Disulfiram

Disulfiram is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals. Disulfiram is also being studied as a treatment for cocaine dependence, as it prevents the breakdown of dopamine (a neurotransmitter whose release is stimulated by cocaine); the excess dopamine results in increased anxiety, higher blood pressure, restlessness and other unpleasant symptoms. Several studies have reported that it has anti-protozoal activity as well. Research for possible disulfiram use in cancer therapy has been announced.

History
The drug's action was discovered by accident in 1948 by the researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the Danish drug company Medicinalco. The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.

Alcohol abuse
Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to the harmless acetic acid. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a "hangover" this produces immediate and severe negative reaction to alcohol intake. Some 5–10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Symptoms include flushing of the skin, accelerated heart rate, shortness of breath, nausea, vomiting, throbbing headache, visual disturbance, mental confusion, postural fainting, and circulatory collapse.

Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body the effects may last for up to two weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction.

A recent nine-year study found that incorporation of supervised disulfiram and a related compound calcium carbimide into a comprehensive treatment program resulted in an abstinence rate of over 50%.

Antiprotozoal and anti-scabies
A study reported that it may be potentially useful in the treatment of Giardia infection. Another study found that it had activity against Trichomonas vaginalis which was resistant to the most common treatment, metronidazole.

Use in the treatment of scabies has also been described.

Cancer
A patient with metastatic ocular melanoma was successfully treated by disulfiram with zinc gluconate . This can be explained as disulfiram creating complexes with metals (dithiocarbamate complexes) is proteasome inhibitor and can represent a new approach to proteasome inhibition. Clinical trials are recommended. There is ongoing clinical trial of disulfiram with copper gluconate against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and clinical trial of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).

Side effects
The most common side effects (in the absence of alcohol) are drowsiness, headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur. Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.

Dosage
Disulfiram is supplied in 200 mg, 250 mg, and 500 mg tablets. The usual initial dose is 500 mg a day for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg–500 mg) per day. The total daily dosage should not exceed 500 mg.

Preparation
Disulfiram may be prepared from oxidation of sodium diethyldithiocarbamate with iodine:


 * 2 NaS2CNEt2 +  I2   &rarr;    Et2NC(S)S-SC(S)NEt2  +  2 NaI (Et = C2H5)

Similarly acting substances
In medicine, the term "disulfiram effect" refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol, similar to the effect caused by disulfiram administration.

Examples:
 * Antibiotics (Nitroimidazoles), e.g. metronidazole
 * 1st generation sulphonylureas, e.g. tolbutamide
 * Several Cephalosporin drugs, including cefoperazone and cefotetan, that have a N-methylyhio-tetrazole moiety
 * Griseofulvin, an oral anti-fungal drug
 * Temposil, or citrated calcium carbimide, has the same function as disulfiram, but is weaker and safer.

Coprine (N5-1-hydroxycyclopropyl-L-glutamine), which metabolises to 1-aminocyclopropanol, a closely-related chemical having the same metabolic effects, occurs naturally in the common ink cap (Coprinopsis atramentaria), an otherwise edible mushroom. Similar reactions have been recorded with Clitocybe clavipes and Boletus luridus, although the agent in those species is unknown.

In popular culture

 * Disulfiram is referenced in the Hunter S. Thompson novel Generation of Swine.