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• General Introduction

  Alcohol dependence is a chronic disorder that may have multiple relapses and remissions, increased mortality and low long-term abstinence rates that lead to increased psychosocial losses. Many drugs have been used in the treatment of this disorder such as the anti-craving agents, acamprosate, naltrexone and the aversive agent, disulfiram^{[1, 2]}. Disulfiram (trade name: Antabuse) has been in use since the early 1940s for the treatment of alcohol dependence and is the first FDA-approved medication for the treatment of this disorder^[3,4,5]. Disulfiram has thus completed almost 60 years of use in alcohol use disorders and has stood the test of time^[6]. A large number of studies have been done on this molecule, ever since some proving its superiority over other drugs while others negating it.;

• Uses

  Disulfiram , is a sulfur- and nitrogen-containing compound with several industrial uses, including applications as a rubber accelerator and vulcanizer, fungicide, and seed disinfectant. It is most commonly known as antabuse, a therapeutic agent for the treatment of alcohol abuse that causes nausea, vomiting, and other adverse effects when ethanol is ingested. Disulfiram is an inhibitor of aldehyde dehydrogenase so that it allows for buildup of the acetaldehyde metabolite of ethanol, causing unpleasant effects that are a deterrent to the ingestion of alcohol. Because of the buildup of acetaldehyde, disulfiram should be given with extreme caution, especially to individuals suffering from liver cirrhosis.;

• Indications

  Disulfiram is used as a second line treatment of alcohol dependence, behind acamprosate and naltrexone^[8]. It is an aid for the management of selected chronic alcohol patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage. However, it should be noted that disulfiram is not a cure for alcoholism. When used alone, without proper motivation and supportive therapy, it is unlikely that it will have any substantive effect on the drinking pattern of the chronic alcoholic dependence^[5]. Disulfiram should not be taken if alcohol has been consumed in the last 12 hours^[9].
  Recently, more and more studies have shown that disulfiram has the potential for the treatment of cancer^{[12, 13]} and HIV infections^{[10, 11]}. Disulfiram (DSF) can reactivate latent HIV-1 expression in a primary cell model of virus latency and has the potential to deplete the latent HIV-1 reservoir in patients on combination antiretroviral therapy. DSF can reactivate latent HIV-1 expression via the Akt signaling pathway through depletion of PTEN^[10]. Recent studies have disclosed a surprising, but mechanistically consistent, anticancer activity of disulfiram. Disulfiram has been successfully used to suppress hepatic metastases originating from ocular melanoma^[12]. The anticancer mechanism of disulfiram is through inhibiting the 26S proteasome (The orderly degradation of cellular proteins is critical for normal cell cycling and function, and inhibition of the proteasome pathway results in cell-cycle arrest and apoptosis)^[12-14]. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development^{[12, 13]}. ;

• Mode of action

  Ethanol undergoes metabolism in the liver initially by alcohol dehydrogenase (ADH) forming acetaldehyde; this is removed from the body primarily by oxidation into acetate by acetaldehyde dehydrogenase (ALDH)^[15], which finally enters the citric acid cycle. Disulfiram acts by inhibiting the enzyme ALDH via its metabolite S-methyl N, N-diethyl-dithio-carbamate-sulphoxide^[16], leading to accumulation of acetaldehyde in blood. This gives rise to various manifestations of disulfiram-alcohol reaction (DER)^[17]. Since the inhibition of ALDH by disulfiram is irreversible, the DER will get terminated only after production of new ALDH oncedisulfiram is stopped. The new ALDH takes about a week’s time to be produced. Hence patients should be advised to take alcohol only after 2 weeks of stopping disulfiram^[18]. In addition to this, disulfiram also acts on the dopaminergic system, both disulfiram and its metabolite carbon disulfide leading to inhibition of dopamine beta-hydroxylase (DBH) that leads to increase in the levels of dopamine. This may give rise to several neuropsychiatric manifestations such as delirium, paranoia, impairment of memory, ataxia, dysarthria and frontal lobe release signs^[19]. Besides this action, disulfiram is also known to inhibit dopamine beta-hydroxylase leading to an increase in dopamine concentrations but decreased norepinephrine in the brain^[20]. This may suggest an anti-craving role of disulfiram in alcohol dependence^[21]. ;

• Adverse reactions

  In severe cases, hepatitis such as both cholestatic and fulminant hepatitis, as well as hepatic failure resulting in transplantation or death, could occur upon treatment of disulfiram^[5]. In a small number of patients, side effects include a transient mild drowsiness, fatigability, impotence, headache, acneform eruptions, allergic dermatitis, or a metallic or garlic-like aftertaste during the first two weeks of therapy. These reactions often disappear spontaneously with the continuation of therapy, or with reduced dosage. High dosage, combined toxicity (with metronidazole or isoniazid), or to the unmasking of underlying psychoses can cause psychotic reactions^[5]. ;

• Mechanism of action

  Disulfiram is an oral drug used for treating alcoholism. Alcohol is converted in the body into acetaldehyde by an enzyme called alcohol dehydrogenase. Another enzyme called acetaldehyde dehydrogenase then converts acetaldehyde into acetic acid. Disulfiram prevents acetaldehyde dehydrogenase from converting acetaldehyde into acetic acid, leading to a buildup of acetaldehyde levels in the blood.;

• Warning and precaution

  The following tips should be pay attention during administration of disulfiram^[9].
  Disulfiram is not allowed if the patients have consumed alcohol within the past 12 hours. Do not drink alcohol while taking disulfiram and for up to 14 days after stop taking disulfiram.
  It is not known whether disulfiram will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine. It is not known whether disulfiram passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine. People less than 18 years old should also disabled.
  Disulfiram should not be used in the following cases:
  Allergic people; those who have recently taken metronidazole (Flagyl) or paraldehyde; or have consumed any foods or products that contain alcohol;
  People of the following cases should consult the doctors:
  Liver or kidney disease; heart disease, high blood pressure, history of heart attack or stroke;
  Underactive thyroid; diabetes; seizures or epilepsy; head injury or brain damage; a history of mental illness or psychosis; an allergy to rubber; or taking phenytoin (Dilantin), tuberculosis medicine, or a blood thinner (warfarin, Coumadin, Jantoven). ;

• Pharmacodynamics

  Disulfiram irreversibly inhibits aldehyde dehydrogenase, which prevents the oxidation of alcohol after the acetaldehyde stage. It interacts with ingested alcohol to produce acetaldehyde levels five to ten times higher than are produced by normal alcohol metabolism. Excess acetaldehyde produces a highly unpleasant reaction (nausea and vomiting) to even a small quantity of alcohol. Tolerance to disulfiram doesn’t occur; rather, sensitivity to alcohol increases with longer duration of therapy.

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• Interactions

  Some individuals should never take disulfiram, and others should use extra caution when taking the drug. Do not take disulfiram if you have a nickel allergy, a sulfur allergy or a hypersensitivity to disulfiram or other derivatives of thiuram, which are commonly found in rubber.

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• References

  1. Bouza, C., Angeles, M., Muñoz, A., & Amate, J. M. (2015). Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction, 99(7), 811-828.
  2. Laaksonen, E., Koskijännes, A., Salaspuro, M., Ahtinen, H., & Alho, H. (2008). A randomized, multicentre, open-label, comparative trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol dependence. Alcohol & Alcoholism, 43(1), 53.
  3. Petrakis, I.L., Nich, C. and Ralevski, E. (2006) Psychotic spectrum disorders and alcohol abuse: A review of pharmacotherapeutic strategies and a report on the effective-ness of naltrexone and disulfiram. Schizophrenia Bulletin, 32, 644-654.
  4. De Sousa, A. (2010) The pharmacotherapy of alcohol dependence: A state of the art review. Mens Sana Monographs, 8, 69-82.
  5. https://www.rxlist.com/antabuse-drug.htm
  6. Krampe, H., & Ehrenreich, H. (2010). Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16(19), (60 years)
  7. Johansson, B. (1992) A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatrica Scandanavica, 362, 15-26.
  8. https://www.ncbi.nlm.nih.gov/books/NBK459340/
  9. https://www.drugs.com/pro/disulfiram.html
  10. Doyon, G., Zerbato, J., Mellors, J. W., & Sluiscremer, N. (2013). Disulfiram reactivates latent hiv-1 expression through depletion of the phosphatase and tensin homolog. Aids, 27(2), F7-F11.
  11. Rasmussen, TA; Lewin, SR (July 2016). "Shocking HIV out of hiding: where are we with clinical trials of latency reversing agents?". Current Opinion in HIV and AIDS.
  12. 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), 716-722.
  13. Kona, F. R., Buac, D., & A, M. B. (2011). Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies. Current Cancer Drug Targets, 11(3).
  14. Rajkumar, S. V., Richardson, P. G., Hideshima, T., & Anderson, K. C. (2005). Proteasome inhibition as a novel therapeutic target in human cancer. Journal of Clinical Oncology, 23(3), 630-639.
  15. Deitrich, R.A., Petersen, D. and Vasiliou, V. (2007) Removal of acetaldehyde from the body. Novartis Foundation Symposia, 285, 23-40.
  16. Pike, M.G., Mays, D.C., Macomber, D.W. and Lipsky, J.J. (2001) Metabolism of a disulfiram metabolite S-methyl N,N-diethyldithiocarbamate by flavinmonooxygenase in human renal microsomes. Drug Metabolism & Disposition, 29, 127-132.
  17. Larsen, V. (1948) The effects on experimental animals of antabuse (tetraethylthiuram disulfide) in combination with alcohol. Acta Pharmacologica Toxicology, 4, 321-332. 
  18. Krampe, H. and Ehrenreich, H. (2010) Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Current Pharmaceutical Design, 16, 2076-2090. 
  19. Fuller, R.K. and Gordis, E. (2004) Does disulfiram have a role in alcoholism treatment today? Addiction, 99, 21-24. 
  20. Vaccari, A., Saba, P.L., Ruiu, S., Collu, M. and Devoto, P. (1996) Disulfiram and diethyldithiocarbamate intoxica-tion affects the storage and release of striatal dopamine. Toxicology & Applied Pharmacology, 139, 102-108. 
  21. Muller, C.A. and Banas, R. (2011) Disulfiram: An anti-craving substance? American Journal of Psychiatry, 168, 98. 
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