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PubMed1994

In vivo pharmacodynamic studies of the disulfiram metabolite S-methyl N,N-diethylthiolcarbamate sulfoxide: inhibition of liver aldehyde dehydrogenase.

S-methyl N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) is proposed to be the metabolite of disulfiram responsible for the in vivo inhibition of liver low Km aldehyde dehydrogenase (ALDH) in the rat. Studies were conducted in male Sprague-Dawley rats and also in vitro using both rat liver mitochondrial and purified bovine mitochondrial low Km ALDH to investigate further the pharmacodynamic and pharmacokinetic characteristics of DETC-MeSO. Administration of DETC-MeSO to rats produced a rapid and maximal inhibition of liver mitochondrial low Km ALDH within 2 hr, which was still inhibited 30% after 168 hr. After DETC-MeSO treatment, the maximum plasma concentration of DETC-MeSO was reached within 0.5 hr, with DETC-MeSO being undetectable 2 hr after DETC-MeSO dosing. Although a trace amount of DETC-Me was detected in the plasma 0.5 hr after DETC-MeSO administration to rats, this disappeared within 1 hr. When rats were treated with disulfiram, the maximal plasma concentration of DETC-MeSO was found within 2 hr, with only a very small quantity of DETC-MeSO still detectable after 8 hr. Rats also were given the disulfiram metabolites diethyldithiocarbamate (DDTC), diethyldithiocarbamate-methyl ester (DDTC-Me), and S-methyl N,N-diethylthiolcarbamate (DETC-Me), and plasma analyzed for DETC-MeSO 2 hr after the administration of these metabolites. DETC-MeSO was detected in plasma, further illustrating that DETC-MeSO can be found in plasma after the administration of either disulfiram, or the subsequent in vivo metabolites DDTC, DDTC-Me, or DETC-Me.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1989

Inhibition of acute CNS-tolerance to hexobarbital and prolongation of hexobarbital anaesthesia by disulfiram treatment in rats.

In many studies disulfiram treatment has been found to prolong hexobarbital anaesthesia, but the underlying mechanisms have not been clarified. In the present study, the effect of disulfiram on the development of acute tolerance to hexobarbital was studied in 2 age groups of rats (80 and 130 days old). Acute tolerance was measured as the increase in the brain concentration of hexobarbital (in 4 brain regions) needed to keep the rats on a constant EEG-monitored anaesthetic level for 1 hr. The effects of disulfiram on the metabolism in vitro and elimination in vivo of hexobarbital were also measured. The results suggest that the prolonged hexobarbital anaesthesia found after disulfiram treatment was the result of an inhibition of at least two different mechanisms: (1) the ability of the brain to develop acute tolerance to hexobarbital, and (2) the metabolism of hexobarbital by the liver, the latter resulting in a decreased elimination of the anaesthetic from the brain. The impaired development of acute tolerance was apparent only in the older rats. The inhibition of hexobarbital metabolism was most obvious in the younger ones.

Age Factors↗
PubMed1985

Inhibition of the rate of 14CO2 production from [14C]ethanol in rats given beta-lactam antibiotics with disulfiram-like effects.

An animal model has been developed to investigate the potentials of various beta-lactam antibiotics for inducing (or producing) disulfiram-like effects. The method, which measures the rate of 14CO2 production in rats after [14C]ethanol administration, is simple to operate and sensitive. On the basis of available clinical information the model appears to be highly predictive for the likely incidence of disulfiram-like side effects in humans. Rats were pretreated intravenously with beta-lactam antibiotics (420 or 500 mg/kg-1) 18 h before ethanol administration or with N-methyl tetrazole thiol (NMTT; 1-methyl-5-mercaptotetrazole) at 96 mg kg-1, 6 h before ethanol administration. The rate of 14CO2 production was decreased to 70 to 80% of control levels by NMTT and the NMTT-containing beta-lactam antibiotics moxalactam, cefamandole, and cefoperazone. Cefotaxime, cephalothin, and cefuroxime which do not contain the NMTT side chain had no significant effect on 14CO2 production. Oral administration of moxalactam (500 mg kg-1) and NMTT (96 mg kg-1) 18 and 6 h, respectively, before ethanol administration significantly decreased 14CO2 production. Intravenous administration of moxalactam (500 mg kg-1) to rats with cannulated bile ducts 18 h before ethanol administration had no statistically significant effect on 14CO2 production, although the rate of 14CO2 production was decreased to 89% of the control level. The effect of dose level and dose interval was also investigated by using moxalactam. The results obtained support the hypothesis that disulfiram-like side effects associated with beta-lactam antibiotics are mediated by NMTT which is released and reabsorbed from the gut after biliary elimination of the parent beta-lactam antibiotic. The time course of inhibition of ethanol metabolism by moxalactam appears to differ from that of disulfiram.

Animals↗
PubMed1990

Peripheral nerve functions in chronic alcoholic patients on disulfiram: a six month follow up.

The peripheral nerve functions of chronic alcoholic patients were studied clinically and electrophysiologically before they were placed on disulfiram (Antabuse). The evaluations were repeated while they were treated with 250 mg (n = 33) and 125 mg (n = 9) of disulfiram for one, three and six months. The data were compared with that of 24 untreated chronic alcoholic patients. None of the patients developed overt symptoms of peripheral neuropathy during the period of study. The patients on 250 mg disulfiram showed a significant decline in several components of the peripheral nerve functions, but no significant electrophysiological abnormalities were noted in patients taking 125 mg of disulfiram. Interestingly, the control group showed a significant electrophysiological improvement during the same period of observation.

Alcoholism↗
PubMed1992

Lesions of basal ganglia due to disulfiram neurotoxicity.

Three cases of disulfiram induced Parkinsonism and frontal lobe-like syndrome associated with bilateral lesions of the lentiform nuclei on CT scan are reported. Symptoms developed either after an acute high dose of disulfiram (one case) or after several days to weeks of disulfiram treatment (two cases) and persisted over several years in two patients. These observations suggest that basal ganglia are one of the major targets of disulfiram neurotoxicity. The mechanisms of the lesions of basal ganglia may involve carbon disulfide toxicity.

Adult↗
PubMed2002

Could honey have a place in colitis therapy? Effects of honey, prednisolone, and disulfiram on inflammation, nitric oxide, and free radical formation.

BACKGROUND/AIMS: The purpose of this study was to investigate the potential therapeutic roles of honey, prednisolone and disulfiram in an experimental model of inflammatory bowel disease. Another aspect of the study was to find out whether these substances have any effect on nitric oxide (NO) and free radical production. METHODS: After the induction of colitis with trinitrobenzene sulfonic acid in 64 male rats, physiological saline, honey, prednisolone and disulfiram enemas were applied to the rats once daily for 3 days (acute treatment groups) or 7 days (chronic treatment groups). Control groups received only saline enemas. Rats were killed on the 4th or 8th days and their colonic mucosal damage was quantitated using a scoring system. Acute and chronic inflammatory responses were determined by a mucosal injury score, histological examination and measurement of the myeloperoxidase (MPO) activity of tissues. The content of malonylaldehyde (MDA) and NO metabolites in colon homogenates was also measured to assess the effects of these substances on NO and free oxygen radical production. RESULTS: Estimation of colonic damage by mucosal injury scoring was found to be strongly correlated with the histologic evaluation of colon specimens. On the other hand, mucosal injury scores were not correlated with MPO, MDA or NO values. There were significant differences between the MPO results of chronic-control and chronic-honey groups, as well as chronic-control and chronic-prednisolone groups (p = 0.03 and p = 0.0007). The acute honey, prednisolone, and disulfiram groups had significantly lower MDA results compared to the acute control group (p = 0.04, p = 0.02, and p = 0.04). In terms of NO, there was no significant difference between the treatment and control groups. NO was found to have a strong relationship with MDA (p = 0.03) and MPO values (p = 0.001). On the other hand, MPO results were not found to be correlated with MDA values (p > 0.05). CONCLUSIONS: MPO activity is not directly proportional to the severity of the inflammation, but it may only determine the amount of neutrophil in the tissues. Inflammatory cells are not the sole intensifying factor in colitis. Therefore, mucosal injury scores may not correlate well with MPO activities. In an inflammatory state NO and MPO levels have a strong relationship, since NO is released from the neutrophils. In an inflammatory model of colitis, intrarectal honey administration is as effective as prednisolone treatment. Honey may have some features in the treatment of colitis, but this issue requires further investigation. Honey, prednisolone and even disulfiram also have some value in preventing the formation of free radicals released from the inflamed tissues. Prednisolone may also have some possible benefits in the inhibition of NO production in colitis therapy.

Animals↗
PubMed1984

Mechanism of tyramine-induced migraine: similarity with dopamine and interactions with disulfiram and propranolol in migraine patients.

In a double-blind crossover study, 8 patients with classical migraine received disulfiram (400 mg/day) for 6 days, alternating with matched placebo tablets at 2 weekly intervals. Intravenous dopamine and tyramine pressor tests were performed on the 3rd and 6th days of each phase, respectively. 50-75% of patients experienced migraine attacks within 24 h of a test. There was no difference in the incidence of attacks between dopamine and tyramine injections. The number of migraine-free days was more during the placebo week than during disulfiram treatment (p less than 0.05). The post-tyramine migraine index correlated directly with the amount of tyramine administered during the dose-response test (r = 0.66), but no such relationship was found with dopamine. In a further study, post-tyramine migraine was observed in only 1 of 5 patients treated with propranolol (80 mg/day) for 4 weeks. Neither disulfiram nor propranolol influenced the tyramine pressor sensitivity. It is concluded that increased adrenergic activity is responsible for more frequent attacks during disulfiram medication. A similar mechanism probably is responsible for post-dopamine/tyramine migraine in susceptible subjects. It is unlikely that tyramine plays any specific role, except via its effect on the adrenergic system, in the pathogenesis of migraine attacks. However, the tyramine challenge test can be useful in the evaluation of a putative antimigranous activity of a new drug.

Adult↗
PubMed1979

The role of plasma amine oxidase, platelet monoamine oxidase, and red cell catechol-O-methyl transferase in severe behavioral reactions to disulfiram.

The authors assayed platelet monoamine oxidase (MAO), plasma amine oxidase (AO), and red cell catechol-O-methyl transferase (COMT) in 32 male alcoholics before they began disulfiram treatment. Seven subjects developed psychotic reactions to disulfiram; these 7 had significantly lower pretreatment MAO and AO levels and significantly higher COMT than the patients who had no adverse reactions to disulfiram, which suggests that severe behavioral reactions to disulfiram are associated with differences in enzyme activities.

Adolescent↗
PubMed1982

Disulfiram neuropathy: a neurofilamentous distal axonopathy.

Disulfiram is used to treat alcoholism and is known to cause peripheral neuropathy: few reports of biopsied human nerves have revealed axonal degeneration and loss of myelinated fibers. We studied a 22-year-old woman with severe sensorimotor neuropathy following treatment with disulfiram for 6 months. Histologic studies of the sural nerve revealed a neurofilamentous axonopathy with rare enlarged axons distended by neurofilaments. Disulfiram is converted enzymatically to carbon disulfide, which causes neurofilamentous distal axonopathy in animals. Similar changes in human nerve after disulfiram administration suggest that carbon disulfide is the toxic agent.

Action Potentials↗
PubMed1987

Pharmacokinetics of latamoxef and N-methyltetrazolethiol in rats associated with the development of disulfiram-like effects.

The disulfiram-like effect of beta-lactam antibiotics, having an N-methyltetrazolethiol (NMTT) as a 3'-position substituent of the cephalosporin nucleus, was determined in rats using latamoxef (LMOX) as a model. Intravenous and subcutaneous administrations of these antibiotics caused a decrease in the low Km aldehyde dehydrogenase (ALDH) activity in liver mitochondria and an increase in blood acetaldehyde level during ethanol metabolism, as in the case of disulfiram. When the antibiotic was administered intravenously to biliary fistula rats, the blood acetaldehyde level did not increase. On the other hand, oral administration of antibiotic to normal and biliary fistula rats caused pronounced development of disulfiram-like effects in both animals. When LMOX was injected to normal rats, the rapid and slow eliminations of LMOX and NMTT, respectively, were observed from blood and liver. After oral administration of LMOX, NMTT remained in the blood and liver for a long time with higher concentrations, although LMOX could not be detected in the body. With biliary fistula rats, intravenous injection of LMOX led to rapid urinary excretion of both LMOX and NMTT. These results indicate that the development of disulfiram-like effects of NMTT-containing antibiotics is closely related to the pharmacokinetic profile of NMTT released from its parent drugs.

Acetaldehyde↗
PubMed2000

Disulfiram revisited.

Disulfiram can be important in helping motivated alcoholics to remain abstinent. Prescribers should be aware of disulfiram's toxicity, and how to recognize and manage reactions. A number of other agents are available to help alcoholics remain sober, although these do not necessarily obviate use of disulfiram. Also, disulfiram may have a wider role in the management of the addictions, e.g. in cocaine use.

Alcohol Deterrents↗
PubMed1984

Mood-altering effects of disulfiram in alcoholics.

The effects of disulfiram on depression and anxiety were examined. In a 3-week double-blind study, 40 inpatients in al alcohol rehabilitation unit (ARU) were randomly assigned to receive placebo, 250 mg/day of disulfiram or 500 mg/day of disulfiram. During their first week in the ARU and prior to beginning medications, all subjects were administered the Zung self-rating depression scale, the Hamilton observer rating scale for depression, the Zung self-rating scale for anxiety and the Hamilton observer rating scale for anxiety. All subjects were rescored on these instruments at the end of their third week in the ARU. Three psychiatrists, blind to the medication condition, sequentially scored the Hamilton items. To evaluate intergroup differences at baseline as well as changes in scale scores during the 3 weeks, scale scores were subjected to analyses of variance. No statistically significant effect attributable to disulfiram was found but significant changes due to a time effect were noted.

Adult↗
PubMedDate not supplied

Inhibition of 1,2-dimethylhydrazine metabolism by disulfiram.

1. The effects of disulfiram on the metabolism of 1,2-dimethylhydrazine were studied in CDF rats. 2. Treatment with disulfiram causes enhanced elimination of azomethane in the expired air, inhibition of CO2 production, and decreased levels of 1,2-dimethylhydrazine metabolites in the urine. 3. These results suggest that disulfiram inhibits the N-oxidation of azomethane to azoxymethane, thus preventing further metabolism to the ultimate carcinogenic species, and provide an explanation for the observations that disulfiram inhibits 1,2-dimethylhydrazine-induced neoplasia of the large intestine.

Animals↗
PubMed1990

Alcoholics' attitudes toward and experiences with disulfiram.

We studied 345 alcoholic inpatients utilizing a 43-item questionnaire designed to assess these patients' attitudes toward and experiences with disulfiram. A surprisingly high number of patients who had received disulfiram drank ethanol while taking or within 1 week of stopping disulfiram and experienced a disulfiram ethanol reaction. This finding and others derived from the questionnaire are reported, and the potential implications of the findings are discussed.

Adult↗
PubMed1986

Cisplatin chronotherapy and disulfiram rescue reduce toxicity without interfering with anticancer activity: animal findings and preliminary clinical experiences.

Cisplatin-induced mortality and nephrotoxicity are each predictably worse when the drug is given at certain points within the circadian schedule. Oral disulfiram protects rats from toxic effects at some circadian stages but not others. This manuever does not diminish the anticancer activity of cisplatin in these rats. Human beings given 2 g of oral disulfiram and high doses of cisplatin at the circadian stage associated with least cisplatin nephrotoxicity (prospectively determined potassium excretion acrophase) suffer little or no kidney damage. Disulfiram administration apparently does not interfere with the antineoplastic activity of cisplatin in humans. This is the first demonstration of the feasibility of assignment of treatment time according to a measure of the patient's 'internal clock' as assessed by pretreatment marker rhythmometry. It also establishes the feasibility of giving disulfiram to human beings.

Aged↗
PubMed1975

[Disulfiram and digestive motility; effect on absorption of ethanol in the rat].

The influence of disulfiram, ethanol and the association disulfiram-ethanol on gastro-intestinal motility and ethanol absorption was studied in rats. It was observed that disulfiram (25 mg/kg) and ethanol (0,8 g/kg), separately administered, decrease gastric emptying a nd increase propulsion in the small intestine; association of the two treatments results in the addition of the particular effects, except in the first intestinal segment. Disulfiram reduces ethanol absorption; very significant correlations have been noted between gastric emptying and ethanol absorption.

Animals↗
PubMed2002

[Psychosis during and after disulfiram use].

A 47-year-old man was registered for treatment of his alcohol abuse problem. Disulfiram was administered as part of the treatment, the intake of which was supervised by his wife. During the treatment with disulfiram and two weeks after the withdrawal of this treatment he developed a psychosis. He stated that he had not taken alcohol. During the second psychotic period he was successfully treated with antipsychotic drugs. Afterwards it was discovered that his family history was positive for schizophrenia; it is therefore possible that the patient was more vulnerable for a psychosis due to disulfiram use. Although a psychotic reaction during and after disulfiram therapy is not common, it should nonetheless be taken into consideration when prescribing the drug.

Alcohol Deterrents↗
PubMedDate not supplied

[Low dose of disulfiram and l-dopa evoked synergistic modification in behavior of Wistar and WAG/Rij rats].

Comparative analysis of behaviors of two rat strains, Wistar and WAG/Rij, was performed. No behavioral differences between Wistar and WAG/Rij were found in the emotional resonance test. Disulfiram injection produced similar effects in both rat strains. Animals of the first group (with slow acquisition of emotional resonance reaction) transformed into the animals of the second group (with fast acquisition). Passive avoidance conditioning was successfully reproduced in Wistar and was significantly impaired in WAG/Rij. A low dose of disulfiram injected before or immediately after conditioning substantially improved the reproduction to a greater extent in WAG/Rij than Wistar strains thus eliminating in interstrain differences. Active avoidance conditioning was more successful in WAG/Rij than in Wistar rats However, on the next day conditioning in WAG/Rij was substantially impaired. Administration of the low dose of disulfiram or L-DOPA prior to conditioning impaired the acquisition but improved the reproduction on the following day in both strains, but disulfiram injection after conditioning improved conditioning in WAG/Rij to a greater extent than in Wistar. Thus, the pharmacologic enhancement of the reward system substantially changed animal behavior and improved memory consolidation.

Affect↗