Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “DISULFIRAM”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 163 records · Page 9Linked to original sources
PubMed2000

Preparation and in vivo ocular absorption studies of disulfiram solid dispersion.

Disulfiram, a dimer of diethyldithiocarbamate (DDC) which is a strong radical scavenger, is known to prevent cataract development. However, disulfiram is hardly absorbed from the cornea and its bioavailability is extremely low. In this study, we attempted to prepare disulfiram solid dispersion for the improvement of ocular bioavailability. Solid dispersions of disulfiram were prepared by either an evaporation method or a spray-drying method, using polyvinylpyrrolidone (PVP) as a carrier. Preparations were analyzed by scanning electron microscopy, powder X-ray diffractometry and differential scanning calorimetry, and confirmed to be a solid dispersion. The particle size of the solid dispersion prepared by the spray-drying method was smaller than the preparation by the evaporation method (spray-drying: 3.3+/-0.04 microm, evaporation: 34.3+/-18.0 microm). An in vivo ocular absorption experiment was conducted by instilling solid dispersions to rabbit eye and measuring the DDC in the aqueous humor. After instillation of disulfiram and PVP physical mixture, DDC was not detected in the aqueous humor. On the other hand, DDC appeared in the aqueous humor after the instillation of a solid dispersion. Maximal concentration and the area under the aqueous humor concentration-time curve were greater in the solid dispersion prepared by the spray-drying method than the preparation by the evaporation method. Disulfiram solid dispersion, especially prepared by the spray-drying method, improved ocular bioavailability.

Absorption↗
PubMed2005

Hepatitis C in alcohol dependence:drinking versus disulfiram.

Hepatitis C virus (HCV) infects alcohol dependent (AD) individuals disproportionately. Disulfiram for timely abstinence in HCV + AD cases remains controversial. Our literature review suggests that (1) active drinking accelerates HCV-related liver damage and that abstinence is associated both (2) with a slower course of HCV+ hepatic deterioration and (3) with enhanced response to antiviral HCV treatment. Further, (4) the risk of disulfiram liver injury appears much lower than that from alcohol, (5) HCV+AD individuals require close monitoring during the first 6 months of disulfiram treatment, and (6) early discontinuation of disulfiram usually reverses harmful effects when these occur. Although systematic data are sparse, continued drinking appears much more liver toxic than does disulfiram in this group. Disulfiram therapy may allow (1) prolonged abstinence leading to successful antiviral therapy for HCV, and (2) time to begin behavioral treatments that facilitate long-term abstinence. Sizeable prospective studies of HCV + AD treatment are badly needed.

Alcohol Deterrents↗
PubMed2002

Lack of disulfiram-like reaction with metronidazole and ethanol.

BACKGROUND: Metronidazole, an effective antianaerobic agent, has been reported to have aversive properties when ingested with ethanol. This is thought to be due to the blocking of hepatic aldehyde dehydrogenase (ALDH) enzyme followed by the accumulation of acetaldehyde in the blood. However, based on animal studies and on only 10 human case reports, the existence of metronidazole-related disulfiram-like reaction has recently been questioned. OBJECTIVE: To investigate the possible disulfiram-like properties of metronidazole and ethanol in human volunteers. METHODS: Of 12 healthy male volunteers in this double-blind study, one-half received metronidazole for 5 days and the other half received placebo. All volunteers received ethanol 0.4 g/kg at the beginning of the study. Repeated blood samples were taken every 20 minutes for 4 hours, and blood acetaldehyde and ethanol concentrations were determined. Blood pressure, heart rate, and skin temperature were also measured every 20 minutes for objective signs of a possible disulfiram-like reaction. Volunteers also completed a questionnaire focusing on the subjective signs of disulfiram-like reaction. RESULTS: Metronidazole did not raise blood acetaldehyde or have any objective or subjective adverse effects when used together with ethanol. CONCLUSIONS: This study shows that metronidazole does not have an effect on blood acetaldehyde concentrations when ingested with ethanol and does not have any objective or subjective disulfiram-like properties. However, it is possible that disulfiram-like reaction can occur in some subgroups and by other mechanisms than the inhibition of hepatic ALDH.

Acetaldehyde↗
PubMed1978

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↗
PubMed1979

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↗
PubMed1989

Disulfiram neuropathy: a review (1971-1988) and report of a case.

Neuropathy is one of the most severe side effects of disulfiram therapy. We report the case of a young man who developed a neuropathy following disulfiram administration, with a virtually complete recovery in 14 months. We then discuss 37 cases of disulfiram neuropathy reported since 1971. Evidence is given that: (1) there is no numerical sex prevalence, although the incidence of the disease in women is probably disproportionately high; (2) symptom onset latency is dose-dependent, being longer at 250 mg/day or less; (3) neurological deficits are also dose-dependent, being milder at 250 mg/day or less; (4) the two previous findings and single observations suggest that disulfiram neuropathy is a dose-dependent phenomenon; (5) recovery probably follows a course which depends primarily on the initial degree of impairment; (6) the genetic mechanism probably involves carbon disulfide and a hypothesis as to the possible biochemical mechanism is proposed; (7) chloral hydrate can bear a potentiation effect on neuropathy, and the association with disulfiram is best avoided. Further, we give guidelines for the differentiation between alcoholic and disulfiram neuropathy, advise prescribing the drug at 250 mg daily or less, if possible, and stress the utmost importance of an early diagnosis.

Adult↗
PubMed1985

Stability of an injectable disulfiram formulation sterilized by gamma irradiation.

Stability of an injectable disulfiram suspension sterilized by gamma(gamma) irradiation was tested. Single doses of disulfiram powder in plastic syringes were subjected to 50,000 rads of gamma radiation. Culture media were inoculated with the irradiated drug to test for growth of bacteria, fungi, and mycobacteria. The irradiated drug and nonirradiated controls were analyzed by high-performance liquid chromatography (HPLC) for disulfiram and its major degradation product, diethyldithiocarbamate (DDC). Ultraviolet absorption spectra of irradiated and nonirradiated disulfiram were obtained. No organisms grew in any of the culture media. HPLC analysis indicated that disulfiram content of the irradiated specimens was not reduced, and DDC was not detected. There were no important differences between the ultraviolet spectra of the irradiated and nonirradiated samples. Disulfiram can be sterilized by gamma irradiation without chemical degradation.

Chromatography, High Pressure Liquid↗
PubMed1986

Inhibition of peptide amidation by disulfiram and diethyldithiocarbamate.

Peptidylglycine alpha-amidating monooxygenase is a copper- and ascorbate-dependent enzyme that converts peptides with COOH-terminal glycine residues into the corresponding alpha-amidated product peptides. The relatively selective copper chelator N,N-diethyldithiocarbamate (DDC) and its disulfide dimer, disulfiram (Antabuse), were used to determine whether the availability of copper affects the production of two alpha-amidated pro-ACTH/endorphin-derived peptides, alpha-melanotropin (alpha MSH) and joining peptide. When mouse pituitary corticotropic tumor cells (AtT-20) were grown in medium containing micromolar concentrations of disulfiram or DDC, alpha-amidation of newly synthesized joining peptide was specifically inhibited in a dose-dependent manner. In rats injected twice with disulfiram or DDC, the ability of the intermediate pituitary to alpha-amidate newly synthesized alpha MSH and joining peptide was inhibited in a dose-dependent manner; at disulfiram doses equivalent to those used in alcohol abuse therapy (4 mg/kg/day), only about 10% of the newly synthesized peptides were correctly alpha-amidated. Chronic treatment of rats with DDC or disulfiram produced a dose-dependent increase in the pituitary content of glycine-extended alpha MSH and joining peptide; the total amount of pro-ACTH/endorphin-related material was unaltered. After 11 days of treatment with 4 mg/kg/day disulfiram, about one-third of the pituitary alpha MSH and joining peptide were present in the glycine-extended rather than the alpha-amidated form; pituitary extracts normally contain almost entirely alpha-amidated peptides.

Animals↗
PubMed1986

[A study on the disulfiram-like reaction of T-2588. Influence of the consecutive administration of T-2588 on hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and blood levels of ethanol and acetaldehyde].

A study on disulfiram-like reaction of T-2588 was carried out using Sprague-Dawley male rats. A 500 mg/kg/day dose of T-2588 was given orally to 14 male rats once daily for 7 days. Disulfiram (200 mg/kg/day X 3 days, p.o.), cephalexin (CEX) (500 mg/kg/day X 7 days, p.o.) and cefmetazole (CMZ) (500 mg/kg/day X 7 days, i.v.) were used as the positive control and 2 comparative controls, respectively. The results obtained were summarized below. Each parameter (aldehyde dehydrogenase activity and the blood aldehyde level) in the disulfiram-like reaction was not affected by the T-2588 administration. A marked inhibition of aldehyde dehydrogenase activity (low-Km ALDH, Enzyme I) and a significant increase of the blood aldehyde level were observed in the rats receiving disulfiram. No drug-related disulfiram-like reaction was induced in the male rats receiving CEX, while alterations similar to the disulfiram action were recognized in rats receiving CMZ.

Acetaldehyde↗
PubMed1986

Patterns of compliance and evasion in treatment programmes which include supervised disulfiram.

Examination of the compliance patterns of 84 patients offered supervised disulfiram in aqueous suspension, and for whom adequate supervision by family members, friends or colleagues was possible, showed that 38 took disulfiram regularly and remained abstinent throughout the minimum six-month period for which it was prescribed. Twenty risked drinking alcohol while taking disulfiram, half of whom did not experience a significant reaction on doses of 200-300 mg daily. In nine patients there was a temporary lapse of supervision. Two patients induced vomiting of disulfiram. Four substituted inert medication. Nine dropped out of treatment--usually after separating from their partner--and two refused to start disulfiram. Apart from these 11 patients, attempts to sabotage or evade treatment were not necessarily associated with a poor response. In most cases it was possible to out-manoeuvre the patients by increasing the dosage or modifying the supervision techniques. Awareness of these possible patient responses is essential if the considerable potential of supervised disulfiram is to be maximised.

Alcoholism↗
PubMed1979

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↗
PubMed1981

Mathematical analysis of a phenytoin--disulfiram interaction.

A case of phenytoin-disulfiram drug interaction is analyzed with a mathematical technique used in enzyme kinetics. Serum anticonvulsant levels, obtained before, during, and after disulfiram administration, were collected from hospital records retrospectively. Phenytoin kinetic constants--maximal velocity of metabolism (Vmax) and Michaelis-Menten constant (km)--before, during, and after disulfiram administration, were compared. The slopes (km) of the regression lines analyzed by a small sample t test for parallelism were not significantly different (p greater than 0.05). Y-intercept (Vmax) values obtained before (433 mg/day) and after (463 mg/day) disulfiram are both significantly different when compared with the y-intercept during (264 mg/day) disulfiram administration, by a small-sample t test for common intercept (p less than 0.05). Changes in the elimination rate of phenytoin or changes in y-intercept result from noncompetitive drug effects. It is concluded that disulfiram affects phenytoin's elimination rate by noncompetitive mechanisms.

Disulfiram↗
PubMed1993

Peptide alpha-amidation and peptidylglycine alpha-hydroxylating monooxygenase: control by disulfiram.

The final two steps in the biosynthesis of alpha-amidated bioactive peptides are catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM; EC 1.14.17.3) and peptidyl-alpha-hydroxyglycine alpha-amidating lyase (PAL; EC 4.3.2.5). These enzymes are derived from the bifunctional precursor protein, peptidylglycine alpha-amidating monooxygenase. Because PHM is rate-limiting in peptide amidation and is copper-dependent, we examined the consequences of in vivo treatments with the copper-chelating drug disulfiram (Antabuse) on levels of alpha-amidated peptides and expression of PHM and PAL. Decreases in two amidated peptides (alpha-melanotropin and cholecystokinin) after disulfiram treatment were extremely pronounced outside the blood-brain barrier, with moderate decreases in the central nervous system. Unexpectedly, when assayed under optimal conditions in vitro, PHM activity was increased by disulfiram treatment, whereas PAL activity was unaltered. The increase in PHM activity in pituitary and atrium occurred within a few hours after the start of disulfiram treatment and was sustained up to 2 weeks after the cessation of treatment, whereas levels of alpha-amidated peptides remained low. Northern and Western blot analyses demonstrated that disulfiram had no influence on levels of peptidylglycine alpha-amidating monooxygenase mRNA or protein. Thus, inhibition of alpha-amidation by disulfiram in vivo occurs despite an increased Vmax of PHM assayed in vitro. The increase in PHM activity may result from induction of a physiologic mechanism that normally regulates this rate-limiting enzyme.

Amides↗
PubMed1977

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↗
PubMed2005

Delirium-associated disulfiram and ethanol interactions.

BACKGROUND: Disulfiram, an agent used for the treatment of alcohol dependence, can exacerbate psychiatric syndromes (including psychosis, catatonia, delirium, depression, and mania) after extended use. However, delirium has yet to be reported following the short-term use of disulfiram in the setting of alcohol use. OBJECTIVES: We report a case with a neuropsychiatric presentation and discuss the prevention and the progression of delirium associated with an interaction of disulfiram and ethanol. CASE REPORT: We report the case of a 51-year-old woman who developed disorganized speech, diminished communication, a decrease in appetite, and thoughts of suicide 10 days after she began taking disulfiram (250 mg/day), to which she added 1 glass of alcoholic beverage for 2 days. Delirium developed in association with an interaction between disulfiram and alcohol. The patient met DSM-IV criteria for major depressive disorder, alcohol dependence, and delirium. DISCUSSION: Neuropsychiatric manifestations may develop in association with co-administration of disulfiram and alcohol; timely recognition and treatment are recommended.

Journal Article↗
PubMed1976

Disulfiram-induced encephalopathy.

Two patients with disulfiram-(Antabuse-)induced encephalopathy exhibited paranoid ideas, disorientation, impaired memory, ataxia, dysarthria, snout and grasp reflexes, and abnormal electroencephalograms. The first patient developed symptoms on two occasions, each time after disulfiram administration. The second patient experienced a generalized seizure followed by fulminant psychosis three weeks after starting disulfiram therapy. Spinal fluid examination in the latter patient revealed a low homovanillic acid (HVA) level. Since disulfiram inhibits dopamine oxidation, disulfiram-induced encephalopathy may be related to excess dopaminergic activity in the central nervous system.

Adult↗
PubMed1984

Sustained-release characteristics of a new implantable formulation of disulfiram.

The object of this study was to evaluate the sustained-release characteristics of a new formulation of disulfiram. Solid rods (500 mg) made of a composite of 80% poly(glycolic-co-L-lactic acid) and 20% 14C-labeled disulfiram were implanted subcutaneously in five Wistar CD-1 rats; a control group received 100 mg of 14C-labeled disulfiram subcutaneously. Excretion of radiolabeled material in the urine and feces was monitored for 88 d. Sustained mobilization of drug was observed in the copolymer-disulfiram implant group, reaching a peak value 30 d after implantation. The control group exhibited first-order kinetics of drug mobilization. At necropsy, there was no encapsulation of the residual rods. The copolymer-disulfiram composite performed as a true sustained-release system, and improved formulations may have clinical applications in the treatment of alcoholic humans.

Animals↗
PubMed2001

Disulfiram is a potent in vitro inhibitor of DNA topoisomerases.

The drug disulfiram is a thiol-reacting drug that is relatively nontoxic when used alone and has been used in the therapy of alcohol abuse for more than 40 years. Several effects of this drug have been reported for DNA synthesis and cell proliferation. In this study, the inhibitory effect of disulfiram on topoisomerase I and II activity was investigated by measuring the relaxation of superhelical plasmid pBR322 DNA. Disulfiram (1-100 microM) inhibited topoisomerase I and II in a concentration-dependent manner (IC(50) congruent with 42 +/- 8 and 30 +/- 9 microM, respectively). Consistent with the assumption that a thiol residue is involved, dithiothreitol (1 mM) markedly prevented the inhibitory effect of disulfiram on the activity of both classes of topoisomerases. These findings might explain certain aspects of disulfiram toxicity and encourage new studies to determine the usefulness of this drug and its analogues as antineoplastic agent.

Antineoplastic Agents↗