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Toxicological information

Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
other: review article
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication meeting basic scientific principles

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2009

Materials and methods

Type of study / information:
Review on disulfiram: The anti-alcoholism drug disulfiram (Antabuse), which is an inhibitor of aldehyde dehydrogenase, induces an aversive reaction to alcohol consumption and thereby helps patients reduce alcohol intake.
Endpoint addressed:
basic toxicokinetics
repeated dose toxicity: oral
Principles of method if other than guideline:
Recent clinical trials, initiated to investigate whether disulfiram could be used to treat individuals who abuse both alcohol and cocaine, have indicated that disulfiram effectively decreases cocaine consumption. Yet the ability of disulfiram to curb cocaine intake cannot be explained by the disruption of ethanol metabolism. Here, we synthesize clinical and animal data that point to dopamine β-hydroxylase inhibition as a mechanism underlying the efficacy of disulfiram in the treatment of cocaine dependence.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Disulfiram

Method

Details on study design:
Review article

Results and discussion

Results:
Conclusion: Disulfiram has been used as an alcohol deterrent for decades, and recent studies indicate that it is also an effective pharmacotherapy for the treatment of cocaine dependence; however, the mechanisms behind its efficacy for alcohol and for cocaine addiction are distinct. Whereas aldehyde dehydrogenase is the primary target in treating alcoholism, human laboratory, genetic, and preclinical animal studies indicate that its beneficial effects on cocaine use result from the inhibition of dopamine b-hydroxylase (DBH). Despite the potential of DBH and its inhibition to modulate cocaine reward and aversion, the authors argue that the most important clinical effect of disulfiram-mediated DBH inhibition arises from the drug’s ability to reduce relapse, particularly, relapse precipitated by stress.

Any other information on results incl. tables

Disulfiram-Ethanol reaction:

Ethanol is converted to acetaldehyde by the enzyme alcohol dehydrogenase, and acetaldehyde is further metabolized to acetate by aldehyde dehydrogenase.Disulfiram is an inhibitor of aldehyde dehydrogenase. The high levels of acetaldehyde that accumulate following alcohol ingestion in patients taking disulfiram cause the mild to moderate levels of facial flushing, weakness, throbbing headache, nausea, vomiting, sweating, vertigo, hypotension, and other unpleasant symptoms that typify the disulfiram-ethanol reaction (also known as the Antabuse reaction).

 

Metabolism of disulfiram:

Upon absorption, disulfiram is immediately reduced to diethyldithiocarbamate (DDC) when it reacts with thiol groups. This metabolite of disulfiram is a potent copper chelator, and it can thereby affect the activity of copper-dependent enzymes such as monooxygenases, amine oxidase, cytochrome oxidase, microsomal carboxylesterase, and plasma cholinesterase.

 

Clinical trials:

To date, there have been eight supervised clinical trials, ranging from 56 to 270 days in duration, that assess oral disulfiram for the treatment of alcoholics. The percentage of disulfiram-treated patients who completed these trials, ranging from 18 to 58%, was higher for those populations in which drug administration was supervised by clinic staff or a family member. Only one study (comprising four disulfiram-treated patients and one placebo control) reported adverse side effects as a factor in patient drop-out. Four trials had a completely randomized design; three of these compared supervised versus unsupervised disulfiram administration (13–15). All groups reported better abstinence from drinking after supervised disulfiram administration compared with unsupervised administration or placebo.

 

Disulfiram Treatment for Dual Cocaine and Alcohol Dependence - Clinical Trials:

The groundbreaking trial addressed cocaine use both with and without comorbidity for alcohol abuse, showing that the benefits of disulfiram therapy were most pronounced in patients who either were not alcohol dependent at baseline or who fully abstained from alcohol during treatment. These observations directly suggest that disulfiram undermines cocaine addiction in a manner independent of its action in inhibiting alcohol intake.

 

Proposed Disulfiram inhibition of the norepinephrine (NE) biosynthetic pathway:

In the catecholamine synthesis pathway, tyrosine is converted into 3,4-dihydroxy-L-phenylalanine (L-DOPA) by tyrosine hydroxylase (TH), which is then transformed into dopamine by aromatic amino acid decarboxylase (AADC), whereupon dopamine b-hydroxylase (DBH) converts dopamine into norepinephrine. Disulfiram inhibits DBH, reducing the production of norepinephrine and increasing the pool of dopamine.

 

Applicant's summary and conclusion