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A comparative study on the effects of disulfiram and beta-lactam antibiotics on the acetaldehyde-metabolizing system in rats.

Several beta-lactam antibiotics, especially those containing N-methyltetrazolylthiomethyl groups at the 3-position of the cephalosporin nucleus, affect the alcohol-metabolizing system in rats. These effects were compared those with disulfiram, well-known as a potent inhibitor of aldehyde dehydrogenase (ALDH). Both disulfiram and antibiotics containing the N-methyltetrazolylthiomethyl group inhibited both mitochondrial low Km ALDH and acetaldehyde oxidation in rat livers. The high Km ALDH and alcohol dehydrogenase activities in livers were not affected by these treatments. When ethanol was given to rats pretreated with disulfiram or these antibiotics, the blood acetaldehyde concentration increased markedly concomitant with a decrease in activity of the low Km ALDH. Administration of N-methyltetrazolethiol alone suppressed the low Km enzyme activity and also increased the blood acetaldehyde level; both effects were pronounced and observed several hours after administration. beta-Lactam antibiotics without N-methyltetrazolethiol in their molecule did not affect the liver mitochondrial enzyme activity or the blood acetaldehyde level.

Acetaldehyde↗

Inhibition of ifosfamide-induced urotoxicity by disulfiram in mice.

The effect of disulfiram on the urotoxicity induced by ifosfamide was studied in mice. Ifosfamide administered intraperitoneally to mice caused a dose-related increase in bladder weight within 48 hr of treatment. Disulfiram prevented ifosfamide-induced bladder damage when administered orally within 1 hr of ifosfamide treatment. The results indicate that disulfiram is an effective protective agent against bladder damage caused by ifosfamide treatment.

Administration, Oral↗

Disulfiram implantation. A placebo-controlled trial with two-year follow-up.

Ten alcoholics implanted with disulfiram had longer periods of abstinence after treatment than did 10 alcoholics implanted with placebo; 7 of the disulfiram-implanted patients experienced a disulfiram-ethanol reaction in uncontrolled drinking situations, while none of the placebo-implanted patients did.

Adult↗

A one-year follow-up of men alcoholics given disulfiram.

A total of 348 consecutive primary alcoholics entering an alcoholism treatment program comprised Group 1 (172 men who were offered disulfiram and agreed to take it) and Group 2 (176 who were eligible to take the drug but refused). Information was gathered at the time of intake into the program through personal interviews with patients and two resource persons. The clinical course in the 12 months after discharge was determined by follow-up interviews with patients and one resource person. The two groups were demographically similar at intake and there were no significant differences in outcome. However, at intake those men who agreed to take disulfiram and subsequently did well were more affluent, more likely to be married and less likely to have spent time in jail prior to treatment, and drank less often than those men who refused. Thus, although agreeing to take disulfiram was not associated with an improved outcome overall, men with more social stability and less pervasive problems may be the ones most likely to benefit from the drug.

Alcohol Drinking↗

Filamentous axonopathy in disulfiram neuropathy.

A 52-year-old female developed a sensorimotor polyneuropathy while on treatment with disulfiram. Electron microscopic examination of a sural nerve biopsy disclosed occasional axons distended by intermediate filaments. Identical changes can be induced in animals by carbon disulfide (CS2), a metabolite of disulfiram. Our findings suggest that disulfiram neurotoxicity is mediated by CS2 and is exerted on the distal axon.

Alcoholism↗

Secretion and irrigation of gastric mucosa during disulfiram effect. Experimental study in the dog.

The effect of ethyl alcohol and disulfiram (Antabuse) on the secretion and the irrigation of an isolated and denervated gastric pouch has been studied in the dog. In these conditions, disulfiram increased the differential acidity; the association of ethanol with disulfiram impaired the proteolytic activity of the secretion and induced a hyperirrigation of the gastric mucosa more definite than with ethanol alone. Effects on ethanol absorption from stomach are discussed.

Animals↗

Compliance to supervised disulfiram therapy: a comparison of voluntary and court-ordered patients.

We hypothesized that court mandate would significantly enhance compliance with supervised disulfiram therapy. We conducted a twelve-week prospective study of outpatient compliance with court-ordered, monitored disulfiram treatment as compared to voluntary, monitored treatment. The court ordered group (n=19) was significantly more compliant than the voluntary group (n=22). Legally mandated subjects attended an average of 87% (+/-21%) of scheduled visits, versus 42% (+/-35%) for the group without court order. Court mandate roughly doubles the compliance rate of monitored disulfiram therapy, effectively enhancing clinic attendance during the first twelve weeks of treatment.

Alcohol Deterrents↗

[The influence of disulfiram on the metabolism of ethanol].

The author discusses the metabolism of disulfiram and the enzymes which metabolize ethanol. The restraining of the activity of ALDH in the liver by disulfiram causes an accumulation of acetaldehyde which in their turn cause a series of psychophysical symptoms which are unpleasant and in some instances dangerous for the patient. Thus, it is important to monitor changes in the activity of ALDH after administration of disulfiram.

Alcohol Dehydrogenase↗

[Anterior myocardial infarction in a chronic alcoholic man on disulfiram therapy: a case report].

Disulfiram is a drug used since 1940 in the treatment of alcohol dependence. However, it is not a completely safe drug; there are in the literature some case reports of more severe reaction than the usual "acetaldehyde syndrome" secondary to ingestion of disulfiram and alcohol. We describe a case of a 45-year-old, chronic alcoholic man in treatment with disulfiram, who suffered an acute anterior myocardial infarction, successfully treated with thrombolysis. The possible factors precipitating acute myocardial infarction in this patient are discussed.

Alcohol Deterrents↗

Disulfiram administration affects substance P-like immunoreactive and monoaminergic neural systems in rodent brain.

The biosynthetic enzyme peptidylglycine alpha-amidating monooxygenase catalyzes the formation of a variety of biologically active alpha-amidated peptides from respective COOH-terminal glycine-extended peptide precursors. Peptidylglycine alpha-amidating monooxygenase activity is dependent on copper, ascorbate, and molecular oxygen and is inhibited by the relatively selective copper chelator N,N-diethyldithiocarbamate or its disulfide dimer disulfiram (Antabuse). In the present study, chronic disulfiram treatment (100 mg/kg/day, for 12-25 days) resulted in significant changes in several neurochemical parameters in the mouse central nervous system, including levels of substance P-like, unamidated substance P-Gly-like, and protease-generated substance P-Gly-Lys-like immunoreactivities (SP-LI, SP-G-LI, and SP-G-K-LI, respectively). Combined high performance liquid chromatography/radioimmunoassay analyses of the extracted SP-LI, SP-G-LI, and SP-G-K-LI species indicated very similar chromatographic and immunochemical behavior as demonstrated for chemically authentic peptide standards. Additionally, changes in levels of monoamines and their metabolites were observed after drug administration. Complementary immunohistochemical analyses using affinity-purified anti-SP-G sera localized these drug-induced changes in levels of immunoreactive unamidated precursor to neural elements that normally express SP. As a functional corollary to alterations in neurochemical parameters, we observed significant disulfiram-induced increases in pain thresholds, potentiated by capsaicin treatment. Overall, our results indicate that the observed changes in steady state levels of immunoreactive SP and of the immature COOH-terminal extended forms of SP may reflect compensatory biosynthetic and posttranslational processing events in SP-containing neural systems after pharmacological challenge.

Amino Acid Sequence↗

Disulfiram: a guide to clinical use in alcoholism treatment.

One option for helping chronic alcoholics remain sober is disulfiram therapy. Patients who take disulfiram develop a sensitivity to alcohol, resulting in unpleasant reactions to even small amounts of alcohol. When it is used as part of a comprehensive program for alcoholics who wish to remain sober, disulfiram can be an effective treatment aid.

Alcoholism↗

[Ambulatory, disulfiram-(Antabuse)-assisted management of the alcoholic patient].

The treatment of patients suffering from alcoholism is notoriously difficult. Ambulatory supportive therapy using disulfiram and supervised by the practicing physician has many advantages. Foremost among these is the maintenance of the patient within his working and social environment. For achievement of longterm abstinence, psychological aspects (patients motivation and agreement, understanding care by the physician) may be more important than the aversive effects of disulfiram. Although disulfiram is generally a safe drug, careful preliminary work-up represents the key to proper assessment of risk versus benefit.

Alcoholism↗

[Disulfiram-like effect of cefonicid: first observation].

The disulfiram-like reaction is linked to the assumption of ethyl alcohol during therapy with the cephalosporin latamoxef, cefamandole and cefoperazone. The reaction is commonly ascribed to the methyl-thiotetrazole group, resembling part of the disulfiram molecule. We describe the case of a patient who experienced on two different occasions a disulfiram-like effect during therapy with cefonicid. This cephalosporin contains the methylsulphothiotetrazole group in place of the methylthiotetrazole group. Our observation is the first related to cefonicid.

Aged↗

Sympathetic component of the pressor response to angiotensin II in the pithed rat after pretreatment with disulfiram.

Pressor responses to angiotensin II in the pithed rat were unaffected or slightly increased by procedures such as reserpine pretreatment, alpha and beta adrenoceptor blocking agents or bethanidine which inhibit the sympathetic system. Disulfiram-induced inhibition of angiotensin II pressor responses was unaffected by pretreatment with either alpha-adrenoceptor blockers or bethanidine. Pretreatment with disulfiram prevented infusions of angiotensin II from increasing the responses to spinal sympathetic outflow stimulation. After inhibition of pressor responses to angiotensin II by disulfiram the responses were restored by infusions of noradrenaline, or alpha-methyldopa. The restored responses, unlike control responses, were inhibited by phentolamine. The results suggest that angiotensin II facilitates neuronal release of noradrenaline and that this effect is revealed most clearly when post-synaptic angiotensin II receptors are blocked.

Adrenergic alpha-Antagonists↗

Effects of disulfiram, diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate on glutathione transferase activities in mouse organs.

Four sulfur compounds known to inhibit tumorigenic effects of chemical carcinogens were administered to female CD-1 mice at 0.5% of the diet for 14 days, and their effects on cytosolic glutathione transferase (EC 2.5.1.18) specific activities were examined in liver, lung, kidney, urinary bladder, forestomach, proximal small intestine, and colon. Disulfiram, sodium diethyldithiocarbamate, bisethylxanthogen, and benzyl isothiocyanate elevated glutathione transferase specific activities in most of the organs examined. The four sulfur compounds differed in the extents and organ specificities of their effects on these enzyme activities. In the liver, bisethylxanthogen and benzyl isothiocyanate increased glutathione transferase activities to at least 3 times control levels and caused differential increases in the isozyme patterns observed after isoelectric focusing of the cytosols. Bisethylxanthogen also increased immunoreactive glutathione transferase in liver cytosol. Recrystallized disulfiram was less effective in enhancing hepatic glutathione transferase activities than was commercial (97%) disulfiram. Among the six extrahepatic organs examined, the small intestine and the forestomach exhibited the greatest response of glutathione transferase activities to each of the four sulfur compounds. Benzyl isothiocyanate was most effective in these "portal of entry" organs but less effective than bisethylxanthogen in the other extrahepatic organs examined. Bisethylxanthogen elicited significant increases in glutathione transferase activities in liver, lung, and small intestine even when administered at 0.01% to 0.05% of the diet, suggesting that this compound may have considerable potential as an inhibitor of carcinogens susceptible to enzymatic conjugation with glutathione.

Animals↗

Diethyldithiocarbamate, but not disulfiram, inhibits alloxan-induced dye accumulation of isolated mouse islet beta-cells.

The diabetogenic action of alloxan on pancreatic beta-cells is thought to be mediated by hydroxyl radicals. The initial attack of the radicals is probably at the plasma membrane level. Diethyldithiocarbamate (DDTC) and its dimer disulfiram (Antabuse) have recently been shown to protect against damage by free radical generating agents. The ability of DDTC and disulfiram to inhibit alloxan-induced dye accumulation of isolated ob/ob mice islet beta-cells was therefore studied. Evans blue was used as an indicator of plasma membrane permeability. DDTC (100 microM 1 mM) but not disulfiram (100 microM 1 mM) inhibited alloxan-induced dye uptake of beta-cells. The effect of DDTC on oxygen consumption in a mixture of reduced glutathione (GSH), alloxan and FeSO4 was studied with a Clark-type oxygen electrode. DDTC (20, 100 microM) had no effect on the oxygen consumption of this mixture. It is suggested that the DDTC inhibition of alloxan-induced dye uptake of isolated beta-cells takes place at a step beyond the generation of free radicals.

Alloxan↗

Some adverse effects of disulfiram in the treatment of nickel-allergic patients.

A retrospective follow-up study is reported of 58 women and 3 men with nickel allergy and hand eczema, of at least 4 months duration, treated with 50 to 400 mg disulfiram per day for 4 to 56 weeks. 2 patients were given 2 treatment series, making a total of 63 treatment series. 11 patients (20%) developed biochemical evidence of hepatotoxicity. 5 of them developed clinical evidence of hepatitis, which, for 4, was verified by liver biopsy. The patients with hepatotoxcity were significantly older than those who did not have this side effect. No correlation could be seen between the cumulative or maximum dose of disulfiram, the duration of the therapy and whether or not the patients showed evidence of hepatotoxicity. In 29 treatment series the dermatitis healed, while improvement was seen in 19 and no change in 15. There was no difference in the results whether maximum daily doses of 50, 200 or 400 mg were given. Follow-up examinations showed that the eczema recurred within a month after termination of therapy in 50% of the patients who improved during disulfiram therapy. Recurrence was seen within 6 months for another 40% of the patients.

Adolescent↗

[Effect of disulfiram on the interconnected activity of cortical neurons in trained cats].

The action of disulfiram on interconnected activity of neurones in the visual and motor cortical areas was studied in cats with food-procuring conditioned responses to light. Multiunit activity was recorded from the areas and, by means of amplitude discrimination, separated into impulse flows. Crosscorrelation analysis of the impulse series was used to reveal the character and temporal parameters of interconnected activities of neurones firing in correlation within the limits both of the same cortical area and of the two different ones. A depressing action was shown of the disulfiram on the food-procuring reaction, accompanied by a decrease of the number of pairs of neurones from the visual and motor cortical areas mostly acting in interconnection, interactions with long time delays being mostly affected. The character of action of neighbouring neurones in the visual and motor cortical areas changed in the same direction, expressed in their firing by a "common source" type. The question is discussed of disulfiram influence on interneuronal connections of both types suggesting a decrease of alimentary motivation as well as disturbance of food-procuring conditioned motor coordination.

Action Potentials↗