Use Of Disulfiram Research Articles

Les innovations thérapeutiques en alcoologie

Psychosocial support remains the key element of treatment of alcohol-dependent patients in order to either decrease or cease their alcohol consumption. DrugsTwo drugs can now be used to reduce alcohol consumption: nalmefene and baclofen in the context of a “temporary use recommendation”. Currently available studies have shown weak to moderate effect sizes in this indication, but better results have been reported in populations confined to heavy drinkers. Four molecules are available to help patients maintain abstinence: acamprosate, naltrexone, disulfiram and baclofen. Effect sizes calculated by various meta-analyses are also low to moderate. Disulfiram appears to be more effective when the patient has understood its mechanism action and when it is used under supervision. However, the use of disulfiram is limited by the risk of rare, but potentially serious adverse effects. Identification of patient subgroups obtaining better responses to certain drugs constitutes a major research challenge, but only a few criteria have been defined to date. However, regardless of the drug considered, heavy drinking and difficulty to maintain abstinence significantly improve the effect size of the drug. After an initially promising period, especially concerning polymorphism of the OPMR1 gene coding for the morphine μ receptor, identification of genetic markers has not yet resulted in any clinical applications. Promising molecules currently under evaluation include sodium oxybate and topiramate. Among non-pharmacological treatmentsInteresting results have been demonstrated with acceptance and commitment therapy (mindfulness-based cognitive therapy). Studies have also been conducted on cognitive disorders that constitute risk factors for relapse and that limit the efficacy of treatment. The elaboration of cognitive remediation therapy programmes is an important objective for the future. Magnetic or continuous current transcranial brain stimulation methods also open up interesting perspectives, but further studies are necessary to define the place of these treatments in the management of addictive behaviours. PerspectivesFinally, the development of e-health opens up particularly encouraging perspectives to provide patients with information, to help them evaluate and monitor their consumption, to propose assistance and responses in high-risk settings or relapse or to use various therapeutic methods integrated in smartphone applications.

Disulfiram/copper causes ROS levels alteration, cell cycle inhibition, and apoptosis in acute myeloid leukaemia cell lines with modulation in the expression of related genes

The majority of acute myeloid leukaemia (AML) patients will die from their disease or therapy-related complications. There is an inevitable need to improve the survival of AML patients. Previous studies show that disulfiram (DSF), an anti-alcoholism drug with a low toxicity profile, demonstrates anticancer behaviors. Here, we evaluated the cytotoxicity and mechanistic action of DSF on the AML cell lines KG-1, NB4, and U937. The microculture tetrazolium test revealed that DSF alone or in combination with copper (Cu) is highly toxic to the AML cells at concentrations lower than those achievable in the clinical setting, with Cu increasing the DSF-induced inhibition of metabolic activity. Flow cytometric analysis and QRT-PCR indicated that in the two cell lines, NB4 and U-937, DSF/Cu increased reactive oxygen species (ROS) levels in association with the induction of superoxide dismutase 2 (SOD2) expression and suppression of catalase (CAT). In the KG-1 cell line, DSF/Cu reduced the ROS levels in agreement with the induction of CAT expression. The cell cycle and apoptosis assessment by flow cytometry demonstrated that DSF/Cu induced G0/G1 cell cycle arrest and apoptosis. These were associated with the increased expression of FOXO tumor suppressors, decreased expression of the MYC oncogene and the modulation of their known target genes related to the cell cycle and apoptosis. Therefore, DSF/Cu caused the disturbance of the ROS balance, cell cycle arrest and apoptosis in AML cells in coordination with the modulation in expression of their related genes. These results propose the possible use of DSF in AML therapies.

Abstract 2041: High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy

Abstract Introduction and Objectives Gemcitabine and cisplatin chemotherapy (GC) is the current standard regimen for locally advanced and metastatic bladder cancer (BC). Despite a relatively high initial response rate, some cases do not regress (intrinsic resistance) and the remaining cases often show regrowth after initial shrinkage (acquired resistance). To identify novel therapeutic agents for overcoming these resistances, we applied a high-throughput screening of chemicals administered in combination with GC. Methods As a high-throughput screening, 2100 compounds were administered alone or in combination with GC to human BC cell lines (J82, UMUC-3). Cell viability was determined after 3-day incubation and chemicals that enhanced inhibitory effect of GC were screened. The in vivo effect of disulfiram (DSF) was studied in UMUC-3 cell xenografts, and western blot, immunofluorescence, induced coupled plasma spectrometry and measurement of reactive oxygen species (ROS) were done in vitro for mechanistic exploration. Results The initial screening identified 26 compounds and further validation narrowed them into the most synergistic agent DSF, an FDA-approved drug for alcoholism. Combination index assay showed synergistic effects of DSF with cisplatin but not with gemcitabine in J82, UMUC-3, T24, HT1197 and HT1376 cells. Co-administration of DSF significantly increased DNA-platinum adducts by regulating cisplatin efflux transporter ATP7A and enhanced apoptosis by GC treatment in UMUC-3 cells, with significant increase of ROS production. Use of DSF in combination with GC (GCD) significantly inhibited tumor growth of UMUC-3 subcutaneous xenograft on athymic mice (by 39% compared with GC alone, p = 0.02). GCD regimen was as tolerable as GC and no significant differences were observed in body weight of treated mice between the two regimens. Conclusions Repositioning of DSF to a chemotherapy sensitizer is a promising treatment strategy, which can be translated rapidly in the future. Citation Format: Yuki Kita, Takashi Kobayashi, Ryouichi Saito, Toshinari Yamasaki, Takahiro Inoue, Osamu Ogawa. High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2041. doi:10.1158/1538-7445.AM2017-2041

Review article: pharmacotherapy for alcohol dependence - the why, the what and the wherefore.

The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended. To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors' unwillingness to prescribe these agents, will be explored. Relevant papers were selected for review following extensive, language- and date-unrestricted, electronic and manual searches of the literature. Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost-effectiveness while the risks associated with the use of disulfiram are well-known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co-occurring drug-related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine. Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition.

Inhibition of Urease by Disulfiram, an FDA-Approved Thiol Reagent Used in Humans.

Urease is a nickel-dependent amidohydrolase that catalyses the decomposition of urea into carbamate and ammonia, a reaction that constitutes an important source of nitrogen for bacteria, fungi and plants. It is recognized as a potential antimicrobial target with an impact on medicine, agriculture, and the environment. The list of possible urease inhibitors is continuously increasing, with a special interest in those that interact with and block the flexible active site flap. We show that disulfiram inhibits urease in Citrullus vulgaris (CVU), following a non-competitive mechanism, and may be one of this kind of inhibitors. Disulfiram is a well-known thiol reagent that has been approved by the FDA for treatment of chronic alcoholism. We also found that other thiol reactive compounds (l-captopril and Bithionol) and quercetin inhibits CVU. These inhibitors protect the enzyme against its full inactivation by the thiol-specific reagent Aldrithiol (2,2′-dipyridyl disulphide, DPS), suggesting that the three drugs bind to the same subsite. Enzyme kinetics, competing inhibition experiments, auto-fluorescence binding experiments, and docking suggest that the disulfiram reactive site is Cys592, which has been proposed as a “hinge” located in the flexible active site flap. This study presents the basis for the use of disulfiram as one potential inhibitor to control urease activity.

Disulfiram's Anticancer Activity: Evidence and Mechanisms.

Disulfiram (DSF), a derivative of thiuram, has been used in humans to treat alcoholism for more than 60 years. Over the past decade, however, increasing evidence indicates that DSF possesses a great potential for the treatment of human cancers. DSF's anticancer activity has been demonstrated in both in vitro and in vivo model systems, and has been tested in human clinical trials for various cancer types. It is also evident that DSF can sensitize tumor cells to radiotherapy and enhance the cytotoxicity of anticancer drugs, thus DSF may serve as an adjuvant therapy. The key to DSF's anticancer action relates to its ability to suppress cancer stem cells by targeting aldehyde dehydrogenase (ALDH), a marker of cancer stem cells, and inhibit proteasome activity in cancer cells by forming complexes with metal ions. In addition, DSF targets epigenetic mechanisms and modulates cellular signaling pathways to slow down tumor progression. DSF also induces apoptosis, inhibits cancer cell proliferation, and suppresses cancer cell metastasis. Considering that the pharmacokinetics of DSF are well-established and a safety profile has been recorded, this compound is an attractive "old" drug that has great potential for rapid development into a new cancer therapeutic. This article provides a brief review of the history of DSF use in humans, evidence for its anticancer activities, the molecular mechanisms of DSF action that have been illustrated by recent studies, and the potential for repurposing DSF as a new chemotherapeutic drug in the near future.

Causes and strategies of limiting psychoactive substance use by female escort agency sex workers

IntroductionPurpose of the article is to analyse the motives of the decision to limit or stop using psychoactive substances (mainly alcohol) by female escort agency sex workers. Also presented are sex workers’ strategies to realise those objectives despite easy access to psychoactive substances and co-worker or client pressure to use them. MethodThe empirical basis of the article is in the form of 43 in-depth interviews with female escort agency sex workers. All interviewees declared they have attempted to limit consumption of psychoactive substances. Transcriptions and notes from the interview underwent analysis according to Grounded Theory methodology; that is open, selective, axial and theoretical coding. A constant comparative method was also employed. ResultsIndoor sex workers undertake activities intended to limit the amount of used substances, resulting from self-reflection, influence of significant others or pressure from agency managers. The researched women tried to achieve the objective through several strategies: limitation of amount and type of consumed substances, controlled alcohol/drug consumption, change of the agency to one with a less liberal approach to substance use and application of disulfiram. ConclusionsEscort agency sex workers use the public support system for addicted individuals to an insignificant extent. They also do not participate in the Anonymous Alcoholics meetings. The crossing stigma related to prostitution and psychoactive substance abuse encourage them to undertake independent attempts to limit consumption, especially such that do not require participation in a therapy or in self-help groups.

Abstract 5046: High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy

Abstract Background Gemcitabine and cisplatin chemotherapy (GC) is the current standard regimen for locally advanced and metastatic bladder cancer (BC). Despite a relatively high initial response rate, some cases do not regress (intrinsic resistance) and the remaining cases often show regrowth after initial shrinkage (acquired resistance). To identify novel therapeutic agents for overcoming these resistances, we applied a high-throughput screening of chemicals administered in combination with GC. Methods and Findings As a high-throughput screening, 2100 compounds were administered alone or in combination with GC to human BC cell lines (J82, UMUC-3). Cell viability was determined after 3-day incubation and chemicals that enhanced inhibitory effect of GC were screened. The initial screening identified 26 compounds and further validation narrowed them into the most synergistic agent disulfiram (DSF), an FDA-approved drug for alcoholism. Combination index assay showed synergistic effects of DSF with cisplatin but not with gemcitabine in J82, UMUC-3, T24, HT1197 and HT1376 cells. Co-administration of DSF significantly enhanced apoptosis by GC treatment in UMUC-3 and T24 cells, with significant increase of reactive oxygen species (ROS) production. DSF-induced apoptosis was attenuated in the presence of N-acetyl L-cysteine and Trolox, ROS scavengers. Use of DSF in combination with GC (GCD) significantly inhibited tumor growth of UMUC-3 subcutaneous xenograft on athymic mice (by 39% compared with GC alone, p = 0.02). GCD regimen was as tolerable as GC and no significant differences were observed in body weight of treated mice between the two regimen. Conclusion Repositioning of DSF to a chemotherapy sensitizer is a promising treatment strategy, which can be translated rapidly in the future. Citation Format: Yuki Kita, Takashi Kobayashi, Norihiko Masuda, Atsuro Sawada, Yoshiyuki Matsui, Takahiro Inoue, Tomomi Kamba, Osamu Ogawa. High-throughput chemical screening for sensitization of bladder cancer to gemcitabine and cisplatin chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5046.

Non-physiological mechanisms influencing disulfiram treatment of alcohol use disorder: A grounded theory study

BackgroundThe mechanism of action of disulfiram is not clear and recent systematic reviews have reached differing conclusions. The purpose of this research was to develop a conceptual model of the mechanisms that underpin the effective use of disulfiram in management of alcohol used disorder. MethodsGrounded theory was used, based on anonymized transcripts of in-depth interviews with 14 individual clients who experienced taking disulfiram for alcohol use disorder within the context of a specialized clinic setting from New Zealand. ResultsThe central concept was that of abstinence being a psychosocial construction, with the taking of disulfiram, being a physical manifestation of the decision not to drink. The main subthemes included the importance of participants believing in the potential for disulfiram producing a negative reaction, the increased autonomy achieved by disulfiram removing the need to ruminate on drinking decisions, and the importance of external structure, routine, and social contact with others to support ongoing engagement with disulfiram therapy. ConclusionsThe physiological effects of disulfiram, in particular its adverse reaction when combined with alcohol, explains only part of its effect on problem drinking behaviour. The act of taking a disulfiram pill is also partly symbolic of making an absolute decision not to drink for a short period, allowing people with alcohol use disorder to explore other options for managing life without alcohol. Drug trials involving disulfiram need to treat it not simply as pharmaceutical but as part of a complex psychosocial intervention conducted within a supportive social context.

The practical use of placebo effect in psychotherapeutic treatment of patients with substance use disorders: therapeutic and ethic consequences

The article discusses therapeutic potential of placebo and nocebo effects in treatment of substance use disorders. The authors review the background of the issue, describe neurobiological and psychological mechanisms of placebo effects and demonstrate their impact on psychotherapy of patients with substance use disorders. Attention is drawn to the clinical and ethical issues of practical use of placebo effects including that in terms of placebo-therapy, indirect suggestion psychotherapy, motivational interventions and cognitive-behavioral psychotherapy, psychotherapy with the use of disulfiram, psychopharmacotherapy with opioid antagonists. The authors conclude that the ethical use of placebo-effects in treatment of substance use disorders may improve its overall efficiency.

Disulfiram inhibition of cyanide formation after acetonitrile poisoning

Context Cyanide poisoning may be caused by acetonitrile, a common industrial organic solvent and laboratory agent. Objective To describe the potential use of disulfiram in treating acetonitrile poisoning in a human clinical case and to further study its effect in human liver microsomes in vitro. Case details A 30-year-old man initially presented with a cholinergic toxic syndrome following ingestion of aldicarb. Toxicological analysis revealed coingestion of ethanol. He subsequently developed severe metabolic acidosis caused by the cyanogenic compound acetonitrile which was erroneously interpreted as acetone in the chromatogram. After three treatments with hydroxocobalamin (5 g i.v.) and sodium thiosulfate (12.5 g i.v.) on days 2, 3, and 5, he had transient improvement but recurrent lactic acidosis. Treatment with disulfiram was associated on day 7 with resolution of metabolic acidosis and slowing of the decrease in acetonitrile concentration. He recovered from acetonitrile toxicity completely. The time course of acetonitrile, thiocyanate, and cyanide concentrations suggested that disulfiram inhibited cyanide formation. Results In vitro experiments with human liver microsomes showed the cyanide concentration was significantly lower after incubation with acetonitrile and disulfiram than acetonitrile alone (a mean 60% reduction in cyanide level). Discussion Although disulfiram was given late in the course of the poisoning it is possible that it contributed to the recovery.

Use of Disulfiram for Alcohol Relapse Prevention in Patients in Opioid Maintenance Treatment

The aim of this study was to assess the effectiveness, tolerability, and safety of alcohol relapse prevention with disulfiram in alcohol-dependent patients in opioid maintenance treatment under routine treatment conditions. Twenty-nine opioid maintenance treatment patients were observed from the beginning of outpatient disulfiram treatment for up to 6 months. Patients received disulfiram (mostly 300 mg/d) together with their daily opioid dose. Patients were assessed through urine screens for alcohol (ethyl gluconoride) and other drugs at least twice monthly; blood chemistry analyses after 1, 3, and 6 months; and clinical interviews after 3 and 6 months. Most patients presented with somatic and/or psychiatric comorbidity and/or polydrug use at baseline. Half of the patients completed 6 months of disulfiram treatment. Alcohol use was low during disulfiram treatment. Levels of other drug use did not change. For most patients, 1 or more adverse events were reported, often mild and/or short lived. Three patients experienced severe adverse events attributable to disulfiram. Disulfiram is a viable treatment option for the high-risk population studied here. A close monitoring of side effects and adverse events is necessary, in particular, in patients with polysubstance use.

SY18-2 * EFFICACY OF DISULFIRAM FOR THE TREATMENT OF ALCOHOL DEPENDENCE ASSESSED WITH A MULTI-CENTER RANDOMIZED CONTROLLED TRIAL

Introduction. The efficacy of disulfiram in preventing an alcoholic relapse has been controversial. The aim of our study was to assess the efficacy of supervised disulfiram for the treatment of alcohol dependence with a multi-institutional study in Japan. Methods. In a single-blinded, randomized placebo-controlled study, we recruited 109 patients diagnosed with alcohol dependence under ICD-10 criteria. The patients were randomly allocated to four treatment groups, depending on whether they took disulfiram (200 mg daily) or a placebo or whether they received adjunctive therapy consisting of mailed letters which delineated and emphasized the harmful effect of alcohol and the management of alcohol craving. The proportion of abstinence among the four groups at 26 weeks after discharge was the primary outcome measure. Furthermore, we examined the proportion of abstinence in patients with inactive aldehyde dehydrogenase-2 (ALDH2). Results. There were no significant differences among the four groups in terms of abstinent patients or study drop-outs. Patients with inactive ALDH2 significantly sustained abstinence with the use of disulfiram (P = 0.044). Conclusions. Supervised oral disulfiram use followed by intervention via letters seems to be ineffective for increasing abstinence. We indicated the effectiveness of disulfiram for the maintenance of abstinence in patients with inactive ALDH2.

SY30-3 * THE USE OF SOPHISMS IN SUSTAINING DISULFIRAM

Disulfiram's use is not supported by scientific evidence but nevertheless largely advocated and used. This would be less odd in case of lacking or just preliminary evidence. What is peculiar in the case of disulfiram's prescription is its persistence against evidence. Hence arise the question how it is possible that its use can be supported, i.e. by what type of arguments. The goal of an argument is to persuade, the goal of logic and argumentation is additionally to persuade for good reasons. In this sense, a good argument would give good reasons to believe the conclusion. Fallacies are bad arguments, either because they have weak logic, or because they rely on a false premise. Sophisms are intentionally used fallacies, an attempt to persuade opponents that a specific conclusion is true, by means other than by proposing relevant evidence. Proponents of fallacious arguments may use them either because they are incapable or because they are unwilling to accept their arguments to be fallacious. We therefore formulate the hypothesis that the frequency use of fallacious arguments within our otherwise supposedly evidence based discipline may be indicative of (a) a scientifically immature discipline, and/or (b) a moralistically intermingled discipline.

P34: Unexpected cardiac arrhythmias during the course of a disulfiram-ethanol reaction

Disulfiram-ethanol reactions may sometimes be accompanied by some serious cardiocirculatory complications, including tachycardia and profound hypotension. Life-threatening cardiac arrhythmias are infrequent and cardiac manifestations are usually limited in time. We describe a recent case with unexpected electrocardiographic findings and cardiac arrhythmias during the course of a disulfiram-ethanol reaction. A 57-year-old man, chronic ethanol abuser, was brought by the relatives to the Emergency Department (ED). Fifteen hours before hospital admission, he had ingested one litre of whisky together with 20 grams of disulfiram. His chronic medications also included prothipendyl and citalopram. An electrocardiogram (ECG) performed one year before had showed a QTc interval < 450 msec. The patient had no personal or familial history of serious cardiac events. He rapidly developed during the night symptoms consisting with a disulfiram/ethanol reaction (facial flush, nausea, vomiting, diarrhea…) and that were still present on ED arrival. Admission heart rate was 126/min, with arterial blood pressure 179/107 mm Hg. Initial ECG showed atrial fibrillation with high ventricular response (126/min), and QTc 435 msec. The admission troponin-I concentration was 0.01 ng/ml (<0.08). Toxicological analysis showed: ethanol serum level 0,6 g/l, prothipendyl and citalopram < 5 ng/ml. Routine laboratory investigations showed normal potassium, magnesium and calcium serum concentrations. The patient was transferred to the observation unit for further ECG monitoring during the night. No specific treatment was applied. After spontaneous return to sinus rhythm, he became progressively bradycardic (HR < 50/min), but arterial blood pressure was well preserved. By the next morning (> 34 hours after exposure to disulfiram), the ECG revealed sinus rhythm (39/min) with a QTc interval at 588 msec and a few minutes later, the patient presented “torsades de pointe” and ventricular fibrillation. He was successfully resuscitated by electric counter shock. The troponin-I concentration was slightly increased (0.26 ng/ml), no electrolytes disorders were observed. Coronary angiography was normal. The QTc interval remained > 500 msec during the hospital stay. The patient was observed one month later, with a normal QTc interval on the ECG. Sinus tachycardia with ischemic-like ST segment changes is a usual feature of disulfiram-ethanol reaction. The onset of an acute prolongation of the QT interval in the context of drug poisoning raises a concern about a causative link between both factors. A direct effect of disulfiram alone or in combination with ethanol on the QT interval seems, however, unlikely. Indeed, despite the wide use of disulfiram, the drug has not been reported to modify the QT interval. Moreover, as the disulfiram-ethanol reaction appears usually soon after ingestion, the first ECG (15 h postingestion) did not reveal QT prolongation. The role of the autonomic nervous system and genetic predispositions has to be kept in mind. QTc prolongation may be absent on routine ECG and may be only revealed when several co-factors are present. Ionic disturbances were ruled out in the present case. It was supposed that the intense stimulation of the autonomic nervous system due to the disulfiram-ethanol reaction may have influenced the QT interval in a patient who could be an asymptomatic carrier of an ion channel mutation responsible of a latent congenital long QT syndrome.

Isidore of Seville, eels and disulfiram.

In 2010 I corresponded with this journal (Mac Suibhne, 2010) about intriguing parallels between a comment made by the 17th Century English botanist, physician, astrologer and herbalist Thomas Culpeper in his ‘Complete Herbal’ and the use of disulfiram. Culpeper's specific words were ‘eels, being put into wine or beer, and suffered to die in it, he that …

Diethyldithiocarbamate complexes with metals used as food supplements show different effects in cancer cells

Diethyldithiocarbamate (ditiocarb), a metabolite of the old anti-alcoholic drug disulfiram (Antabuse), forms proteasome-inhibiting metal complexes with copper or zinc that suppress cancer cells both in vitro and in vivo. The drug has been used in a clinical trial (NCT00742911) along with copper gluconate as a dietary supplement in patients with cancer spreading to the liver. In this study, we demonstrate the effect of synthetic complexes of disulfiram with four various metals (Mn, Fe, Cr and Cu) used as food supplements. These complexes may be spontaneously formed in the blood during the use of disulfiram with divalent metals and thus may suppress the growth of cancer in vivo. The cytotoxic effect of the compounds and the compounds’ ability to inhibit the cellular proteasome were tested in the osteosarcoma cell line U2OS. After 48h, copper and manganese complexes exhibited cytotoxic effect on the cell line, in sharp contrast to both iron and chromium complexes.

Use of disulfiram and risk of cancer

Experimental studies have indicated that disulfiram (Antabuse) has antineoplastic effects against melanoma, breast, and prostate cancer. To explore this hypothesis, we examined the association between disulfiram use and these cancers in a nationwide register-based case-control study nested within ever-users (≥one prescription) of disulfiram. Cases were all Danish individuals with a histologically verified first-time diagnosis of malignant melanoma, breast, or prostate cancer during 2000-2009. For each case, we selected four cancer-free controls matched for age, sex, and year of first disulfiram prescription using risk set sampling. Similarly, for secondary analyses, we selected case-control populations for selected tobacco-related and alcohol-related cancer types, that is, cancers of the buccal cavity, liver, lung, and colorectal cancer. Disulfiram use 1 year before cancer diagnosis and the corresponding date for controls were disregarded. We estimated crude and adjusted odds ratios and 95% confidence intervals (CI) for cancer associated with long-term (≥500 daily defined doses) versus one-time (one prescription) use of disulfiram. Among 53 856 disulfiram users, we identified 166, 644, and 464 cases, respectively, of melanoma, breast, or prostate cancer. Adjusted odds ratios for melanoma, breast, or prostate cancer associated with long-term disulfiram use were 1.04 (95% CI: 0.60-1.78), 0.92 (95% CI: 0.70-1.22), and 0.77 (95% CI: 0.56-1.06), respectively. For prostate cancer, dose-response analyses showed a further risk reduction with the highest cumulative dose level of disulfiram; however, the test for trend did not reach statistical significance. Our study provides some epidemiological support for a protective effect of disulfiram against prostate and breast cancer.

Disulfiram Efficacy in the Treatment of Alcohol Dependence: A Meta-Analysis

BackgroundDespite its success with compliant or supervised patients, disulfiram has been a controversial medication in the treatment of alcoholism. Often, study designs did not recognize a pivotal factor in disulfiram research, the importance of an open-label design. Our objectives are: (1) to analyze the efficacy and safety of disulfiram in RCTs in supporting abstinence and (2) to compare blind versus open-label studies, hypothesizing that blinded studies would show no difference between disulfiram and control groups because the threat would be evenly spread across all groups.Methods and FindingsWe searched PubMed, EMBASE and the Cochrane Central Register for RCTs on disulfiram use with alcoholics in comparison to any alcoholic control group. The primary outcome was defined by the authors of each trial. Additional analyses included: blind vs. open-label, with or without supervision, cocaine study or not, and type of control. Overall, the 22 included studies showed a higher success rate of disulfiram compared to controls Hedges'g = .58 (95%CI = .35–.82). When comparing blind and open-label RCTs, only open-label trials showed a significant superiority over controls g = .70 (95%CI = .46–.93). RCTs with blind designs showed no efficacy of disulfiram compared to controls. Disulfiram was also more effective than the control condition when compared to naltrexone g = .77, 95%CI = .52–1.02, to acamprosate g = .76, 95%CI = .04–1.48, and to the no disulfiram groups g = .43, 95%CI = .17–.69. Limits include: (1) a population of 89% male subjects and (2) a high but unavoidable heterogeneity of the studies with a substantial I-square in most subgroups of studies.ConclusionsBlinded studies were incapable of distinguishing a difference between treatment groups and thus are incompatible with disulfiram research. Based on results with open-label studies, disulfiram is a safe and efficacious treatment compared to other abstinence supportive pharmacological treatments or to no disulfiram in supervised studies for problems of alcohol abuse or dependence.

Medications for Alcohol Use Disorders in a Primary Care Practice-Based Research Network Implementation Study

National Institute on Alcohol Abuse and Alcoholism recommendations encourage clinicians to consider the use of alcohol medications (ARx), acamprosate, disulfiram, naltrexone, or topiramate, for patients with alcohol use disorders (AUD). These recommendations have not yet been implemented in U.S. primary care practices. This mixed-methods substudy reports overall ARx use and facilitators to ARx use observed during a group-randomized trial in 19 practices. Nine percent of patients with a documented AUD diagnosis (n = 149 patients) received an ARx prescription. Facilitators to ARx use were exposure to evidence, limited referral options, receptive patients, successful outcomes, low cost of oral naltrexone, and familiarity with topiramate. Findings may affect the development of future primary care implementation programs.