[Electrographic study (polygraph technic) of impregnation by disulfiram (antabuse) and the disulfiram-alcohol reaction].
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Alcoholism↗
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Distribution of S35 disulfiram and metabolites in mice, and metabolism of S35 disulfiram in the dog.
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Animals↗
Disulfiram (antabuse) contracts in treatment of alcoholism.
Although studies repeatedly demonstrate that alcoholics who consistently take disulfiram experience more favorable drinking outcomes, serious problems with compliance among the majority of alcoholic patients have reduced the effectiveness of disulfiram as a therapeutic adjunct. In general, alcoholism counseling with disulfiram simply prescribed seems no more effective than counseling without disulfiram (Fuller et al. 1986). Problems with compliance as well as problems with acceptance by patients and likely by clinical staff reduce the utility of disulfiram in the treatment of alcoholism. Implants, incentives, and various forms of observed or supervised disulfiram have been studied as possible solutions to the problems with compliance. Disulfiram implants appear largely ineffective due to failure to release adequate levels of disulfiram and risks of surgical complications and rejection. Newer techniques (see Allen and Litten 1992) may ultimately lead to a more effective implant. Incentives with personally relevant and obvious reinforcement value such as money, avoidance of incarceration, remaining employed, and continuation of methadone for opiate addicts, have been used effectively. Enhancement strategies with less tangible incentives also show promise. Among these are feedback on results of biochemical measures of disulfiram compliance and continuation in a familiar treatment program. Although each of the studies of incentives suffers from specific methodological limitations, the findings uniformly demonstrate better disulfiram compliance, less drinking, and better clinical outcomes for those who received a meaningful incentive for taking disulfiram. External monitoring of the patient taking disulfiram to assure compliance is typically used in studies evaluating incentives for taking the medication. Observed or supervised disulfiram in its own right and without tangible incentives also has received increasing attention as a method for enhancing compliance. Incorporation of such a strategy would seem to have potential for wide applicability in alcoholism treatment programs. Three forms of supervised disulfiram have been studied: (1) a written disulfiram contract, such as in BMT, with instructions about the benefits of the disulfiram contract and methods to establish disulfiram use as a daily habit and specifying that the alcoholic will take disulfiram daily while the spouse observes, that the couple will mutually thank each other, and that they will refrain from arguments or discussions about the alcoholic's drinking; (2) the disulfiram contract used in CRA, which is identical in form to the BMT contract except that talk about drinking is not prohibited; and (3) supervised disulfiram without a written contract, special instructions, or explicit verbal thanking. Studies of these three forms of observed disulfiram have been among the better controlled studies. Each approach has produced very promising results. A disulfiram contract with BMT produced less short-term drinking than disulfiram accompanied either by couples or individual counseling. Unfortunately, the superior BMT drinking results eroded because many couples discontinued their disulfiram contract after treatment ended (O'Farrell et al. 1985, 1992). Adding couples RP sessions after BMT led to better fulfillment of the disulfiram contract and better drinking and marital outcomes than BMT alone. These better RP outcomes persisted for 18 to 24 months after BMT for the entire sample and throughout the entire 30-month followup after BMT for those with more severe drinking and marital problems (O'Farrell et al. 1993). Thus, disulfiram contracts used with BMT are associated with less drinking and greater disulfiram compliance, while the specific contribution of disulfiram contracts to BMT remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
Alcohol Deterrents↗
Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects.
AIMS: Short-term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities. METHODS: Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N-acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose. RESULTS: Disulfiram administration markedly inhibited chlorzoxazone 6-hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3-demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16-fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP-mediated dapsone N-hydroxylation was not significantly altered. CONCLUSIONS: These data suggest that disulfiram-mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3-demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1.
Adult↗
Disulfiram inhibition of the alternative respiratory pathway in plant mitochondria.
Disulfiram (tetraethylthiuram disulfide) was found to be a potent and selective inhibitor of the alternative respiratory path of plant mitochondria. The onset of inhibition by disulfiram takes several minutes and the inhibition is not readily reversed by washing, nor by metal ions. By contrast, thiols such as dithiothreitol not only reverse, but also prevent, disulfiram inhibition. Inhibition by disulfiram and by hydroxamic acids are not mutually exclusive. Structural analogs of disulfiram are far less potent inhibitors, with the exception of bisethyl xanthogen. Inhibition is due to disulfiram, per se, and not to its reduction product, diethyldithiocarbamate, a powerful chelator. Accordingly, the inhibitory effect of disulfiram is considered to involve the formation of mixed disulfides with one or more sulfhydryl groups in the alternative path. Disulfiram does not act as an electron sink diverting electron flow from oxygen.Disulfiram inhibition was observed only with isolated mitochondria or submitochondrial particles. In intact cells or tissues either a failure to absorb disulfiram, or its dissipation in the cytosol, precludes inhibition. In vitro, bovine serum albumin reduces disulfiram inhibition by complexing free inhibitor.The binding of (35)S-disulfiram by cyanide-resistant mitochondria displays the same kinetics as disulfiram inhibition. A comparison was made of (35)S-disulfiram binding by cyanide-sensitive and cyanide-resistant potato mitochondria. Cyanide-resistant mitochondria were obtained from ethylene-treated potato tubers. Incorporation of label proved essentially the same in both types of mitochondria, suggesting that the disulfiram-sensitive component of the alternative path is present in untreated potato tubers, and is not induced by ethylene.
Journal Article↗
The status of disulfiram: a half of a century later.
For more than 55 years, disulfiram has been approved by the Food and Drug Administration for the treatment of alcohol dependence. It is a unique medication that relies on "psychological threat" to avoid disulfiram-ethanol reactions. This paper reviews the history of disulfiram treatment, the current status of disulfiram treatment, the ensuing developments in disulfiram use in treating various addictions, and future directions. Clinical trials using disulfiram for the treatment of alcohol, cocaine, or co-occurring alcohol + cocaine dependence were included in this review. Disulfiram efficacy studies focusing on supervised, implant, and combination pharmacotherapies were also examined. In clinical trials, disulfiram has demonstrated inconsistent results in helping patients to abstain from alcohol, and patients poorly adhere to a disulfiram-treatment regimen. This has raised questions about disulfiram's practicality in the treatment of alcohol dependence. Recently, however, disulfiram has gained attention as a complementary agent to newer pharmacological medications, such as an opiate antagonist that specifically reduces alcohol craving. One hypothesis is that disulfiram would assist patients in gaining psychological control over drinking when given in conjunction with an opiate antagonist that would act directly on reducing alcohol craving. Preliminary evidence also suggests that disulfiram treatment could be a viable treatment for cocaine dependence because it was shown to reduce cocaine use among nonalcoholic, cocaine-dependent patients.
Alcohol Deterrents↗
A breath test to assess compliance with disulfiram.
AIMS: To evaluate the ability of a hand-held breath analyser, the Zenalyser((R)) (Zenics Medical), to identify alcohol-dependent patients receiving disulfiram therapy and to assess the sensitivity and specificity of the instrument at different time intervals post-disulfiram dosing. DESIGN: Breath samples were taken from two groups of alcohol-dependent patients, one group on a daily disulfiram regimen and one group receiving no disulfiram. The breath samples were analysed for the combined concentration of carbon disulphide and acetone produced from the metabolism of disulfiram. From these data, two reference ranges were prepared and used for sensitivity and specificity assessments. SETTING: Breath samples for the reference ranges were obtained from patients at Shelton Hospital, Shrewsbury. Breath samples used to assess the sensitivity and specificity of the instrument were obtained from patients at the Edinburgh Alcohol Problems Clinic. PARTICIPANTS: Twenty in-patients from Shelton Hospital receiving a daily 200 mg disulfiram regimen and 20 in-patients receiving no disulfiram. At the Edinburgh Clinic, 54 patients taking a thrice-weekly disulfiram regimen and 22 patients not on disulfiram. MEASUREMENTS: A total of 489 breath samples from Shelton Hospital and 391 breath samples from the Edinburgh Clinic were analysed for the combined concentrations of carbon disulphide and acetone. FINDINGS: The breath analyser produced results that distinguished between the disulfiram-treated and untreated groups (P < 0.001). At 1 day post-dose, the sensitivity was 100% and the specificity was 100%. At 2 and 3 days post-dose, the sensitivities and specificities were 84.6% and 100% and 88.2% and 100%, respectively. CONCLUSION: The breath analyser can improve the assessment of the compliance status of patients receiving a daily dose regimen of disulfiram, but is less useful for this purpose if disulfiram is taken on a thrice-weekly regimen.
Acetone↗
Disulfiram treatment increases plasma and red blood cell acetaldehyde in abstinent alcoholics.
BACKGROUND: Much of alcohol's toxicity is due to its product, acetaldehyde. The role of acetaldehyde derived from endogenous sources was assessed in alcoholic patients administered disulfiram, an inhibitor of aldehyde dehydrogenase. METHODS: The first part of the study included 23 subjects without biochemical or clinical evidence of chronic liver disease who were abstinent for 2 weeks; 11 patients were started on disulfiram (250 mg/day), whereas the other 12 were not given disulfiram and served as controls. The second part of the study included 13 alcoholic patients with clinical or pathological evidence of cirrhosis who also were administered disulfiram for 2 weeks. Plasma and red blood cell (RBC) acetaldehyde as well as serum transaminases were measured at baseline and after 1 and 2 weeks of treatment. RESULTS: In the disulfiram-treated group of alcoholics without known cirrhosis, RBC acetaldehyde levels increased from the pretreatment value of 2.98+/-0.18 microM to 4.14+/-0.33 microM after 1 week and to 4.14+/-0.26 microM after 2 weeks of treatment (p < 0.001). Compared with the pretreatment values (2.07+/-0.24 microM), plasma acetaldehyde levels also increased after 1 week (3.18+/-0.32 microM) and 2 weeks (3.15+/-0.26 microM) of disulfiram treatment (p < 0.001). There were no significant differences in sequential levels measured in either plasma or RBC acetaldehyde levels in patients who were not administered disulfiram. In the group of cirrhotic patients, the mean baseline RBC acetaldehyde value (3.60+/-0.22 microM) was significantly higher than in noncirrhotics. Disulfiram therapy increased the RBC acetaldehyde after 1 week (4.63+/-0.27 microM, p < 0.001) and 2 weeks of treatment (4.06+/-0.28 microM, p < 0.05). Compared with baseline values, plasma acetaldehyde levels were significantly higher after 1 week but not after 2 weeks of disulfiram. There were no significant differences among serum transaminases in alcoholics administered disulfiram, although three cirrhotic patients did have clinically significant elevations. CONCLUSIONS: In abstaining subjects given disulfiram, acetaldehyde concentrations increase, possibly due to diminished catabolism of endogenously generated acetaldehyde. Disulfiram should be given cautiously, especially in patients with cirrhosis.
Acetaldehyde↗
Disulfiram effects on responses to intravenous cocaine administration.
UNLABELLED: Disulfiram has been studied as a treatment for cocaine dependence. We report results of a randomized, double-blind, placebo-controlled, within-subject study to examine the interaction of disulfiram with intravenous cocaine. METHODS: Non-treatment-seeking, cocaine-dependent, volunteers participated in serial experiments in which they received disulfiram placebo, 62.5 or 250 mg/day on days 1-6. On days 4-6, participants received a morning disulfiram dose 2 h prior to a scheduled session in which they were administered intravenous cocaine placebo, 0.25 mg/kg (n=9) or 0.5 mg/kg (n=3) over 1 min. Blood, cardiovascular and subjective measures were collected. Seven days of washout occurred between disulfiram conditions. RESULTS: Following active disulfiram treatments and cocaine 0.25 mg/kg administration, plasma cocaine AUC (0-480 min) was increased (p=0.003 and 0.001) and cocaine clearance decreased (p<0.001). Disulfiram treatments also decreased cocaine clearance for the 0.5 mg/kg cocaine dose (p=0.002 and<0.001). Neither disulfiram dose with cocaine altered cardiovascular responses relative to cocaine alone. Following cocaine 0.25 mg/kg, 'any high' (p=0.021 and 0.019), 'cocaine high' (p=0.017 and 0.018) and 'rush' (p=0.013 and 0.047) significantly decreased with either disulfiram dose. CONCLUSIONS: Disulfiram decreased cocaine clearance without toxicity. Cocaine 'high' and 'rush' were diminished. Disulfiram may be a promising pharmacotherapy in selected cocaine dependent individuals.
Adult↗
Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism.
BACKGROUND: P-glycoprotein (P-gp) pumps a wide range of cytotoxic drugs out of cells. Inhibiting maturation of P-gp would be a novel method for circumventing P-gp-mediated multidrug resistance, which complicates cancer chemotherapy and treatment of patients infected with human immunodeficiency virus. We examined the effect of disulfiram (Antabuse(TM)) on the maturation and activity of P-gp. METHODS: Embryonic kidney cells were transfected with a complementary DNA for the P-pg gene, and the effects of disulfiram on the sensitivity of the transfected cells to cytotoxic agents were determined. Enzyme assays were used to determine the effects of disulfiram on the verapamil-stimulated adenosine triphosphatase (ATPase) activity of P-gp. Disulfiram modifies cysteine residues, and mutant forms of P-gp that lack individual cysteines were used to determine whether particular cysteine residues mediate disulfiram's effects on P-gp activity. Maturation of recombinant P-gp was followed on immunoblots. RESULTS: Disulfiram increased the sensitivity of P-gp-transfected cells to vinblastine and colchicine and inhibited P-gp's verapamil-stimulated ATPase activity. Half-maximal inhibition of ATPase activity occurred at 13.5 microM disulfiram. Disulfiram (at 100 microM) inhibited a P-gp mutant by 43% (95% confidence interval [CI] = 37%-48%) when cysteine was present at position 431 only and by 72% (95% CI = 66%-77%) when cysteine was present at position 1074 only. Treatment of P-gp-transfected cells with 50 nM disulfiram blocked maturation of recombinant P-gp. CONCLUSIONS: Disulfiram can potentially reduce P-gp-mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation. These results suggest that disulfiram has the potential to increase the efficacy of drug therapies for cancer and acquired immunodeficiency syndrome.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Disulfiram produces a non-carbon disulfide-dependent schwannopathy in the rat.
Disulfiram is a dithiocarbamate drug used for alcohol aversion therapy that produces a distal sensorimotor peripheral neuropathy in certain individuals. Because carbon disulfide, a disulfiram metabolite, produces a peripheral neuropathy clinically similar to disulfiram, it has been postulated that disulfiram neuropathy results from CS2 release in vivo. The current study evaluated the morphological changes produced by disulfiram and the contribution of CS2-mediated protein cross-linking to disulfiram-induced neuropathy. Male Sprague-Dawley rats were administered 1% w/w disulfiram in their feed for 2, 4, 5, or 7 wk, and erythrocyte spectrin, hemoglobin, and neurofilament preparations were isolated and the extent of cross-linking assessed by SDS-PAGE, RP-HPLC, and Western blotting, respectively. Spinal cord and peripheral nerve sections were obtained from separate treated animals and assessed by light and electron microscopy. Significant protein cross-linking was only detected in neurofilament preparations obtained after 7 wk of exposure. Morphological changes were observed after 4 wk exposure and consisted of vacuoles within the Schwann cell cytoplasm and segmental demyelination. No neurofilamentous axonal swellings were detected and no significant changes were observed in the CNS. Because disulfiram neuropathy lacks both the morphological changes and intermolecular cross-linking characteristic of CS2, we conclude that disulfiram neuropathy is not mediated by the axonal toxicant CS2; instead, disulfiram appears to be a primary Schwann cell toxicant. Recognition of a diethylcarbamoyl adduct on globin and axonal proteins presents a novel putative neurotoxic mechanism for disulfiram.
Administration, Oral↗
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↗
Lack of single-dose disulfiram effects on cytochrome P-450 2C9, 2C19, 2D6, and 3A4 activities: evidence for specificity toward P-450 2E1.
Disulfiram and its primary metabolite diethyldithiocarbamate are effective mechanism-based inhibitors of cytochrome P-450 2E1 (CYP2E1)1 in vitro. Single-dose disulfiram diminishes CYP2E1 activity in vivo and has been used to identify CYP2E1 participation in human drug metabolism and prevent CYP2E1-mediated toxification. Specificity of single-dose disulfiram toward CYP2E1 in vivo, however, remains unknown. This investigation determined single-dose disulfiram effects on human CYP 2C9, 2C19, 2D6, and 3A4 activities in vivo. In four randomized crossover experiments, volunteers received isoform-selective probes (oral tolbutamide, mephenytoin, dextromethorphan, or i.v. midazolam) on two occasions, 10 h after oral disulfiram or after no pretreatment (controls). Plasma and/or urine parent and/or metabolite concentrations were measured by HPLC or gas chromatography-mass spectrometry. CYP2C9, 2C19, 2D6, and 3A4 activities were determined from the tolbutamide metabolic ratio, 4'-hydroxymephenytoin excretion, and dextromethorphan/dextrorphan ratios in urine and midazolam systemic clearance, respectively. Midazolam clearance (670 +/- 190 versus 700 +/- 240 ml/min, disulfiram versus controls), dextromethorphan/dextrorphan metabolic ratio (0.013 +/- 0.033 versus 0.015 +/- 0.035), 4'-hydroxymephenytoin excretion (122 +/- 22 versus 128 +/- 25 micromol), and tolbutamide metabolite excretion (577 +/- 157 versus 610 +/- 208 micromol) were not significantly altered by disulfiram pretreatment, although the tolbutamide metabolic ratio was slightly diminished after disulfiram (60 +/- 17 versus 81 +/- 40, p <.05). Results show that single-dose disulfiram does not cause clinically significant inhibition of human CYP2C9, 2C19, 2D6, and 3A4 activities in vivo. When single-dose disulfiram is used as an in vivo probe for P-450, inhibition of drug metabolism suggests selective involvement of CYP2E1. Single-dose disulfiram should not cause untoward drug interactions from inhibition of other P-450 isoforms.
Adult↗
Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial.
CONTEXT: Disulfiram has emerged as a promising treatment for cocaine dependence, but it has not yet been evaluated in general populations of cocaine users. OBJECTIVES: To compare the effectiveness of disulfiram therapy with that of a placebo condition in reducing cocaine use and to compare the effectiveness of 2 active behavioral therapies-cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT)-in reducing cocaine use. DESIGN: Randomized, placebo-controlled, double-masked (for medication condition), factorial (2 x 2) trial with 4 treatment conditions: disulfiram plus CBT, disulfiram plus IPT, placebo plus CBT, and placebo plus IPT. SETTING: A community-based outpatient substance abuse treatment program. PATIENTS: A total of 121 individuals meeting the criteria for current cocaine dependence. INTERVENTIONS: Patients received either disulfiram (250 mg/d) or placebo in identical capsules. Medication compliance was monitored using a riboflavin marker procedure. Both behavioral therapies (CBT and IPT) were manual guided and were delivered in individual sessions for 12 weeks. MAIN OUTCOME MEASURES: Random regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens. RESULTS: Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo, and those assigned to CBT reduced their cocaine use significantly more than those assigned to IPT (P<.01 for both). Findings were consistent across all study samples (eg, intention to treat, treatment initiators, and treatment completers). Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment. Adverse effects experienced by participants who received disulfiram were mild and were not considerably different from those experienced by participants who received placebo. CONCLUSIONS: Disulfiram and CBT are effective therapies for general populations of cocaine-dependent individuals. Disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use.
Adult↗
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↗
Effects of disulfiram on hepatic P450IIE1, other microsomal enzymes, and hepatotoxicity in rats.
Disulfiram, widely used in avoidance therapy for alcohol abuse, has been shown to have protective effects against chemically induced toxicity and carcinogenesis. The purpose of this work was to elucidate the biochemical mechanisms of this protective action by examining its effects on cytochrome P450IIE1 and other related microsomal enzyme activities. When a dose of disulfiram was given intragastrically to rats, a very rapid decrease of N-nitrosodimethylamine (NDMA) demethylase activity, possibly due to the inactivation of P450IIE1, was seen. The loss of P450IIE1 protein from the microsomal membrane was observed at 18 hr after receiving disulfiram, but not within the first 5 hr after the treatment. P450IIB1, on the other hand, was induced markedly between 15 and 72 hr after the disulfiram treatment. The treatment, however, caused only moderate changes in some other P450 isozymes. Carbon disulfide, a putative metabolite of disulfiram, produced similar effects on P450IIE1, but with shorter duration. Carbon disulfide, however, did not induce P450IIB1. Diethyldithiocarbamate, a reductive product of disulfiram, was an inhibitor of P450IIE1 activity in vitro, and upon preincubation with microsomes, it produced an NADPH-dependent inactivation of NDMA demethylase activity. The results suggest that this or other metabolites of disulfiram are inhibitors of P450IIE1 and are responsible for the inactivation of P450IIE1 in vivo. Hepatotoxicity of NDMA or CCI4 in rats was blocked by pretreatment with disulfiram. The present work demonstrates that P450IIE1 was inhibited and inactivated by disulfiram, and this mechanism can account for many of the reported inhibitory actions of disulfiram against chemically induced toxicity and carcinogenesis.
Animals↗
Veterans Administration cooperative study of disulfiram in the treatment of alcoholism: study design and methodological considerations.
Disulfiram treatment of alcoholism has been difficult to evaluate in controlled studies because the study design must contend with problems unique to this drug. The therapeutic effect may be a result of the patient's fear of the disulfiram-ethanol reaction rather than a direct pharmacological effect on the craving for alcohol. Good outcome may not be directly related to compliance with the drug regimen; a patient may remain abstinent even if he does not take his medication. The Veterans Administration Cooperative Study "Disulfiram in the Treatment of Alcoholism," is a multicenter, randomized, blinded, controlled clinical trial designed to evaluate the efficacy of disulfiram while addressing these issues. Two control groups are used. The members of one control group will not receive disulfiram and will be told they are not receiving disulfiram. The members of the other control group will be given disulfiram and will be told they are receiving disulfiram; however, the dose of their disulfiram will be measured by doing pill counts and obtaining urine specimens at each clinic visit and measuring urinary diethylamine, a metabolite of disulfiram, and riboflavin (a medication marker).
Adolescent↗
Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients.
The thiocarbamate drug disulfiram has been used for decades in the treatment of alcohol abuse. Disulfiram induces apoptosis in a number of tumor cell lines and was recently by us proposed to act as a 26S proteasome inhibitor. In this work we characterized disulfiram in vitro with regard to tumor-type specificity, possible mechanisms of action and drug resistance and cell death in human tumor cell lines and in 78 samples of tumor cells from patients using the fluorometric microculture cytotoxicity assay and the automated fluorescence-imaging microscope ArrayScan((R)). Disulfiram induced cytotoxicity in a biphasic pattern in both cell lines and patient tumor cells. Disulfiram induced apoptosis as measured by cell membrane permeability, nuclear fragmentation/condensation and caspase-3/7 activation using high content screening assays. For many of the cell lines tested disulfiram was active in sub-micromolar concentrations. When comparing the logIC(50) patterns with other cytotoxic agents, disulfiram showed low correlation (R<0.5) with all drugs except lactacystin (R=0.69), a known proteasome inhibitor, indicating that the two substances may share mechanistic pathways. Disulfiram was more active in hematological than in solid tumor samples, but substantial activity was observed in carcinomas of the ovary and the breast and in non-small cell lung cancer. Disulfiram also displayed higher cytotoxic effect in cells from chronic lymphocytic leukemia than in normal lymphocytes (p<0.05), which may indicate some tumor selectivity. These results together with large clinical experience and relatively mild side effects encourage clinical studies of disulfiram as an anti-cancer agent.
Cell Line, Tumor↗