Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DISULFIRAM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 415 records · Page 23Linked to original sources
PubMed1998

Identification of the human P-450 enzymes responsible for the sulfoxidation and thiono-oxidation of diethyldithiocarbamate methyl ester: role of P-450 enzymes in disulfiram bioactivation.

Diethyldithiocarbamate methyl ester (DDTC-Me) is a precursorto the formation of S-methyl-N,N-diethylthiolcarbamate sulfoxide, the active metabolite proposed to be responsible for the alcohol deterrent effects of disulfiram. The present study investigated the role of human cytochrome P-450 (CYP) enzymes in sulfoxidation and thiono-oxidation of DDTC-Me, intermediary steps in the activation of disulfiram. Several approaches were used in an attempt to delineate the particular P-450 enzyme(s) involved in the sulfoxidation and thiono-oxidation of DDTC-Me. These approaches included the use of cDNA-expressed human P-450 enzymes, correlation analysis with sample-to-sample variation in human P-450 enzymes in a bank of human liver microsomes, and chemical and antibody inhibition studies. Multiple human P-450 enzymes (CYP3A4, CYP1A2, CYP2A6, and CYP2D6) catalyzed the sulfoxidation of DDTC-Me, as determined with cDNA-expressed enzymes. Several lines of evidence suggest that the sulfoxidation of DDTC-Me by human liver microsomes is primarily catalyzed by CYP3A4/5, including (1) a high correlation between DDTC-Me sulfoxidation and testosterone 6beta-hydroxylation; (2) increased DDTC-Me sulfoxidation in the presence of alpha-naphthoflavone, an activator of CYP3A enzymes; (3) inhibition of this reaction by inhibitors of CYP3A4/5 enzymes, such as troleandomycin and ketoconazole; and (4) inhibition of DDTC-Me sulfoxidation by antibodies against CYP3A enzymes. On the other hand, several lines of evidence suggested that the thiono-oxidation of DDTC-Me by human liver microsomes is catalyzed in part by CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5, including (1) these human P450 enzymes among others have the capacity to catalyze this reaction, as determined with cDNA-expressed enzymes; (2) a high correlation between DDTC-Me thiono-oxidation and testosterone 6beta-hydroxylation, weak inhibition by ketoconazole, troleandomycin, and anti-CYP3A antibodies suggested a minor role for CYP3A4; (3) a high correlation with immunoreactive CYP2B6 suggested involvement of this enzyme; (4) weak inhibition of DDTC-Me thiono-oxidation by furafylline and anti-CYP1A antibody suggested involvement of CYP1A2; and (5) inhibition of DDTC-Me thiono-oxidation by DDTC and anti-CYP2E antibodies suggested a role for CYP2E1. Collectively, these data suggested CYP3A4/5 enzymes are the major contributors to the sulfoxidation of DDTC-Me by human liver microsomes, and CYP1A2, CYP2B6, CYP2E1, and CYP3A4/5 contribute toward DDTC-Me thiono-oxidation by human liver microsomes. This study, in conjunction with others (Madan et al., Drug Metab. Dispos. 23:1153-1162, 1995), may help explain the variability in disulfiram's effectiveness as an alcohol deterrent.

Alcohol Deterrents↗
PubMed1976

[Attempt at potentiation of the action of L-dopa on the secretion of growth hormone by benserazide, disulfiram and propranolol].

Two tests of stimulation of growth hormone secretion were performed in 3 groups of normal children. In the first test L-Dopa was used on its own; in the second, L-Dopa was combined with Benserazide (group A), with Disulfirame (group B), or with Propranolol (group C). In group A the mean peak value after L-Dopa was 9.1 +/- 1.6 ng/ml; with the combination of L-Dopa and Benserazide it was 12.4 +/- 2.4 ng/ml. The difference between the means is not significant. In group B the mean peak value after L-Dopa was 8.9 +/- 3.6 ng/ml; with the combination of L-Dopa and Disulfirame it was 14.5 +/- 4.4 ng/ml. The difference is not significant. In group C the mean peak value after L-Dopa was 9.8 +/- 2.6 ng/ml; with the combination of L-Dopa and Propranolol, it was 10.1 +/- 1.9 ng/ml. Again the difference is not significant. These findings do not provide evidence in favour of the effect of L-Dopa on the secretion of growth hormone being facilitated by an inhibitor of L-Dopa decarboxylase (Benserazide) or of Dopamine beta hydroxylase (Disulfirame), or by a beta blocking agent (Propranolol). The mechanisms of action of L-Dopa and of the various combinations studied are discussed.

Adolescent↗
PubMed1988

Sites of inhibition by disulfiram in thylakoid membranes.

Disulfiram (tetraethylthiuram disulfide), a metal chelator, inhibits photosynthetic electron transport in broken chloroplasts. A major site of inhibition is detected on the electron-acceptor side of photosystem II between Q(A), the first plastoquinone electron-acceptor, and the second plastoquinone electron-acceptor, Q(B). This site of inhibition is shown by a severalfold increase in the half-time of Q(-) (A) oxidation, as monitored by the decay of the variable chlorophyll a flourescence after an actinic flash. Another site of inhibition is detected in the functioning of the reaction center of photosystem II; disulfiram is observed to quench the room temperature variable chlorophyll a fluorescence, as well as the intensity of the 695 nm peak, relative to the 685 nm peak, in the chlorophyll a fluorescence spectrum at 77 K. Electron transport from H(2)O to the photosystem II electron-acceptor silicomolybdate is also inhibited. Disulfiram does not inhibit electron flow before the site(s) of donation by exogenous electron donors to photosystem II, and no inhibition is detected in the partial reactions associated with photosystem I.

Journal Article↗
PubMed1978

Disulfiram neuropathy.

A 35-year-old man developed a distal sensorimotor polyneuropathy after taking disulfiram, 500 mg daily for five months. His symptoms improved after the drug therapy was discontinued. Clinical, electrophysiological, and pathological observations during the acute stage and during recovery suggest that disulfiram produces a distal axonopathy.

Adult↗
PubMed1989

'Catatonia' due to disulfiram toxicity.

In an alcoholic patient, catatonia developed while he was receiving disulfiram (Antabuse). Resolution of the question whether his state was classically catatonic required a detailed review of the literature on the subject. The conclusion reached is that the original definition still holds for psychiatric illness, but application of the term to neurological and metabolic states has often been based on imprecise criteria and failure to consider akinetic mutism and extrapyramidal motor disturbances as factors. The action of disulfiram as an inhibitor of dopamine beta hydroxylase provides a possible mechanism for the cerebral toxic effect, but nonetheless the various interpretations remain largely speculative.

Alcoholism↗
PubMed1976

The medical safety of the combined usage of disulfiram and methadone. Pharmacological treatment for alcoholic heroin addicts.

The results of hematology and blood chemistry tests were examined in eight methadone maintenance patients who had been treated concurrently for alcoholism with disulfiram (Antabuse). There were no apparent major differences between the results of tests run prior to the initiation of the disulfiram treatment and subsequent tests run up to 16 months after treatment was begun. There was a trend toward normalization of serum glutamic oxaloacetic transaminase (SGOT) values. The results suggested no contraindications to this combined pharmacological treatment.

Adult↗
PubMed1985

Reversible, late-onset disulfiram-induced neuropathy and encephalopathy.

Disulfiram toxicity is a well-recognized cause of peripheral neuropathy and encephalopathy, usually developing within a few months of the start of therapy. We describe a patient who insidiously developed a peripheral neuropathy and encephalopathy after thirty years of disulfiram ingestion. Both complications partially resolved after the medication was stopped.

Aged↗
PubMed1991

Plasma concentrations of disulfiram after injection of suspended micropellets into alcoholic subjects.

The disposition of disulfiram after administration in a new formulation was studied in rats and alcoholic patients. The suspension consisted of microcrystals suspended in a mixture of propylene glycol and water and injected subcutaneously into rats and humans; the course of the plasma concentration of diethyldithiocarbamate with time was followed by gas-liquid chromatography. Systemic delivery of disulfiram was observed to occur for a month. The data demonstrate that this form has the properties of a sustained-release formulation when implanted subcutaneously. There was no evidence of local or systemic adverse reactions.

Adult↗
PubMed1981

Effect of disulfiram on the ultrastructure of the peptidergic and aminergic cells in the pars intercerebralis of Galleria mellonella (Lepidoptera).

Injection of disulfiram, a specific inhibitor of noradrenaline synthesis, evokes changes in two different types of neurons in the brain of Galleria mellonella: neurones containing dense-core vesicles (60-80 nm) and peptidergic cells containing 180-200 nm neurosecretory granules. The lowering of the electron density of the dense-core vesicles of 60-80 nm seems to be directly connected with disulfiram administration, while the decrease of the amount of neurosecretory material in the neurosecretory cells of type I seems to be a secondary effect of the drug injection. The participation of noradrenaline in the regulation of the secretory activity of type I peptidergic neurosecretory cells of the pars intercerebralis is postulated.

Animals↗
PubMed1984

Metabolism of methylazoxymethanol acetate in the F344 rat and strain-2 guinea pig and its inhibition by pyrazole and disulfiram.

The basic parameters of the metabolism of methylazoxymethanol-(N,N'-methyl-14C) acetate, in terms of exhaled 14CO2, urinary metabolites, and inhibition by pyrazole and disulfiram, were examined in F344 rats and strain-2 guinea pigs. After a 18.7 mg/kg SC dose, 45% (6 h) and 49.5% (24 h) was exhaled as 14CO2, and 6.6% (24 h) of the radioactivity was excreted in the urine by the rats. After identical treatment, 36.5% (6 h) and 39.5% (24 h) was exhaled as 14CO2 and 3.5% (24 h) was excreted in the urine by the guinea pigs. Urea-14C and methylazoxymethanol(-14C) were the major urinary metabolites. In both species, pretreatment with pyrazole (40 or 360 mg/kg, IP) caused a significant reduction of exhaled 14CO2 and an increase in the amount of urinary methylazoxymethanol(-14C). Similar but less pronounced effects were observed after pretreatment of rats with disulfiram (1 g/kg, PO). These results are discussed with respect to possible enzyme systems involved in the metabolic activation of methylazoxymethanol in vivo.

Alcohol Dehydrogenase↗
PubMed1980

Effect of disulfiram on the alkylation of rat liver DNA by nitrosodiethylamine.

The extent of ethylation of guanine in 7 N and O 6 position in rat liver DNA was studied after chronic feeding with unlabelled nitrosodiethylamine followed by a single application of the 14C labelled drug. Disulfiram inhibits the alkylation of rat liver DNA. It was also shown that a discontinuous dosage of disulfiram protects against the alkylating effect of 14C nitrosodiethylamine only for a distinct period of time.

Alkylation↗
PubMed1983

[Polyneuropathy caused by disulfiram poisoning].

Disulfiram is known to produce toxic encephalopathy and peripheral neuropathy. The case of a 37-year-old alcoholic who attempted to commit suicide by taking 22.5 g disulfiram is described. During the first 6 days after the intoxication he was stuporous and had cerebellar ataxia and dysarthric speech. Then he became comatose, and as he recovered from coma, he showed peripheral neuropathy including diplegia faciei and severe tetraparesis. Denervation potentials were detected in both facial muscles and distal muscles of the upper and lower limbs, while conduction velocity was normal. Axonal degeneration was verified by sural nerve biopsy. In addition neurofilamentous axonopathy was documented. The recovery from his paresis lasted 2 years.

Adult↗
PubMed1977

Electron microscopic studies on the cerebral lesions of rats in experimental chronic disulfiram poisoning.

Following chronic administration of disulfiram to rats, changes of the brain were examined electron-microscopically. Pathological findings were observed in the nerve cells of the cerebral cortex and hypothalamus at later stage and synaptic changes in the hypothalamus from initial stage. On the other hand, changes of myelinated fibers, neuroglias and capillaries were very slight. It was considered that neurons were affected more predominantly than other neuronal elements by the cytotoxic action of the drug, and that the synaptic changes of the hypothalamus might reveal chronic disturbance of noradrenergic transmission by inhibition of dopamine-beta-hydroxylase. These ultrastructural findings might relate to the pathogenic mechanism of the disulfiram psychosis.

Animals↗
PubMed1984

The time course of the interaction of sheep liver cytoplasmic aldehyde dehydrogenase with 2,2'- and 4,4'-dithiodipyridine: a comparison with the action of disulfiram.

2,2'-Dithiodipyridine reacts rapidly with sheep liver cytoplasmic aldehyde dehydrogenase in the presence of NAD +, resulting in activation of the enzyme by 2 to 2.5-fold (when assayed in the usual way). This is followed by the slow loss of most of the enzyme activity during the next few hours at 25 degrees C. 2-Thiopyridone is displaced from the labeled enzyme at approximately the same rate as activity is lost. This is explained in terms of the initial modification of an enzymatic thiol group (giving activation) followed by the reaction of the labeled group with a second enzymatic thiol group, resulting in the formation of a disulfide bond and the inactivation of the enzyme. 4,4'-Dithiodipyridine reacts in a broadly similar way, although both the loss of label and loss of activity are faster and do not correlate with each other as well as for the 2,2' isomer. The results suggest that the dithiodipyridines act to produce the same enzymatic disulfide bond as has been shown to arise from the reaction of the enzyme with disulfiram (a drug used in alcoholism treatment). The implications of the results are discussed with reference to the proposed mechanism of action of aldehyde dehydrogenase. It is concluded that the thiol group initially modified by disulfiram is unlikely to be catalytically essential to the dehydrogenase action of the enzyme.

2,2'-Dipyridyl↗
PubMed1995

Olfactory toxicity of diethyldithiocarbamate (DDTC) and disulfiram and the protective effect of DDTC against the olfactory toxicity of dichlobenil.

Disulfiram and its breakdown product diethyldithiocarbamate (DDTC) have been investigated for their potential to protect against chemically-induced toxicity and carcinogenesis because of their inhibitory effects on cytochrome P450 2E1. We used DDTC in order to examine the role that cytochrome P450 2E1 plays in the bioactivation of beta,beta'-iminodipropionitrile (IDPN) and 2,6-dichlorobenzonitrile (dichlobenil), resulting in site-specific olfactory lesions in the Long-Evans rat and C57B1 mouse. DDTC and disulfiram themselves produced olfactory mucosal lesions in the rat, whereas DDTC protected against the olfactory toxic effects of dichlobenil in the mouse. A dose-response study revealed that approximately twice the dose of DDTC was required in mice to cause the same olfactory toxic effects seen in the rat. A study to determine the catalytic activity of P450 2E1 by p-nitrophenol (PNP) hydroxylation indicated that the Long-Evans rat nasal mucosa is 2.4 times more active than the C57B1 mouse, which may account for the greater susceptibility of the rat to the olfactory toxic effects of DDTC. PNP hydroxylation assays confirmed that DDTC decreased P450 2E1 activity in both the rat and mouse liver and nasal mucosa. Whereas the results of the mouse study strengthen the hypothesis that dichlobenil is bioactivated to a toxic metabolite by cytochrome P450 2E1 in the C57B1 mouse, rats pretreated with a marginally toxic dose of DDTC prior to the administration of IDPN displayed olfactory mucosal damage, indicating that an alternative or additional pathway may be operative in the metabolism of IDPN and/or DDTC.

Analysis of Variance↗
PubMed1976

Studies on the biochemical aspects of the 'disulfiram-like' reaction induced by oral hypoglycemics.

In vitro experiments, using rat liver homogenates, were designed to examine certain of the proposed enzymatic mechanisms for the interaction of oral hypoglycemic drugs with monoamine and ethanol metabolism. The oxidative degradation of tryptamine was studied by measuring indoleacetic acid (IAA) production and conclusions were drawn with regard to the activity of monoamine oxidase, aldehyde dehydrogenase and ethanol dehydrogenase. Acetohexamide, hydroxyhexamide, tolazamide, tolbutamide and chlorpropamide failed to reveal any specific inhibition of the three enzymes. Ethanol (0.2% w/v) and disulfiram decreased IAA formation, as did a lack of available aldehyde dehydrogenase and NAD, but these reductions were not enhanced by the hypoglycemic agents. The results suggest that the 'disulfiram-like' reaction which occurs in certain patients imbibing ethanol while receiving oral hypoglycemic drugs, depends upon some factor(s) other than, or additional to, a specific interference with monoamine and/or ethanol metabolism.

Administration, Oral↗
PubMed1995

Effects of cigarette smoke and disulfiram on tumorigenicity and clastogenicity of ethyl carbamate in mice.

Exposure of male Balb/C mice to mainstream cigarette smoke for 4 months, starting 10 or 30 days before the administration of ethyl carbamate (0.3% in drinking water for 3 weeks), resulted in an up to 57.6% (P < 0.05) decrease of lung adenoma multiplicity. However, the number of ethyl carbamate-induced lung tumors was not significantly affected by exposure to cigarette smoke when ethyl carbamate was injected i.p. in single doses of 0.5 or 1.0 g/kg, irrespective of the different treatment schedules used, i.e. (a) 10 days before and 4 days after the ethyl carbamate injection; (b) throughout the experiment starting 10 days before the ethyl carbamate injection, and (c) until the end of the experiment, starting 30 days after the ethyl carbamate injection. Disulfiram (500 mg/kg), given by gavage 24 h and 1 h before the ethyl carbamate injection, decreased by 88.5% (P < 0.001) the multiplicity of lung adenomas but had no effect on tumorigenesis when administered after the carcinogen injection. Proadifen (SKF-525 A, 50 mg/kg) injected i.p. 24 h and 1 h before and 24 h and 48 h after the injection with ethyl carbamate tended to decrease the multiplicity of lung adenomas, but not to a significant extent. Furthermore, disulfiram given 24 h and 1 h before the i.p. administration of ethyl carbamate completely prevented its clastogenicity in mouse bone marrow. On the other hand, cigarette smoke, which was per se a weak clastogen in bone marrow erythroblasts, synergistically potentiated the clastogenic response to ethyl carbamate in a more than additive fashion.

Animals↗