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 19 recordsLinked to original sources
PubMed1989

Comparative aspects of disulfiram and its metabolites in the disulfiram-ethanol reaction in the rat.

Diethyldithiocarbamate-methyl ester (DDTC-Me), a metabolite of disulfiram, has been shown recently to produce a disulfiram-ethanol reaction (DER). Studies were carried out to compare the ethanol-sensitizing properties of DDTC-Me with those of disulfiram and diethyldithiocarbamate (DDTC) in the rat. All three drugs inhibited liver mitochondrial low Km aldehyde dehydrogenase (ALDH) in vivo, with maximal ALDH inhibition occurring 8 hr after drug administration. The onset of ALDH inhibition was most rapid after DDTC-Me administration. ALDH was inhibited approximately 50% 0.5 hr after DDTC-Me, whereas ALDH was inhibited only 5 and 10%, respectively, after disulfiram and DDTC. Not until 8 hr after drug treatment was ALDH inhibition the same for disulfiram, DDTC and DDTC-Me. The degree of ALDH inhibition from 8 to 172 hr after dosing was the same for all three drugs. An ethanol (1 g/kg, 20% v/v) challenge administered to rats treated with disulfiram (75 mg/kg), DDTC (114 mg/kg), or DDTC-Me (41.2 mg/kg) for 8 hr produced similar blood acetaldehyde/ethanol concentration-time profiles. In addition, all three agents produced a DER (hypotension, tachycardia). No DER occurred if ethanol was administered more than 24 hr after drug pretreatment. The hypotension associated with the DER correlated with the increased blood acetaldehyde but not blood ethanol. A threshold blood acetaldehyde of 110 microM appeared to be required for hypotension to occur, and this was related to ALDH inhibition of approximately 40%. The tachycardia associated with the DER correlated more with blood ethanol. After DDTC-Me administration, no disulfiram or DDTC could be detected in the plasma. Furthermore, no DDTC-Me was found in the plasma 8 hr after DDTC-Me administration, suggesting that no correlation exists between the DER and plasma concentration of DDTC-Me and most likely disulfiram. These data suggest that the alcohol-sensitizing properties of DDTC-Me are similar to those observed with disulfiram and DDTC. Since DDTC-Me is an active metabolite and more potent than disulfiram and DDTC in producing a DER, disulfiram metabolism is an important consideration in the disulfiram-ethanol reaction.

Acetaldehyde↗
PubMedDate not supplied

Diethyldithiocarbamic acid-methyl ester: a metabolite of disulfiram and its alcohol sensitizing properties in the disulfiram-ethanol reaction.

Diethyldithiocarbamic-acid-methyl ester (DDTC-Me) is a major metabolite of disulfiram. When given to rats, DDTC-Me was found to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) without having any effect on the high Km isoenzyme. Inhibition of low Km ALDH by DDTC-Me in vivo exhibited a dose-response relationship, with inhibition of ALDH from 11% to 90% found when DDTC-Me was administered in a dose range from 1.8 to 158 mg/kg, IP. After a single dose of DDTC-Me (41.2 mg/kg, IP), the low Km ALDH was inhibited for 168 hours suggesting an irreversible enzyme inhibition. After an ethanol challenge to DDTC-Me-treated rats, a decrease in mean arterial pressure (MAP) and increase in heart rate was observed. Decreases in MAP occurred almost immediately after ethanol challenge and remained low throughout a four hour post-ethanol period. These results suggest that in vivo administration of DDTC-Me can cause an alcohol-sensitizing reaction, and that DDTC-Me actually may be the metabolite of disulfiram which produces the disulfiram-ethanol reaction. It is proposed the reaction be more correctly identified as the DDTC-Me-Ethanol Reaction or D-MER.

Aldehyde Dehydrogenase↗
PubMed1991

Dose-effect relationship of disulfiram in human volunteers. II: A study of the relation between the disulfiram-alcohol reaction and plasma concentrations of acetaldehyde, diethyldithiocarbamic acid methyl ester, and erythrocyte aldehyde dehydrogenase activity.

The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.

Acetaldehyde↗
PubMed1987

Inactivation of horse liver mitochondrial aldehyde dehydrogenase by disulfiram. Evidence that disulfiram is not an active-site-directed reagent.

The inhibition of mitochondrial (pI 5) horse liver aldehyde dehydrogenase by disulfiram (tetraethylthiuram disulphide) was investigated to determine if the drug was an active-site-directed inhibitor. Stoichiometry of inhibition was determined by using an analogue, [35S]tetramethylthiuram disulphide. A 50% loss of the dehydrogenase activity was observed when only one site per tetrameric enzyme was modified, and complete inactivation was not obtained even after seven sites per tetramer were modified. Modification of only two sites accounted for a loss of 75% of the initial catalytic activity. The number of functioning active sites per tetrameric enzyme, as determined by the magnitude of the pre-steady-state burst of NADH formation, did not decrease until approx. 75% of the catalytic activity was lost. These data indicate that disulfiram does not modify the essential nucleophilic amino acid at the active site of the enzyme. The data support an inactivation mechanism involving the formation of a mixed disulphide with a non-essential cysteine residue, resulting in a lowered specific activity of the enzyme.

Aldehyde Dehydrogenase↗
PubMed1984

Side effects after disulfiram. Comparison of disulfiram and placebo in a double-blind multicentre study.

A double-blind, randomized study was carried out on the side effects of disulfiram in 241 men and women with alcohol abuse. Of the 158 patients completing the study, 83 received disulfiram and 75 placebo. Each patient was questioned on side effects after a 2-week wash-out period and thereafter once a week during the 6-week treatment period.. There was no statistically significant difference between the two groups, apart from over-representation of complaints of sexual problems in the placebo group. The patients who dropped out of the study were equally distributed between the two groups with regard to the number, diagnosis, and reasons for dropping out.

Adult↗
PubMed1984

How effective is the standard dose of disulfiram? A review of the alcohol-disulfiram reaction in practice.

The current maximum recommended dose of disulfiram, 200 mg daily, is often inadequate. Of 63 patients taking disulfiram under supervision who either risked drinking alcohol or who had a medically supervised challenge with alcohol, only half produced a significant response on a dose of 200-300 mg daily. Some patients need as much as 1.5 g daily but even at high dosage significant side effects are uncommon, reversible and rarely serious. A modification to the recommended technique for a medically supervised alcohol challenge is described, which minimises distress.

Adult↗
PubMed1989

Can disulfiram (Antabuse) be safely co-administered with the monoamine oxidase inhibitor (MAOI) antidepressants? Despite the ability of the major metabolite of disulfiram (diethyldithiocarbamate) to inhibit the enzyme dopamine beta-hydroxylase and a report of the induction in rats of central motor disturbances, convulsions, and death following the co-administration of tranylcypromine, there appears to be surprisingly little in the literature that directly addresses this question.

Explore the source record for details and available documents.

Animals↗
PubMed1989

Effects of perinatal treatment with lead and disulfiram on ALAD activity in blood, liver and kidney and urinary ALA excretion in rats.

Disulfiram, which is metabolized to diethyldithiocarbamate, is known to greatly influence the tissue distribution of lead (Pb) and potentiate the toxic effect of lead in the central nervous system. Effects on delta-aminolevulinic acid dehydratase (ALAD) activity and urinary delta-aminolevulinic acid (ALA) excretion were studied in rats pre- and postnatally exposed to lead and disulfiram, singly or in combination. Pregnant rats were treated with lead (0.25% Pb in the drinking water), with disulfiram (0.1 mmol/kg orally twice a week) or with both lead and disulfiram from day 1 of pregnancy until weaning. After parturition the disulfiram was given subcutaneously directly to the offspring. ALAD activity in blood was inhibited to a similar extent in the group treated with lead alone and in the group treated with lead and disulfiram (7 and 10% of control activity, respectively). Liver and kidney ALAD activities were not affected by the combined treatment with lead and disulfiram. However, urinary excretion of ALA was increased twice as much in the group treated with lead and disulfiram as in the group treated with only lead. The haematocrits were also significantly more depressed after combined exposure to lead and disulfiram. Two weeks after cessation of exposure ALAD activity in blood was inhibited to 47% of control activity in both the lead- and the lead plus disulfiram-treated groups. At this time there was no effect due to treatment on urinary ALA excretion of haematocrit. The results indicate that disulfiram probably influences the effects of lead on ALAD activity at the site of haem synthesis in the bone marrow.2+t is

Aminolevulinic Acid↗
PubMed1991

Disulfiram metabolism as a requirement for the inhibition of rat liver mitochondrial low Km aldehyde dehydrogenase.

In humans and animals, disulfiram produces a disulfiram-ethanol reaction after an ethanol challenge, the basis of which is the inhibition of liver aldehyde dehydrogenase (ALDH). Disulfiram and the metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl-N,N-diethylthiolcarbamate (DETC-Me) were studied in order to determine the role of bioactivation in disulfiram's action as an inhibitor of rat liver mitochondrial low Km ALDH (RLM low Km ALDH). In in vitro studies, disulfiram and DDTC (0.01 to 2.0 mM) both inhibited RLM low Km ALDH in a concentration-dependent manner. The addition of rat liver microsomes to the mitochondrial incubation did not further increase disulfiram-induced RLM low Km ALDH inhibition. However, DDTC-induced RLM low Km ALDH inhibition was increased further, but only at DDTC concentrations less than 0.05 mM. DDTC-Me and DETC-Me (2.0 mM) similarly exhibited an increased RLM low Km ALDH inhibition after the addition of liver microsomes. In in vivo studies, disulfiram (75 mg/kg), DDTC (114 mg/kg), DDTC-Me (41.2 mg/kg) or DETC-Me (18.6 mg/kg) administered i.p. to female rats inhibited RLM low Km ALDH. Inhibition of drug metabolism by pretreatment of rats with the cytochrome P450 inhibitor N-octylimidazole (NOI) (20 mg/kg, i.p.) prior to either disulfiram, DDTC, DDTC-Me or DETC-Me administration blocked the inhibition of RLM low Km ALDH. The in vitro and in vivo data support the conclusion that bioactivation of disulfiram to a reactive chemical species is required for RLM low Km ALDH inhibition and a disulfiram-ethanol reaction.

Aldehyde Dehydrogenase↗