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{{Short description|NSAID anti-inflammatory veterinary drug}}
{{redirect|Zubrin|the aerospace engineer|Robert Zubrin}}
{{cs1 config|name-list-style=vanc}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 447758368


{{Drugbox
| verifiedrevid = 443322535
| IUPAC_name = 3--''N''-hydroxy-''N''-methylpropanamide
| image = Tepoxalin.png | image = Tepoxalin.png
| alt = Skeletal formula of tepoxalin
| width = 160
| image2 = Tepoxalin-3D-spacefill.png
| alt2 = Space-filling model of the tepoxalin molecule


<!--Clinical data--> <!--Clinical data-->
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| Drugs.com = {{drugs.com|international|tepoxalin}} | Drugs.com = {{drugs.com|international|tepoxalin}}
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B / C / D / X -->
| pregnancy_category = | pregnancy_category =
| routes_of_administration = ]
| ATCvet = yes
| ATC_prefix = M01
| ATC_suffix = AE92
| ATC_supplemental =

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled--> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = <!-- Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA = Rx-only
| legal_CA_comment =
| legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C --> | legal_UK = <!-- GSL, P, POM, CD, or Class A, B, C -->
| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US = Rx-only
| legal_status = Veterinary use only | legal_status =
| routes_of_administration = Oral


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
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| metabolism = | metabolism =
| elimination_half-life = | elimination_half-life =
| excretion = | excretion =


<!--Identifiers--> <!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number =
| CAS_number = 103475-41-8
| ATCvet = yes
| ATC_prefix = M01
| ATC_suffix = AE92
| ATC_supplemental =
| PubChem = 59757 | PubChem = 59757
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
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| KEGG_Ref = {{keggcite|correct|kegg}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D06075 | KEGG = D06075
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 76277
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 53906


<!--Chemical data--> <!--Chemical data-->
| IUPAC_name = 3--''N''-hydroxy-''N''-methylpropanamide
| chemical_formula =
| C=20 | H=20 | Cl=1 | N=3 | O=3 | C=20 | H=20 | Cl=1 | N=3 | O=3
| smiles = CN(C(=O)CCc1cc(n(n1)c2ccc(cc2)OC)c3ccc(cc3)Cl)O
| molecular_weight = 385.844 g/mol
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C20H20ClN3O3/c1-23(26)20(25)12-7-16-13-19(14-3-5-15(21)6-4-14)24(22-16)17-8-10-18(27-2)11-9-17/h3-6,8-11,13,26H,7,12H2,1-2H3
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = XYKWNRUXCOIMFZ-UHFFFAOYSA-N

}} }}


'''Tepoxalin''', sold under the brand name '''Zubrin'''<ref name="Papich 2016">{{cite book| vauthors = Papich MG |title=Saunders Handbook of Veterinary Drugs Small and Large Animal|date=2016|publisher=Elsevier|isbn=978-0-323-24485-5|edition=4th|page=762|chapter=Tepoxalin}}</ref> among others, is a non-steroidal anti-flammatory drug (NSAIDs) generally used in veterinary medicine to reduce swelling in animals with osteoarthritis.<ref name="Papich 2016" /> In rare circumstances, tepoxalin can also be used in human pharmacology to relieve pain caused by musculoskeletal conditions such as arthritis and hip dysplasia.<ref name=":3">{{cite web | title = epoxalin (Zubrin) | url = https://www.petcoach.co/article/tepoxalin-zubrin-sup-r-sup/ | work = PetCoach | publisher = Petco Animal Supplies Stores, Inc. }}</ref>
'''Tepoxalin''' is a ] approved for veterinary use (in dogs) in the United States and the European Union. It is primarily used to reduce inflammation and relief of pain caused by musculoskeletal disorders such as ] and ].


In 1997, tepoxalin was patented for veterinary use, replacing ] for treating inflammation.<ref name=":0" /> In 2017, the drug was withdrawn from the American market and can no longer be administered in the United States.<ref name=":0" />
It is generally marketed under the brand name '''Zubrin'''.


Tepoxalin (C<sub>20</sub>H<sub>20</sub>ClN<sub>3</sub>O<sub>3</sub>) has been synthesized by several methods.<ref name="Papich 2016" /> There are many perspectives on whether the consumption of tepoxalin on its own is more effective than combining it with antihistamines, but when applied in veterinary medicine, tepoxalin is regularly administered with antihistamines.<ref name="Papich 2016" />
==References==


== Approval ==
{{See also|European Medicines Agency|Food and Drug Administration}}
The ] (CVMP) approved tepoxalin as a drug for animals to reduce inflammation and control pain.<ref name=":0">{{Cite journal| vauthors = Murray WV, Hadden SK |date=2010-08-20|title=ChemInform Abstract: A Facile Synthesis of Tepoxalin, 5-(4-Chlorophenyl)-N-hydroxy-1- (4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide. |journal=ChemInform|volume=24|issue=13|pages=no|doi=10.1002/chin.199313189 }}</ref> Additionally, in the European Union, tepoxalin was 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.<ref name=":1">{{cite journal | title = Special issue |date=December 2008 |journal=American Journal of Veterinary Research|volume=69|issue=12|doi=10.2460/ajvr.2008.69.issue-12 }}</ref>


Tepoxalin was first medically approved in the United States in 1998. The drug was taken off the market in 2017 and cannot be administered in the United States.<ref name=":1" /> However, it still has ] (FDA) approval.<ref name=":1" />
]

In September 2017, an application was submitted to the ] (EMEA) asking for an extension of marketing authorisation for tepoxalin.<ref name=":0" /> The EMEA criticised the quality, safety and efficacy data submitted and the application was declined.<ref name=":0" />

== Pharmacology and biochemistry ==
Tepoxalin (C<sub>20</sub>H<sub>20</sub>ClN<sub>3</sub>O<sub>3</sub>) has been synthesized by several methods.<ref name=":0" />  

The drug works as a ] (NSAID). It inhibits both cyclooxygenase (COX-2) and lipoxygenase (5-LOX) enzymes suppressing biosynthesis of prostaglandins and leukotrienes, respectively. .<ref name=":2">{{Cite journal| vauthors = Kahan BD |date=August 1998|title=FTY720: a new immunosuppressive agent with novel mechanism(s) of action |journal=Transplantation Proceedings|volume=30|issue=5|pages=2210–2213|doi=10.1016/s0041-1345(98)00593-4|pmid=9723444|issn=0041-1345}}</ref>

Tepoxalin is marketed as white, flavourless tablets that rapidly disintegrate when consumed by an animal. These tasteless tablets are branded as ''Zubrin'' on the market.<ref name=":1" /> After consumption, Zubrin has a half-life of 120 minutes in the ], whereas the entire metabolite has a ] of 13 hours.<ref name=":1" /> It is therefore usually prescribed to be taken once a day.<ref name=":0" />

== Canine and feline uses ==
Available in an oral formulation, tepoxalin is used to treat ] in canine and feline species.<ref name=":1" /> The use of tepoxalin was more effective than the NSAID (nonsteroidal anti-flammatory drug), ] when administered in canines. As a result, the usage of carprofen was replaced with tepoxalin in 1998.<ref name=":5">{{cite book | vauthors = Lothrop CD |title=Veterinary Medical Specialization - Bridging Science and Medicine|chapter=Veterinary medical specialization|date=1995| doi = 10.1016/s0065-3519(06)80019-4|series=Advances in Veterinary Science and Comparative Medicine|volume=39|pages=141–190|publisher=Elsevier|pmid=8578975|isbn=978-0-12-039240-7 }}</ref>

Tepoxalin can only be administered to dogs that weigh {{convert|3|lbs}} or larger at a dose of 10–20&nbsp;mg/kg at a daily schedule.<ref name=":4">{{cite book | vauthors = Carey FA, Sundberg RJ | chapter = Reaction of Carbon Nucleophiles with Carbonyl Groups|doi = 10.1007/0-306-47380-1_2| title = Advanced Organic Chemistry| year = 2002|pages=57–139|publisher=Kluwer Academic Publishers|isbn=0-306-46244-3 }}</ref> The approximate duration of complete treatment is at most 14 days.<ref name="Papich 2016" /> If treated for a prolonged period of time (more than 180 days), it may result in gastrointestinal irritation and gastric ulceration. The ] concentration of tepoxalin when administered varies between every dog.<ref name="Papich 2016" />  Since tepoxalin has 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.<ref name=":5" />

In felines, tepoxalin has an inhibitory action on COX-1 and 5-LOX enzymes. For felines, tepoxalin is prescribed in doses between 5 and 10&nbsp;mg/kg once daily for 3 consecutive days. Additionally, tepoxalin can only be prescribed to felines over the weight of {{convert|3|lbs}}.<ref name=":6" />
When tepoxalin is administered in cats, a drunken-like state afflicting the ] has been recorded on rare occasions.<ref name=":6">{{Cite journal|date=August 2007|title=Pink Pages 4+5: Further qualifications in feline medicine |journal=Journal of Feline Medicine & Surgery|volume=9|issue=4|pages=VIII–IX|doi=10.1016/s1098-612x(07)00128-3|pmid=28058970 |pmc=10822635 |issn=1098-612X}}</ref>
]

== Equine use ==
When administered to horses, the formulation can be a paste, powder or feed-in form which can be fed orally or it can be injected intravenously but no other place in the equine body, as it can cause tissue damage.<ref name=":8">{{cite journal | vauthors = Giorgi M, Cuniberti B, Ye G, Barbero R, Sgorbini M, Vercelli C, Corazza M, Re G | display-authors = 6 | title = Oral administration of tepoxalin in the horse: a PK/PD study | journal = Veterinary Journal | volume = 190 | issue = 1 | pages = 143–9 | date = October 2011 | pmid = 21036634 | doi = 10.1016/j.tvjl.2010.09.013 | hdl-access = free | hdl = 2318/80291 | s2cid = 26545966 }}</ref> However, if tepoxalin is injected repeatedly in the vein for a prolonged period of time, it can also cause tissue damage and ] (trapped fluid in tissue).<ref name=":8" />

Chronic inflammatory diseases are the most common diseases in horses. ] was formerly used as treatment, but when administered to horses at high doses, it can cause ulcers of the glandular stomach, oral cavity and colon.<ref name=":9">{{Cite journal|date=January 1976|title=Acta Orthopaedica Scandinavica 1976 |journal=Acta Orthopaedica Scandinavica|volume=47|issue=1|pages=1–2|doi=10.3109/17453677608998964|issn=0001-6470|doi-access=free}}</ref> Due to the major adverse effects of phenylbutazone, the replacement by tepoxalin was made to reduce muscular pain in 2003.<ref name=":8" />

In horses, the drug is ] administered at 10&nbsp;mg/kg on a daily dose for 10 days.<ref name=":8" /> Doses may be doubled or tripled to treat severe pain, such as ]. The ] (cytoplasm; the main part of the capsule) half-life of tepoxalin is 4–8 hours, although the entire metabolite half-life is 24 hours, so single dosing is efficient for horses. When given at reasonable doses, the drug is non-toxic even when used repeatedly.<ref name=":8" />
]]]

== Adverse effects ==
There is a high incidence of adverse reports received for tepoxalin by the '']''.<ref name=":7">{{Cite book|last=New Zealand Veterinary Association.|url=http://worldcat.org/oclc/946530381|title=New Zealand veterinary journal : the complete archive in full-text on CD-ROM.|date=2002 |publisher=New Zealand Veterinary Association|oclc=946530381}}</ref> Common side effects of the consumption of tepoxalin include vomiting, diarrhoea, blood in faeces, loss of appetite, fatigue, thirst, an increase in urination and behavioural changes.<ref name=":5" /> In older and sensitive animals, loss of hair and abrasion of the skin may occur.<ref name=":9" /> The drug cannot be used by animals during breeding, pregnancy or lactation as the drug can affect the foetus or infants.<ref name=":9" /> In animals with a history of internal bleeding or low blood pressure, it can result in perforation of the stomach walls or intestinal mucosa.<ref name=":9" />

Older dogs are more prone to the adverse effects.<ref name=":7" /> When administered to male canines, there are no effects to fertility. However, when a female canine is treated during the organogenetic period, it may result in embryo foetal toxicity.<ref name=":9" /> The outcome of this toxicity is a major reduction in foetal weight, incomplete formation of various bones and other skeletal malformations. In extreme cases,  it can result in the death of the foetus.<ref name=":9" />

Overdose can occur if administered in an excessive large dose. Signs of overdose or toxicity in canines and felines include tremors, seizures, abnormal behaviour, vomiting and weakness.<ref name=":0" />
==Synthesis==
Tepoxalin is synthesized by the following method:<ref>Murray, William; Wachter, Michael; Barton, Donald; Forero-Kelly, Yolanda (1991). "The Regioselective Synthesis of Tepoxalin, 3--N-hydroxy-N-methylpropanamide and Related 1,5-Diarylpyrazole Anti-inflammatory Agents". Synthesis. 1991 (01): 18–20. doi:10.1055/s-1991-26367.</ref> ~71%:<ref>Murray, William V.; Hadden, Susan K. (1992). "A facile synthesis of tepoxalin, 5-(4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-propanamide". The Journal of Organic Chemistry. 57 (24): 6662–6663. doi:10.1021/jo00050a059.</ref> Patent:<ref>EP00248594 idem Michael P. Wachter, Michael P. Ferro {{US patent|4826868}} (1989 to Ortho Pharmaceutical Corporation).</ref>
]
The starting dione is obtained by acylation of the anion from 4-chloroacetophenone with succinic anhydride. The Fischer indole synthesis between 4-methoxyphenylhydrazine HCl: (1) and 1-(4-Chlorophenyl)-6-hydroxyhexan-1,3-dione (2) gives 5-(4-Chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)pyrazole, PC14497416 (3). Oxidation with Jones reagent gives 3-propanoic acid (4). The reaction with sodium hydroxide gives PC23709163 (5). Halogenation with oxalyl chloride and reaction with N-Hydroxymethylamine gives Tepoxalin (6).
== References ==
{{Reflist}}

{{Anti-inflammatory products}}
{{Prostanoidergics}}

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