Biochemical Pharmacology of Disulfiram

Faiman, Morris D.

doi:10.1007/978-1-4684-3450-7_19

Cited by 21 publications

(7 citation statements)

References 105 publications

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“…However, in this sample, baseline differences in alcohol use by sex were comparatively infrequent and alcohol use within treatment was very rare in Study 2. (2) Disulfiram is an inhibitor of dopamine-β-hydroxylase (DBH; Faiman, 1979;Haley, 1979;Wright & Moore, 1990). Inhibitors of this enzyme are known to alter central ratios of dopamine to norepinephrine (Stanley et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Sex differences in cocaine-dependent individuals' response to disulfiram treatment

Nich

McCance‐Katz

Petrakis

et al. 2004

Addictive Behaviors

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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.

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Section: Discussionmentioning

confidence: 99%

Sex differences in cocaine-dependent individuals' response to disulfiram treatment

Nich

McCance‐Katz

Petrakis

et al. 2004

Addictive Behaviors

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“…It is a non-specific inhibitor of sulfhydryl-containing enzymes found in many biochemical pathways throughout the body. It is known to inhibit liver microsomal carboxylesterases and plasma cholinesterase enzymes which are involved in cocaine metabolism (Faiman, 1979). It also is an inhibitor of the dopamine-β-hydroxylase (DBH) enzyme that converts dopamine to norepinephrine (Goldstein et al, 1964; Musacchio et al, 1964) which has been proposed as one possible mechanism by which disulfiram could reduce the positive or rewarding effects of cocaine (Haile et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

Roache

Kahn

Newton

et al. 2011

Drug and Alcohol Dependence

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BACKGROUND A majority of cocaine addicts have a comorbid alcohol use disorder. Previous studies demonstrated efficacy of disulfiram in the treatment of cocaine dependence among patients with comorbid alcohol use disorder or opioid dependence. However, the cardiac risks of a disulfiram-ethanol reaction (DER) in individuals who drink, when coupled with the cardiac effects of cocaine, could result in significant toxicity or lethality due to the 3-way drug interaction. AIMS This study examined the safety of combining cocaine (30 mg i.v.) and ethanol (0.4 g/kg i.v.) in disulfiram-treated (0, 250, and 500 mg/d, p.o.) cocaine-dependent research volunteers. RESULTS The results showed that disulfiram did not enhance the cardiovascular effects of cocaine and may have reduced the subjective high from cocaine. In contrast, ethanol produced adverse ECG changes including QTc prolongation and a DER consisting of hypotension, tachycardia, nausea, and flushing in disulfiram-treated subjects. The severity of the DER was related to disulfiram dose and the trial with 500 mg/d was stopped prematurely due to safety concerns. The DER-related hypotension and tachycardia seen with ethanol infusion alone in disulfiram-treated subjects, was not exacerbated when combined with cocaine. In fact, cocaine tended to counteract the ethanol-related hypotension though it did exacerbate the tachycardia in two of seven subjects. CONCLUSIONS Though conclusions are limited by the moderate doses of cocaine, ethanol, and disulfiram tested, the data do suggest that the risks of the moderate use of cocaine and ethanol in individuals treated with moderate doses of disulfiram (≤250 mg/d) may not be as problematic as some may assume.

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“…At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) 1 (9) that is a potent and selective carbamoylating agent for sulfhydryl groups (10).…”

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confidence: 99%

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

Nagendra¹,

Faiman²,

Davis³

et al. 1997

Journal of Biological Chemistry

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Considerable effort has been devoted to discovery of glutamate antagonists (1, 2) in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders (3). Unfortunately, while known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects (1, 2). To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy (4). Unlike classical antagonists, that can give complete inhibition by interaction at the glutamate receptor (e.g. CGS 19755) or directly at receptor-linked, calcium ion channels (e.g. phencyclidine or MK-801) (2), inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism (4). At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) 1 (9) that is a potent and selective carbamoylating agent for sulfhydryl groups (10). We now report that DETC-MeSO also partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen. MATERIALS AND METHODS Animals-MaleSwiss Webster mice (20 -30 g) or male SpragueDawley rats (250 -300 g) were used in the study. All experiments that employed animals were conducted in strict compliance with the National Institutes of Health guidelines on animal use and institutional regulations concerning animal experimentation. Animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as described previously (11, 12). The time to first clonic-tonic seizure after bringing animals to a final pressure of 5 atmospheres of 100% oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously (11, 12). Unless otherwise specified, the ability of DETC-MeSO to prevent seizures was tested by intraperitoneal injection of 5.2 mg/kg DETC-MeSO 1-2 h prior to bringing the animal to a final pressure of 5 atmospheres of 100% oxygen or intraperitoneal injection of N-methyl-D-aspartate (NMDA) (125 mg/kg) or L-methionine sulfoximine (MetSOX) (250 mg/kg). Evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of DETC-MeSO was conducted by use of the program GraphPAD InStat from GraphPAD Software (San Diego, CA).Binding Studies-Synap...

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Biochemical Pharmacology of Disulfiram

Cited by 21 publications

References 105 publications

Sex differences in cocaine-dependent individuals' response to disulfiram treatment

Sex differences in cocaine-dependent individuals' response to disulfiram treatment

A double-blind, placebo-controlled assessment of the safety of potential interactions between intravenous cocaine, ethanol, and oral disulfiram

Carbamoylation of Brain Glutamate Receptors by a Disulfiram Metabolite

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