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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
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
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
review article or handbook
Title:
A comparative review of the pharmacological and toxicological properties of disulfiram and calcium carbimide.
Author:
Peachey, J.E. et al.
Year:
1981
Bibliographic source:
J Clin Psychopharmacol.; 1(1):21-6.

Materials and methods

Study type:
other:
Endpoint addressed:
repeated dose toxicity: oral
Principles of method if other than guideline:
The toxicity of disulfiram as antialcoholic drug therapy was reviewed including aspects of possible medical complications, drug toxicity upon repeated administration and drug-drug interactions and acetaldehyde-induced hepatotoxicity and cardiotoxicity.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Disulfiram (tetraethylthiuram disulfide; Antabuse, Abstinyl)

Results and discussion

Results of examinations:
Disulfiram-ethanol reaction (DER):
Mild facial flushing, tachycardia, and a slight increase in pulse pressure, due mainly to a decrease in diastolic blood pressure, occur in individuals pre-treated with therapeutic doses of disulfiram, following only 0.1 g/kg of ethanol (unpublished observations). These physiological effects occur at the time of increased blood acetaldehyde levels and are accompanied by self-reports of mild facial warmth, palpitations, and shortness of breath. As the ethanol dose is increased, heart rate and pulse pressure are increased further and the flushing spreads over the body. Increasingly severe palpitations and shortness of breath are accompanied by mounting discomfort and apprehension. With severe reactions there is usually nausea and vomiting. Pallor, a "floating feeling", and a sensation of coldness usually precede a fall in blood pressure.

Any other information on results incl. tables

Medical complications during disulfiram-ethanol reaction (DER):

Myocardial infarction, shock, and death can occur during the DER. Cerebrovascular hemorrhage and infarction, causing loss of consciousness during the DER followed by death after several days, are also reported. Although most fatal DERs have been associated with excessive dosages of disulfiram (> 1500 mg daily) followed by consumption of large amounts of ethanol, deaths have also been reported with therapeutic disulfiram dosages and relatively small amounts of ethanol. Reversible electrocardiographic changes are recorded during the DER.

Toxicity associated with disulfiram administration in humans:

Disulfiram and ist metabolite diethyldithiocarbamate (DDC) inhibit dopamine-b-hydroxylase (DBH) causing increased dopamine levels and decreased norepinephrine levels in the brain and other tissues. Drowsiness, lethargy, disturbed sexual function, and neuropsychological dysfunction occur as a result of the DBH inhibition. More serious behavioural changes include psychosis and acute encephalopathy which occur particularly in individuals with low cerebral spinal fluid DBH activity or low pretreatment levels of platelet monoamine oxidase and amine oxidase and high levels of red cell catechol-O-methyltransferase. Patients with a diagnosis of depression or borderline schizophrenia may manifest more psychopathology while taking disulfiram. The development of neuropathy, muscle weakness, and motor incoordination are the result of CS2-induced toxicity during disulfiram treatment. In addition, disulfiram may cause hepatotoxicity, atherosclerosis, and increased blood pressure. Limb anomalies have been reported in infants born on disulfiram-treated alcoholic mothers.

Drug-drug interactions:

Disulfiram inhibits the metabolism of other drugs including antipyrine, phenytoin, warfarin, isoniazid, rifampin, diazepam, and chlordiazepoxide causing increased blood levels of these drugs. Is is noteworthy that a similar reaction does not occur with short- and intermediate acting benzodiazepines. The simultaneous administration of disulfiram with warfarin may result in prolongation of the prothrombin time with subsequent haemorrhage. Similarly, cumulative toxicity to phenytoin has been reported in alcoholics receiving disulfiram. On the other hand, with cessation of disulfiram administration, dosages of the other drugs may need to be adjusted downward. Diazepam induces the intensity of the DER, while amitriptyline enhances DER.

Toxicity due to acetaldehyde:

Blood acetaldehyde levels are raised appreciably in disulfiram-treated alcoholics following the ingestion of relatively small amounts of ethanol. It is possible that alcoholics who receive disulfiram and who continue to drink may experience some degree of acetaldehyde-induced cardiotoxicity and/or hepatotoxicity.

Applicant's summary and conclusion