Tepoxalin

Tepoxalin, marketed under the brand name Zubrin[1] among many others;  is a non-steroidal anti-flammatory drug (NSAIDs) generally used in Veterinary Medicine to reduce swelling in animals with osteoarthritis.[1] However in rare circumstances, Tepoxalin can also be used in human pharmacology to relieve pain caused by musculoskeletal conditions such as arthritis and hip dysplasia.[2]

Tepoxalin
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral
ATCvet code
Legal status
Legal status
  • Veterinary use only
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard100.166.553
Chemical and physical data
FormulaC20H20ClN3O3
Molar mass385.85 g·mol−1
3D model (JSmol)
 NY (what is this?)  (verify)

In 1997, the drug was patented for Veterinary Medicine, replacing isoxazole for treating inflammation.[3] Conversely, in 2017, the Tepoxalin was withdrawn from the American market and cannot be administered in the United States.[3]

Tepoxalin (C20H20ClN3O3) is produced by the condensation of a carboxyl group and an amino group. [1]There are many perspectives on whether the consumption of Tepoxalin on its own is more effective than combining it with other antihistamines, but when applied in Veterinary Medicine, Tepoxalin is regularly synthesised with other antihistamines.[1]

Approval of Drug
See also: European Medicines Agency and Food and Drug Administration

The Committee for Medicinal Products for Veterinary Use (CVMP) approves Tepoxalin to be used as a drug for animals to reduce inflammation and pain control.[3] Additionally, in Europe, Tepoxalin is approved by the EU Community Register of Medicinal Products and European Medicines Agency in the product categories of Veterinary Drug and Veterinary Pharmacotherapeutic Group categorised into the Musculo-skeletal System subcategory.[4]

Tepoxalin was first medically approved in the United States in 1998. However, due to circumstances the drug was entirely taken off the market in 2017 and cannot be administered in the United States.[4] However, Tepoxalin still has FDA (Food and Drug Administration) approval.[4]

On the 4th September 2017, an application was submitted to the EMEA (European Medicines Agency) asking for an extension of marketing authorisation for Tepoxalin.[3] The EMEA (European Medicines Agency) critiqued on the quality, safety and efficacy data submitted and the application was declined.[3]

Pharmacology and Biochemistry

Tepoxalin (C20H20ClN3O3) is produced by the condensation of a carboxyl group of 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)pyrazol-3-yl] propanoic acid and an amino group of N-methylhydroxylamine.[3]  Condensation is a chemical reaction in which two or more molecules merge into form a larger molecule, with the simultaneous loss of a small molecule such as water or methanol.[3]

The drug works as a NSAIDs (Non-Steroidal Anti-Inflammatory Drug) to suppress both cyclooxygenase and lipoxygenase.[5] Cyclooxygenase and lipoxygenase produces COX-2 and 5-LOX enzymes respectively, these enzymes activate the swelling and inflammation that causes pain in animals. Tepoxalin is an inhibitor which blocks out theses enzymes to reduce the swelling and inflammation.  Additionally, it can be also used as a “dual-action” inhibitor to additionally suppress leukotriene and prostaglandin (E2).[5]Leukotriene and prostaglandin are also enzymes that activates inflammation in the body.[6]

Tepoxalin is produced into white, flavourless tablets that rapidly disintegrate when consumed by an animal. These tasteless tablets are branded as Zubrin on the market.[4] After the consumption of Zubrin, it has a short half-life of 120 minutes in the plasma (cytoplasm; the main part of the capsule) itself, whereas, the entire metabolite (entirety of the capsule) has a half-life of 13 hours.[4] Thereby, the dosage is only prescribed once a day.[3]

Canine and Feline Uses

Available in an oral formulation, Tepoxalin is used to treat osteoarthritis in canine and feline species.[4] The use of Tepoxalin was more effective than the NSAID (nonsteroidal anti-flammatory drug), carprofen when administered in canines. As a result, the usage of carprofen was replaced with Tepoxalin in 1998.[7]

Tepoxalin can only be administered to dogs that weigh 3 pounds (~1.36kgs) or larger at a dose of 10–20 mg/kg at a daily schedule.[6] The approximate duration of complete treatment is at most 14 days.[1] If treated for a prolonged period of time (more than 180 days), it may result in gastrointestinal irritation and gastric ulceration. The plasma concentration of Tepoxalin when administered varies between every dog, so there is no difference in administering between fed or fasted canines.[1]  However, there is a low water solubility and a high fat solubility, it is often prescribed to fed canines rather than fasted as this is more effective for Tepoxalin.[7]

In felines, Tepoxalin has an inhibitory action on COX-1 and 5-LOX enzymes in contrary in canines, Tepoxalin causes inhibition for COX-2 and 5-LOX enzymes. For felines, Tepoxalin is prescribed in doses between 5 and 10 mg/kg once daily for 3 consecutive days. Additionally, Tepoxalin can only be prescribed to felines over the weight of 3 pounds (~1.36kgs).[8] When Tepoxalin is administered in cats, a rare response recorded in felines is ADE reaction (drunken-like state) occurring in the central nervous system.[8]

Ill cat injected with NSAID, Tepoxalin

After the consumption of Tepoxalin to canines or felines, the administration of aspirin or corticosteroids (type of steroid) cannot be administered at the same time as Tepoxalin.[7] When prescribed Tepoxalin by a veterinarian, the pet's owner is also provided with a Client Information Sheet (also known as the Information for Dog/Cat Owner Sheet) listing the drug’s side effects.[9] This sheet is a user-friendly guide to inform pet owners of potential side effects and the need to seek veterinary attention if problems occur.[9] Based off the Information Dog Owner Sheet that is accompanied with every prescribed Tepoxalin, a reference of safety information and drug company contact information is readily available to the owner.[9]

Equine Use

When administered for horses, the formulation can be in a paste, powder or feed-in form which can be fed orally or it can be injected through the vein but no other place in the equine body, as it can cause tissue damage.[10] However, if Tepoxalin is injected repeatedly in the vein for a prolonged period of time, it can also cause tissue damage and edema (trapped fluid in tissue).[10]

Chronic inflammatory diseases are the most common diseases in horses, phenylbutazone was used as an anti-inflammatory drug for horses, however when administered at high doses horses can develop ulcers of the glandular stomach, oral cavity and colon.[11] Due to the major adverse effects of phenylbutazone, the replacement for Tepoxalin was made to be administered to horses to reduce muscular pain in 2003.[10]

In horses, the drug is intravenously administered at 10 mg/kg on a daily dose for 10 days respectively.[10] Doses are doubled, even tripled to treat severe pain, such as laminitis. The plasma (cytoplasm; the main part of the capsule) half-life of Tepoxalin is 4–8 hours, however the inflammatory entire metabolite (entirety of the capsule) half-life is 24 hours, so single dosing is more efficient for horses. When given at reasonable doses, the drug is non-toxic even when used repeatedly.[10]

Case of laminitis

Adverse Effects

Common side effects of the consumption of Tepoxalin include:[7]

  • Vomiting
  • Diarrhoea
  • Blood in faeces
  • Decreased appetite
  • Fatigue/Drowsiness
  • Increase in thirst
  • Increase in urination
  • Behavioural changes

In older and sensitive animals, loss of hair and abrasion of the skin may occur.[11] The drug cannot be used by animals during breeding, pregnancy or lactation as the drug can affect the foetus or infants.[11] Any animals with a history of internal bleeding or low blood pressure should avoid consumption of Tepoxalin as it can result in perforation of the stomach walls or intestinal mucosa.[11]

Factors that has contributed to a high incidence of adverse reports received for Tepoxalin by the Centre of Veterinary Medicine include:[9]

  • Type of drug; brands of Tepoxalin available on the market[9]
  • Wide use; Not only in veterinary medicine, also in humans. [9]
  • Duration of use; The side-effects of Tepoxalin are known to occur in the short period of administration, if used in a long period of time there is a higher risk for these adverse reactions.[9]
  • Senior dog use; Senior dogs are more prone to the adverse effects.[9]

When administered to male canines, there are no effects to the male's fertility. Whereas, when a female canine is treated during the organogenetic period, it may result in embryo foetal toxicity.[11] The outcome of this toxicity is a major reduction in foetal weight, incomplete formation of various bones and other skeletal malformations. At extreme circumstances,  it can result in the death of the foetus.[11]

Overdose can occur if administered in an excessive large dose. Signs of overdose or toxicity in canines/felines include:[3]

  • Tremors
  • Seizures
  • Abnormal behaviour
  • Vomiting
  • Weakness

Immediately contact/seek a veterinarian if any signs are present.

Alternatives
See also: Nonsteroidal anti-inflammatory drug and Carprofen

There are many adverse effects to the consumption of Tepoxalin thereby many other alternatives of NSAID (Nonsteroidal Anti-Inflammatory Drugs) are available.[2] Tepoxalin acts as a NSAID to help control signs of osteoarthritis and reduce inflammation, whereas many other NSAID can perform those factors in addition to many other properties such as reduction of joint pains and swelling with the absence or fewer adverse effects.[3]

Alternatives include:

References
  1. Papich, Mark G. (2016). "Tepoxalin". Saunders Handbook of Veterinary Drugs Small and Large Animal (4th ed.). Elsevier. p. 762. ISBN 978-0-323-24485-5.
  2. http://www.peteducation.com/article.cfm?c=26+1303&aid=3213
  3. MURRAY, W. V.; HADDEN, S. K. (2010-08-20). "ChemInform Abstract: A Facile Synthesis of Tepoxalin, 5-(4-Chlorophenyl)-N-hydroxy-1- (4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide". ChemInform. 24 (13): no–no. doi:10.1002/chin.199313189. ISSN 0931-7597.
  4. American Journal of Veterinary Research. 69 (12). December 2008. doi:10.2460/ajvr.2008.69.issue-12. ISSN 0002-9645 http://dx.doi.org/10.2460/ajvr.2008.69.issue-12. Missing or empty |title= (help)
  5. Kahan, B.D. (August 1998). "FTY720: a new immunosuppressive agent with novel mechanism(s) of action". Transplantation Proceedings. 30 (5): 2210–2213. doi:10.1016/s0041-1345(98)00593-4. ISSN 0041-1345.
  6. "Reaction of Carbon Nucleophiles with Carbonyl Groups", Advanced Organic Chemistry, Kluwer Academic Publishers, pp. 57–139, ISBN 0-306-46244-3, retrieved 2020-05-29
  7. Lothrop, Clinton D. (1995), "Veterinary medical specialization", Advances in Veterinary Science and Comparative Medicine, Elsevier, pp. 141–190, ISBN 978-0-12-039240-7, retrieved 2020-05-29
  8. "Pink Pages 4+5: Further qualifications in feline medicine". Journal of Feline Medicine & Surgery. 9 (4): VIII–IX. August 2007. doi:10.1016/s1098-612x(07)00128-3. ISSN 1098-612X.
  9. New Zealand Veterinary Association. (©2002-). New Zealand veterinary journal : the complete archive in full-text on CD-ROM. New Zealand Veterinary Association. OCLC 946530381. Check date values in: |date= (help)
  10. Giorgi, Mario; Cuniberti, Barbara; Ye, Guisheng; Barbero, Raffaella; Sgorbini, Micaela; Vercelli, Cristina; Corazza, Michele; Re, Giovanni (October 2011). "Oral administration of tepoxalin in the horse: A PK/PD study". The Veterinary Journal. 190 (1): 143–149. doi:10.1016/j.tvjl.2010.09.013. hdl:2318/80291. ISSN 1090-0233.
  11. "Acta Orthopaedica Scandinavica 1976". Acta Orthopaedica Scandinavica. 47 (1): 1–2. January 1976. doi:10.3109/17453677608998964. ISSN 0001-6470.
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