Disulfiram

Disulfiram

Systematic (IUPAC) name
1,1',1'',1'''-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
Clinical data
Trade names	Antabuse
AHFS/Drugs.com	monograph
MedlinePlus	a682602
Pregnancy cat.	C (US)
Legal status	?
Routes	Oral, subdermal implant
Pharmacokinetic data
Metabolism	Hepatic to diethylthiocarbamate
Half-life	60–120 hours
Identifiers
CAS number	97-77-8 Y
ATC code	N07BB01 P03AA04
PubChem	CID 3117
DrugBank	DB00822
ChemSpider	3005 Y
UNII	TR3MLJ1UAI Y
KEGG	D00131 Y
ChEBI	CHEBI:4659 Y
ChEMBL	CHEMBL964 Y
Synonyms	1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
Chemical data
Formula	C10H20N2S4
Mol. mass	296.539 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C10H20N2S4/c1-5-11(6-2)9(13)15-16-10(14)12(7-3)8-4/h5-8H2,1-4H3 Y Key:AUZONCFQVSMFAP-UHFFFAOYSA-N Y
N(what is this?)  (verify)

Disulfiram is a drug discovered in the 1920s^[1] and 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.^[2][3] 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.^[4] The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.

Uses

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.^[5] 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.^[6]

A nine-year study published in 2006 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%.^[7]

Antiprotozoal and anti-scabies

A study reported that it may be potentially useful in the treatment of Giardia infection.^[2] Another study found that it had activity against Trichomonas vaginalis which was resistant to the most common treatment, metronidazole.^[3]

It is also useful in the treatment of scabies as a combination drug of Benzyl benzoate/disulfiram.^[8]

Cancer

A patient with metastatic ocular melanoma was successfully treated by disulfiram with zinc gluconate.^[9] This can be explained as disulfiram creating complexes with metals (dithiocarbamate complexes) is proteasome inhibitor^[10] and can represent a new approach to proteasome inhibition.^[11] Clinical trials are recommended.^[12] 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.^[13] Tryptophol is a chemical compound that induces sleep in humans. It is formed in the liver after disulfiram treatment.^[14]

Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.^[15]

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.^[16]

Preparation

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

2 NaS₂CNEt₂ + I₂ → 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.^{[citation needed]}

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.

See also

• Naltrexone
• Acamprosate

References

1. ^ US Patent 1782111 - Method of Manufacturing Tetra-alkylated Thiuramdisulphides
2. ^ ^{a b} Nash T, Rice WG (1998). "Efficacies of Zinc-Finger-Active Drugs against Giardia lamblia". Antimicrob. Agents Chemother. 42 (6): 1488–92. PMC 105627. PMID 9624499. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=105627. 
3. ^ ^{a b} Bouma MJ, Snowdon D, Fairlamb AH, Ackers JP (1998). "Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and -resistant Trichomonas vaginalis and Tritrichomonas foetus". J. Antimicrob. Chemother. 42 (6): 817–20. doi:10.1093/jac/42.6.817. PMID 10052908. 
4. ^ Hvad er antabus, a Danish site describing the discovery of the drug’s effects.
5. ^ "Disulfiram Official FDA information, side effects and uses.". http://www.drugs.com/pro/disulfiram.html. Retrieved 2011-04-11. 
6. ^ Wright C, Moore RD (June 1990). "Disulfiram treatment of alcoholism". Am. J. Med. 88 (6): 647–55. doi:10.1016/0002-9343(90)90534-K. PMID 2189310. 
7. ^ Krampe H, Stawicki S, Wagner T, et al. (January 2006). "Follow-up of 180 alcoholic patients for up to 7 years after outpatient treatment: impact of alcohol deterrents on outcome". Alcoholism, clinical and experimental research 30 (1): 86–95. doi:10.1111/j.1530-0277.2006.00013.x. ISSN 0145-6008. PMID 16433735. 
8. ^ Landegren J, Borglund E, Storgårds K (1979). "Treatment of scabies with disulfiram and benzyl benzoate emulsion: a controlled study". Acta Derm. Venereol. 59 (3): 274–6. PMID 87094. 
9. ^ Brar SS, Grigg C, Wilson KS, et al. (Sep 2004). "Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease". Molecular Cancer Therapeutics 3 (9): 1049–60. PMID 15367699. http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15367699. 
10. ^ Cvek B, Dvorak Z (2007). "Targeting of nuclear factor-kappaB and proteasome by dithiocarbamate complexes with metals". Current Pharmaceutical Design 13 (30): 3155–67. doi:10.2174/138161207782110390. PMID 17979756. http://www.bentham-direct.org/pages/content.php?CPD/2007/00000013/00000030/0010B.SGM. 
11. ^ Cvek B, Dvorak Z (Aug 2008). "The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor?". Drug Discovery Today 13 (15–16): 716–22. doi:10.1016/j.drudis.2008.05.003. PMID 18579431. 
12. ^ Wickström M, Danielsson K, Rickardson L, et al. (Jan 2007). "Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients". Biochem Pharmacology 73 (1): 25–33. doi:10.1016/j.bcp.2006.08.016. PMID 17026967. 
13. ^ "Disulfiram Side Effects". Drugs.com. http://www.drugs.com/sfx/disulfiram-side-effects.html. Retrieved 6 November 2010. 
14. ^ Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues. E M Cornford, W D Bocash, L D Braun, P D Crane, W H Oldendorf and A J MacInnis, J Clin Invest. 1979 June; 63(6), pp. 1241–1248, doi:10.1172/JCI109419, PMC PMC372073
15. ^ Boukriche, Y.; Weisser, I., Aubert, P., Masson, C. (2000). "MRI findingss in a case of late onset disulfiram-induced neurotoxicity". J Neurol 247 (9): 714–715. doi:10.1007/s004150070119. PMID 11081815. 
16. ^ AJ Giannini. Drugs of Abuse.(1997). Los Angeles, Practice Management Information Corp. ISBN I-57066-053-0

External links

• Disulfiram (patient information)
• Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine