Disulfiram

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Disulfiram
Disulfiram.svg
Disulfiram-from-xtal-Mercury-3D-bs.png
Clinical data
Trade names Antabuse, Antabus, other
Other namestetraethyldisulfanedicarbothioamide; 1-(Diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
AHFS/Drugs.com Monograph
MedlinePlus a682602
Pregnancy
category
  • AU:B2
Routes of
administration 		By mouth, subdermal implant
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver to diethylthiocarbamate
Elimination half-life 60–120 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 InfoCard 100.002.371 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H20N2S4
Molar mass 296.52 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 Yes check.svgY
  • Key:AUZONCFQVSMFAP-UHFFFAOYSA-N Yes check.svgY
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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]

Contents

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 (Disulfiram-alcohol reaction). Disulfiram should be used in conjunction with counseling and support.[ citation needed ]

Medical uses

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

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 ]

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.[ citation needed ]

Examples:[ citation needed ]

History

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. [17]

In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms. [17]

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. [17] [18] : 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. [17] [18] : 98–105  That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics. [17] They published their work starting in 1948. [17] [19]

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). [17]

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. [17]

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. [17] [20] The FDA later approved other drugs for treatment of alcoholism, namely naltrexone in 1994 and acamprosate in 2004. [17]

Society and culture

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. [21]

Research

Disulfiram has been studied as a possible treatment for cancer, [22] parasitic infections, [23] anxiety disorder, [24] and latent HIV infection. [25]

Disulfiram has shown reversing of retinitis pigmentosa in rats. [26] [27] [28]

Cancer

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. [22] [29] Various clinical trials of copper depletion agents have been carried out.[ citation needed ]

Parasitic infections

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. [23] [30]

HIV

Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA). [31] [32] 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. [25] 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. [31] [33] Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV. [34]

COVID-19

Disulfiram has been shown to inhibit the papain-like proteases of MERS-CoV and SARS-CoV. [35] It has been examined in a small inconclusive retrospective observational study for its effects on COVID-19 symptoms. [36] In a small randomized controlled trial that has yet to be published in a medical journal, seven COVID patients received disulfiram. No serious adverse events were reported in these patients. [37]

Related Research Articles

Acetaldehyde (IUPAC systematic name ethanal) is an organic chemical compound with the formula CH3CHO, sometimes abbreviated as MeCHO. It is a colorless liquid or gas, boiling near room temperature. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale in industry. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants. It is also produced by the partial oxidation of ethanol by the liver enzyme alcohol dehydrogenase and is a contributing cause of hangover after alcohol consumption. Pathways of exposure include air, water, land, or groundwater, as well as drink and smoke. Consumption of disulfiram inhibits acetaldehyde dehydrogenase, the enzyme responsible for the metabolism of acetaldehyde, thereby causing it to build up in the body.

<span class="mw-page-title-main">Acetaldehyde dehydrogenase</span> Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

<span class="mw-page-title-main">Abacavir</span> Chemical compound

Abacavir, sold under the brand name Ziagen among others, is a medication used to treat HIV/AIDS. Similar to other nucleoside analog reverse-transcriptase inhibitors (NRTIs), abacavir is used together with other HIV medications, and is not recommended by itself. It is taken by mouth as a tablet or solution and may be used in children over the age of three months.

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

<span class="mw-page-title-main">Alcoholic polyneuropathy</span> Medical condition

Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol.

<span class="mw-page-title-main">Alcohol flush reaction</span> Effect of alcohol consumption on the human body

Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, ears, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

<span class="mw-page-title-main">Calcium carbimide</span> Chemical compound

Calcium carbimide, sold as the citrate salt under the trade name Temposil, is a disulfiram-like medication. Its effects are similar to the medication disulfiram (Antabuse) in that it interferes with the normal metabolism of alcohol by preventing the breakdown of the metabolic byproduct acetaldehyde. The result is that when alcohol is consumed by users of calcium carbimide, they experience severe reactions which include symptoms such as sweating, difficulty breathing, rapid heartbeat, rash, nausea and vomiting, and headache.

<span class="mw-page-title-main">Fomepizole</span> Medication

Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning. It may be used alone or together with hemodialysis. It is given by injection into a vein.

<span class="mw-page-title-main">Alcohol tolerance</span> Bodily responses to the functional effects of ethanol in alcoholic beverages

Alcohol tolerance refers to the bodily responses to the functional effects of ethanol in alcoholic beverages. This includes direct tolerance, speed of recovery from insobriety and resistance to the development of alcohol use disorder.

<span class="mw-page-title-main">Acamprosate</span> Medication

Acamprosate, sold under the brand name Campral, is a medication used along with counseling to treat alcohol use disorder.

<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.

<span class="mw-page-title-main">Hangover</span> Discomfort following alcohol consumption

A hangover is the experience of various unpleasant physiological and psychological effects usually following the consumption of alcohol, such as wine, beer, and liquor. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, hyper-excitability, irritability, and anxiety.

<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

The short-term effects of alcohol consumption range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), to stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once it is in the bloodstream, it can diffuse into nearly every cell in the body.

<span class="mw-page-title-main">Coprine</span> Chemical compound

Coprine is a mycotoxin. It was first isolated from common inkcap. It occurs in mushrooms in the genera Coprinopsis. When combined with alcohol, it causes "Coprinus syndrome". It inhibits the enzyme acetaldehyde dehydrogenase, which is involved in the metabolism of alcohol. This inhibition leads to a buildup of acetaldehyde, causing an alcohol flush reaction. Because of this, the mushroom is commonly referred to as Tippler's Bane.

<span class="mw-page-title-main">Tryptophol</span> Chemical compound

Tryptophol is an aromatic alcohol that induces sleep in humans. It is found in wine as a secondary product of ethanol fermentation. It was first described by Felix Ehrlich in 1912. It is also produced by the trypanosomal parasite in sleeping sickness.

<span class="mw-page-title-main">Metadoxine</span> Medication used for alcohol intoxication

Metadoxine, also known as pyridoxine-pyrrolidone carboxylate, is a drug used to treat chronic and acute alcohol intoxication. Metadoxine accelerates alcohol clearance from the blood.

<span class="mw-page-title-main">Alcohol (drug)</span> Active ingredient in alcoholic beverages

Alcohol, sometimes referred to by the chemical name ethanol, is a depressant drug that is the active ingredient in fermented drinks such as beer, wine, and distilled spirits. It is one of the oldest and most commonly consumed recreational drugs, causing the characteristic effects of alcohol intoxication ("drunkenness"). Among other effects, alcohol produces happiness and euphoria, decreased anxiety, increased sociability, sedation, impairment of cognitive, memory, motor, and sensory function, and generalized depression of central nervous system (CNS) function.

<span class="mw-page-title-main">Alcohol intolerance</span> Medical condition

Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.

<span class="mw-page-title-main">Disulfiram-like drug</span> Drug that causes an adverse reaction to alcohol

A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.

<span class="mw-page-title-main">Disulfiram-alcohol reaction</span> Medical condition

Disulfiram-alcohol reaction (DAR) is the effect of the interaction in the human body of alcohol drunk with disulfiram or some mushrooms. The DAR is key to disulfiram therapy that is widely used for alcohol-aversive treatment and management of other addictions. Once disulfiram-treated patients take alcohol, even in small doses, they experience strong unpleasant sensations.

References

  1. ↑ 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.
  2. ↑ "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.
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  12. ↑ Boukriche Y, Weisser I, Aubert P, Masson C (September 2000). "MRI findings in a case of late onset disulfiram-induced neurotoxicity". Journal of Neurology. 247 (9): 714–715. doi:10.1007/s004150070119. PMID   11081815. S2CID   1982036.
  13. ↑ Watson CP, Ashby P, Bilbao JM (July 1980). "Disulfiram neuropathy". Canadian Medical Association Journal. 123 (2): 123–126. PMC   1704662 . PMID   6266628.
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  17. 1 2 3 4 5 6 7 8 9 10 Kragh H (2008). "From Disulfiram to Antabuse: The Invention of a Drug" (PDF). Bulletin for the History of Chemistry. 33 (2): 82–88.
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  24. ↑ Gallagher A (23 April 2022). "Drug Used to Treat Alcoholism Shows Promise for Anxiety, Study Results Show". Pharmacy Times. Retrieved 2022-04-25.
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  28. ↑ Papadopoulos L (2022-03-19). "A drug once used to treat alcoholism may cure retinal degeneration". interestingengineering.com. Retrieved 2022-04-13.
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  30. ↑ 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.
  31. 1 2 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ Clinical trial number NCT03198559 for "Combination Latency Reversal With High Dose Disulfiram Plus Vorinostat in HIV-infected Individuals on ART" at ClinicalTrials.gov
  35. ↑ Lin MH, Moses DC, Hsieh CH, Cheng SC, Chen YH, Sun CY, Chou CY (February 2018). "Disulfiram can inhibit MERS and SARS coronavirus papain-like proteases via different modes". Antiviral Research. 150: 155–163. doi:10.1016/j.antiviral.2017.12.015. PMC   7113793 . PMID   29289665.
  36. ↑ Tamburin S, Mantovani E, De Bernardis E, Zipeto D, Lugoboni F, et al. (Gruppo InterSERT di Collaborazione Scientifica (GICS)) (September 2021). "COVID-19 and related symptoms in patients under disulfiram for alcohol use disorder". Internal and Emergency Medicine. 16 (6): 1729–1731. doi:10.1007/s11739-021-02633-y. PMC   7814518 . PMID   33464469.
  37. ↑ Clinical trial number NCT04485130 for "DISulfiram for COvid-19 (DISCO) Trial" at ClinicalTrials.gov
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