Phenylbutazone

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Phenylbutazone
Phenylbutazone.svg
Phenylbutazone-3D-balls.png
Clinical data
Trade names Butazolidine
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
  • 4-Butyl-1,2-diphenyl-pyrazolidine-3,5-dione
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
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ChEBI
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ECHA InfoCard 100.000.027 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H20N2O2
Molar mass 308.381 g·mol−1
3D model (JSmol)
  • O=C2N(c1ccccc1)N(C(=O)C2CCCC)c3ccccc3
  • InChI=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 Yes check.svgY
  • Key:VYMDGNCVAMGZFE-UHFFFAOYSA-N Yes check.svgY
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Phenylbutazone, often referred to as "bute", [1] is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals.

Contents

In the United States and United Kingdom, it is no longer approved for human use (except in the United Kingdom for ankylosing spondylitis), as it can cause severe adverse effects such as suppression of white blood cell production and aplastic anemia. This drug was implicated in the 2013 meat adulteration scandal. Positive phenylbutazone tests in horse meat were uncommon in the UK, however. [2]

Uses

In humans

Phenylbutazone was originally made available for use in humans for the treatment of rheumatoid arthritis and gout in 1949. However, it is no longer approved, and therefore not marketed, for any human use in the United States. [3] In the UK it is used to treat ankylosing spondylitis, but only when other therapies are unsuitable. [4]

In horses

Phenylbutazone is the most commonly used NSAID for horses in the United States. [5] It is used for the following purposes:

History of phenylbutazone in racing

In the 1968 Kentucky Derby, Dancer's Image, the winner of the race, was disqualified after traces of phenylbutazone were allegedly discovered in a post-race urinalysis. Owned by prominent Massachusetts businessman Peter D. Fuller and ridden by jockey Bobby Ussery, Dancer's Image was the first horse to win the Kentucky Derby and then be disqualified. Phenylbutazone was legal on most tracks around the United States in 1968, but had not yet been approved by Churchill Downs.

Controversy and speculation still surround the incident. In the weeks prior to the race, Fuller had given previous winnings to Coretta Scott King, the widow of slain civil rights activist Martin Luther King Jr., which brought both praise and criticism. The previous year, King held a sit-in against housing discrimination which disrupted Derby week. Forty years later, Fuller still believed Dancer's Image was disqualified due to these events. [6] [7]

Although Forward Pass 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 Churchill Downs, both Dancer's Image and Forward Pass are listed as the 1968 winner of the Kentucky Derby. [8]

In dogs

Phenylbutazone is occasionally used in dogs for the longer-term management of chronic pain, particularly due to osteoarthritis. 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 (etodolac, and carprofen). Gastrointestinal-protectant drugs, such as misoprostol, cimetidine, omeprazole, ranitidine, or sucralfate, 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. [9]

Side effects of phenylbutazone in dogs include gastrointestinal (GI) ulceration, bone marrow depression, rashes, malaise, blood dyscrasias, and diminished renal blood flow.

Dosage and administration in horses

Phenylbutazone has a plasma elimination half-life of 4–8 hours, however the inflammatory exudate half life is 24 hours, [10] so single daily dosing can be sufficient, although it is often used twice per day. [5] The drug is considered fairly non-toxic when given at appropriate doses (2.2-4.4 mg/kg/day), even when used repeatedly. [11] This dose has been doubled for diseases that cause severe pain, such as laminitis, 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. [12]

Phenylbutazone can be administered orally (via paste, powder or feed-in) or intravenously. It should not be given intramuscularly or injected in any place other than a vein, as it can cause tissue damage. Tissue damage and edema may also occur if the drug is injected repetitively into the same vein.

Side effects and disadvantages

Side effects of phenylbutazone are similar to those of other NSAIDs. Overdose or prolonged use can cause gastrointestinal ulcers, blood dyscrasia, kidney damage (primarily dose-dependant renal papillary necrosis), oral lesions if given by mouth, and internal hemorrhage. [12] This is especially pronounced in young, ill, or stressed horses which are less able to metabolize the drug. [13] 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 agranulocytosis.

Phenylbutazone amplifies the anticoagulant effect of vitamin K antagonists such as warfarin or phenprocoumon. Phenylbutazone displaces warfarin from plasma binding sites, and toxic blood levels leading to haemorrhage can occur. It may aggravate kidney or liver problems.

Phenylbutazone may be toxic to the embryo and can be transferred via the umbilical cord and by milk.

Phenylbutazone can be used in foals. Premature foals, septicemic foals, foals with questionable kidney or liver function and foals with diarrhea require careful monitoring. Drugs to protect the GI tract such as omeprazole, cimetidine, and sucralfate are frequently used with phenylbutazone.

High doses of phenylbutazone may be considered a rules violation under some equestrian organizations, as the drug may remain in the bloodstream four to five days after administration.

The International Agency for Research on Cancer places it in Group 3; i.e., "not classifiable as to its carcinogenicity to humans".

Use in horses is limited to those not intended for food. Metabolites of phenylbutazone can cause aplastic anaemia in humans. [14] [15]

Investigations into potential carcinogenicity

Opinions are conflicting regarding the carcinogenicity of phenylbutazone in animals; no evidence indicates it causes cancer in humans at therapeutic doses. Maekawa et al. (1987) found no increased cancer incidence in DONRYU rats fed a diet containing 0.125% or 0.25% phenylbutazone over two years. [16] On the other hand, Kari et al. (1995) found a rare type of kidney 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. [17] Tennant (1993) listed phenylbutazone as a non-mutagenic carcinogen. [18] Kirkland and Fowler (2010) acknowledged that, while phenylbutazone is not predicted to be a mutagen by computer software that simulates the chemicals interaction with DNA, [19] one laboratory study indicated phenylbutazone subtly altered the structure of chromosomes of bone marrow cells of mice. [20] 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 mM). [19] The World Health Organization's International Agency For Research On Cancer (IARC) stated in 1987 that there was inadequate evidence for a carcinogenic effect in humans. [21]

Interactions

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.

Phenylbutazone may affect blood levels and duration of action of phenytoin, valproic acid, sulfonamides, sulfonylurea antidiabetic agents, barbiturates, promethazine, rifampicin, chlorpheniramine, diphenhydramine, and penicillin G. [22]

Overdose

Overdoses of phenylbutazone can cause kidney failure, liver injury, bone marrow suppression, and gastric ulceration or perforation. Early signs of toxicity include loss of appetite, and depression. [22]

Chemistry

Phenylbutazone is a crystalline substance. It is obtained by condensation of diethyl n-butylmalonate with hydrazobenzene in the presence of base. In effect, this represents the formation of the heterocyclic system by simple lactamization.

Oxyphenbutazone, the major metabolite of phenylbutazone, differs only in the para location of one of its phenyl groups, where a hydrogen atom is replaced by a hydroxyl group (making it 4-butyl-1-(4-hydroxyphenyl)-2-phenyl-3,5-pyrazolidinedione).

Related Research Articles

Ketoprofen Chemical compound

Ketoprofen is one of the propionic acid class of nonsteroidal anti-inflammatory drugs (NSAID) with analgesic and antipyretic effects. It acts by inhibiting the body's production of prostaglandin.

Nonsteroidal anti-inflammatory drug Class of theraputic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

Paracetamol Common medication for pain and fever

Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. At a standard dose, paracetamol only slightly decreases body temperature; it is inferior to ibuprofen in that respect, and the benefits of its use for fever are unclear. Paracetamol may relieve pain in acute mild migraine but only slightly in episodic tension headache. However, the aspirin/paracetamol/caffeine combination helps with both conditions where the pain is mild and is recommended as a first-line treatment for them. Paracetamol is effective for post-surgical pain, but it is inferior to ibuprofen. The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone. The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant. The evidence in its favor for the use in low back pain, cancer pain and neuropathic pain is insufficient.

Ibuprofen Medication used for treating pain, fever, and inflammation

Ibuprofen is a medication in the nonsteroidal anti-inflammatory drug (NSAID) class that is used for treating pain, fever, and inflammation. This includes painful menstrual periods, migraines, and rheumatoid arthritis. It may also be used to close a patent ductus arteriosus in a premature baby. It can be used by mouth or intravenously. It typically begins working within an hour.

Diclofenac Nonsteroidal anti-inflammatory drug

Diclofenac, sold under the brand name Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout. It is taken by mouth, rectally in a suppository, used by injection, or applied to the skin. Improvements in pain last for as much as eight hours. It is also available in combination with misoprostol in an effort to decrease stomach problems.

Naproxen Nonsteroidal anti-inflammatory drug (NSAID) used to treat pain

Naproxen, sold under the brand name Aleve or Apronax among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and last for up to twelve hours.

Indometacin Anti-inflammatory drug

Indometacin, also known as indomethacin, is a nonsteroidal anti-inflammatory drug (NSAID) commonly used as a prescription medication to reduce fever, pain, stiffness, and swelling from inflammation. It works by inhibiting the production of prostaglandins, endogenous signaling molecules known to cause these symptoms. It does this by inhibiting cyclooxygenase, an enzyme that catalyzes the production of prostaglandins.

Mefenamic acid Chemical compound

Mefenamic acid is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs), and is used to treat mild to moderate pain. It is not widely used in the United States due to its side effects and high cost compared to other NSAIDs.

Cinchophen

Cinchophen is an analgesic drug that was first produced by Doebner & Gieskel in 1887, it was commercially introduced in 1908 as a treatment for gout. This drug is still used, in combination with Prednisolone, by veterinarians to treat arthritis in animals. It can be prepared starting from anilin, benzaldehyde and pyruvic acid in absolute ethanol. Use of this drug in humans ceased in the 1930s due to the discovery that cinchophen can cause serious liver damage. There is some evidence that it stimulates C-Fos.

Meloxicam Nonsteroidal anti-inflammatory drug (NSAID)

Meloxicam, sold under the brand name Mobic among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammation in rheumatic diseases and osteoarthritis. It is used by mouth or by injection into a vein. It is recommended that it be used for as short a period as possible and at a low dose.

Etodolac

Etodolac is a nonsteroidal anti-inflammatory drug (NSAID).

Flunixin Chemical compound

Flunixin is a nonsteroidal anti-inflammatory drug (NSAID), analgesic, and antipyretic used in horses, cattle and pigs. It is often formulated as the meglumine salt. In the United States, it is regulated by the U.S. Food and Drug Administration (FDA), and may only be lawfully distributed by order of a licensed veterinarian. There are many trade names for the product.

Carprofen A non-steroidal anti-inflammatory drug

Carprofen is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class that was previously for use in humans and animals, but is now only available to veterinarians for prescribing as a supportive treatment for various conditions in only animals. Carprofen reduces inflammation by inhibition of COX-1 and COX-2; its specificity for COX-2 varies from species to species. Marketed under many brand names worldwide, carprofen provides day-to-day treatment for pain and inflammation from various kinds of joint pain, as well as post-operative pain.

Diflunisal Nonsteroidal anti-inflammatory (NSAID), Used as an analgesic & anti inflammatory

Diflunisal is a salicylic acid derivative with analgesic and anti-inflammatory activity. It was developed by Merck Sharp & Dohme in 1971, as MK647, after showing promise in a research project studying more potent chemical analogs of aspirin. It was first sold under the brand name Dolobid, marketed by Merck & Co., but generic versions are now widely available. It is classed as a nonsteroidal anti-inflammatory drug (NSAID) and is available in 250 mg and 500 mg tablets.

Flucytosine

Flucytosine, also known as 5-fluorocytosine (5-FC), is an antifungal medication. It is specifically used, together with amphotericin B, for serious Candida infections and cryptococcosis. It may be used by itself or with other antifungals for chromomycosis. Flucytosine is used by mouth and by injection into a vein.

Tepoxalin

Tepoxalin, marketed under the brand name Zubrin among many others, is a non-steroidal anti-flammatory drug (NSAIDs) generally used in veterinary medicine to reduce swelling in animals with osteoarthritis. In rare circumstances, Tepoxalin can also be used in human pharmacology to relieve pain caused by musculoskeletal conditions such as arthritis and hip dysplasia.

Tolmetin

Tolmetin is a nonsteroidal anti-inflammatory drug (NSAID) of the heterocyclic acetic acid derivative class. It is used primarily to reduce hormones that cause pain, swelling, tenderness, and stiffness in conditions such as osteoarthritis and rheumatoid arthritis, including juvenile rheumatoid arthritis. In the United States it is marketed as Tolectin and comes as a tablet or capsule.

Meclofenamic acid Chemical compound

Meclofenamic acid is a drug used for joint, muscular pain, arthritis and dysmenorrhea. It is a member of the anthranilic acid derivatives class of nonsteroidal anti-inflammatory drugs (NSAIDs) and was approved by the US FDA in 1980. Like other members of the class, it is a cyclooxygenase (COX) inhibitor, preventing the formation of prostaglandins.

Benoxaprofen, also known as Benoxaphen, is a chemical compound with the formula C16H12ClNO3. It is a non-steroidal anti-inflammatory drug (NSAID) of the propionic acid class, and was marketed under the brand name Opren in the United Kingdom and Europe by Eli Lilly and Company (commonly referred to as Lilly), and as Oraflex in the United States of America (USA). Lilly suspended sales of Oraflex in 1982 after reports from the British government and the United States Food and Drug Administration (US FDA) of adverse effects and deaths linked to the drug.

Maropitant

Maropitant (INN; trade name: Cereniasə-REE-nee-ə), used as maropitant citrate (USAN), is a neurokinin-1 (NK1) receptor antagonist which was developed by Zoetis specifically for the treatment of motion sickness and vomiting in dogs. It was approved by the FDA in 2007 for use in dogs and in 2012 for cats.

References

  1. ↑ Bogdanich W, Drape J (24 March 2012). "Death and Disarray at America's Racetracks". The New York Times.
  2. ↑ "Horse meat investigation. Advice for consumers". Enforcement and regulation. Food Standards Agency . Retrieved 19 May 2013.
  3. ↑ "FDA Order Prohibits Extralabel Use of Phenylbutazone in Certain Dairy Cattle". Food and Drug Administration. 28 February 2003.
  4. ↑ NHS: Drugs used in Rheumatic Diseases and Gout Archived 2013-04-29 at the Wayback Machine
  5. 1 2 McIlwraith CW, Frisbie DD, Kawcak CE. Nonsteroidal Anti-Inflammatory Drugs. Proc. AAEP 2001 (47): 182-187.
  6. ↑ Boston Globe article about the 40th Anniversary of the Race
  7. ↑ "Sports: Dancer's tainted image". Archived from the original on 2007-01-01. Retrieved 2007-10-07.
  8. ↑ "Kentucky Derby 132". 2006. Retrieved 2007-10-07.
  9. ↑ "Wedgewood Pharmaceuticals-Phenylbutazol".
  10. ↑ Lees P, Taylor JB, Higgins AJ, Sharma SC (June 1986). "Phenylbutazone and oxyphenbutazone distribution into tissue fluids in the horse". Journal of Veterinary Pharmacology and Therapeutics. 9 (2): 204–12. doi:10.1111/j.1365-2885.1986.tb00031.x. PMID   3723663.
  11. ↑ Collins LG, Tyler DE (March 1984). "Phenylbutazone toxicosis in the horse: a clinical study". Journal of the American Veterinary Medical Association. 184 (6): 699–703. PMID   6725103.
  12. 1 2 MacKay RJ, French TW, Nguyen HT, Mayhew IG (May 1983). "Effects of large doses of phenylbutazone administration to horses". American Journal of Veterinary Research. 44 (5): 774–80. PMID   6869982.
  13. ↑ 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.
  14. ↑ Scanaill PÓ. "Phenylbutazone and its availability in ireland – prudent prescribing and dispensing" (PDF). Irish Veterinary Journal. 63 (12): 766–8. Archived from the original (PDF) on 2012-04-02.
  15. ↑ "Ante and Post-mortem Procedures, Dispositions, Monitoring and Controls - Red Meat Species, Ostriches, Rheas and Emus". Canadian Food Inspection Agency. 2013-05-31.
  16. ↑ Meakawa A, Onodera H, Tanigawa H, Furuta K, Kanno J, Matsuoka C, et al. (September 1987). "Long-term studies on carcinogenicity and promoting effect of phenylbutazone in DONRYU rats". Journal of the National Cancer Institute. 79 (3): 577–84. doi:10.1093/jnci/79.3.577. PMID   3476793.
  17. ↑ Kari F, Bucher J, Haseman J, Eustis S, Huff J (March 1995). "Long-term exposure to the anti-inflammatory agent phenylbutazone induces kidney tumors in rats and liver tumors in mice". Japanese Journal of Cancer Research. 86 (3): 252–63. doi:10.1111/j.1349-7006.1995.tb03048.x. PMC   5920813 . PMID   7744695.
  18. ↑ Tennant RW (October 1993). "A perspective on nonmutagenic mechanisms in carcinogenesis". Environmental Health Perspectives. 101 Suppl 3 (Suppl 3): 231–6. doi:10.1289/ehp.93101s3231. PMC   1521175 . PMID   8143623.
  19. 1 2 Kirkland D, Fowler P (November 2010). "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". Mutagenesis. 25 (6): 539–53. doi: 10.1093/mutage/geq041 . PMID   20720197.
  20. ↑ Giri AK, Mukhopadhyay A (December 1998). "Mutagenicity assay in Salmonella and in vivo sister chromatid exchange in bone marrow cells of mice for four pyrazolone derivatives". Mutation Research. 420 (1–3): 15–25. doi:10.1016/S1383-5718(98)00138-7. PMID   9838026.
  21. ↑ IARC (1987). IARC monographs on the evaluation of the carcinogenic risk of chemicals to man. International Agency for Research on Cancer. p. 316.
  22. 1 2 "Phenylbutazol for veterinary use". Wedgewood Pharmacy.
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