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Primary care physicians can play an important role in managing alcoholic patients. Identifying and treating alcoholism early, before it has interfered with patients' relationships and work, may increase the likelihood of prolonged recovery. Simple office interventions can help motivate patients to abstain and seek treatment. People who abuse alcohol and are unwilling to abstain can benefit from a recommendation to reduce their intake of alcohol. For alcohol-dependent patients who decide to stop drinking, primary care physicians often can manage withdrawal on an outpatient basis. Selecting an appropriate treatment program for each alcoholic patient is important, and referral to a specialist to assist in matching patients to treatments is often necessary. Primary care physicians also can help prevent relapse. Although disulfiram is of limited value, primary care physicians can support recovery by identifying coexistent psychosocial problems, helping patients to restructure their lives, and ensuring continuity of care.
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Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Edition (DSM-5), is a heterogeneous disorder stemming from a complex interaction of neurobiological, genetic, and environmental factors. As a result of this heterogeneity, there is no one treatment for AUD that will work for everyone. During the past 2 decades, efforts have been made to develop a menu of medications to give patients and clinicians more choices when seeking a therapy that is both effective and which has limited side effects. To date, 3 medications have been approved by the US Food and Drug Administration (FDA) to treat alcohol dependence: disulfiram, naltrexone, and acamprosate. In addition to these approved medications, researchers have identified new therapeutic targets and, as a result, a number of alternative medications are now being evaluated for treatment of AUD in human studies. Although not approved by the FDA for the treatment of AUD, in some cases, these alternative medications are being used off-label by clinicians for this purpose. These potential medications are reviewed here. They include nalmefene, varenicline, gabapentin, topiramate, zonisamide, baclofen, ondansetron, levetiracetam, quetiapine, aripiprazole, and serotonin reuptake inhibitors. The effectiveness of these medications has been mixed-some show good efficacy with side effects that are mild to moderate in intensity; others have mixed or promising results but are awaiting findings from ongoing studies; and still others show poor efficacy, despite promising preliminary results. Medications development remains a high priority. Key initiatives for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) include supporting the discovery and development of more effective and safer medications, advancing the field of personalized medicine, and forging public and private partnerships to investigate new and more effective compounds.
There have been several reports of disulfiram intoxication, but little evidence of neurologic conditions resulting from disulfiram-induced brain damage combined with Wernicke encephalopathy-associated lesions. We report a rare patient with both Wernicke encephalopathy and disulfiram intoxication. This 50-year-old woman, who was taking disulfiram for chronic alcohol abuse, presented with an acute confusional state, dysarthria, nystagmus, supranuclear ophthalmoplegia, and paraparesis. Biochemical serum and cerebrospinal fluid analyses were normal. An electromyogram detected a motor polyneuropathy. Cognitive assessment revealed severe impairment of memory, attention, and logical and executive abilities. Magnetic resonance imaging with gadolinium enhancement showed brain lesions consistent with Wernicke encephalopathy, but also symmetric hyperintensities on T2-weighted images in the globus pallidus. Stopping the disulfiram and treating with hydration, high-dose thiamine supplements, and benzodiazepines significantly improved the patient's consciousness and oculomotor function. A magnetic resonance imaging scan after 1 month of treatment showed complete disappearance of the brain lesions and the hyperintensities in the globus pallidus. After a further month of intensive neurorehabilitation, the patient was able to interact with the medical staff, and her neuropsychological tests showed only mild memory impairment. Patients with alcoholism who present at emergency departments are at high risk for misdiagnosis, especially because there is no specific routine laboratory test for detecting asymptomatic disulfiram intoxication. Although uncommon, the combination of Wernicke encephalopathy and disulfiram intoxication should be suspected in patients with alcoholism. The disorder can be detected through a careful history and prompt clinical evaluation, together with characteristic magnetic resonance imaging findings.
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Disulfiram reduced extracellular NA in the medial prefrontal (mPF) cortex, occipital cortex, accumbens and caudate nuclei, while it markedly increased DA not only in mPF but also in the occipital cortex, despite its scanty dopaminergic afferences, and modestly increased DA in the accumbens and caudate nuclei, despite their dense dopaminergic innervation. Disulfiram-induced DA accumulation was reversed in both cortices by tetrodotoxin infusion and by systemic administration of the α(2)-adrenoceptor agonist clonidine, but was not modified by the α(2)-adrenoceptor antagonist RS 79948 or the D(2)-like agonist quinpirole. Disulfiram prevented cocaine-induced NA release in the mPF cortex and nucleus accumbens, potentiated cocaine-induced DA release in the mPF cortex but failed to modify cocaine effect in the nucleus accumbens. DA release induced by disulfiram-cocaine combination in the mPF cortex was prevented by clonidine but not by quinpirole.
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Disulfiram is superior to naltrexone in preventing a relapse among alcohol-dependent men with family support. Comparison between these treatments in other settings and in different types of alcoholics is warranted.
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This study demonstrates that during ethanol challenge, intracolonic acetaldehyde level is regulated not only by intracolonic microbes, but also by colonic mucosal cells.
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This study examined the results of two previous studies that evaluated African Americans and whites who were undergoing treatment for cocaine dependence to determine whether the groups differed in pretreatment characteristics, treatment retention, compliance, and cocaine use outcome.
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The author discusses the metabolism of disulfiram and the enzymes which metabolize ethanol. The restraining of the activity of ALDH in the liver by disulfiram causes an accumulation of acetaldehyde which in their turn cause a series of psychophysical symptoms which are unpleasant and in some instances dangerous for the patient. Thus, it is important to monitor changes in the activity of ALDH after administration of disulfiram.
The interest in health benefits associated with consumption of anti-oxidants has led to investigations examining the possibility that diets rich in anti-oxidants promote lifespan extension. Studies using the standard fruit fly (Drosophila melanogaster) model of longevity have shown that the antioxidants vitamin E and N-acetyl cysteine prolong lifespan. Turmeric is a spice which has been consumed and used for medicinal purposes for many centuries in Asia. Interestingly, turmeric contains the powerful antioxidant, curcumin. To test the hypothesis that dietary curcumin prolongs lifespan, groups of 30 male D. melanogaster were cultured on media containing 1) no additive; 2) 0.5 mg of curcumin/gram of media; 3) 1.0 mg of curumin/gram of media; 4) 1.0μg of the superoxide dismutase inhibitor, disulfiram/gram of media; 5) 10 g of disulfiram/gram of media; 6) 0.5 mg curcumin and 1.0 g disulfiram/ gram of media; 7) 1.0 mg curcumin and 1.0 g disulfiram/ gram of media; 8) 0.5 mg curcumin and 10 g disulfiram/gram of media; or 9) 1.0 mg curcumin and 10 g disulfiram/gram of media. The number of live fruitflies was noted daily and mean lifespan determined for each treatment group. A significant (P≤0.05) increase in mean lifespan was noted only for the fruitflies maintained on 1.0 mg of curcumin/gram of media; this effect was reversed by addition of disulfiram. These results demonstrate that dietary curcumin prolongs lifespan and that this effect is associated with enhanced superoxide dismutase activity.
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To further investigate prolactin (PRL) secretion in polycystic ovary syndrome (PCO), the authors evaluated immunoreactive (immuno) and bioactive (bio) PRL levels in the basal state and in response to provocative testing with intravenous dopamine (DA), metoclopramide (MCP), and gonadotropin-releasing hormone (GnRH), before and after disulfiram. Basal measurements of immuno-PRL, bio-PRL, and the ratio of bio/immuno-PRL were similar in PCO and controls. The immuno-PRL decrement after DA was greater than that of bio-PRL in both groups (P less than 0.05). After MCP, immuno-PRL increased more than bio-PRL in PCO (P less than 0.01), and this immuno-PRL increment was greater than that of controls (P less than 0.05). Bio-PRL and immuno-PRL increased after GnRH in PCO, but not controls, and these responses were inhibited by disulfiram. These data confirm PRL hypersecretion in some women with PCO, which is better expressed by immunoreactivity than bioactivity. Given the assay systems and patients studied, bioactivity
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Disulfiram (DSF) is an aldehyde dehydrogenase inhibitor currently used for the treatment of alcoholism. Here, we show that multiple myeloma (MM) cell lines and primary cells from newly diagnosed and relapsed/resistant patients affected by MM, acute myeloid and lymphoblastic leukemia are significantly sensitive to DSF alone and in combination with copper. These effects are present at doses lower than those achievable in vivo after DSF standard administration. The cytotoxic effect achieved by this treatment is comparable to that obtained by conventional chemotherapy and is absent in normal hematopoietic cells. In addition, we found that DSF plus copper induces loss of mitochondrial membrane potential, triggers reactive oxygen species (ROS) production and activates executioner caspases. DSF-copper-induced apoptosis and caspases activation are strongly reversed by antioxidant N-acetylcysteine, thus indicating a critical role of ROS. These results might suggest the use of the old drug DSF, alone or in combination with copper, in the treatment of hematological malignancies.
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A directed detoxication mechanism for acetaldehyde (AcH) is described wherein ethanol-derived AcH, circulating in the blood of rats given ethanol-1-14C and disulfiram or pargyline, was sequestered by condensation with administered D(-)-penicillamine (1). The product of this condensation, 2,5,5-trimethylthiazolidine-4-carboxylic acid (3), which was excreted in the urine without acetyl conjugation, was quantitatively determined by inverse isotope dilution measurements. Acetylation of the urine permitted the isolation of the corresponding N-acetyl derivative in crystalline form. The chirality of 3 was deduced by NMR analysis to be 72% 2S, 4S and 28% 2R, 4S. Although acetylation selectively acetylated the predominant isomer, this acetylated derivative was identical in all respects with a chemically synthesized product. This suggests that the in vivo condensation of AcH and 1 is not enzyme mediated.
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Disulfiram hepatitis, although sometimes fatal, is a very rare complication of alcoholism treatment. A disproportionate number of cases are associated with disulfiram treatment for nickel allergy and unrecognized nickel sensitivity may partly explain the surprisingly high proportion of female victims- about 60%. US guidelines formulated in 1988 suggest that alcoholic patients should not be started on disulfiram unless liver toxicity tests have been done and, if elevated, returned to normal. This advice is unsound and contrasts with medical attitudes to the prevention of other rare side effects. It has led to significant delays in starting treatment which are probably much more hazardous than the very slight risks of hepatotoxicity. We recommend that the guidelines be modified in favour of an approach which emphasizes the education of patients and their carers and clinical rather than laboratory monitoring.
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The in vitro reaction between disulfiram (DSF) and N-nitroso[14C]dimethylamine [( 14C]NDMA) was studied. Incubations of DSF with [14C]NDMA were carried out in the presence of rat liver microsomes, control 9000 g (S9) supernatant fraction and phenobarbital-induced S9 fraction. H.p.l.c. analysis and liquid scintillation measurement provided evidence for the formation of methyldiethyldithiocarbamate (MeDDTC) as a product of the reaction between diethyldithiocarbamate (DDTC), the main active metabolite of DSF and the 'methyl-cation' released by NDMA after enzymatic activation. The amount of MeDDTC found here was consistent with the rate of oxidation of NDMA to formaldehyde. Scintillation counting confirmed that other radioactive peaks, not due to MeDDTC, were unrelated to the methylation of L-cysteine by [14C]NDMA.
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Male Sprague-Dawley rats were pretreated with various chemicals to determine their effects on the microsomal activation of the esophageal carcinogen N-nitrosomethylbenzylamine [( NMBzA ) CAS: 937-40-6; N-methyl-N- nitrosobenzylamine ] in the rat esophagus and, for comparative purposes, in the rat liver. When rats were pretreated with NMBzA , little change in hepatic NMBzA - debenzylase activity was observed. In contrast, NMBzA metabolism in the esophagus was significantly (60-65%) reduced. Similarly, pretreatment of rats with disulfiram [CAS: 97-77-8; bis( diethylthiocarbamoyl )disulfide] caused a 40% decrease in esophageal metabolism, but it had no significant effect in the liver. Pretreatments with the methylenedioxybenzenes safrole [CAS: 94-59-7; 4-allyl-1,2-(methylenedioxy)benzene], isosafrole [CAS: 120-58-1; 1,2-(methylenedioxy)-4-propenylbenzene], and dihydrosafrole (CAS: 94-58-6; 1,2-(methylenedioxy)-4- propylbenzene ) caused a marked induction (twofold to fivefold) of the hepatic metabolism of NMBzA , but again esophageal metabolism was suppressed. The results indicate that esophageal metabolism of NMBzA is either unchanged or suppressed by the various chemical pretreatments, but hepatic metabolism of the nitrosamine is induced by the methylenedioxybenzenes .
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The major soluble protein in bovine corneal epithelial extracts is a 54 kD protein (BCP 54) which has recently been identified as the corneal aldehyde dehydrogenase. Although ALDH activity has been reported in human corneal extracts it was not yet clear whether this was identical with the 54 kD protein described in bovine corneas. To investigate this question, we studied human corneal extracts for the presence of ALDH using enzyme analysis, SDS-PAGE, native electrophoresis, isoelectric focusing and immunoblotting techniques. The corneal epithelium was the most active layer (8.46 +/- 1.9 IU/mg protein) followed by the stroma (2.83 +/- 0.56 IU/mg protein) and endothelium (0.06-3.6 IU/mg protein). When comparing substrate specificity between human and bovine corneal ALDH, using NADP as coenzyme, it was shown that the human enzyme preferred benzaldehyde whereas the bovine enzyme revealed the strongest enzymatic activity with hexanal. Human corneal ALDH was partly inhibited by disulfiram. Bovine and human cornea ALDH lost their enzymatic activity after heating at temperatures above 56 degrees C. Both human and bovine corneal extracts contained a prominent 54 kD protein which reacted with a rabbit anti BCP 54 antibody. Isoelectric focusing followed by enzyme staining in the gel revealed 5 human corneal isozyme species and 4 in bovine corneal extracts, migrating at a pH between 6.5 and 7.0. All isozymes could also be detected after immunoblotting with a rabbit anti BCP 54 antibody.
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We show that acidic pH significantly potentiates toxicity of DSF/Cu(2+) complex to breast and colon cancer cells. This phenomenon is associated with changes in cell metabolism, altered Akt kinase and NFκB activity and increased reactive oxygen species production.
We previously reported a synergistic anticancer action of clioquinol and docosahexaenoic acid (DHA) in human cancer cells. However, clioquinol has been banned from the clinic due to its neurotoxicity. This study identified disulfiram (DSF) as a substitute compound to clioquinol, acting in concert with DHA to more effectively kill cancer cells and suppress tumor growth. Treatment with DSF and DHA induced greater apoptotic cell death and suppression of tumor growth in vitro and in vivo, as compared to DSF and DHA used alone. Mechanistic studies demonstrated that DSF enhances DHA-induced cellular oxidative stress as evidenced by up-regulation of Nrf2-mediated heme oxygenase 1 (HO-1) gene transcription. On the other hand, DHA was found to enhance DSF-induced suppression of mammosphere formation and stem cell frequency in a selected cancer model system, indicating that alterations to cancer cell stemness are involved in the combinatory anticancer action of DSF and DHA. Thus, DHA and DSF, both clinically approved drugs, act in concert to more effectively kill cancer cells. This combinatory action involves an enhancement of cellular oxidative stress and suppression of cancer cell stemness.
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The effect of flomoxef, a newly developed oxacephem antibiotic with an N-hydroxyethyltetrazolethiol (HTT) side chain, on blood coagulation and alcohol metabolism was compared with that of a series of cephalosporin antibiotics with N-methyltetrazolethiol (NMTT), thiadiazolethiol (TDT) or methylthiadiazolethiol (MTDT) side chains in position 3' of the cephalosporin nucleus known to cause hypoprothrombinemia and bleeding in patients who are malnourished, debilitated and/or of high age. A disulfiram-like effect caused by inhibition of aldehyde dehydrogenase was observed for NMTT-containing antibiotics. Studies were carried out on healthy volunteers and on rats. Eight-day treatment with 2 g flomoxef i.v. once or twice daily in five and six healthy male volunteers, respectively, did not cause any significant changes in prothrombin time (PT), coagulation factors II, VII, IX or X, in hepaplastin values or fibrinogen levels, activated partial thromboplastin time (APTT), platelet counts, bleeding time, or collagen- and ADP-induced platelet aggregation. Inhibition of vitamin K epoxide reductase was observed in rats treated with flomoxef, yet to a much lesser extent than observed for cephalosporins with NMTT, TDT or MTDT side chains. This defect was quickly normalized by vitamin K injection. There were no differences between oxacephem (1-O) and cephem (1-S) compounds with respect to effects on blood clotting and platelet aggregation. Flomoxef and its side chain HTT showed no influence on alcohol metbolism.
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Factorial randomized double blind (for medication condition) clinical trial where CBT served as the platform and was delivered in weekly individual sessions in a community-based outpatient clinic. 99 outpatients who met DSM-IV criteria for current cocaine dependence were assigned to receive either disulfiram or placebo, and either CM or no CM. Cocaine and other substance use was assessed via a daily calendar with thrice weekly urine sample testing for 12 weeks with a one-year follow-up (80% interviewed at one year).
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Amongst validated psychological treatments, brief intervention appears to be the best suited for primary care. It aims at increasing motivation for change after a screening for an alcohol use disorder. The first therapeutic step for an alcohol-dependent patient aiming at abstinence is alcohol detoxification. At this stage, benzodiazepines should be briefly prescribed if the patient manifests clinically significant withdrawal symptoms. The next step is relapse prevention, for which only three medications are currently validated in France, acamprosate, naltrexone, and disulfiram.
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A cohort study of n = 209 alcoholic patients (DSM-IV) during 6 months of outpatient treatment. Eight medical doctors from two hospitals were involved. Co-responsible participation in treatment was a necessary condition. At admission, we documented socio demographic factors, use of other drugs and severity of alcohol consumption. During the 6 months, we observed medication for prevention of alcohol relapse [disulfiram (DIS), acamprosate], number of sessions with the doctor, number of phases of the consultation and medication for depression. Primary outcome variables were time to first heavy relapse and abstinence of heavy alcohol consumption. These were measured with Timeline Followback. Five or more alcohol units of 10 g in one relapse day were considered heavy relapse.
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Most models for the study of the mechanism of intestinal absorption of Cadmium (Cd) have been using intestinal tissue in vitro or in situ. The in vivo experiments reported in this article were performed in an attempt to localize the site for gastrointestinal absorption of cadmium chloride during natural physiological conditions by oral exposure of mice to 109Cd-labelled CdCl2. Independent of exposure via drinking water or oral administration of a single dose, Cd was primarily deposited in the most proximal duodenum. Thus the present study as well as others indicate that absorption takes place in the proximal part of the intestine. Absorbed Cd is initially transported to the liver and deposited before being redistributed and accumulated in the kidneys. In this experimental model, dietary tetraethylthiuram disulfide exposure was shown to change the intestinal labelling profile and increase the whole-body retention as well as the intestinal deposition of Cd.
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All relevant randomised controlled trials (RCTs) and clinical control trials (CCTs) were included. Participants were people with alcohol dependence, diagnosed by any set of criteria, except alcohol dependence who were currently abstinent. Naltrexone (NTX), nalmefene (NMF) and other opioid antagonists with/without other biological or psychosocial treatments were examined. A variety of clinical outcomes, for example alcohol consumption, duration of abstinence, were considered.
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BEN had a plasma t½ <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold (AUC0-inf from 0.11 to 40.5 mg/L min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0-1.5 % of dose), while BA excretion was unchanged. Hematocrit, white blood cell counts, and percentage lymphocytes decreased after BEN administration. Coadministration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN.
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The quite diffused habit of a significant assumption of alcohol drinks, can interfere with the professional exposure to chemical substances. The interaction may result in increasing their toxicity and/or modifying the parameters of the biological monitoring. It may also act as a confounding factor, not only in epidemiologic researches but also at individual level when the assessment of the occupational exposure and/or the diagnosis of an occupational diseases, is under consideration. We review available references in the literature summarizing major scientific evidences.