関: disulfiram、refusal

WordNet

a drug (trade name Antabuse) used in the treatment of alcoholism; causes nausea and vomiting if alcohol is ingested (同)Antabuse
a message refusing to accept something that is offered
the act of refusing

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〈U〉〈C〉『拒否』,拒絶 / 〈U〉《しばしばthe~》(諾否を決める)優先権,取捨選択権

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/31 23:11:09」(JST)

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Disulfiram (sold under the trade names Antabuse and Antabus) is a drug discovered in the 1920s^[1] that is used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, which means many of the effects of a "hangover" are felt immediately after alcohol is consumed.

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, 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 treatment of cancer and HIV (to activate the reservoir of HIV-infected resting CD4 cells).^[4]

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 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.^{[citation needed]} 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

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 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.^[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 paracetamol (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.

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.^{[citation needed]}
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

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.

However, other sources cite it as originally being used to vulcanize (make heat-resistant) rubber tires.^[19]

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.^[20]

References

^ US Patent 1782111 - Method of Manufacturing Tetra-alkylated Thiuramdisulphides
^ 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.
^ 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.
^ 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.
^ "Disulfiram Official FDA information, side effects and uses.". Retrieved 2011-04-11.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ "Disulfiram Side Effects". Drugs.com. Retrieved 6 November 2010.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ Hvad er antabus, a Danish site describing the discovery of the drug’s effects.
^ http://jama.jamanetwork.com/article.aspx?articleid=318202
^ "NIOSH Pocket Guide to Chemical Hazards #0244". National Institute for Occupational Safety and Health (NIOSH).

External links

Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine
CDC - NIOSH Pocket Guide to Chemical Hazards

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. アルコール使用障害に対する薬物療法 pharmacotherapy for alcohol use disorder
2. 不安障害および物質使用障害を併発した場合の治療 treatment of co occurring anxiety disorders and substance use disorders
3. 成人におけるコカイン関連疾患の治療 treatment of cocaine use disorder in adults
4. 統合失調症と物質使用障害の併発に対する治療 treatment of co occurring schizophrenia and substance use disorder
5. アレルギー性接触皮膚炎の一般的なアレルゲン common allergens in allergic contact dermatitis

English Journal

Use of the disulfiram/copper complex for breast cancer chemoprevention in MMTV‑erbB2 transgenic mice.

Yang Y1, Deng Q2, Feng X3, Sun J1.
Molecular medicine reports.Mol Med Rep.2015 Jul;12(1):746-52. doi: 10.3892/mmr.2015.3426. Epub 2015 Mar 4.
The disulfiram/copper complex (DS/Cu) has been demonstrated to exert potent anti-tumor effects in various types of cancer. At present, whether DS/Cu has chemopreventive effects on breast cancer development remains to be fully elucidated. In the present study, using MMTV‑erbB2 transgenic mice, it w
PMID 25738885

(13) C magnetic resonance spectroscopic imaging of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation can be used to assess aldehyde dehydrogenase activity in vivo.

Dzien P1, Kettunen MI, Marco-Rius I, Serrao EM, Rodrigues TB, Larkin TJ, Timm KN, Brindle KM.
Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine.Magn Reson Med.2015 May;73(5):1733-40. doi: 10.1002/mrm.25286. Epub 2014 May 6.
PURPOSE: Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate
PMID 24800934

Disulfiram/Copper-Disulfiram Damages Multiple Protein Degradation and Turnover Pathways and Cytotoxicity is Enhanced by Metformin in Oesophageal Squamous Cell Carcinoma Cell Lines.

Jivan R1, Damelin LH, Birkhead M, Rousseau AL, Veale RB, Mavri-Damelin D.
Journal of cellular biochemistry.J Cell Biochem.2015 Apr 3. doi: 10.1002/jcb.25184. [Epub ahead of print]
Disulfiram (DSF), used since the 1950s in the treatment of alcoholism, is reductively activated to diethyldithiocarbamate and both compounds are thiol-reactive and readily complex copper. More recently DSF and copper- DSF (Cu-DSF) have been found to exhibit potent anticancer activity. We have previo
PMID 25846272

Japanese Journal

抗菌薬の副作用と発現機序　　抗菌薬の副作用とその発現機序―濃度依存的な副作用を中心に―:濃度依存的な副作用を中心に

日本化学療法学会雑誌 52(6), 293-303, 2004
NAID 130004102690

シアナミドによる苔せん型薬疹の１例

西日本皮膚科 65(3), 269-271, 2003
NAID 130004474911

Safety Evaluation and Drug Development based on Biological Fate of Drugs —Efforts Made to Overcome Drug Interaction in Drug Development—

Drug Metabolism and Pharmacokinetics 17(5), 379-394, 2002
NAID 130004462854

「refusal」

Disulfiram
Systematic (IUPAC) name
	1,1',1'',1'''-[disulfanediylbis(carbonothioylnitrilo)]tetraethane
Clinical data
Trade names	Antabuse
AHFS/Drugs.com	monograph
MedlinePlus	a682602
Pregnancy; category	US: C (Risk not ruled out); ;
Legal status	UK: POM (Prescription only); US: ℞-only;
Routes of; administration	Oral, subdermal implant
Pharmacokinetic data
Metabolism	Hepatic to diethylthiocarbamate
Biological half-life	60–120 hours
Identifiers
CAS Number	97-77-8
ATC code	N07BB01 P03AA04
PubChem	CID: 3117
IUPHAR/BPS	7168
DrugBank	DB00822
ChemSpider	3005
UNII	TR3MLJ1UAI
KEGG	D00131
ChEBI	CHEBI:4659
ChEMBL	CHEMBL964
NIAID ChemDB	010293
Synonyms	1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
Chemical data
Formula	C10H20N2S4
Molecular mass	296.539 g/mol
	SMILES CCN(CC)C(=S)SSC(=S)N(CC)CC ;
	InChI InChI=1S/C10H20N2S4/c1-5-11(6-2)9(13)15-16-10(14)12(7-3)8-4/h5-8H2,1-4H3 ; Key:AUZONCFQVSMFAP-UHFFFAOYSA-N ;
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