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PubMed1987

Determinants of disulfiram acceptance among alcohol patients: a test of the theory of reasoned action.

The utility of disulfiram in the treatment of alcohol abuse has been limited by the high frequency with which clients refuse the regimen. The present study identified variables influencing disulfiram acceptance/rejection within the framework of the theory of reasoned action. Eighty male inpatients on an alcohol treatment unit completed a questionnaire operationalizing the components of the model. The theoretical components were then used to predict requests for the drug. Multiple regression analyses revealed significant correlations among components of the model consistent with the assumptions of the theory. In addition, significant differences were found between disulfiram requestors and rejectors in terms of behavioral and normative beliefs about the consequences of being placed on the drug. Implications of these results for the design of effective interventions are discussed.

Adult↗
PubMedDate not supplied

Ferrous sulfate combined with ascorbic acid does not significantly reduce acetaldehyde accumulation in the blood of alcoholized rats treated with disulfiram or betalactam antibiotics.

Adult female SPF Sprague-Dawley rats treated orally by gavage with disulfiram (1 g/kg b.wt.) or betalactam antibiotics (3.38 mmol/kg b.wt.) with a 1-methyltetrazole-5-thiol side chain (cefmenoxime, latamoxef, cefotetan, cefoperazone, cefamandole) produced a marked, statistically significant rise of acetaldehyde in the blood 1 and 3 hr following IP administration of ethanol [2 g/kg b.wt., 20% (g/v) solution]. This accumulation of blood acetaldehyde remained unchanged or was reduced only very slightly by a mixture of iron sulfate [Fe(II)SO4.7H2O, 2.64 mg/kg b.wt.] and ascorbic acid (6.67 mg/kg b.wt.) injected intravenously. This slight decrease is considered to be due to a formation of a complex between ferrous sulfate and agents (disulfiram and the betalactam antibiotics as well as their metabolites) producing acetaldehyde by inhibition of acetaldehyde metabolizing enzymes. A possible coaction of ascorbic acid cannot be explained satisfactorily; ascorbic acid may support cellular redox potentials. The combination of ferrous sulfate and ascorbic acid was used for examination since both chemicals are recommended to reduce adverse symptoms of an ethanol incompatibility reaction in the course of a therapy with the mentioned antibiotics or disulfiram. Since acetaldehyde augmentation in the blood is regarded as a cause of complaints and because the acetaldehyde rise was not depressed significantly by ferrous sulfate and ascorbic acid it can be concluded that these two agents are not potent enough for a rational therapy of ethanol incompatibility symptoms initiated by the investigated drugs.

Acetaldehyde↗
PubMed1994

Effect of disulfiram administration on glutamate uptake by synaptosomes in the rat brain.

Although disulfiram used as a pharmacological agent in the treatment of alcoholism is reported to act on both peripheral and central nervous systems with several adverse effects, the neurotoxic property of the drug has not been properly elucidated. We observed that the chronic administration of the drug to rats significantly inhibited synaptosomal (Na+,K+)-ATPase and basal Mg(2+)-ATPase activities. Further, the uptake of gamma-aminobutyric acid and L-glutamate which rely on the energy provided by this system was depleted following chronic drug administration. Similar findings were observed when the isolated synaptosomes were treated with the drug in an in vitro system. Further, treatment of synaptosomes with ouabain, a known inhibitor of (Na+, K+)-ATPase resulted in significant depletion of 3H-GABA and L-[3H]glutamate uptake into synaptosomes indicating the importance of the enzyme in the uptake mechanism. However, diethyldithiocarbamate, a major metabolite of disulfiram did not elicit any change in either the enzyme activity or the uptake of these neurotransmitters. On the basis of these evidences, we suggest that the chronic disulfiram administration attenuated the neurotransmitter uptake mechanism and resulted in higher extracellular concentration of glutamate that could lead to glutamate-induced neurotoxicity.

Animals↗
PubMed1976

Method for the detection of diethylamine, a metabolite of disulfiram, in urine.

Disulfiram is a drug used in the treatment of chronic alcoholism in man. Accurate assessment of patient compliance is important in this treatment. This paper describes a method for the detection and quantitative analysis of diethylamine, a metabolite of disulfiram, in urine. The method involves conversion of the water-soluble diethylamine in the urine to a derivative, N,N-diethyl-3,5-dinitrobenzamide, that is soluble in an organic solvent. This derivative is extracted from urine with diethyl ether and then subjected to thin-layer chromatography. A spectrophotometric procedure is used for quantification. This method provides a means of determining whether or not a patient is taking his prescribed disulfiram.

Benzamides↗
PubMed2001

Molecular targets of disulfiram action on song maturation in zebra finches.

Disulfiram, an aldehyde dehydrogenase inhibitor, interferes with normal song maturation when applied to brain nucleus HVC of male zebra finches. We present here evidence from Western blots and enzymatic assays showing that known disulfiram targets other than retinaldehyde-specific aldehyde dehydrogenase (zRalDH) are absent in HVC. These findings are consistent with the conclusion that disulfiram disrupts song maturation by interfering with retinoic acid production.

Aldehyde Dehydrogenase↗
PubMed1978

Inhibition of azoxymethane-induced intestinal cancer by disulfiram.

Sprague--Dawley rats, both intact and colostomized animals, were given 24 weekly injections of azoxymethane. Rats were fed either Rat Purina Chow or the same diet plus 0.25% disulfiram. In the intact animals, disulfiram reduced tumors from an average of 6.3 to 0.95. The number of rats developing tumors was reduced from 100% to 60%. In colostomized animals, the reduction was from an average of 5.0 to 0.13. Marked inhibition occurred even in the defunctionalized colon. The results suggest that disulfiram blocks the metabolism of azoxymethane to methylazoxymethanol, and also that the inhibitor may act systemically.

Animals↗
PubMed1988

Determination of disulfiram and two of its metabolites in urine by reversed-phase liquid chromatography and spectrophotometric detection after post-column complexation.

A selective method was developed for the determination of disulfiram and two of its metabolites, diethyldithiocarbamate (DTC) and copper (II) diethyldithiocarbamate [Cu(DTC)2], in complex (biological) samples by reversed-phase liquid chromatography (RP-LC) with post-column derivatization. In the first step, DTC is converted into lead (II) diethyldithiocarbamate [Pb (DTC)2] by adding lead (II) acetate. Disulfiram, Pb (DTC)2 and Cu (DTC)2 can be easily pre-concentrated on C18-bonded silica. After separation by isocratic RP-LC, derivation takes place in two solid state post-column reactors packed with metallic copper and copper (II) phosphate. Disulfiram reacts with metallic copper to form Cu (DTC)2. The same product is obtained by the ligand-exchange reaction between Pb (DTC)2 and copper (II) phosphate. Cu (DTC)2 can be detected selectively at 435 nm with good sensitivity (molar absorptivity, epsilon = 13,000). The derivatization reactions proceed rapidly and quantitatively, which was confirmed by comparison of absorption spectra. The applicability of this method is demonstrated for undiluted urine samples which, apart from the addition of lead (II) acetate and pre-concentration of C18-bonded silica, require no clean-up procedure.

Biotransformation↗
PubMed2004

Adherence to court-ordered disulfiram at fifteen months: a naturalistic study.

Previously, we observed that the presence of a court-mandate doubled adherence to supervised disulfiram treatment over voluntary supervised disulfiram treatment during the initial twelve weeks. To assess persistence, we conducted a naturalistic followup study of adherence at 15 months in 19 voluntary and 17 court-ordered patients from the original groups. Treatment adherence, measured by the percentage of completed disulfiram clinic visits during the study period, was significantly higher in court-ordered subjects: 61.0% vs. 18.2% in the voluntary group (p<.0001). The data suggest that court assistance can exert a significant effect in maintaining adherence. Factors mediating adherence, as well as the effects of adherence on behavior change and abstinence, must be determined through prospective, controlled study.

Alcohol Deterrents↗
PubMed1982

On the disulfiram-like activity of moxalactam.

A three-way crossover study was undertaken in 10 healthy subjects to characterize the reported disulfiram-like activity of moxalactam and to assess its influence on ethanol and acetaldehyde metabolism. On different occasions separated by at least 2 wk subjects were given in random order: 0.5 gm/kg ethanol orally, 0.5 gm/kg ethanol followed in 1 hr by 1.0 gm IV moxalactam, and 1.0 gm IV moxalactam every 8 hr for four doses followed by 0.5 gm/kg ethanol. Mean ethanol elimination rates of 13.1 +/- 0.76, 10.1 +/- 1.11, and 10.9 +/- 1.06 mg/dl/hr (mean +/- SEM) were observed in the three protocols, respectively. Corresponding mean estimated acetaldehyde clearance rates were 103.7 +/- 15.55, 92.8 +/- 13.79, and 97.3 +/- 10.41 l/min (mean +/- SEM). While no consistent moxalactam effect on ethanol or acetaldehyde elimination was observed, two subjects experienced mild disulfiram-like reactions to ethanol after moxalactam pretreatment. In one subject this reaction was associated with markedly elevated blood acetaldehyde concentrations. We conclude that moxalactam pretreatment may induce a disulfiram-like reaction after ethanol ingestion in some, probably due to inhibition of aldehyde dehydrogenase, and that alcoholic beverages are contraindicated in patients receiving moxalactam. We suggest, however, that such reactions will not occur when moxalactam is given after ethanol ingestion.

Acetaldehyde↗
PubMed1981

The inactivation of aldehyde dehydrogenase by disulfiram in the presence of glutathione.

It is shown that in vitro glutathione provides little protection of cytoplasmic aldehyde dehydrogenase against the inactivatory action of disulfiram. This observation provides support for the current explanation of how disulfiram acts in vivo. The results show that the disulfiram-sensitive thiol groups of aldehyde dehydrogenase have an unusually high reactivity; possible mechanisms by which this might arise are discussed.

Aldehyde Dehydrogenase↗
PubMed1992

[Disulfiram neuropathy].

Two chronically alcohol-addicted patients, a 37-year old woman and a 22-year old man, developed a severe polyneuropathy after being treated with very high doses of disulfiram. In the first case there was a high-grade proximal tetraparesis, especially of the legs; in the other there was a similar largely motor, but predominantly distal, neuropathy. Electrophysiological tests established a pattern of axonal damage. Guillain-Barré syndrome was excluded by analysis of cerebrospinal fluid. Over a period of observation of 6 months and 2 1/2 years, respectively, the paresis continued even after disulfiram had been discontinued. 2 1/2 years later the electrophysiological changes were still present. As disulfiram treatment may cause severe side effects it is recommended that the lowest possible dosage by employed.

Adult↗
PubMedDate not supplied

PKC sulfhydryl targeting by disulfiram produces divergent isozymic regulatory responses that accord with the cancer preventive activity of the thiuram disulfide.

The protein kinase C (PKC) isozyme family plays key roles in cell growth regulation and influences neoplastic disease development and progression. For example, PKCepsilon is oncogenic, and PKCdelta tumor-suppressive. PKC isozymes are characterized by distinct activation mechanisms entailing phosphatidylserine-dependent cofactor binding to the regulatory domain. Evidence is now emerging that redox signaling offers another platform of PKC regulation. We have established that PKC isozymes are regulated by S-thiolation, a posttranslational modification entailing disulfide linkage of low-molecular-weight species to select protein sulfhydryls. Our recent studies demonstrate that physiologically occurring disulfides with cysteinyl constituents, e.g., cystine, regulate cellular PKC isozymes by S-thiolation-triggered mechanisms. This report shows that PKC isozymes are also molecular targets of a chemically distinct class of disulfides. Disulfiram is a thiuram disulfide with potent cancer preventive activity in in vivo models of chemical carcinogenesis. Our results indicate that PKC Sthiolation by disulfiram induces differential regulatory effects on PKC isozymes that correlate with the cancer preventive activity of the drug. The implication of these findings is that PKC-regulatory effects of thiuram disulfides may offer a useful pharmacological guide for development of disulfiram analogues with superior cancer preventive activity.

Animals↗
PubMedDate not supplied

Disulfiram-like reactions with newer cephalosporins: cefmenoxime.

A 54-year-old woman with recurrent adenocarcinoma of the uterus was treated with new third-generation cephalosporin, cefmenoxime, for a urinary tract infection. She received an alcohol-containing tylenol elixir while receiving the drug on two occasions. A disulfiram-like reaction was noticed each time. Such reactions have been described in patients receiving certain drugs such as 5-nitroimidazoles, nitrofurans, sulfonylureas and certain newer cephalosporins with a methyltetrazolethiol side chain. This is the first report of a disulfiram-like reaction with cefmenoxime. The mechanism, causes, and significance of disulfiram-like reactions are discussed.

Acetaminophen↗
PubMed1981

A comparative review of the pharmacological and toxicological properties of disulfiram and calcium carbimide.

Disulfiram and calcium carbimide are widely used alcohol deterrents. Their safe use, however, requires a knowledge of their pharmacology, toxicity, and interactions with alcohol and other drugs. The absorption, metabolism, and elimination of these compounds are described, and elimination of these compounds are described, as is the mechanism of their reaction with ethanol. The effects and limitations of the interaction between ethanol and disulfiram and calcium carbimide are discussed. Four areas of concern regarding toxicity are discussed, including medical complications of the reactions with alcohol, toxicity associated with repeated doses of disulfiram or calcium carbimide, possible interactions with other drugs, and acetaldehyde-induce hepatotoxicity and cardiotoxicity.

Acetaldehyde↗
PubMed1987

Capgras delusion and seizures in association with therapeutic dosages of disulfiram.

We have described a patient in whom EEG abnormalities, a seizure disorder, and Capgras syndrome developed two weeks after she started taking disulfiram. That disulfiram has been shown to inhibit dopamine beta-hydroxylase in vitro suggests an etiologic role for dopaminergic pathways in at least some cases of Capgras syndrome. Our experience with this patient suggests that convulsions and psychosis may occur as a side effect of standard dosages of disulfiram in patients with no previous history of psychosis or brain disease. Furthermore, the symptoms may resolve spontaneously without the long-term use of antipsychotic or anticonvulsant medication.

Adult↗
PubMed1990

Disulfiram-induced hepatitis.

We reported a case of disulfiram-induced hepatitis with unique clinical features and compared our case with others in the literature. Our patient had headache, mild fever, nausea, vomiting, rash, and eosinophilia after 3 weeks of disulfiram therapy. Subsequent liver biopsy showed low-grade lobular hepatitis. After disulfiram therapy was discontinued, symptoms subsided and results of liver function tests returned to normal.

Alcoholism↗
PubMed1983

Disulfiram-like reaction to certain cephalosporins.

Semisynthetic cephalosporins, containing the methyltetrazolethiol substituent at the 3-position of the fused beta-lactam dihydrothiazine nucleus, can clearly produce disulfiram-like reactions in certain subjects who consume ethanol after treatment with these cephalosporins. So far, cefamandole, cefoperazone, and moxalactam have been repeatedly reported to produce this reaction, which is strictly related to the chemical structure of the cephalosporin. Similar to the characteristic symptoms and signs observed with disulfiram and these cephalosporins, increased acetaldehyde concentrations in blood were also measured. The phenomenon can be studied in an animal (rat) model. Patients experiencing these often frightening disulfiram-type reactions seldom need specific treatment; however, it is mandatory to strongly caution patients not to consume alcoholic beverages for a few days after treatment with these cephalosporins. Other aspects and ramifications of this phenomenon are also reviewed.

Adolescent↗
PubMed1990

Giving ethanol to alcoholics in a research setting: its effect on compliance with disulfiram treatment.

In order to evaluate the effect of experimental ethanol administration on disulfiram compliance, a 6-month follow-up study was conducted with inpatient alcoholics. Two groups of patients were studied. Though not randomly assigned, the groups were matched on a variety of demographic and alcoholic-related variables. One group (N = 15) received ethanol in a laboratory-based study while the other group (N = 21) underwent treatment as usual. Days of disulfiram use did not differ between groups at follow-up. Studies concerning compliance with disulfiram support the validity of this measure as an indicator of treatment outcome. Our findings are consistent with other studies of the effect of experimental administration of ethanol to alcoholics, in that there were no immediate adverse effects and treatment outcome did not appear to suffer as a consequence of ethanol exposure.

Adult↗