| Revision as of 12:12, 5 December 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 457135650 of page Phenylbutazone for the Chem/Drugbox validation project (updated: 'DrugBank'). |
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{{Short description|Nonsteroidal anti-inflammatory drug (NSAID)}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{Redirect-distinguish|Butadione|Butanedione}} |
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{{Drugbox |
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{{More medical citations needed|date=November 2017}}{{Drugbox |
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| Watchedfields = changed |
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| verifiedrevid = 408955546 |
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| verifiedrevid = 464201077 |
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| IUPAC_name = 4-butyl-1,2-diphenyl-pyrazolidine-3,5-dione |
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| IUPAC_name = 4-Butyl-1,2-diphenyl-pyrazolidine-3,5-dione |
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| image = Phenylbutazone.svg |
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| image = Phenylbutazone.svg |
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| alt = Skeletal formula |
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| width = 200px |
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| width = 220px |
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| drug_name = Phenylbutazone |
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| image2 = Phenylbutazone-3D-balls.png |
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| alt2 = Ball-and-stick model |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = Butazolidine |
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| tradename = Butazolidine |
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| pregnancy_category = |
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| pregnancy_category = |
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| legal_status = rx-only |
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| legal_status = rx-only |
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| routes_of_administration = |
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| routes_of_administration = |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| bioavailability = |
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| protein_bound = |
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| protein_bound = |
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| metabolism = |
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| metabolism = |
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| elimination_half-life = |
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| elimination_half-life = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 7270 |
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| CASNo_Ref = {{cascite|correct|CAS}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number = 50-33-9 |
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| CAS_number = 50-33-9 |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG_Ref = {{keggcite|correct|kegg}} |
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| KEGG = D00510 |
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| KEGG = D00510 |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 48574 |
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| ChEBI = 48574 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 101 |
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| ChEMBL = 101 |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=19 | H=20 | N=2 | O=2 |
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| C=19 | H=20 | N=2 | O=2 |
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| molecular_weight = 308.374 g/mol |
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| smiles = O=C2N(c1ccccc1)N(C(=O)C2CCCC)c3ccccc3 |
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| smiles = O=C2N(c1ccccc1)N(C(=O)C2CCCC)c3ccccc3 |
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| InChI = 1/C19H20N2O2/c1-2-3-14-17-18(22)20(15-10-6-4-7-11-15)21(19(17)23)16-12-8-5-9-13-16/h4-13,17H,2-3,14H2,1H3 |
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| InChIKey = VYMDGNCVAMGZFE-UHFFFAOYAL |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C19H20N2O2/c1-2-3-14-17-18(22)20(15-10-6-4-7-11-15)21(19(17)23)16-12-8-5-9-13-16/h4-13,17H,2-3,14H2,1H3 |
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| StdInChI = 1S/C19H20N2O2/c1-2-3-14-17-18(22)20(15-10-6-4-7-11-15)21(19(17)23)16-12-8-5-9-13-16/h4-13,17H,2-3,14H2,1H3 |
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| StdInChIKey = VYMDGNCVAMGZFE-UHFFFAOYSA-N |
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| StdInChIKey = VYMDGNCVAMGZFE-UHFFFAOYSA-N |
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}} |
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}} |
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'''Phenylbutazone''', often referred to as "'''bute'''",<ref>{{Cite news|url=https://www.nytimes.com/2012/03/25/us/death-and-disarray-at-americas-racetracks.html|title=Death and Disarray at America's Racetracks|date=24 March 2012|newspaper=The New York Times| vauthors = Bogdanich W, Drape J }}</ref> is a ] (NSAID) for the short-term treatment of pain and fever in animals. |
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In the United States and United Kingdom, it is no longer approved for human use (except in the United Kingdom for ]), as it can cause severe adverse effects such as suppression of ] production and ]. This drug was implicated in the ]. Positive phenylbutazone tests in horse meat were uncommon in the UK, however.<ref name=fsa>{{cite web|title=Horse meat investigation. Advice for consumers|url=http://www.food.gov.uk/enforcement/monitoring/horse-meat/horse-meat-consumer-advice/|work=Enforcement and regulation|publisher=]|access-date=19 May 2013}}</ref> |
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==Uses== |
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===In humans=== |
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Phenylbutazone was originally made available for use in humans for the treatment of ] and ] in 1949. However, it is no longer approved, and therefore not marketed, for any human use in the United States.<ref>{{cite web|url=https://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm124078.htm|title=FDA Order Prohibits Extralabel Use of Phenylbutazone in Certain Dairy Cattle|publisher=Food and Drug Administration|date=28 February 2003}}</ref> In the UK it is used to treat ], but only when other therapies are unsuitable.<ref> {{webarchive|url=https://web.archive.org/web/20130429161039/http://www.iow.nhs.uk/index.asp?record=1655 |date=2013-04-29 }}</ref> |
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===In horses=== |
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Phenylbutazone is the most commonly used NSAID for ]s in the United States.<ref name="McIlwraith">McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal Anti-Inflammatory Drugs. Proc. AAEP 2001 (47): 182-187.</ref> It is used for the following purposes: |
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* ]: It is used for pain relief from ] and ], including ]s, overuse injuries, ], ]s, ], and ]. Like other NSAIDs, it acts directly on ] ] to control ], thereby reducing secondary inflammatory damage, alleviating pain, and restoring ]. It does not ] musculoskeletal ailments or work well on ] pain. |
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* ]: It is used for reduction of fevers. Its antipyretic qualities may mask other ]. |
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====History of phenylbutazone in racing==== |
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In the ], ], the winner of the race, was disqualified after traces of phenylbutazone were allegedly discovered in a post-race ]. Owned by prominent ] businessman ] and ridden by ] ], Dancer's Image was the first horse to win the ] and then be disqualified. Phenylbutazone was legal on most tracks around the United States in 1968, but had not yet been approved by ]. |
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Controversy and speculation still surround the incident. In the weeks prior to the race, Fuller had given previous winnings to ], the ] of slain ] activist ], which brought both praise and criticism. The previous year, King held a ] against housing discrimination which disrupted Derby week. Forty years later, Fuller still believed Dancer's Image was disqualified due to these events.<ref></ref><ref>{{cite web |url=http://www.seacoastonline.com/1999news/4_25_s1.htm |title=Sports: Dancer's tainted image |access-date=2007-10-07 |url-status=dead |archive-url=https://web.archive.org/web/20070101024216/http://www.seacoastonline.com/1999news/4_25_s1.htm |archive-date=2007-01-01 }}</ref> |
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Although ] had been named the winner, after many appeals the Kentucky Derby official website lists both Dancer's Image and Forward Pass as the winner. The website's race video commentary states that on the winner's plaque at ], both Dancer's Image and Forward Pass are listed as the 1968 winner of the Kentucky Derby.<ref>{{cite web |url=http://www.kentuckyderby.com/2006/derby_history/derby_charts/years/1968.html |title=Kentucky Derby 132 |access-date=2007-10-07 |year=2006}}</ref> |
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===In dogs=== |
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Phenylbutazone is occasionally used in dogs for the longer-term management of chronic pain, particularly due to ]. About 20% of adult dogs are affected with osteoarthritis, which makes the management of musculoskeletal pain a major component of companion animal practice. The margin of safety for all NSAIDs is narrow in the dog, and other NSAIDs are more commonly used (], and ]). Gastrointestinal-protectant drugs, such as ], ], ], ], or ], are frequently included as a part of treatment with any NSAID. Dogs receiving chronic phenylbutazone therapy should be followed with regular blood work and renal monitoring.<ref>{{cite web |url=http://www.wedgewoodpharmacy.com/monographs/phenylbutazone.asp |title=Wedgewood Pharmaceuticals-Phenylbutazol}}</ref> |
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Side effects of phenylbutazone in dogs include gastrointestinal (GI) ulceration, bone marrow depression, rashes, malaise, blood dyscrasias, and diminished renal blood flow. |
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==Dosage and administration in horses== |
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Phenylbutazone has a ] of 4–8 hours, however the inflammatory ] half life is 24 hours,<ref name="pmid3723663">{{cite journal | vauthors = Lees P, Taylor JB, Higgins AJ, Sharma SC | title = Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse | journal = Journal of Veterinary Pharmacology and Therapeutics | volume = 9 | issue = 2 | pages = 204–212 | date = June 1986 | pmid = 3723663 | doi = 10.1111/j.1365-2885.1986.tb00031.x }}</ref> so single daily dosing can be sufficient, although it is often used twice per day.<ref name=McIlwraith/> The drug is considered fairly non-toxic when given at appropriate doses (2.2-4.4 mg/kg/day), even when used repeatedly.<ref name="pmid6725103">{{cite journal | vauthors = Collins LG, Tyler DE | title = Phenylbutazone toxicosis in the horse: a clinical study | journal = Journal of the American Veterinary Medical Association | volume = 184 | issue = 6 | pages = 699–703 | date = March 1984 | pmid = 6725103 }}</ref> This dose has been doubled for diseases that cause severe pain, such as ], but is toxic if repeated long-term, and exceptionally high doses (15 mg/kg/d or higher) can kill the animal in less than a week.<ref name="MacKay">{{cite journal | vauthors = MacKay RJ, French TW, Nguyen HT, Mayhew IG | title = Effects of large doses of phenylbutazone administration to horses | journal = American Journal of Veterinary Research | volume = 44 | issue = 5 | pages = 774–780 | date = May 1983 | pmid = 6869982 }}</ref> |
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Phenylbutazone can be administered orally (via paste, powder or feed-in) or ]ly. It should not be given ]ly or ] in any place other than a ], as it can cause tissue damage. Tissue damage and ] may also occur if the drug is injected repetitively into the same vein. |
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==Side effects and disadvantages== |
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Side effects of phenylbutazone are similar to those of other NSAIDs. Overdose or prolonged use can cause ], ], ] damage (primarily dose-dependant renal papillary necrosis), oral lesions if given by mouth, and internal ].<ref name="MacKay"/> This is especially pronounced in young, ill, or stressed horses which are less able to metabolize the drug.<ref>Lees P, Higgins AJ. Clinical pharmacology in therapeutic uses of non-steroidal anti-inflammatory drugs in the horse. Equine Vet J 1985;17:83–96.</ref> Effects of gastrointestinal damage include edema of the legs and belly secondary to leakage of blood proteins into the intestines, resulting in decreased appetite, excessive thirst, weight loss, weakness, and in advanced stages, kidney failure and death. Phenylbutazone can also cause ]. |
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Phenylbutazone amplifies the ] effect of ]s such as ] or ]. Phenylbutazone displaces warfarin from plasma binding sites, and toxic blood levels leading to haemorrhage can occur. It may aggravate kidney or liver problems. |
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Phenylbutazone may be ] to the ] and can be transferred via the ] and by ]. |
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Phenylbutazone can be used in foals. Premature foals, ] foals, foals with questionable kidney or liver function and foals with diarrhea require careful monitoring. Drugs to protect the ] such as omeprazole, cimetidine, and sucralfate are frequently used with phenylbutazone. |
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High doses of phenylbutazone may be considered a rules violation under some ] organizations, as the drug may remain in the ] four to five days after administration. |
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The ] places it in Group 3; i.e., "not classifiable as to its ]icity to humans". |
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Use in horses is limited to those not intended for food. Metabolites of phenylbutazone can cause ] in humans.<ref>{{cite journal |journal=Irish Veterinary Journal |volume=63 |issue=12|title=Phenylbutazone and its availability in ireland – prudent prescribing and dispensing | vauthors = Scanaill PÓ |pages=766–8 |url=http://www.veterinaryirelandjournal.com/Links/PDFs/CE-Large/CELA_Dec_2010.pdf.pdf|url-status=dead |archive-url= https://web.archive.org/web/20120402205619/http://www.veterinaryirelandjournal.com/Links/PDFs/CE-Large/CELA_Dec_2010.pdf.pdf |archive-date=2012-04-02 }}</ref><ref>{{cite web|url=http://www.inspection.gc.ca/english/fssa/meavia/man/ch17/annexee.shtml|title=Ante and Post-mortem Procedures, Dispositions, Monitoring and Controls - Red Meat Species, Ostriches, Rheas and Emus|publisher=Canadian Food Inspection Agency|date=2013-05-31}}</ref> |
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==Investigations into potential carcinogenicity== |
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Opinions are conflicting regarding the ] of phenylbutazone in animals; no evidence indicates it causes cancer in humans at therapeutic doses. Maekawa ''et al.'' (1987) found no increased ] incidence in ] rats fed a diet containing 0.125% or 0.25% phenylbutazone over two years.<ref name=Maekawa1987>{{cite journal | vauthors = Meakawa A, Onodera H, Tanigawa H, Furuta K, Kanno J, Matsuoka C, Ogiu T, Hayashi Y | display-authors = 6 | title = Long-term studies on carcinogenicity and promoting effect of phenylbutazone in DONRYU rats | journal = Journal of the National Cancer Institute | volume = 79 | issue = 3 | pages = 577–584 | date = September 1987 | pmid = 3476793 | doi = 10.1093/jnci/79.3.577 }}</ref> On the other hand, Kari ''et al.'' (1995) found a rare type of ] cancer in rats (13 of 100) and an increased rate of liver cancer in male rats fed 150 and 300 mg/kg body weight of phenylbutazone for two years.<ref name=Kari1995>{{cite journal | vauthors = Kari F, Bucher J, Haseman J, Eustis S, Huff J | title = Long-term exposure to the anti-inflammatory agent phenylbutazone induces kidney tumors in rats and liver tumors in mice | journal = Japanese Journal of Cancer Research | volume = 86 | issue = 3 | pages = 252–263 | date = March 1995 | pmid = 7744695 | pmc = 5920813 | doi = 10.1111/j.1349-7006.1995.tb03048.x }}</ref> Tennant (1993) listed phenylbutazone as a non-mutagenic carcinogen.<ref name=Tennant1993>{{cite journal | vauthors = Tennant RW | title = A perspective on nonmutagenic mechanisms in carcinogenesis | journal = Environmental Health Perspectives | volume = 101 | issue = Suppl 3 | pages = 231–236 | date = October 1993 | pmid = 8143623 | pmc = 1521175 | doi = 10.1289/ehp.93101s3231 }}</ref> Kirkland and Fowler (2010) acknowledged that, while phenylbutazone is not predicted to be a ] by computer software that simulates the chemicals interaction with DNA,<ref name=Kirkland2010>{{cite journal | vauthors = Kirkland D, Fowler P | title = Further analysis of Ames-negative rodent carcinogens that are only genotoxic in mammalian cells in vitro at concentrations exceeding 1 mM, including retesting of compounds of concern | journal = Mutagenesis | volume = 25 | issue = 6 | pages = 539–553 | date = November 2010 | pmid = 20720197 | doi = 10.1093/mutage/geq041 | doi-access = free }}</ref> one laboratory study indicated phenylbutazone subtly altered the structure of ]s of ] cells of mice.<ref name=Giri1998>{{cite journal | vauthors = Giri AK, Mukhopadhyay A | title = Mutagenicity assay in Salmonella and in vivo sister chromatid exchange in bone marrow cells of mice for four pyrazolone derivatives | journal = Mutation Research | volume = 420 | issue = 1–3 | pages = 15–25 | date = December 1998 | pmid = 9838026 | doi = 10.1016/S1383-5718(98)00138-7 | bibcode = 1998MRGTE.420...15G }}</ref> Kirkland and Fowler (2010) furthermore explained that the theoretical carcinogenic effects of phenylbutazone in humans cannot be studied because patients prescribed the drug were given doses far below the level any effect may become apparent (<1 ]).<ref name=Kirkland2010/> The ]'s ] (IARC) stated in 1987 that there was inadequate evidence for a carcinogenic effect in humans.<ref name=IARC1987>{{Cite book | publisher = International Agency for Research on Cancer | pages = 316 | author = IARC | title = IARC monographs on the evaluation of the carcinogenic risk of chemicals to man. | year = 1987 }}</ref> |
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== Interactions == |
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Other anti-inflammatory drugs that tend to cause GI ulcers, such as corticosteroids and other NSAIDs, can potentiate the bleeding risk. Combination with anticoagulant drugs, particularly coumarin derivatives, also increases the risk of bleeding. Avoid combining with other hepatotoxic drugs. |
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Phenylbutazone may affect blood levels and duration of action of ], ], ], ] antidiabetic agents, ]s, ], ], ], ], and ].<ref name="Wedgewood">{{cite web |url=http://www.wedgewoodpharmacy.com/monographs/phenylbutazone.asp|title=Phenylbutazol for veterinary use|publisher=Wedgewood Pharmacy}}</ref> |
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==Overdose== |
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Overdoses of phenylbutazone can cause ], liver injury, ], and ] or perforation. Early signs of toxicity include ], and ].<ref name="Wedgewood" /> |
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==Chemistry== |
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Phenylbutazone is a ]line ]. It is obtained by condensation of diethyl ''n''-butylmalonate with ] in the presence of base. In effect, this represents the formation of the heterocyclic system by simple ]. |
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<gallery> |
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File:1,2-Diphenylhydrazin.svg|Hydrazobenzene |
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File:Diethyl-butylmalonate skeletal.svg|Diethyl ''n''-butylmalonate |
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</gallery> |
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], the major ] of phenylbutazone, differs only in the '']'' location of one of its ]s, where a ] ] is replaced by a ] (making it 4-butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5-pyrazolidinedione). |
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== References == |
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{{reflist}} |
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{{Anti-inflammatory and antirheumatic products}} |
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{{Topical products for joint and muscular pain}} |
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] |
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