Disulfiram

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Disulfiram
Disulfiram2.svg
Disulfiram-space-filling.png
Systematic (IUPAC) name
1,1',1'',1'''-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
Clinical data
Trade namesAntabuse
AHFS/Drugs.commonograph
MedlinePlusa682602
Pregnancy cat.C (US)
Legal status ?
RoutesOral, subdermal implant
Pharmacokinetic data
MetabolismHepatic to diethylthiocarbamate
Half-life60–120 hours
Identifiers
CAS number97-77-8 YesY
ATC codeN07BB01 P03AA04
PubChemCID 3117
DrugBankDB00822
ChemSpider3005 YesY
UNIITR3MLJ1UAI YesY
KEGGD00131 YesY
ChEBICHEBI:4659 YesY
ChEMBLCHEMBL964 YesY
NIAID ChemDB010293
Synonyms1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
Chemical data
FormulaC10H20N2S4 
Mol. mass296.539 g/mol
 N (what is this?)  (verify)
 
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Disulfiram
Disulfiram2.svg
Disulfiram-space-filling.png
Systematic (IUPAC) name
1,1',1'',1'''-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
Clinical data
Trade namesAntabuse
AHFS/Drugs.commonograph
MedlinePlusa682602
Pregnancy cat.C (US)
Legal status ?
RoutesOral, subdermal implant
Pharmacokinetic data
MetabolismHepatic to diethylthiocarbamate
Half-life60–120 hours
Identifiers
CAS number97-77-8 YesY
ATC codeN07BB01 P03AA04
PubChemCID 3117
DrugBankDB00822
ChemSpider3005 YesY
UNIITR3MLJ1UAI YesY
KEGGD00131 YesY
ChEBICHEBI:4659 YesY
ChEMBLCHEMBL964 YesY
NIAID ChemDB010293
Synonyms1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
Chemical data
FormulaC10H20N2S4 
Mol. mass296.539 g/mol
 N (what is this?)  (verify)

Disulfiram (sold under the trade names Antabuse and Antabus) is a drug discovered in the 1920s[1] and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. It blocks the processing of alcohol in the body by inhibiting acetaldehyde dehydrogenase, thus causing an unpleasant reaction when alcohol is consumed. Disulfiram should be used in conjunction with counseling and support. 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.[citation needed] Several studies have reported that it has antiprotozoal activity, as well.[2][3] Disulfiram is the subject of research for use in cancer therapy and as a treatment in HIV cure research (to activate the reservoir of HIV-infected resting CD4 cells).[4]

Uses[edit]

Alcohol abuse[edit]

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 acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be five 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 five to 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 syncope, 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]

Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. A classic study by Fuller (1986) that followed chronic alcoholics for a period of one year found no statistically significant differences in abstinence rates between the group that received disulfiram and the group that only received counseling. The reason for this finding was that only 20% of subjects in disulfiram group were estimated to be in good compliance with the drug regimen.[8] Methods to improve compliance include subdermal implants, which release the drug continuously over a period of up to 12 weeks, and supervised administration practices, for example, having the drug regularly administered by one's spouse.

Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse till the end of the 20th century, today it is often replaced or accompanied with newer drugs, primarily the combination of naltrexone and acamprosate, which directly attempt to address physiological processes in the brain associated with alcohol abuse.

Cancer[edit]

When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor[9] and can represent a new approach to proteasome inhibition.[10] Clinical trials are recommended.[11] A clinical trial of disulfiram with copper gluconate against liver cancer is being conducted in Utah (ClinicalTrials.gov Identifier: NCT00742911) and a clinical trial of disulfiram as adjuvant against lung cancer is happening in Israel (ClinicalTrials.gov Identifier: NCT00312819).

Side effects[edit]

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.[12] Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment.[13]

Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.[14]

Disulfiram disrupts metabolism of several other compounds, including acetaminophen,[15] theophylline[16] and caffeine.[17] However, in most cases, this disruption is mild and presents itself as a 20-40% increase in the half-life of the compound at typical dosages of disulfiram.

Preparation[edit]

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[edit]

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:

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 common ink cap mushroom (Coprinopsis atramentaria), hence its colloquial name "tippler's bane". Similar reactions have been recorded with Clitocybe clavipes and Boletus luridus, although the agent in those species is unknown.

History[edit]

The drug's action was discovered by accident in 1948 by researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the Danish drug company Medicinalco.[18] The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.

Disulfiram is currently sold under the trade names Antabuse and Antabus, manufactured by Odyssey Pharmaceuticals.

See also[edit]

References[edit]

  1. ^ US Patent 1782111 - Method of Manufacturing Tetra-alkylated Thiuramdisulphides
  2. ^ Nash, T; Rice, WG (1998). "Efficacies of zinc-finger-active drugs against Giardia lamblia". Antimicrobial agents and chemotherapy 42 (6): 1488–92. PMC 105627. PMID 9624499. 
  3. ^ Bouma, M. J.; Snowdon, D.; Fairlamb, A. H.; Ackers, J. P. (1998). "Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and - resistant Trichomonas vaginalis and Tritrichomonas foetus \In Process Citation]". Journal of Antimicrobial Chemotherapy 42 (6): 817–20. doi:10.1093/jac/42.6.817. PMID 10052908. 
  4. ^ Doyon, Geneviève; Zerbato, Jennifer; Mellors, John W.; Sluis-Cremer, Nicolas (2013). "Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog". AIDS 27 (2): F7–F11. doi:10.1097/QAD.0b013e3283570620. PMID 22739395. 
  5. ^ "Disulfiram Official FDA information, side effects and uses.". Retrieved 2011-04-11. 
  6. ^ Wright, Curtis; Moore, Richard D. (1990). "Disulfiram treatment of alcoholism". The American Journal of Medicine 88 (6): 647–55. doi:10.1016/0002-9343(90)90534-K. PMID 2189310. 
  7. ^ Krampe, Henning; Stawicki, Sabina; Wagner, Thilo; Bartels, Claudia; Aust, Carlotta; Ruther, Eckart; Poser, Wolfgang; Ehrenreich, Hannelore (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. PMID 16433735. 
  8. ^ Fuller, Richard K.; Branchey, L; Brightwell, DR; Derman, RM; Emrick, CD; Iber, FL; James, KE; Lacoursiere, RB et al. (1986). "Disulfiram Treatment of Alcoholism: A Veterans Administration Cooperative Study". JAMA 256 (11): 1449–55. doi:10.1001/jama.1986.03380110055026. PMID 3528541. 
  9. ^ Cvek, B.; Dvorak, Z. (2007). "Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals". Current Pharmaceutical Design 13 (30): 3155–67. doi:10.2174/138161207782110390. PMID 17979756. 
  10. ^ Cvek, Boris; Dvorak, Zdenek (2008). "The value of proteasome inhibition in cancer". Drug Discovery Today 13 (15–16): 716–22. doi:10.1016/j.drudis.2008.05.003. PMID 18579431. 
  11. ^ Wickström, Malin; Danielsson, Katarina; Rickardson, Linda; Gullbo, Joachim; Nygren, Peter; Isaksson, Anders; Larsson, Rolf; Lövborg, Henrik (2007). "Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients". Biochemical Pharmacology 73 (1): 25–33. doi:10.1016/j.bcp.2006.08.016. PMID 17026967. 
  12. ^ "Disulfiram Side Effects". Drugs.com. Retrieved 6 November 2010. 
  13. ^ Cornford, E M; Bocash, W D; Braun, L D; Crane, P D; Oldendorf, W H; MacInnis, A J (1979). "Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues". Journal of Clinical Investigation 63 (6): 1241–8. doi:10.1172/JCI109419. PMC 372073. PMID 447842. 
  14. ^ Boukriche, Yassine; Weisser, Isabelle; Aubert, Pascale; Masson, Catherine (2000). "MRI findings in case of late onset disulfiram-induced neurotoxicity". Journal of Neurology 247 (9): 714–5. doi:10.1007/s004150070119. PMID 11081815. 
  15. ^ Poulsen, H. E.; Ranek, L.; Jørgensen, L. (1991). "The influence of disulfiram on acetaminophen metabolism in man". Xenobiotica 21 (2): 243–9. doi:10.3109/00498259109039466. PMID 2058179. 
  16. ^ Loi, Cho-Ming; Day, John D; Jue, Sandra G; Bush, Ernie D; Costello, Patrick; Dewey, Larry V; Vestal, Robert E (1989). "Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics". Clinical Pharmacology and Therapeutics 45 (5): 476–86. doi:10.1038/clpt.1989.61. PMID 2721103. 
  17. ^ Beach, Cynthia A; Mays, Dennis C; Guiler, Robert C; Jacober, Cynthia H; Gerber, Nicholas (1986). "Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics". Clinical Pharmacology and Therapeutics 39 (3): 265–70. doi:10.1038/clpt.1986.37. PMID 3948467. 
  18. ^ Hvad er antabus, a Danish site describing the discovery of the drug’s effects.

External links[edit]