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PubMed1977

The rapid reduction of disulfiram in blood and plasma.

A gas chromatographic assay procedure was developed to quantitate the reduction product of disulfiram, diethyldithiocarbamate (DDC), in blood and plasma. The procedure involved the in situ methylation of DDC prior to the extraction and chromatography of the methyl ester. The minimal sensitivity achieved was 0.2 microgram/ml from 1 ml of blood or plasma. The coefficient of variation about any concentration was 10.5%. Calibration curves having a reproducible nonlinear form were prepared up to 9 microgram/ml. The assay procedure was used to evaluate the stability of disulfiram and DDC in blood. Disulfiram was rapidly and quantitatively reduced to DDC within 4 minutes. The DDC thus formed decomposed in human and dog blood with half-lives of 70 and 100 minutes, respectively. The implications of these findings are discussed with respect to the chemical form of disulfiram responsible for the ethanol-sensitizing effect.

Animals↗

PubMed1977

A rapid and simple radioactive method for the determination of disulfiram and its metabolites from a single sample of biological fluid or tissue.

An analytical method is described for the determination of radioactive disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, diethyldithiocarbamate-glucuronide, inorganic sulfate, and a protein bound S35 fraction from a single sample of either plasma, urine or tissue. The procedure is based upon quantitative stepwise extraction or precipitation of the individual compounds, and is both specific and precise. The applicability of the methods developed for the determination of S35 disulfiram and its S35 metabolites in plasma and urine from a dog given S35 disulfiram i.v., and in mouse brain from mice given S35 disulfiram i.p. are illustrated.

Animals↗

PubMed1990

[Clinical study of disulfiram in intravenous suspension. A new alternative in the treatment of alcoholism].

A disulfiram suspension (propylenglycol and water) was used to treat 45 alcoholic patients. Inactive suspension was given to 8 control alcoholic patients. Pain, local inflammation, thirst and drowsiness were related to disulfiram suspension, but not to solvent administration. Patients receiving disulfiram who drank alcohol experimented the known reaction which was related to subsequent abstinence from alcohol. 67% of patients receiving disulfiram remained abstinent after 1 year of follow up.

Administration, Oral↗

PubMed1977

Drug therapy reviews: management of the disulfiram-alcohol reaction.

A review of the proposed mechanisms of the disulfiram-alcohol interaction and recommended management of the interaction is presented. The efficacy of disulfiram in the management of alcoholism, the signs and symptoms of the disulfiram-alcohol interaction, and other agents with disulfiram-like activity are discussed. Recommended treatment consists of supportive measures such as Trendelenberg posture, administration of oxygen and intravenous infusion of fluid, solute, colloid, and, if needed, a pressor agent such as norepinephrine. Iron salts, ascorbic acid, antihistamines and phenothiazines are of no established benefit.

Acetaldehyde↗

PubMedDate not supplied

Disulfiram as a radiation modifier.

The radiation modifying effect and toxicity of tetraethylthiuram disulfide (disulfiram) have been studied. Disulfiram (DSM) inhibits aldehyde dehydrogenase, dopamine-beta-oxygenase, microsomal mixed-function oxidases and cytochrome P-450 enzymes. It is widely used for aversion therapy in alcoholism. Disulfiram also inhibits tumor formation by several known carcinogens. A biphasic toxicity pattern of DSM is reported in the L-929 mouse fibroblast culture system. Disulfiram is 100 percent toxic at 2 X 10(-7) M (0.05 micrograms per ml), 23 percent toxic at 3 X 10(-7) M (0.1 microgram per ml), and 100 percent toxic again at 3.4 X 10(-6) M (1.0 microgram per ml). The pattern is similar to the biphasic toxicity pattern of DMS's major metabolite, sodium diethyldithiocarbamate (DTC). Reports of both radiation protection and radiation enhancement by DTC exist. Previously, a radioprotective effect by 2 X 10(-6) M DTC (dose modifying factor = 1.26) has been demonstrated in the L-929 cell system. To date, no radiation modifying properties of DSM have been reported. Our investigation of DSM as a radiation modifier at 3 X 10(-7) M (0.1 microgram per ml) did not show significant improvement in survival of irradiated cells treated with DSM relative to the irradiated control group, as determined by absence of a difference in the Do of the two groups. Considering DSM's close structural relationship to DTC, it is possible that DSM may exhibit a radioprotective effect when applied in a different concentration than what was used in our research.

Animals↗

PubMed1985

Effect of disulfiram in experimentally induced vitamin E deficiency myopathy in lambs.

Vitamin E deficiency myopathy (white muscle disease) was induced in 14 suckling lambs (2 experiments; 7 lambs/experiment) by addition of cod liver oil to the diet. Disulfiram, an antioxidant, was administered orally once each day to 8 of the 14 lambs at 2 different doses. Serum creatine kinase (CK) activity was measured weekly for 5 weeks. Increased CK activity was evident in some lambs beginning at week 3. By week 4, serum CK was abnormally increased in 5 of the 6 nontreated lambs (ie, disulfiram not given) and in 4 of the 8 treated lambs. The combined disulfiram groups had significantly lower serum CK values during the study (P less than 0.05). Serum alpha-tocopherol, measured on samples from week 5 for lambs of experiment 1, was significantly higher in treated lambs (P less than 0.01). Microscopic examination of the vastus lateralis muscle indicated that the most severe lesions, consistent with nutritional myopathy, were seen in nontreated lambs. Therefore, disulfiram may have an antioxidant effect in lambs with vitamin E deficiency.

Animals↗

PubMed1979

Dopamine-beta-hydroxylase in the cerebrospinal fluid: relationship to disulfiram-induced psychosis.

Cerebrospinal fluid (CSF) dopamine-beta-hydroxylase (DBH) activity in 32 male alcoholics was measured using a modification of the radioenzymatic method of Molinoff et al. In most, the CSF was obtained before treatment with disulfiram, while in others it was obtained while they were on the drug (250 or 500 mg). As expected, treatment with this reversible DBH inhibitor had no effect on the activity of the enzyme measured in our in vitro assay. However, low pretreatment DBH activity was found to correlate with adverse reactions to disulfiram. Mean DBH activity of four individuals who went on to become psychotic on disulfiram was 0.13 +/- 0.02 nmole/ml per hr (mean +/- SEM). An additional four individuals who developed dysphoric but nonpsychotic reactions had a mean DBH of 0.23 +/- 0.03. Both these values were significantly lower than the mean DBH activity of the remaining 24 individuals treated with disulfiram who had no adverse side effects, 0.53 +/- 0.06 p less than 0.02 and p less than 0.05, respectively, 2-tailed t-test.

Adolescent↗

PubMed1980

Differential effects of benzodiazepine disposition by disulfiram and ethanol.

The disposition of chlordiazepoxide, diazepam, oxazepam and lorazepam was studied before and after disulfiram administration to normal subjects and alcoholic patients. Similar studies to determine the effect of ethanol administration on diazepam and oxazepam disposition were also performed. After disulfiram, decreases in the plasma clearance of chlordiazepoxide (54%, p < 0.05; diazepam, 41% p < 0.05) and their active metabolites were observed. Oxazepam and lorazepam have no important active metabolites and the effect of disulfiram on their net disposition was minimal. In normal subjects ethanol (> 800 mg/l maintained for 8 h) increased the AUC free diazepam (26.6 +/- 17.3% mean +/- SD, p < 0.05) and decreased the AUC for N-desmethyldiazepam (50.5 +/- 11.7%, p < 0.05) indicating inhibition of diazepam N-desmethylation. In contrast, there was no significant change in the disposition of oxazepam in four healthy subjects after a single oral dose of ethanol. Thus, disulfiram and ethanol appear not to inhibit the metabolic disposition of oxazepam or lorazepam, benzodiazepine derivatives principally biotransformed by glucuronidation. On pharmacokinetic grounds oxazepam and lorazepam may be the drugs of choice if benzodiazepine therapy is required in chronic alcoholics.

Adult↗

PubMed1982

Effect of disulfiram (tetraethylthiuram disulfide) amd diethyldithiocarbamate on the bladder toxicity and antitumor activity of cyclophosphamide in mice.

Cyclophosphamide is the most commonly prescribed alkylating agent in clinical medicine. The usefulness of cyclophosphamide is often limited, however, by its propensity to cause hemorrhagic cystitis especially in children or patients receiving concomitant radiotherapy. Administration i.p. of cyclophosphamide at doses of 100 mg/kg or more to mice produced a significant increase in urinary bladder weight within 48 hr of treatment. The present studies demonstrate that disulfiram prevented cyclophosphamide-induced bladder damage when administered p.o. within 1 hr of cyclophosphamide treatment. Diethyldithiocarbamate, a sulfhydryl-containing metabolite of disulfiram, had identical uroprotective activity. Unlike disulfiram, diethyldithiocarbamate was effective only when administered 2 to 4 hr after cyclophosphamide. Disulfiram augmented slightly the antitumor activity of cyclophosphamide against L1210 murine leukemia in vivo when administered 30 min prior to cyclophosphamide. In contrast, diethyldithiocarbamate had no effect on the antitumor activity of cyclophosphamide when administered 4 hr after cyclophosphamide.

Animals↗

PubMed1978

Variable inhibition of human hepatic drug metabolizing enzymes by disulfiram.

In healthy adult males, oral treatment with disulfiram exerted variable inhibitory effects on various metabolic parameters of the hepatic microsomal enzyme system: Two 10 mg/kg doses, given at an interval of 24 hr produced only a marginally significant prolongation of the plasma elimination half-life of antipyrine. This effect was not detectable when using as a criterion the formation of 4-OH-antipyrine (aromatic C-hydroxylation), as measured by its renal excretion. In contrast, a single dose of disulfiram (10 mg/kg) was followed by a significant decrease in the formation of D-glucaric acid, which was demonstrable for 6 days and was measured by the renal excretion of D-glucaric acid over 24-hr periods. The same single dose of disulfiram (10 mg/kg) did not affect the activity of the serum gamma-glutamyl transpeptidase. However, a single dose as small as 5 mg/kg caused a temporary but significant reduction in the formation of 4-aminoantipyrine from aminophenazone (oxidative demethylation), where the renal excretion of 4-aminoantipyrine provided a measure of the decrease. During the subsequent phase of excretion, the deficit in 4-aminoantipyrine elimination was completely compensated for. It is concluded from the results that in man the impairment of oxidative N-demethylation constitutes the most sensitive criterion of a measurable inhibitory effect of disulfiram on the hepatic mixed-function oxygenase system.

Adult↗

PubMed1982

The prevention of cyclophosphamide-induced cystitis in mice by disulfiram.

Cyclophosphamide administered intraperitoneally to mice at a dose of 100 mg/kg caused a dose related increase in urinary bladder weight within 48 hours of treatment. Disulfiram effectively prevented cyclophosphamide-induced increase in bladder weight when disulfiram was administered by either the oral or intraperitoneal route. Disulfiram (125 mg/kg) was most effective when given within one hour of cyclophosphamide treatment. These results suggest that disulfiram, unlike other putative protectants, is effective when administered orally.

Animals↗

PubMed1982

Cutaneous reactions to lower aliphatic alcohols before and during disulfiram therapy.

Cutaneous reactions to ethyl alcohol (ethanol), N-propyl alcohol (1-propanol), isopropyl alcohol (2-propanol), and acetaldehyde were evaluated in a control group and in patients before and while they were receiving disulfiram therapy. Local cutaneous erythema was observed from patch tests with ethyl alcohol, N-propyl alcohol, and isopropyl alcohol in hydrated skin, and from acetaldehyde in dry skin. Since reactions noted from topically applied alcohols before and while the patients were receiving disulfiram therapy were not statistically different, a localized disulfiram-alcohol reaction is unlikely. Erythema resulting from topically applied alcohols occurred in a dose-related manner and was caused by a direct vasodilatory effect on the cutaneous microvasculature. We believe that all true disulfiram-alcohol reactions are systemic, rather than local, in nature and require a substantial amount of alcohol to enter the system.

1-Propanol↗

PubMed1995

[Liver damage attributed to the use of disulfiram].

In three alcoholic patients, two men aged 30 and 42, and a woman aged 52, hepatitis was diagnosed after the use of disulfiram. In all cases, there was a close temporal relationship between the occurrence of symptoms and disulfiram intake. Other possible causes were excluded. The 30-year-old man died from liver damage. Biopsy showed massive hepatic necrosis without signs of alcoholic hepatitis. In the other patients, symptoms subsided quickly and liver function returned to normal after discontinuation of disulfiram, but there was no confirmation by biopsy. The possibility of drug-induced hepatitis should always be considered in an alcoholic patient treated with disulfiram.

Adult↗

PubMed1995

Identification of the human and rat P450 enzymes responsible for the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-ME). The terminal step in the bioactivation of disulfiram.

The present study investigated the role of rat and human cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-Me) to S-methyl N,N-diathylthiolcarbamate sulfoxide (DETC-Me sulfoxide), the putative active metabolite of disulfiram. DETC-Me sulfoxidation by microsomes from male and female rats treated with various cytochrome P450-enzyme inducers suggested that multiple enzymes can catalyze this reaction, and these include, CYP1A1/2, CYP2B1/2, and CYP3A1/2. All cDNA-expressed human cytochrome P450 enzymes examined catalyzed the sulfoxidation of DETC-Me. The turnover rates (min-1) of DETC-Me sulfoxidation by the cDNA-expressed cytochrome P450 enzymes ranked as follows: CYP3A4 > CYP2A6 = CYP2C9 > CYP1A2 > CYP2B6 = CYP2E1 > CYP1A1 > CYP2D6. Interestingly, CYP3A4 ranked first or last, depending on whether or not additional NADPH-cytochrome P450 reductase was coexpressed in the lymphoblastoid cells. This complicated estimates of the contribution of CYP3A4 to DETC-Me sulfoxidation by human liver microsomes. The sample-to-sample variation in DETC-Me sulfoxidation by bank of human liver microsomes (N=13) correlated highly with coumarin 7-hydroxylation (r=0.88) and testosterone 6beta-hydroxylation (r=0.90), suggesting that CYP2A6 and CYP3A4/5 contribute to the sulfoxidation of DETC-Me by human liver microsomes. Although, chlorzoxazone 6-hydroxylation (a marker for CYP2E1) correlated poorly with DETC-Me sulfoxidation, the correlation improved from r=0.07 to r=0.44 when DETC-Me sulfoxidation was studied in the presence of the CYP2A6 inhibitor, coumarin. Similarly, when DETC-Me sulfoxidation was studied in the presence of diethyldithiocarbamate (DDTC), the inhibited DETC-Me sulfoxidase activity correlated better (r=0.50) with chlorzoxazone 6-hydroxylase, compared with DETC-Me sulfoxidase activity in the absence of DDTC (r=0.09). Polyclonal antibodies against CYP2E1 caused a modest inhibition (30%) of DETC-Me sulfoxidation by human liver microsomes. Anti-CYP3A1 antibodies completely inhibited DETC-Me sulfoxidation by cDNA-expressed CYP3A4. Under similar conditions, DETC-Me sulfoxidation by human liver microsomes was only partially inhibited by anti-CYP3A1 antibodies. Although studies with the rat and cDNA-expressed cytochrome P450 enzymes suggested that CYP1A2 contributed to DETC-Me sulfoxidation, this reaction was not inhibited by either furafylline ( a mechanism-based inhibitor of CYP1A2) or antibodies against CYP1A1/2. A significant role for CYP2C9 was excluded by the inability of sulfaphenazole to inhibit the sulfoxidation of DETC-Me by human liver microsomes. Collectively, these data suggest that multiple cytochrome P450 enzymes can catalyze the sulfoxidation of DETC-Me. In human liver microsomes the CYP2A6, CYP2E1, and CYP3A4/5 all contribute significantly to the sulfoxidation of DETC-Me. It is interesting to note that DDTC, the reduced metabolite of disulfiram, is known to inhibit these same enzymes. The ability of DDTC to block the formation of DETC-Me sulfoxide may explain why the dose of disulfiram required to produce a disulfiram-ethanol reaction in alcoholics is so variable and often inadequate.

Animals↗

PubMed1997

Psychosis during disulfiram therapy for alcoholism.

Fifty-two patients (51 males, one female) of alcohol dependence/abuse diagnosed according to DSM 111 R1 were registered for disulfiram treatment and were admitted for a 4-week period. No alcohol challenge test was given during their hospital stay. Disulfiram tablets were administered 250 mg twice daily after food. After one week's hospital stay with disulfiram therapy they were sent home to be followed up initially after 15 days and later on once a month. Six male patients developed psychotic symptoms. All of them had shown a mood disorder but no thought disorder was observed. Psychotic symptoms remitted completely after withdrawing disulfiram and then a short course of antipsychotic therapy was given, except in one patient who had to be given lithium for remission of symptoms.

Adult↗

PubMed1997

The effect of disulfiram on egg shell formation in adult Trichuris muris.

The effect of disulfiram on egg shell morphology in the parasitic nematode Trichuris muris was studied in vitro and in vivo. Daily disulfiram treatment of mice infected with T. muris beginning 25 days after infection and continuing for 26 days resulted in the production of malformed eggs by adult female worms in all treated groups. In addition, significantly fewer adult worms were found at necropsy in mice treated with 5.0 or 7.5 mg/kg/day of disulfiram as compared with mice treated with 2.5 mg/kg/day or control mice. Adult worms collected from infected, untreated mice and placed in aerobic culture for 5 days in media containing 4 or 8 micrograms/ml of disulfiram released malformed eggs into the culture medium after 30 hr in culture. Oral inoculation of naive mice with malformed eggs did not result in T. muris infections in the mice. The results of these studies suggest that inhibition of phenol oxidase results in disruption of normal egg production by T. muris females and that the enzyme might be a useful target in the development of control strategies aimed at nematode parasites that rely on phenol oxidase for egg shell hardening.

Administration, Oral↗

PubMedDate not supplied

Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein.

The human multidrug resistance P-glycoprotein (P-gp) uses ATP to transport a wide variety of structurally unrelated cytotoxic compounds out of the cell. The relatively high expression of P-gp in organs such as the intestine, kidney, blood-brain/testes barrier and in some tumor cells can compromise chemotherapy treatments for patients with cancer or AIDS/HIV. It has been difficult to inhibit P-gp during chemotherapy with noncovalent inhibitors because the relatively high levels of inhibitors have severe side effects. An alternative approach to inhibit P-gp would be to covalently modify cysteine residues within the NBDs. In this study, we tested whether metabolites of disulfiram, a drug currently used to treat chronic alcoholism, could inhibit P-gp. We show that the disulfiram metabolites, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the verapamil-stimulated ATPase activity of P-gp with IC50 values (concentrations that result in 50% inhibition of activity) of 9 and 4.8 microM, respectively. Similarly, S-methyl N,N-diethylthiocarbamate sulfoxide and S-methyl N,N-diethylthiocarbamate sulfone inhibited the activity of aldehyde dehydrogenase with IC50 values of 3.2 and 1.7 microM, respectively. Inhibition of P-gp by the metabolites was not reversed by addition of the reducing compound, dithiothreitol. We then determined which endogenous cysteine residue was responsible for inhibiting P-gp activity after exposure to the disulfiram metabolites. Treatment of P-gp mutants containing a single cysteine residue showed that inactivation was primarily due to modification of Cys1074 in NBD2. These results indicate that metabolites of disulfiram can covalently inactivate P-gp. Covalent modification of drug transporters could be a useful approach for inhibiting their activities during chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Prenatal exposure to disulfiram implicated in the cause of malformations in discordant monozygotic twins.

Female monozygotic (MZ) twins were discordant for congenital structural anomalies: Twin A had a reduction defect of the right forearm; Twin B had a cleft palate. Both infants were small for gestational age. Specific prenatal exposures were identified at different times in the first trimester of pregnancy: crack cocaine, marijuana, disulfiram, heavy ethanol exposure, and cigarettes. The mother's hospitalization in a drug abuse program and incarceration allowed for identification of exposure timing. The cleft palate could have been related to either disulfiram or alcohol exposure; the limb abnormality most likely corresponded to the timing of disulfiram exposure. Discordance of anomalies in these twins may reflect differences in developmental timing, differences in susceptibility to one or more teratogens, or random events occurring within very complex developmental programs, with the thresholds for malformation affected by one or multiple teratogenic compounds.

Abnormalities, Drug-Induced↗