Disulfiram-ethanol reaction to implanted disulfiram.
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Adult↗
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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↗
Modifications of drug metabolism by disulfiram and diethyldithiocarbamate. I. Mixed-function oxygenase.
Disulfiram and diethyldithiocarbamate were administered to rats for 4 days alone (300 mg/kg, daily, per os) or in combination with phenobarbital (80 mg/kg, daily, i.p.), in order to observe the effects of these compounds on the microsomal membrane components and on the mixed-function oxygenase system. Both disulfiram and diethyldithiocarbamate increased the liver to body weight ratio, and the total hepatic protein content. Disulfiram significantly increased also the microsomal protein and phospholipid contents. Diethyldithiocarbamate and disulfiram partially prevented the increase of microsomal protein and phospholipid contents caused by phenobarbital. Disulfiram and diethyldithiocarbamate decreased the amount of cytochrome P-450 and P-420, and the activity of p-nitroanisole O-demethylase. These changes were more pronounced after diethyldithiocarbamate than after disulfiram treatment. On the contrary, the activity of NADPH-cytochrome c reductase was enhanced only by disulfiram. The induction by phenobarbital of cytochrome P-450 and p-nitrosanisole O-demethylase was partially prevented on concomitant treatment with disulfiram and diethyldithiocarbamate. These compounds. however, had an additive effect with phenobarbital in enhancing the microsomal NADPH-cytochrome c reductase activity.
Animals↗
The effect of disulfiram on the aldehyde dehydrogenases of sheep liver.
1. The effect of disulfiram on the activity of the cytoplasmic and mitochondrial aldehyde dehydrogenases of sheep liver was studied. 2. Disulfiram causes an immediate inhibition of the enzyme reaction. The effect on the cytoplasmic enzyme is much greater than on the mitochondrial enzyme. 3. In both cases, the initial partial inhibition is followed by a gradual irreversible loss of activity. 4. The pH-rate profile of the inactivation of the mitochondrial enzyme by disulfiram and the pH-dependence of the maximum velocity of the enzyme-catalysed reaction are both consistent with the involvement of a thiol group. 5. Excess of 2-mercaptoethanol or GSH abolishes the effect of disulfiram. However, equimolar amounts of either of these reagents and disulfiram cause an effect greater than does disulfiram alone. It was shown that the mixed disulphide, Et2N-CS-SS-CH2-CH2OH, strongly inhibits aldehyde dehydrogenase. 6. The inhibitory effect of diethyldithiocarbamate in vitro is due mainly to contamination by disulfiram.
Aldehyde Oxidoreductases↗
Studies on the interaction between disulfiram and sheep liver cytoplasmic aldehyde dehydrogenase.
The effect of disulfiram, [1-14C]disulfiram and some other thiol reagents on the activity of cytoplasmic aldehyde dehydrogenase from sheep liver was studied. The results are consistent with a rapid covalent interaction between disulfiram and the enzyme, and inconsistent with the notion that disulfiram is a reversible competitive inhibitor of cytoplasmic aldehyde dehydrogenase. There is a non-linear relationship between loss of about 90% of the enzyme activity and amount of disulfiram added; possible reasons for this are discussed. The remaining approx. 10% of activity is relatively insensitive to disulfiram. It is found that modification of only a small number of groups (one to two) per tetrameric enzyme molecule is responsible for the observed loss of activity. The dehydrogenase activity of the enzyme is affected more severely by disulfiram than is the esterase activity. Negatively charged thiol reagents have little or no effect on cytoplasmic aldehyde dehydrogenase. 2,2'-Dithiodipyridine is an activator of the enzyme.
Aldehyde Oxidoreductases↗
On the disulfiram-like effect of coprine, the pharmacologically active principle of Coprinus atramentarius.
Coprine or disulfiram was given to rats in various doses at various time intervals before the administration of 2 g/kg ethanol. The ratio acetaldehyde/ethanol in the alveolar air was measured by gas chromatography and was taken as an index of the aldehyde dehydrogenase (ALDH) activity. The activity of dopamine beta-hydroxylase (DBH) was estimated in the same animals by measuring the amount of 14C-octopamine formed from 14C-tyramine in the heart. Coprine and disulfiram both caused an increase in the acetylaldehyde/ethanol ratio, coprine being more potent than disulfiram. Disulfiram, but not coprine, reduced the net yield of 14C-octopamine. In rats pretreated with either coprine or disulfiram, blood-pressure and heart-rate were recorded before and after intraperitoneal injections of 0.4 g/kg ethanol. In both cases ethanol caused a marked and rapid fall in blood-pressure. However, this effect was accompanied by tachycardia only in animals treated with coprine. It is concluded that coprine like disulfiram inhibits ALDH, but only disulfiram causes an additional inhibition of DBH. This difference may account for differences in the cardiovascular response to ethanol.
Agaricales↗
Disulfiram for the treatment of alcoholism. An evaluation in 128 men.
One hundred twenty-eight alcoholic men were assigned randomly to receive either a regular dose of disulfiram (250 mg), a pharmacologically inactive dose (1 mg), or no disulfiram. There were no statistically significant differences among the three treatment groups in total abstinence, percentage of drinking days, days worked, family stability (living with same relative), or percent of scheduled appointments kept. However, 21% of those who received the regular dose of disulfiram and 25% who received the pharmacologically inactive dose remained abstinent, whereas only 12% of those who received no disulfiram did so. These results indicate that disulfiram may be of limited value in the treatment of alcoholism, fear of the disulfiram-ethanol reaction is important in preventing drinking, and patients willing to take disulfiram are more likely to be abstinent if given the drug. We also found that complete abstinence correlated significantly with compliance and obtaining employment.
Adult↗
Effect of tetraethyl thiuram disulfide (disulfiram) on the multiplication of enveloped viruses.
Disulfiram at concentrations between 0.1 and 0.3 mM inhibits the multiplication of Semliki Forest virus (SFV), fowl plague virus (FPV), Newcastle disease virus (NDV), vesicular stomatitis virus (VSV), and pseudorabies virus (PRV), when administered 1 hour before and during adsorption. There is, however, no inhibition of virus multiplication, when the drug is added after adsorption onto chick embryo cells. Disulfiram interferes neither with the receptors of the virus nor of erythrocytes, and it does not prevent virus adsorption. Possibly an early step in virus multiplication is affected by disculfiram. Infected cells once treated with the drug recover after some time of incubation in an ingibitor-free medium. The inhibitory state can be maintained, however, if relatively low doses of disulfiram are present in the culture medium also after adsorption. Disulfiram has no effect on macromolecular synthesis of the host cells. It has, however, a marked affect on membrane function. While virus multiplication is readily inhibited by disulfiram when chick embryo or BHK cells were investigated, virus multiplication in HeLa cells is almost resestant against the action of disulfiram.
Adsorption↗
Effect of antabuse (disulfiram) on Rous sarcoma virus and on eukaryotic cells.
Antabuse (disulfiram) is widely used in the treatment of chronic alcoholism. We have examined the effect of this drug on malignant transformation by Rous sarcoma virus, on eukaryotic cell synthesis, and on nucleic acid binding. It was found that: (1) Disulfiram inhibits the activity of the RNA dependent DNA polymerase of Rous sarcoma virus and inactivates the ability of the virus to malignantly transform chick embryo cells. The monomer of disulfiram, diethyldithiocarbamate does not affect the virus. (2) Disulfiram induced the synthesis of four proteins in normal chick embryo and human foreskin cells. The monomer diethyldithiocarbamate, induced these proteins also. Cellular DNA synthesis is more sensitive to disulfiram than are RNA and protein synthesis. (3) Disulfiram binds to neither DNA or RNA in the presence or absence of copper. However, diethyldithiocarbamate in the presence of, but not in the absence of, copper binds to HeLa cell DNA and to Rous sarcoma virus 70 S genome RNA. These results indicate that this compound, which causes no symptoms in people who do not consume alcohol, may have significant effects on a cellular level.
Animals↗
Blood pressure response to ethanol in relation to acetaldehyde levels and dopamine-beta-hydroxylase activity in rats pretreated with disulfiram, cyanamide and coprine.
The blood pressure response after ethanol administration was studied in relation to blood acetaldehyde levels, aldehyde-dehydrogenase (ALDH)--and dopamine-beta-hydroxylase (DBH) activities in rats pretreated with the ethanol-sensitizing compounds disulfiram, cyanamide and coprine and the DBH-inhibitor FLA-57. Disulfiram, cyanamide and coprine, but not FLA-57, inhibited the low-Km ALDH in the liver and caused an increased acetaldehyde level in blood. Disulfiram and FLA-57, but not cyanamide and coprine, decreased the DBH-activity in the heart and the levels of norepinephrine in the heart and the brain. In disulfiram-treated rats with a low DBH-activity, a fall in blood pressure was observed at acetaldehyde levels being slightly higher than those found in control rats. In disulfiram-treated rats with a DBH-activity close to control activity and in rats pretreated with cyanamide or coprine, a fall in blood pressure were observed in rats pretreated with FLA-57. In rats pretreated with coprine + FLA-57, the fall in blood pressure was similar, or even lower, than in rats pretreated with coprine alone. The results suggest that acetaldehyde is the main determinant of the hypotension elicited by ethanol in rats pretreated with ALDH-inhibitors, and that the role of DBH in the disulfiram-ethanol reaction has been over-estimated in previous studies.
Acetaldehyde↗
Patient management in disulfiram implant therapy.
Data from 100 disulfiram implant, placebo, and no-implant control patients demonstrate the effectiveness of the disulfiram implant in keeping the alcoholic dry. However, the superiority of the disulfiram implant group over the placebo group is interpreted as evidence of a pharmacological component to the procedure operating independent of the disulfiram-ethanol reaction (DER). Hypotheses involving inhibition of aldehyde dehydrogenase or inhibition of dopamine-beta-hydroxylase are offered as mechanisms by which the pharmacological effect may be mediated. Finally, in view of the low (approximately 0.5) probability with which a DER follows ingestion of alcohol by a disulfiram implant patient, it is suggested that the approach to patient management should be changed to maximize the effectiveness of the disulfiram implant procedure. Guidelines are given.
Acetaldehyde↗
Disulfiram implantation: placebo, psychological deterrent, and pharmacological deterrent effects.
In an effort to examine the placebo, psychological deterrent, and pharmacological deterrent effects associated with implanted disulfiram, subjects were given either disulfiram implants or sham operations. Ethanol challenges elicited no disulfiram-ethanol reactions (DERs), indicating that at the time of the challenge neither a pharmacological deterrent nor a placebo effect was operating. Of the patients who resumed drinking, only those with disulfiram implants experienced DERs. Sham operation subjects continued to drink after their first post-challenge drink; four of five disulfiram implant recidivists remained abstinent following their experience of a DER. It is concluded that the pharmacological deterrent effect of the disulfiram implant may have been underestimated in previous reports.
Alcohol Drinking↗
Effects of disulfiram and pyridoxine on serum cholesterol.
Disulfiram, 500 mg/day, raised serum cholesterol levels in alcoholic persons from a mean of 193 +/- 16.4 mg/dl to 227.2 +/- 17.2 mg/dl after 3 weeks and 264 +/- 40 mg/dl after 6 weeks. This increase was not seen in a group taking pyridoxine 50 mg/day in addition to disulfiram 500 mg/day. In contrast to the disulfiram and disulfiram-pyridoxine treatment groups, control groups receiving pyridoxine alone, or no drug, had a 33 mg/dl reduction in serum cholesterol during the first 3 weeks of abstinence, a finding consistent with other evidence showing a rapid decrease in serum lipids on abstinence from alcohol. Patients taking disulfiram 250 mg/day, with or without pyridoxine, did not have this expected decrease in serum cholesterol. Since increased serum cholesterol is one of the risk factors in a coronary heart disease, chronic disulfirm therapy may increase the incidence of arteriosclerotic cardiovascular disease, as has been the case with chronic exposure to carbon disulfide, a principal metabolite of disulfiram.
Alcoholism↗
Enhancement by disulfiram (Antabuse) of toxic effects of 95 to 97% O2 on the rat lung.
Disulfiram (Antabuse), a drug used in alcohol aversion therapy, has been demonstrated to protect various species against hyperbaric O2 toxicity. In contrast, we have found that disulfiram accelerates the onset of pulmonary edema and death of rats exposed to normobaric 95 to 97% O2. When rats were given 200 mg of disulfiram per kg b.wt., 100% of the rats died at 24 to 48 hr of O2 exposure whereas only 5% of the rats died when exposed to O2 without disulfiram. This effect was not seen with an equal dose of diethyldithiocarbamate, the reduced monomer of disulfiram. The toxic effect was not due to an inhibition of superoxide dismutase, nor did disulfiram significantly affect the level of glutathione or change the reduced to oxidized glutathione ratio in the lung. Concurrent administration of 200 mg per kg b.wt. of ascorbate, vitamin E or reduced glutathione or 100 mg/kg of catalase did not affect the toxic response.
Animals↗
Changes in serotonin turnover and the brain sensitivity to barbiturates by disulfiram treatment in rats.
The influence of intraperitoneal administration of disulfiram on the serotonin (5HT) turnover and the brain sensitivity to barbiturates were investigated in rats. Treatment of the animals with 200 mg/kg disulfiram resulted in the prolongation of duration of barbiturate-induced hypnosis. This indication and increment of the brain sensitivity to barbiturates after disulfiram treatment. Under the identical condition, disulfiram caused both the reduction of turnover of 5HT and the elevation of 5HT levels, although this effect was less potent than that of phenobarbital. Furthermore, simultaneous administration of disulfiram and phenobarbital resulted in the severe retardation of 5HT metabolism. These results strongly suggest that disulfiram potentiates the hypnotic action of barbiturates by altering 5HT metabolism in rat brain.
Animals↗
Development and evaluation of a compliance test for patients taking disulfiram.
A breath test for carbon disulfide, a major excretion product of disulfiram, is described and evaluated. All breath excretions were standardized by collecting a fixed amount based on CO2 control. Excretion of CS2 falls rapidly (half life 8 to 18 hours), so that 20 to 30 hours following the last dose of disulfiram the test becomes negative. Approximately 300 tests in hospitalized patients taking disulfiram were positive; 40 tests in patients not taking this drug were negative. In an active disulfiram outpatient clinic more than one third of the patients who claimed to have taken disulfiram on the previous day had, as determined by this test, failed to do so. Of subjects judged by the professional staff to be almost certainly compliant 20% were not taking medication. Of the total of 52 patients tested in clinic only 25 were taking disulfiram.
Adult↗
Disulfiram toxicity and carbon disulfide poisoning.
The author compared the neurotoxic effects of disulfiram with those of carbon disulfide, a disulfiram metabolite. The results suggest that carbon disulfide is responsible for the behavioral and neurological side effects of disulfiram. If this is so, then some other toxic effects of carbon disulfide, including parkinsonism, choreoathetosis, and thalamic syndrome may follow the ingestion of more than 5 g of disulfiram by adults, and individuals receiving as little as 125 mg of disulfiram per day may be at a three- to four-fold greater risk for arteriosclerotic cardiovascular disease than a comparable population not receiving the drug.
Animals↗
[Abstinence behavior and plasma concentration of disulfiram in alcoholics after esperal implantation].
Abstinence behaviour after disulfiram implantation has been investigated in 21 chronic alcoholics. The blood levels of disulfiram and its metabolites, carbon disulfide (CS2) and reduced disulfiram (diethyldithiocarbamate) were determined and the blood levels of patients with implants were compared with those of patients receiving disulfiram orally. The blood levels in the implanted patients were significantly lower than those of the group taking disulfiram orally. No metabolites were detectable after 3 months, despite the sensitive method employed. Nevertheless, 14 of the 21 chronic alcoholics remained abstinent for 6 months after implantation. This result is probably due in the main to psychotherapeutic guidance.
Adult↗