue, suggesting that ethanol, pyrazole, and disulfiram could affect susceptibility to viral infection.

Animals↗
PubMed1993

Can disulfiram potentiate the dexamethasone suppression test in depressive patients?

Transient DST non-suppression during disulfiram-treatment was fortuitously observed in a depressed patient. A disulfiram-potentiated DST (DSTd) was constructed by giving 800 mg disulfiram on the dexamethasone and postdexamethasone days. DST and DSTd were compared intraindividually in 21 patients and 14 controls. Disulfiram-potentiation was significant in constantly depressed patients, and in questionable controls due to possible subclinical depression or somatic factors which may cause 'false-positive' results. It did not occur in depressed patients during marked improvement or long-term recovery, and not in accurately screened controls. DSTd was significantly correlated with depression ratings, whereas DST was not.

Administration, Oral↗
PubMed1992

Effects of disulfiram, phenoxybenzamine and propranolol on the behaviors evoked by apomorphine and amphetamine in adult cats.

The aim of this work was to study the role that the noradrenergic system could play in the mechanism of production of the behaviors evoked by parenteral injection of apomorphine and amphetamine in adult cats. Ten cats were injected s.c. with 2 mg/kg of apomorphine and 2.5 mg/kg of amphetamine in separate sessions. The behaviors were recorded, until control conditions were again attained. In a second stage, disulfiram was administered ip., followed by apomorphine and amphetamine in the same doses as cited above. The effects on behaviors produced by disulfiram and those of apomorphine and amphetamine were recorded by three independent observers. Comparisons of the pre- and post-disulfiram behavioral results were analyzed with the help of the non-parametric Wilcoxon signed rank test. In another group of ten cats a similar procedure was carried on employing the alpha and beta noradrenergic blocking agents, phenoxybenzamine and propranolol. The noradrenergic blocking drugs, especially disulfiram and phenoxybenzamine produced by themselves a decrease in motility, in alertness and an increase in indifference and inappetence. Apomorphine and amphetamine administered after the blocking drugs showed slight behavioural modifications, reflection most of them the changes produced by the three blocking drugs. It is concluded that probably the nor-adrenergic system could be involved in the hypomotility elicited by amphetamine. NA is not involved in the induction of the other behaviors evoked by apomorphine and amphetamine.

Amphetamine↗
PubMed1982

Disulfiram acceptors and refusers: do they differ?

The present study examined possible personality and mood state correlates of alcoholics' decisions to accept or refuse disulfiram (Antabuse) as past of their treatment program. Subjects were 104 male veterans in an inpatient alcohol treatment program who were offered disulfiram after detoxification and evaluation. All subjects completed the Minnesota Multiphasic Personality Inventory, the Profile of Mood States, and the State-Trait Anxiety Inventory. Subjects were classified as acceptors (n = 78) or refusers (n = 26) based on their response to staff encouragement to undergo a trial of disulfiram. There were no significant group differences on age, racial composition, or any of the personality or mood state measures, with the exception of a trend (p less than .06) for acceptors to score higher than refusers on the masculinity-femininity scale of the MMPI. Examinations of distributions of MMPI profile code types similarly showed no differences between the two groups. Possible contextual explanations of these results are examined. Findings offer no support for the assumption that agreement to take disulfiram signifies greater motivation or intention to remain abstinent.

Alcoholism↗
PubMedDate not supplied

Disulfiram alters dopamine metabolism at sites in rat's forebrain as detected by push-pull perfusions.

The effect of tetraethylthiuramdisulfide (disulfiram) on the catabolism of dopamine within discrete regions of the brain was investigated in the unrestrained rat. After a guide cannula had been implanted stereotaxically, a given subcortical site was radiolabeled with 14C-dopamine (DA) by microinjecting 2.0 mu Ci in 2.0 microliters. Successive push-pull perfusates collected from each tissue were assayed by paper electrophoresis for the separation of DA metabolites. When disulfiram, a potent aldehyde dehydrogenase (ALDH) inhibitor, was given intragastrically in a clinically efficacious dose of 200 mg, the formation of the acids DOPAC and HVA was inhibited within perfusates of the caudate nucleus and nucleus accumbens. However, following disulfiram treatment, the proportion of alcohol metabolites did not differ from the control level in the untreated rat. The level of ALDH decreased by approximately 50% in these subcortical nuclei following the inhibition of the enzyme by disulfiram. Conversely, in samples of perfusate obtained from 14C-labeled sites within inferofrontal cortex, periform cortex, diagonal band of Broca, lateral-posterior caudate nucleus, tuberculum olfactorium, lateral olfactory tract or the olfactory nuclear complex, the proportion of DA metabolites remained stable. Generally, a low rate of deamination of the exogenously injected DA occurred within perfusion sites in the ventrobasal forebrain, whereas an intermediate rate of deamination was noted in samples collected at more dorsal loci. Thus, clearcut regional differences in DA catabolism occur in the brain of the living animal, which may depend upon the characteristics of the dopaminergic-rich area of the rat's brain.

Alcohols↗
PubMed1992

Inhibition of Meth-A tumor cell proliferation in combined use of disulfiram with catalase.

The effect of combined use of disulfiram with catalase on Meth-A tumor cell proliferation was studied. The simultaneous addition of 5 x 10(-7) or 1 x 10(-6) M disulfiram with catalase (4-40 micrograms/ml) induced marked inhibition of cell proliferation. A moderate degree of the antiproliferative effect was also obtained by pretreatment of the target cells with 5 x 10(-6) or 1 x 10(-5) M disulfiram in the presence of catalase (40 micrograms/ml). These results suggest that compounds or metabolites with cytostatic activity are newly formed following the reaction of disulfiram with catalase.

Animals↗
PubMed2006

Disulfiram irreversibly aggregates betaine aldehyde dehydrogenase--a potential target for antimicrobial agents against Pseudomonas aeruginosa.

In the human pathogen Pseudomonas aeruginosa, betaine aldehyde dehydrogenase (PaBADH) may play the dual role of assimilating carbon and nitrogen from choline or choline precursors--abundant at infection sites--and producing glycine betaine, which protects the bacterium against the high-osmolality stress prevalent in the infected tissues. This tetrameric enzyme contains four cysteine residues per subunit and is a potential drug target. In our search for specific inhibitors, we mutated the catalytic Cys286 to alanine and chemically modified the recombinant wild-type and the four Cys-->Ala single mutants with thiol reagents. The small methyl-methanethiosulfonate inactivated the enzymes without affecting their stability while the bulkier dithionitrobenzoic acid (DTNB) and bis[diethylthiocarbamyl] disulfide (disulfiram) induced enzyme dissociation--at 23 degrees C--and irreversible aggregation--at 37 degrees C. Of the four Cys-->Ala mutants only C286A retained its tetrameric structure after DTNB or disulfiram treatments, suggesting that steric constraints arising upon the covalent attachment of a bulky group to C286 resulted in distortion of the backbone configuration in the active site region followed by a severe decrease in enzyme stability. Since neither NAD(P)H nor betaine aldehyde prevented disulfiram-induced PaBADH inactivation or aggregation, and reduced glutathione was unable to restore the activity of the modified enzyme, we propose that disulfiram could be a useful drug to combat infection by P. aeruginosa.

Alanine↗
PubMed2005

Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders.

BACKGROUND: Disulfiram and naltrexone are approved by the Food and Drug Administration (FDA) for the treatment of alcoholism, but these agents have not been rigorously evaluated in dually diagnosed individuals. METHOD: Two-hundred and fifty-four patients with an Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at three Veterans Administration outpatient clinics. Randomization included assignment to one of four groups: 1) naltrexone alone; 2) placebo alone; 3) (open-label) disulfiram and (blinded) naltrexone; or 4) (open-label) disulfiram and (blinded) placebo. Medication compliance was evaluated using the Microelectric Events Monitoring System. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms, alcohol craving, g-GGT levels and adverse events. RESULTS: There was a high rate of abstinence across groups. Subjects treated with an active medication had significantly more consecutive weeks of abstinence and less craving than those treated with placebo, but there were no significant group differences in other measures of alcohol consumption. There was no advantage of the combination of both medications. CONCLUSIONS: These data suggest a modest advantage for the use of disulfiram and naltrexone for this group of dually diagnosed alcohol-dependent individuals but did not suggest an advantage in the combination.

Alcohol Deterrents↗
PubMed2003

Delay of cataract development in hereditary cataract UPL rats by disulfiram and aminoguanidine.

The UPL rat is a newly developed hereditary cataract model. We previously found that the administration of disulfiram, a dimer of diethyldithiocarbamate that possesses antioxidant activity, and aminoguanidine, which is known to inhibit inducible nitric oxide synthase, inhibits cataract development in selenite-induced cataract rats. In this study, we investigated the anti-cataract effects and mechanism of disulfiram and aminoguanidine on UPL rats. The opacities of UPL rat lenses, as documented by the anterior eye segment analysis system, EAS-1000 (Nidek, Aichi, Japan), increased from 39 days, and apparently mature cataracts were observed at 53 days. Accompanied with the increase in lens opacity, glutathione concentrations in UPL rat lenses decreased. The Na(+) to K(+) and water-insoluble to water-soluble protein ratios, as well as the Ca(2+) contents in UPL rat lenses increased with the development of cataracts. Oral administration of disulfiram and aminoguanidine delayed the lens opacification as well as the changes in glutathione, Na(+) to K(+) ratio, water-insoluble to soluble protein ratio, and Ca(2+) content in UPL rat lenses. The opacity and Ca(2+) content of UPL rat lenses were closely associated. The present study demonstrates that disulfiram and aminoguanidine have potency of the delay of cataract development in UPL rats, probably caused by inhibiting the rise in Ca(2+) levels.

Aging↗
PubMed2006

[Wernicke's encephalopathy associated with chronic disulfiram intoxication].

INTRODUCTION: We report the case of a patient with an unusual association of Wernicke encephalopathy and chronic disulfiram intoxication. CASE REPORT: A 41-year-old man presented with progressive frontal decline and akineto-rigid parkinsonism under chronic disulfiram therapy. He also developed acute confusion with ataxia, blepharospasm, and supranuclear ophthalmoplegia following a severe malnutrition due to refusal of food intake. Brain MRI revealed symmetrical and reversible hyperintense lesions on T2 and FLAIR in the posterior putaminal regions, dorso-medial thalamic and subthalamic nuclei, the periaqueducal gray matter, the cerebellar peduncles, and the pontine tegmentum. A slow partial clinical recovery with persistent frontal syndrome was observed after discontinuation of disulfiram and parenteral administration of thiamine. DISCUSSION: The symmetry and reversibility of the MRI lesions in the basal ganglia and brain stem were suggestive of a deficiency, a toxic or a metabolic neurological disease. The dorso-medial thalamo-subthalamic and brainstem localizations, as well as their occurrence in a state of malnutrition, were consistent with Wernicke encephalopathy. Moreover, chronic disulfiram intoxication might explain the frontal syndrome and the akineto-rigid parkinsonism, associated with MRI putaminal lesions. Similar MRI lesions have been described in the so-called "energy deprivation syndromes", which are toxic, genetic or nutritional disorders that disrupt enzymes involved in energy generating metabolic pathways such as glycolysis and pyruvate oxidation.

Adult↗
PubMed1980

Implantation of disulfiram in rats.

The biochemical and pharmacological effects of disulfiram implantation were studied in rats. Sterile disulfiram pellets (1000 mg/kg) were implanted subcutaneously. Groups of 5 rats were killed after 3, 7, 14, 28 and 56 days. The release of disulfiram during the first week corresponded to a daily dose of 12--16 mg/kg and during the following period to 5--8 mg/kg. The activity of the low-Km aldehyde dehydrogenase in liver and brain, the carboxylesterase activity in liver and the dopamine-beta-hydroxylase activity in heart were significantly decreased by approximately 45, 35, 20 and 35% respectively at all periods tested. The rate of ethanol elimination, the activity of monoamine oxidase in the brain, and the content of cytochrome P-450 in the liver were unaffected. The level of norepinephrine in the brain was slightly decreased after 14 days. The acetaldehyde level in blood after ethanol injection (1.0 g/kg) was 55--60 microM in the disulfiram group and 25--30 microM in the control group. Ethanol administration caused a slightly decreased blood pressure and increased respiratory rate 14 days after implantation but not after 28 days.

Acetaldehyde↗
PubMed1980

Determination of disulfiram and metabolites from biological fluids by high-performance liquid chromatography.

A high-performance liquid chromatographic method is described for the determination of disulfiram, diethyldithiocarbamate, diethyldithiocarbamate methyl ester, carbon disulfide, and diethylamine from a single sample of plasma or urine. The analytical procedure is based on a quantitative stepwise extraction of disulfiram and diethyldithiocarbamate methyl ester, or the conversion of diethyldithiocarbamic acid, carbon disulfide and diethylamine to diethyldithiocarbamate methyl ester for chromatographical determination. The procedure is specific, precise and simple. The application of the analytical methods developed for the determination of disulfiram and the various metabolites in plasma from mice given disulfiram intraperitoneally or humans given Antabuse orally is illustrated.

Alcoholism↗
PubMed1986

Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics.

The kinetics of caffeine elimination were investigated in 10 normal male subjects and in 11 recovering alcoholics before and during disulfiram dosing. In normal subjects the total body clearance of caffeine declined 30% (142 to 99 ml/min) at the maintenance dose of disulfiram, 250 mg/day, and 29% (161 to 114 ml/min) at the loading dose of 500 mg/day. In recovering alcoholics, the total body clearance decreased from 333 to 253 ml/min, a 24% change. The mean caffeine t1/2 increased 39% and 34% in normal subjects after 250 and 500 mg disulfiram, respectively, and 29% in recovering alcoholics. The inhibition of caffeine elimination was moderate in most subjects. However, the clearance of caffeine decreased by greater than or equal to 50% after disulfiram in three of the 11 recovering alcoholics. These patients may have an increased risk of cardiovascular and cerebral excitation associated with higher concentrations of caffeine, which could complicate withdrawal from alcohol.

Administration, Oral↗