Disulfiram
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| Clinical data | |
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| Other names | 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide |
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| Routes of administration | Oral, subdermal implant |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Metabolism | Hepatic to diethylthiocarbamate |
| Elimination half-life | 60-120 hours |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| DrugBank | |
| ChemSpider | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.002.371 |
| Chemical and physical data | |
| Formula | C10H20N2S4 |
| Molar mass | 296.539 g/mol g·mol−1 |
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.[2][3] Research for possible disulfiram use in cancer therapy has been announced.
Interaction with alcohol
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 2 weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction. Possible side effects while taking Disulfiram are numbness or tingling of the lower legs and shortness of breath.
Double-blind controlled trials do not definitively establish the efficacy of disulfiram in the treatment of alcohol dependence.
Disulfiram is not given to patients who are not willing to give up alcohol, for consumption of alcohol in large quantity after taking the drug can lead to severe ill effects.
Dosage
Disulfiram is supplied in 200 mg, 250 mg, and 500 mg tablets. The usual initial dose is 500 mg 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.
Other than oral administration, in severe cases of alcoholism disulfiram used to be implanted subdermally to make it harder for the patient to stop treatment and succumb to the treated addiction. Addicts experiencing exceptionally acute alcohol withdrawal symptoms were known to rip out such implants as a last resort.
History and Antiprotozoal use
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.
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]
Similarly acting substances
Coprine (N5-1-hydroxycyclopropyl-L-glutamine) which metabolises to 1-aminocyclopropanol, a closely-related chemical having the same metabolic effects, occurs naturally in the otherwise edible mushroom, the common ink cap (Coprinopsis atramentaria). Similar reactions have been recorded with Clitocybe clavipes and Boletus luridus, although the agent in those species is unknown.
Temposil, or citrated calcium carbamide, has the same function as disulfiram, but is weaker and safer.
Griseofulvin, an oral anti-fungal drug.
Disulfiram and cancer treatment
A patient with metastatic ocular melanoma was successfully treated by disulfiram with zinc gluconate [5]. This can be explained as disulfiram creating complexes with metals (dithiocarbamate complexes) is proteasome inhibitor [6] and can represent a new approach to proteasome inhibition [7]. Clinical trials are recommended [8]. 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).
Organic chemistry
Disulfiram is an example of a thiuram disulfide, that is the oxidized derivative of diethyldithiocarbamate.
Disulfiram Effect
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)
See also
References
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
- ^ a b Nash T, Rice WG (1998). "Efficacies of zinc-finger-active drugs against Giardia lamblia". Antimicrob. Agents Chemother. 42 (6): 1488–92. PMID 9624499.
- ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Hvad er antabus, a Danish site describing the discovery of the drug’s effects.
- ^ Brar SS, Grigg C, Wilson KS; et al. (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.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ Cvek B, Dvorak Z (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.
{{cite journal}}: Unknown parameter|month=ignored (help) - ^ Wickström M, Danielsson K, Rickardson L; et al. (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.
{{cite journal}}: Explicit use of et al. in:|author=(help); Unknown parameter|month=ignored (help)CS1 maint: multiple names: authors list (link)
External links
- Disulfiram (patient information)
- Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine