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Disulfiram

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Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.[3]

Disulfiram
Clinical data
Trade namesAntabuse, Antabus, other
Other namestetraethyldisulfanedicarbothioamide; 1-(Diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
AHFS/Drugs.comMonograph
MedlinePlusa682602
Pregnancy
category
  • AU: B2
Routes of
administration		By mouth, subdermal implant
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver to diethylthiocarbamate
Elimination half-life60–120 hours
Identifiers
  • 1,1′-disulfanediylbis(N,N-diethylmethanethioamide)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard100.002.371 Edit this at Wikidata
Chemical and physical data
FormulaC10H20N2S4
Molar mass296.52 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=S)SSC(=S)N(CC)CC
  • InChI=1S/C10H20N2S4/c1-5-11(6-2)9(13)15-16-10(14)12(7-3)8-4/h5-8H2,1-4H3 checkY
  • Key:AUZONCFQVSMFAP-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. When the dehydrogenase enzyme is inhibited, acetaldehyde builds up, causing unpleasant side effects (see Disulfiram-alcohol reaction). Disulfiram should be used in conjunction with counseling and support.[citation needed]

Medical uses

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Disulfiram is used as a second-line treatment, behind acamprosate and naltrexone, for alcohol dependence.[4]

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 a harmless acetic acid derivative (acetyl coenzyme A). 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. About 5 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 usually include flushing of the skin, accelerated heart rate, low blood pressure, nausea, and vomiting. Uncommon adverse events include shortness of breath, throbbing headache, visual disturbance, mental confusion, postural syncope, and circulatory collapse.[5]

Disulfiram should not be taken if alcohol has been consumed in the last 12 hours.[6] There is no tolerance to disulfiram: the longer it is taken, the stronger its effects.[3] 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.[7]

Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. 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.[medical citation needed]

Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse until 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.[citation needed]

Side effects

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The most common side effects in the absence of alcohol are headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur.[8] Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment.[9] Less common side effects include decrease in libido, liver problems, skin rash, and nerve inflammation.[10] Liver toxicity is an uncommon but potentially serious side effect, and risk groups e.g. those with already impaired liver function should be monitored closely. That said, the rate of disulfiram-induced hepatitis are estimated to be in between 1 per 25,000 to 1 in 30,000,[11] and rarely the primary cause for treatment cessation.

Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.[12] Disulfiram can produce neuropathy in daily doses of less than the usually recommended 500 mg. Nerve biopsies showed axonal degeneration and the neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drug's use is stopped; often there is complete recovery eventually.[13]

Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen),[14] theophylline[15] and caffeine.[16] 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.[citation needed]

Aldehyde dehydrogenase inhibitors (ALDH inhibitors) like disulfiram inhibit the metabolism and consequent detoxification of 3,4-dihydroxyphenylacetaldehyde (DOPAL).[17][18][19] DOPAL is the major metabolite of the monoamine neurotransmitter dopamine and is a known potent dopaminergic neurotoxin.[17][18] It is thought to be involved in aging-related dopaminergic neurodegeneration and Parkinson's disease.[17][18] By inhibiting ALDH, disulfiram and other ALDH inhibitors may accelerate aging-related dopaminergic neurodegeneration.[17][20][19] This has been demonstrated with disulfiram in preclinical research, although dopaminergic neurotoxicity caused by the drug in humans has not been studied or shown and preclinical findings with disulfiram are conflicting.[17][19][20][21] In any case, environmental exposure to known ALDH inhibitors, such as various pesticides, have been associated with dopaminergic neurodegeneration and incidence of Parkinson's disease, among other findings.[17][19]

Similarly acting substances

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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.[citation needed]

Examples:[citation needed]

Pharmacology

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Pharmacodynamics

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Disulfiram acts as an irreversible aldehyde dehydrogenase (ALDH) inhibitor.[22] ALDH is an enzyme that catalyze the oxidation of aldehydes.[22] It is known to inactivate acetaldehyde, a toxic metabolite of alcohol.[22] By inhibiting ALDH, disulfiram prevents the inactivation and detoxification of acetaldehyde and thereby induces a variety of unpleasant symptoms when alcohol is consumed.[22]

Besides inhibiting ALDH, disulfiram is a dopamine β-hydroxylase (DBH) inhibitor.[23][24] DBH is an enzyme that converts the monoamine neurotransmitter dopamine into norepinephrine.[23][24] By inhibiting DBH, disulfiram may increase dopamine levels in the brain and periphery but decrease levels of norepinephrine and its metabolite epinephrine in the brain and periphery.[23][24] However, it is also possible that disulfiram may actually decrease brain dopamine levels.[24] DBH inhibition by disulfiram may explain its possible therapeutic benefits in cocaine dependence as well as cases of psychosis and mania associated with the drug.[23][24][25] There are also cases of disulfiram producing stimulant psychosis in combination with the psychostimulants methylphenidate and amphetamine.[25] DBH inhibition by disulfiram might also explain the hypotension side effect when alcohol is ingested in people taking disulfiram.[23]

Disulfiram is also known to inhibit the cytochrome P450 enzymes CYP2E1 and CYP1A2.[25]

History

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The synthesis of disulfiram, originally known as tetraethylthiuram disulfide, was first reported in 1881. By around 1900, it was introduced to the industrial process of sulfur vulcanization of rubber and became widely used. In 1937, a plant physician in the American rubber industry described adverse reactions to alcohol in workers exposed to tetramethylthiuram monosulfide and disulfide, and proposed that this effect of disulfiram and related compounds might lead to ”the cure for alcoholism”; the effect was also noticed in workers at a Swedish rubber boot factory.[26]

In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms.[26]

Around that time, during the German occupation of Denmark, Erik Jacobsen and Jens Hald at the Danish drug company Medicinalco picked up on that research and began exploring the use of disulfiram to treat intestinal parasites. The company had a group of enthusiastic self-experimenters that called itself the "Death Battalion", and in the course of testing the drug on themselves, accidentally discovered that drinking alcohol while the drug was still in their bodies made them mildly sick.[26][27]: 98–105 

They made that discovery in 1945, and did nothing with it until two years later, when Jacobsen gave an impromptu talk and mentioned that work, which was discussed afterwards in newspapers at the time, leading them to further explore the use of the drug for that purpose.[26][27]: 98–105  That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics.[26] They published their work starting in 1948.[26][28]

The chemists at Medicinalco discovered a new form of disulfiram while trying to purify a batch that had been contaminated with copper. This form turned out to have better pharmacological properties, and the company patented it and used that form for the product that was introduced as Antabus (later anglicized to Antabuse).[26]

This work led to renewed study of the human metabolism of ethanol. It was already known that ethanol was mostly metabolized in the liver, with it being converted first to acetaldehyde and then acetaldehyde to acetic acid and carbon dioxide, but the enzymes involved were not known. By 1950 the work led to the knowledge that ethanol is oxidized to acetaldehyde by alcohol dehydrogenase and acetaldehyde is oxidized to acetic acid by aldehyde dehydrogenase (ALDH), and that disulfiram works by inhibiting ALDH, leading to a buildup of acetaldehyde, which is what causes the negative effects in the body.[26]

The drug was first marketed in Denmark and as of 2008, Denmark is the country where it is most widely prescribed. It was approved by the FDA in 1951.[26][29] The FDA later approved other drugs for treatment of alcoholism, namely naltrexone in 1994 and acamprosate in 2004.[26]

Society and culture

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Though the Occupational Safety and Health Administration (OSHA) in the US has not set a permissible exposure limit (PEL) for disulfiram in the workplace, the National Institute for Occupational Safety and Health has set a recommended exposure limit (REL) of 2 mg/m3 and recommended that workers avoid concurrent exposure to ethylene dibromide.[30]

Research

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Disulfiram has been studied as a possible treatment for cancer,[31] parasitic infections,[32] anxiety disorder,[33] and latent HIV infection.[34]

Cancer

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When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor and as of 2016 it had been studied in in vitro experiments, model animals, and small clinical trials as a possible treatment for liver metastasis, metastatic melanoma, glioblastoma, non-small cell lung cancer, and prostate cancer.[31][35] Various clinical trials of copper depletion agents have been carried out.[citation needed]

Parasitic infections

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In the body, disulfiram is rapidly metabolized to diethyldithiocarbamate (ditiocarb), which binds to metal ions such as zinc or copper to form zinc or copper diethyldithiocarbamate (zinc or copper ditiocarb). The zinc diethyldithiocarbamate (zinc-ditiocarb) metabolite of disulfiram is extremely potent against the diarrhea and liver abscess-causing parasite Entamoeba histolytica and might be active against other deadly parasites.[32][36]

HIV

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Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA).[37][38] Reactivation of latent HIV infection in patients is part of an investigational strategy known as "shock and kill" which may be able to reduce or eliminate the HIV reservoir.[34] Recent phase II dose-escalation studies in patients with HIV who are controlled on antiretroviral therapy have observed an increase in cell-associated unspliced HIV RNA with increasing exposure to disulfiram and its metabolites.[37][39] Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV.[40]

References

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  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
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  6. ^ "Disulfiram Official FDA information, side effects and uses". Drugs.com. Retrieved 2011-04-11.
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  26. ^ a b c d e f g h i j Kragh H (2008). "From Disulfiram to Antabuse: The Invention of a Drug" (PDF). Bulletin for the History of Chemistry. 33 (2): 82–88.
  27. ^ a b Altman LK (1998). Who Goes First?: The Story of Self-Experimentation in Medicine. University of California Press. ISBN 9780520212817.
  28. ^ Hald J, Jacobsen E, Larsen V (July 1948). "The Sensitizing Effect of Tetraethylthiuramdisulphide (Antabuse) to Ethylalcohol". Acta Pharmacologica et Toxicologica. 4 (3–4): 285–296. doi:10.1111/j.1600-0773.1948.tb03350.x.
  29. ^ "New Drug Application (NDA) 007883: Disulfiram (Antabuse)". FDA-Approved Drugs. U.S. Food and Drug Administration (FDA). Retrieved 4 August 2018.
  30. ^ NIOSH Pocket Guide to Chemical Hazards. "#0244". National Institute for Occupational Safety and Health (NIOSH).
  31. ^ a b Jiao Y, Hannafon BN, Ding WQ (2016). "Disulfiram's Anticancer Activity: Evidence and Mechanisms". Anti-Cancer Agents in Medicinal Chemistry. 16 (11): 1378–1384. doi:10.2174/1871520615666160504095040. PMID 27141876.
  32. ^ a b Shirley DA, Sharma I, Warren CA, Moonah S (2021). "Drug Repurposing of the Alcohol Abuse Medication Disulfiram as an Anti-Parasitic Agent". Frontiers in Cellular and Infection Microbiology. 11: 633194. doi:10.3389/fcimb.2021.633194. PMC 7991622. PMID 33777846.
  33. ^ Gallagher A (23 April 2022). "Drug Used to Treat Alcoholism Shows Promise for Anxiety, Study Results Show". Pharmacy Times. Retrieved 2022-04-25.
  34. ^ a b 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. 11 (4): 394–401. doi:10.1097/COH.0000000000000279. PMID 26974532. S2CID 25995091.
  35. ^ Cvek B, Dvorak Z (August 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): 716–722. doi:10.1016/j.drudis.2008.05.003. PMID 18579431.
  36. ^ Ghosh S, Farr L, Singh A, Leaton LA, Padalia J, Shirley DA, et al. (September 2020). "COP9 signalosome is an essential and druggable parasite target that regulates protein degradation". PLOS Pathogens. 16 (9): e1008952. doi:10.1371/journal.ppat.1008952. PMC 7531848. PMID 32960936.
  37. ^ a b Lee SA, Elliott JH, McMahon J, Hartogenesis W, Bumpus NN, Lifson JD, et al. (March 2019). "Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial". Clinical Pharmacology and Therapeutics. 105 (3): 692–702. doi:10.1002/cpt.1220. PMC 6379104. PMID 30137649.
  38. ^ Xing S, Bullen CK, Shroff NS, Shan L, Yang HC, Manucci JL, et al. (June 2011). "Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation". Journal of Virology. 85 (12): 6060–6064. doi:10.1128/JVI.02033-10. PMC 3126325. PMID 21471244.
  39. ^ Knights HD (2017). "A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice". AIDS Research and Treatment. 2017: 8239428. doi:10.1155/2017/8239428. PMC 5390639. PMID 28465838.
  40. ^ Clinical trial number NCT03198559 for "Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART" at ClinicalTrials.gov
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