Disulfiram (sold under the trade names Antabuse and Antabus) is a drug used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, which means that many of the effects of a "hangover" are felt immediately after alcohol is consumed. "Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death." Disulfiram is a disulfiram-like drug. In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. If the dehydrogenase enzyme is inhibited, acetaldehyde builds up and causes unpleasant effects. 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, elevated blood pressure, restlessness, and other unpleasant symptoms. Several studies have reported that it has antiprotozoal activity, as well. Disulfiram is the subject of research for treatment of cancer and HIV (to activate the reservoir of HIV-infected resting CD4 cells). Uses Alcoholism 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 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. 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. A 9-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%. 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. 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 When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor and can represent a new approach to proteasome inhibition. Clinical trials are recommended. 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 in absence of alcohol 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. Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment. Less common side effects include decrease in libido, liver problems, skin rash, and nerve inflammation. 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, and rarely the primary cause for treatment cessation. Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms. Disulfiram (Antabuse) can produce neuropathy in daily doses of less than the usually recommended 500 mg. The four recent cases reported in this paper emphasize the need for greater recognition of this condition. 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. Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen), theophylline and caffeine. 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. 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. Examples: Antibiotics (nitroimidazoles), e.g. metronidazole First-generation sulfonylureas, e.g. tolbutamide and chlorpropamide Several cephalosporin drugs, including cefoperazone, cefamandole and cefotetan, that have a N-methylthio-tetrazole moiety Griseofulvin, an oral antifungal drug Procarbazine Temposil, or citrated calcium carbimide, has the same function as disulfiram, but is weaker and safer. Coprine, which metabolizes to 1-aminocyclopropanol, a chemical having the same metabolic effects as disulfiram. It 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 Suillellus luridus, although the agent in those species is unknown. History Disulfiram, originally known as tetraethylthiuram dilsulfide, was first used around 1881. This chemical and similar compounds were used in the vulcanization of rubber for tires, and it had been noted that workers in those industries often had adverse reactions to alcohol; the connection between the reaction and exposure to these chemicals, though, had not been deduced. However, in 1948 researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the Danish drug company Medicinalco uncovered the connection when they self-dosed with the chemical in the course of testing it as a possible anti-parasitic, and found themselves reacting violently to alcohol consumption. Disulfiram is currently sold under the trade names Antabuse and Antabus, manufactured by Odyssey Pharmaceuticals. Safety 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. See also Acamprosate Naltrexone Temposil Thiram References External links Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine CDC - NIOSH Pocket Guide to Chemical Hazards ) ) ) )
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