Radiation protection by disulfiram: protection of membrane and DNA in vitro and in vivo against gamma-radiation.
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Disufiram (a drug used for the treatment of alcoholism) protected microsomal membranes and plasmid DNA against damages induced by gamma-radiation. The peroxidation of membrane lipids increased linearly with the radiation dose up to 600 Gy, and the presence of disulfiram inhibited membrane lipid peroxidation as assayed by the presence of thiobarbituric acid reacting substances. The reduction of the quantity of the supercoiled (ccc) form of plasmid pBR322 DNA is directly related to the radiation-induced damage, particularly to DNA strand breaks. There was a complete protection of plasmid DNA when exposed to gamma-radiation in the presence of disufiram (0.1 mM) at 300 Gy. This drug also protected deoxyribose against damages caused by hydroxyl radicals produced by the Fenton reaction. The administration of DSF to mice prior to whole-body radiation exposure (4 Gy) resulted in a reduction of peroxidation of membrane lipids in mice liver as well as a decrease in radiation-induced damage to cellular DNA, as assayed by single-cell gel electrophoresis (comet assay). The results thus suggest the possible use of DSF as a radioprotector. (+info)
Ethnic differences in substance abuse treatment retention, compliance, and outcome from two clinical trials.
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OBJECTIVE: 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. METHODS: Data were taken from two trials (N=111 in each), in which patients were randomly assigned to groups that used different behavioral treatments (cognitive-behavioral treatment and 12-step facilitation) and pharmacotherapies (desipramine and disulfiram). RESULTS: Few differences between African Americans and whites were found in terms of demographic characteristics, reasons for seeking treatment, or expectations of treatment. In both studies African Americans and whites did not differ significantly with respect to cocaine use outcomes, but African-American participants completed significantly fewer days of treatment than white participants. In study 2, which was not placebo controlled, African Americans who received disulfiram remained in treatment significantly longer than African Americans who did not receive disulfiram. However, in study 1, in which patients took either desipramine or a placebo, no interactions of ethnicity by medication were found. Among patients who expected improvement to take a month or longer in study 1, African Americans remained in treatment for fewer days than whites. CONCLUSIONS: The behavioral therapies evaluated did not significantly differ in effectiveness for African Americans and whites, suggesting that they are broadly applicable across these ethnic groups. Findings also suggest possible strategies for improving retention of African Americans in treatment. Such strategies might include offering treatment with a medication component and better addressing participants' treatment expectations. (+info)
The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1).
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The overexpression of multidrug resistance protein 1 (MDR1) and multidrug resistance protein 1 (MRP1) gene products is a major cause of multidrug resistance in cancer cells. A recent study suggested that disulfiram, a drug used to treat alcoholism, might act as a modulator of P-glycoprotein. In this study, we investigated the molecular and chemical basis of disulfiram as a multidrug resistance modulator. We demonstrate that in intact cells, disulfiram reverses either MDR1- or MRP1-mediated efflux of fluorescent drug substrates. Disulfiram inhibits ATP hydrolysis and the binding of [alpha-32P]8-azidoATP to P-glycoprotein and MRP1, with inhibition curves comparable with those of N-ethylmaleimide, a cysteine-modifying agent. However, if the ATP sites are protected with excess ATP, disulfiram stimulates ATP hydrolysis by both transporters in a concentration-dependent manner. Thus, in addition to modifying cysteines at the ATP sites, disulfiram may interact with the drug-substrate binding site. We demonstrate that disulfiram, but not N-ethylmaleimide, inhibits in a concentration-dependent manner the photoaffinity labeling of the multidrug transporter with 125I-iodoarylazidoprazosin and [3H]azidopine. This suggests that the interaction of disulfiram with the drug-binding site is independent of its role as a cysteine-modifying agent. Finally, we have exploited MRP4 (ABCC4) to demonstrate that disulfiram can inhibit ATP binding by forming disulfide bonds between cysteines located in the vicinity of, although not in, the active site. Taken together, our results suggest that disulfiram has unique molecular interactions with both the ATP and/or drug-substrate binding sites of multiple ATP binding cassette transporters, which are associated with drug resistance, and it is potentially an attractive agent to combat multidrug resistance. (+info)
Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial.
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CONTEXT: Disulfiram has emerged as a promising treatment for cocaine dependence, but it has not yet been evaluated in general populations of cocaine users. OBJECTIVES: To compare the effectiveness of disulfiram therapy with that of a placebo condition in reducing cocaine use and to compare the effectiveness of 2 active behavioral therapies-cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT)-in reducing cocaine use. DESIGN: Randomized, placebo-controlled, double-masked (for medication condition), factorial (2 x 2) trial with 4 treatment conditions: disulfiram plus CBT, disulfiram plus IPT, placebo plus CBT, and placebo plus IPT. SETTING: A community-based outpatient substance abuse treatment program. PATIENTS: A total of 121 individuals meeting the criteria for current cocaine dependence. INTERVENTIONS: Patients received either disulfiram (250 mg/d) or placebo in identical capsules. Medication compliance was monitored using a riboflavin marker procedure. Both behavioral therapies (CBT and IPT) were manual guided and were delivered in individual sessions for 12 weeks. MAIN OUTCOME MEASURES: Random regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens. RESULTS: Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo, and those assigned to CBT reduced their cocaine use significantly more than those assigned to IPT (P<.01 for both). Findings were consistent across all study samples (eg, intention to treat, treatment initiators, and treatment completers). Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment. Adverse effects experienced by participants who received disulfiram were mild and were not considerably different from those experienced by participants who received placebo. CONCLUSIONS: Disulfiram and CBT are effective therapies for general populations of cocaine-dependent individuals. Disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use. (+info)
Cost effectiveness of disulfiram: treating cocaine use in methadone-maintained patients.
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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. (+info)
Consecutive treatment of disulfiram inhibits ovarian carbonyl reductase activity in rats.
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We investigated the effects of disulfiram (DS) on ovarian carbonyl reductase activity in rats to determine the influence of DS on female reproductive function. Three consecutive treatments with DS significantly inhibited ovarian carbonyl reductase activity as well as ovulation, dose-dependently. Single treatment with DS had no effect on ovarian carbonyl reductase activity. Our observations indicate that consecutive treatment with DS has an inhibitory action on female reproductive function, although DS is well-known to inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase. (+info)
N,N-diethyldithiocarbamate produces copper accumulation, lipid peroxidation, and myelin injury in rat peripheral nerve.
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Previous studies have demonstrated the ability of the dithiocarbamate, disulfiram, to produce a peripheral neuropathy in humans and experimental animals and have also provided evidence that N,N-diethyldithiocarbamate (DEDC) is a proximate toxic species of disulfiram. The ability of DEDC to elevate copper levels in the brain suggests that it may also elevate levels of copper in peripheral nerve, possibly leading to oxidative stress and lipid peroxidation from redox cycling of copper. The study presented here investigates the potential of DEDC to promote copper accumulation and lipid peroxidation in peripheral nerve. Rats were administered either DEDC or deionized water by ip osmotic pumps and fed a normal diet or diet containing elevated copper, and the levels of metals, isoprostanes, and the severity of lesions in peripheral nerve and brain were assessed by ICP-AES/AAS, GC/MS, and light microscopy, respectively. Copper was the only metal that demonstrated any significant compound-related elevations relative to controls, and total copper was increased in both brain and peripheral nerve in animals administered DEDC on both diets. In contrast, lesions and elevated F2-isoprostanes were significantly increased only in peripheral nerve for the rats administered DEDC on both diets. Autometallography staining of peripheral nerve was consistent with increased metal content along the myelin sheath, but in brain, focal densities were observed, and a periportal distribution occurred in liver. These data are consistent with the peripheral nervous system being more sensitive to DEDC-mediated demyelination and demonstrate the ability of DEDC to elevate copper levels in peripheral nerve. Additionally lipid peroxidation appears to either be a contributing event in the development of demyelination, possibly through an increase of redox active copper, or a consequence of the myelin injury. (+info)
Sex differences in cocaine-dependent individuals' response to disulfiram treatment.
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The objective of this study is to evaluate differential response to disulfiram treatment of cocaine dependence by sex. Sex by treatment interactions from two pooled randomized clinical trials involving 191 cocaine-dependent subjects (36% female) were evaluated. Primary outcomes were days of abstinence and percentage of drug-free urine specimens. Significant sex by treatment interactions were found, where men treated with disulfiram had better outcomes than those who were not. Women had an intermediate outcome regardless of whether they received disulfiram. Sex differences in response to disulfiram treatment have important clinical and theoretical implications. Reasons for this apparent sex-based response are not clear, but possible mechanisms worthy of greater study include differences in alcohol use by sex as well as differences in dopamine-mediated responses to cocaine and disulfiram. (+info)