Repurposing Disulfiram as An Anti-Cancer Agent: Updated Review on Literature and Patents.

BACKGROUND: Despite years of success of most anti-cancer drugs, one of the major clinical problems is inherent and acquired resistance to these drugs. Overcoming the drug resistance or developing new drugs would offer promising strategies in cancer treatment. Disulfiram, a drug currently used in the treatment of chronic alcoholism, has been found to have anti-cancer activity. OBJECTIVE: To summarize the anti-cancer effects of Disulfiram through a thorough patent review. METHODS: This article reviews molecular mechanisms and recent patents of Disulfiram in cancer therapy. RESULTS: Several anti-cancer mechanisms of Disulfiram have been proposed, including triggering oxidative stress by the generation of reactive oxygen species, inhibition of the superoxide dismutase activity, suppression of the ubiquitin-proteasome system, and activation of the mitogen-activated protein kinase pathway. In addition, Disulfiram can reverse the resistance to chemotherapeutic drugs by inhibiting the P-glycoprotein multidrug efflux pump and suppressing the activation of NF-kB, both of which play an important role in the development of drug resistance. Furthermore, Disulfiram has been found to reduce angiogenesis because of its metal chelating properties as well as its ability to inactivate Cu/Zn superoxide dismutase and matrix metalloproteinases. Disulfiram has also been shown to inhibit the proteasomes, DNA topoisomerases, DNA methyltransferase, glutathione S-transferase P1, and O6- methylguanine DNA methyltransferase, a DNA repair protein highly expressed in brain tumors. The patents described in this review demonstrate that Disulfiram is useful as an anti-cancer drug. CONCLUSION: For years the FDA-approved, well-tolerated, inexpensive, orally-administered drug Disulfiram was used in the treatment of chronic alcoholism, but it has recently demonstrated anti-cancer effects in a range of solid and hematological malignancies. Its combination with copper at clinically relevant concentrations might overcome the resistance of many anti-cancer drugs in vitro, in vivo, and in patients.

[Ambulatory alcohol withdrawal]. / Der ambulante qualifizierte Alkoholentzug.

Alcohol addiction is a common problem in daily life as well as in medicine. Apart from inpatient therapy programs, ambulatory withdrawal is a relatively new option, which may be done safely, efficient and cost-effective close to the domicile an without stigmatisation of the patient.

Alcohol dependence treatments: comprehensive healthcare costs, utilization outcomes, and pharmacotherapy persistence.

OBJECTIVES: To determine the healthcare costs associated with treatment of alcohol dependence with medications versus no medication and across the 4 medications approved by the US Food and Drug Administration (FDA). STUDY DESIGN: Retrospective claims database analysis. METHODS: Eligible adults with alcohol dependence were identified from a large US health plan and the IMS PharMetrics Integrated Database. Data included all medical and pharmacy claims at all available healthcare sites. Propensity score-based matching and inverse probability weighting were applied to baseline demographic, clinical, and healthcare utilization variables for 20,752 patients, half of whom used an FDA-approved medication for alcohol dependence. A similar comparison was performed among 15,502 patients treated with an FDA-approved medication: oral acamprosate calcium (n = 8958), oral disulfiram (n = 3492), oral naltrexone (NTX) hydrochloride (n = 2391), or extended-release injectable naltrexone (XR-NTX; n = 661). Analyses calculated 6-month treatment persistence, utilization, and paid claims for: alcoholism medications, detoxification and rehabilitation, alcohol-related and nonrelated inpatient admissions, outpatient services, and total costs. RESULTS: Medication was associated with fewer admissions of all types. Despite higher costs for medications, total healthcare costs, including inpatient, outpatient, and pharmacy costs, were 30% lower for patients who received a medication for their alcohol dependence. XR-NTX was associated with greater refill persistence and fewer hospitalizations for any reason and lower hospital costs than any of the oral medications. Despite higher costs for XR-NTX itself, total healthcare costs were not significantly different from oral NTX or disulfiram, and were 34% lower than with acamprosate. CONCLUSION: In this largest cost study to date of alcohol pharmacotherapy, patients who received medication had lower healthcare utilization and total costs than patients who did not. XR-NTX showed an advantage over oral medications in treatment persistence and healthcare utilization, at comparable or lower total cost.

Comparison of healthcare utilization among patients treated with alcoholism medications.

OBJECTIVES: To determine in a large claims database the healthcare utilization and costs associated with treatment of alcohol dependence with medications vs no medication and across 4 US Food and Drug Administration (FDA)-approved medications. STUDY DESIGN: Claims database analysis. METHODS: Eligible adults with alcohol dependence claims (n = 27,135) were identified in a commercial database (MarketScan; Thomson Reuters Inc, Chicago, Illinois). Following propensity score-based matching and inverse probability weighting on demographic, clinical, and healthcare utilization variables, patients who had used an FDA-approved medication for alcohol dependence (n = 2977)were compared with patients who had not (n =2977). Patients treated with oral naltrexone hydrochloride(n = 2064), oral disulfiram (n = 2076), oral acamprosate calcium (n = 5068), or extended-release injectable naltrexone (naltrexone XR) (n = 295) were also compared for 6-month utilization rates of alcoholism medication, inpatient detoxification days, alcoholism-related inpatient days, and outpatient services, as well as inpatient charges. RESULTS: Patients who received alcoholism medications had fewer inpatient detoxification days (706 vs 1163 days per 1000 patients, P <.001), alcoholism-related inpatient days (650 vs 1086 days, P <.001), and alcoholism-related emergency department visits (127 vs 171, P = .005). Among 4 medications, the use of naltrexone XR was associated with fewer inpatient detoxification days (224 days per 1000 patients) than the use of oral naltrexone (552 days, P = .001), disulfiram (403 days, P = .049), or acamprosate (525 days, P <.001). The group receiving naltrexone XR also had fewer alcoholism-related inpatient days than the groups receiving disulfiram or acamprosate. More patients in the naltrexone XR group had an outpatient substance abuse visit compared with patients in the oral alcoholism medication groups. CONCLUSION: Patients who received an alcoholism medication had lower healthcare utilization than patients who did not. Naltrexone XR showed an advantage over oral medications in healthcare utilization and costs.

Availability of addiction medications in private health plans.

Health plans have implemented cost sharing and administrative controls to constrain escalating prescription expenditures. These policies may impact physicians' prescribing and patients' use of these medications. Important clinical advances in the pharmacological treatment of addiction highlight the need to examine how pharmacy benefits consider medications for substance dependence. The extent of restrictions influencing the availability of these medications to consumers is unknown. We use nationally representative survey data to examine the extent and stringency of private health plans' management of naltrexone and disulfiram for alcohol dependence, and buprenorphine for opiate dependence. Thirty-one percent of insurance products excluded buprenorphine from formularies, whereas 55% placed it on the highest cost-sharing tier. Generic naltrexone is the only substance dependence medication that is both rarely excluded from formularies and usually placed on a lower cost-sharing tier. These findings demonstrate that pharmacy benefits have an impact on access to medications for substance abuse.

Cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients.

Converging evidence suggests that disulfiram is a promising treatment for cocaine dependence. We study the cost-effectiveness of providing disulfiram to methadone-maintained opioid addicts in a randomized clinical trial setting. Our economic evaluation is based on a double blind clinical trial in which 67 cocaine-dependent methadone-maintained opioid-dependent subjects were randomized to get the additional treatment of disulfiram or placebo in a 12-week trial. Outcome measures used are the number of days of cocaine use and grams of cocaine per week. Cost measures used are the cost of providing standard methadone treatment and the incremental cost of adding disulfiram to the standard treatment. Cost measures of standard and disulfiram-enhanced treatment were collected retrospectively from the provider. Results from this cost-effectiveness analysis imply that, even though disulfiram increases slightly the cost of methadone treatment, its increase in effectiveness may be important enough to warrant its addition for treating cocaine dependence in methadone-maintained opiate addicts.

Comorbid dysthymia and substance disorder: treatment history and cost.

OBJECTIVE: The purpose of this study was to determine the treatment history and cost of previous treatment among patients with comorbid substance-related disorder and dysthymia, as compared to patients with substance-related disorder only. METHOD: Retrospective data were obtained regarding past treatment. Treatment cost was calculated on the basis of the 1996 cost of various treatment modalities. The setting was alcohol-drug programs located within departments of psychiatry in two centers. A total of 642 patients were assessed, of whom 39 had substance-related disorder and dysthymia and 308 had substance-related disorder only (the remaining patients had other comorbid conditions). Data collection instruments included an interview-based questionnaire regarding previous psychiatric and substance abuse treatment. Current cost of treatment in various settings was assessed on the basis of a survey of facilities used by patients in this area. RESULTS: Patients with substance-related disorder and dysthymia had received more substance-related disorder treatment in 18 of 20 measures. Patients with substance-related disorder and dysthymia used 4.7 times more substance-related disorder treatment dollars than patients with substance-related disorder only, although their demographic characteristics were similar. Past self-help activities and pharmacotherapy were remarkably similar for both groups. Although substance-related disorder treatment differed considerably between the two groups of patients, other types of psychiatric treatment (i.e., non-substance-related treatment) did not differ between the two groups. CONCLUSIONS: Patients with substance-related disorder and dysthymia are referred to (or seek) substance-related disorder treatment more often than patients with substance-related disorder only but are referred to (or seek) non-substance-related psychiatric treatment no more often than patients with substance-related disorder only. The cost of previous substance-related disorder treatment was several times higher for the patients with substance-related disorder and dysthymia.