View source for Amlexanox

{{short description|Chemical compound}}
{{Drugbox
| Watchedfields = changed
| verifiedrevid = 456689729
| IUPAC_name = 2-amino-7-isopropyl-5-oxo-5''H''-chromeno[2,3-''b'']pyridine-3-carboxylic acid
| image = Amlexanox.svg
<!--Clinical data-->
| tradename = Aphthasol
| Drugs.com = {{drugs.com|monograph|amlexanox}}
| MedlinePlus = a601017
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_US = <!-- A / B            / C / D / X -->
| pregnancy_category =  
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->
| legal_CA = <!--             / Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_UK = <!-- GSL         / P       / POM / CD / Class A, B, C -->
| legal_US = <!-- OTC                   / Rx-only  / Schedule I, II, III, IV, V -->
| legal_status =  
| routes_of_administration = Topical
<!--Pharmacokinetic data-->
| bioavailability =  
| protein_bound =  
| metabolism =  
| elimination_half-life = 3.5 hours
| excretion = [[Kidney|Renal]] (17%)
<!--Identifiers-->
| IUPHAR_ligand = 7113
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 68302-57-8
| ATC_prefix = A01
| ATC_suffix = AD07
| ATC_supplemental = {{ATC|R03|DX01}}
| PubChem = 2161
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01025
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2076
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = BRL1C2459K
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01828
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 31205
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1096
<!--Chemical data-->
| C=16 | H=14
| N=2 | O=4
| smiles = O=C1c3cc(ccc3Oc2nc(c(cc12)C(=O)O)N)C(C)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H14N2O4/c1-7(2)8-3-4-12-9(5-8)13(19)10-6-11(16(20)21)14(17)18-15(10)22-12/h3-7H,1-2H3,(H2,17,18)(H,20,21)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SGRYPYWGNKJSDL-UHFFFAOYSA-N
}}
'''Amlexanox''' (trade name '''Aphthasol''') is an [[anti-inflammatory]] [[antiallergic]] [[immunomodulator]] used to treat recurrent [[aphthous ulcer]]s (canker sores), and (in Japan) several [[inflammation|inflammatory conditions]]. This drug has been discontinued in the U.S.<ref>{{cite web|title=Amlexanox (Aphthasol®)|url=http://www.childrensdmc.org/HealthLibrary/default.aspx?sid=1&pTitle=&ContentTypeID=26&ContentID=665&pTitle=Drug&alpha=A&AdditionalTitle=Aphthasol%C2%AE|archive-url=https://archive.today/20131120174828/http://www.childrensdmc.org/HealthLibrary/default.aspx?sid=1&pTitle=&ContentTypeID=26&ContentID=665&pTitle=Drug&alpha=A&AdditionalTitle=Aphthasol%C2%AE|url-status=dead|archive-date=20 November 2013|access-date=20 November 2013}}</ref>

==Medical uses==
Amlexanox is the active ingredient in a common topical treatment for recurrent [[aphthous ulcers]] of the mouth (canker sores),<ref name=gonsalves_2007/> reducing both healing time<ref name=medline_2009/> and pain.<ref name=medscape_aphthous_2012/>  Amlexanox 5% paste is well tolerated,<ref name=pubchem/> and is typically applied four times per day directly on the ulcers.<ref name=medline_2009/>  A 2011 review found it to be the most effective treatment of the eight treatments investigated for recurrent canker sores.<ref name=bailey_2011/>  It is also used to treat ulcers associated with [[Behçet disease]].<ref name=medscape_behcet_2012/>

In Japan, it is used to treat [[bronchial asthma]], allergic [[rhinitis]] and [[conjunctivitis]].<ref name=bell_2005/>

==Contraindications==
The drug is contraindicated in those with known allergies to it.<ref name=medline_2009/>

==Adverse effects==
Amlexanox may cause a slightly painful stinging or burning sensation, nausea or diarrhea.<ref name=medline_2009/><!--==Overdose==--><!--== Interactions ==
-->

==Mechanism of action==
Its mechanism of action is not well-determined, but it might inhibit inflammation by inhibiting the release of [[histamine]] and [[leukotrienes]].<ref name=bell_2005/> It has been shown to selectively inhibit [[TANK-binding kinase 1|TBK1]] and [[IKBKE|IKK-ε]], producing reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake in obese mice.<ref name=reilly_2013/> It produced a statistically significant reduction in [[glycated hemoglobin]] and [[fructosamine]] in obese patients with [[type 2 diabetes]] and [[nonalcoholic fatty liver disease]]<ref name="pmid28683283">{{cite journal | vauthors = Oral EA, Reilly SM, Gomez AV, Meral R, Butz L, Ajluni N, Chenevert TL, Korytnaya E, Neidert AH, Hench R, Rus D, Horowitz JF, Poirier B, Zhao P, Lehmann K, Jain M, Yu R, Liddle C, Ahmadian M, Downes M, Evans RM, Saltiel AR | display-authors = 6 | title = Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes | journal = Cell Metabolism | volume = 26 | issue = 1 | pages = 157–170.e7 | date = July 2017 | pmid = 28683283 | pmc = 5663294 | doi = 10.1016/j.cmet.2017.06.006 }}</ref>

==Chemistry==
The chemical itself is an odorless, white to yellowish-white powder.<ref name=bell_2005/>

The 5% preparation for patient use is an adherent beige paste,<ref name=medline_2009/><ref name=bell_2005/> and it is also available in some countries as a tablet that adheres to the ulcer in the mouth.<ref name=medscape_aphthous_2012/>

==Pharmacokinetics==
Amlexanox applied to an aphthous ulcer is largely absorbed through the [[gastrointestinal tract]]; an insignificant amount enters the [[bloodstream]] through the ulcer itself.<!-- ref name=bell_2005 /-->  After a single 100&nbsp;mg dose, mean maximum [[serum (blood)|serum]] concentration occurs 2.4 +/- 0.9 hours after application, with a half-life of elimination (through urine) of 3.5 +/- 1.1 hours.<!-- ref name=bell_2005 /-->  With multiple daily applications (four doses per day), steady state serum levels occur after one week, with no accumulation occurring after four weeks.<ref name=bell_2005/>

==History==
The patent for its use as a treatment for aphthous ulcers was issued in November 1994 to inventors Kakubhai R. Vora, Atul Khandwala and Charles G. Smith, and assigned to Chemex Pharmaceuticals, Inc.<ref name=patent/>

==Society and culture==

===Economics===
A 2011 review found a one-week supply of amlexanox 5% paste to cost $30.<ref name=bailey_2011/>

==Research==
A review found that, {{asof|2011|7|lc=y}}, robust studies investigating its effectiveness alongside other canker sore treatments were still needed.<ref name=kuteyi_2012/>

Because it is an [[enzyme inhibitor|inhibitor]] of the [[protein kinase]]s [[TANK-binding kinase 1|TBK1]] and [[IκB kinase|IKK-ε]],<ref name=reilly_2013/> which are implicated in the [[etiology]] of [[type II diabetes]] and [[obesity]],<ref name=Chiang/> amlexanox may be a candidate for human clinical trials testing in relation to these diseases.<ref name=reilly_2013/>

==Synthesis==
[[File:Amlexanoxsynthesis.png|thumb|center|600px|Amlexanox synthesis:<ref>{{cite journal | vauthors = Nohara A, Ishiguro T, Ukawa K, Sugihara H, Maki Y, Sanno Y | title = Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines | journal = Journal of Medicinal Chemistry | volume = 28 | issue = 5 | pages = 559–568 | date = May 1985 | pmid = 3989816 | doi = 10.1021/jm50001a005 }}</ref>]]

== References ==
{{reflist|35em|refs=

<ref name=bailey_2011>{{cite journal | vauthors = Bailey J, McCarthy C, Smith RF | title = Clinical inquiry. What is the most effective way to treat recurrent canker sores? | journal = The Journal of Family Practice | volume = 60 | issue = 10 | pages = 621–632 | date = October 2011 | pmid = 21977491 | url = http://www.jfponline.com/Pages.asp?AID=9930 }}</ref>

<ref name=bell_2005>{{cite journal | vauthors = Bell J | title = Amlexanox for the treatment of recurrent aphthous ulcers | journal = Clinical Drug Investigation | volume = 25 | issue = 9 | pages = 555–566 | year = 2005 | pmid = 17532700 | doi = 10.2165/00044011-200525090-00001 | s2cid = 24492356 }}</ref>

<!-- Not in use
<ref name=elad_2011>{{cite journal |vauthors=Elad S, Epstein JB, von Bültzingslöwen I, Drucker S, Tzach R, Yarom N | title = Topical immunomodulators for management of oral mucosal conditions, a systematic review; Part II: miscellaneous agents | journal = Expert Opin Emerg Drugs | volume = 16 | issue = 1 | pages = 183–202 | date = March 2011 | pmid = 21244328 | doi = 10.1517/14728214.2011.528390 }}</ref>
Not in use-->

<ref name=gonsalves_2007>{{cite journal | vauthors = Gonsalves WC, Chi AC, Neville BW | title = Common oral lesions: Part I. Superficial mucosal lesions | journal = American Family Physician | volume = 75 | issue = 4 | pages = 501–507 | date = February 2007 | pmid = 17323710 | url = http://www.aafp.org/afp/2007/0215/p501.html }}</ref>

<ref name=kuteyi_2012>{{cite journal | vauthors = Kuteyi T, Okwundu CI | title = Topical treatments for HIV-related oral ulcers | journal = The Cochrane Database of Systematic Reviews | volume = 1 | pages = CD007975 | date = January 2012 | pmid = 22258979 | doi = 10.1002/14651858.CD007975.pub2 | veditors = Kuteyi T }}</ref>

<ref name=medline_2009>{{cite web |url=https://www.nlm.nih.gov/medlineplus/druginfo/meds/a601017.html |title=Amlexanox |date=February 2009 |work=MedlinePlus |publisher=U.S. National Library of Medicine |access-date=12 February 2013}}</ref>

<ref name=medscape_behcet_2012>{{cite web |vauthors=Yousefi M, Ferringer T, Lee S, Bang D | title=Dermatologic Aspects of Behcet Disease Treatment & Management |date=July 2012 |work=Medscape Reference|publisher=Medscape |access-date=14 February 2013 |url=http://emedicine.medscape.com/article/1122381-treatment}}</ref>

<ref name=medscape_aphthous_2012>{{cite web | author = Plewa MC | title=Pediatric Aphthous Ulcers Treatment & Management |date=March 2012 |work=Medscape Reference|publisher=Medscape |access-date=14 February 2013 |url=http://emedicine.medscape.com/article/909213-treatment}}</ref>

<!-- Not in use
<ref name=mesh_2009>{{cite web |url=https://www.nlm.nih.gov/cgi/mesh/2009/MB_cgi?mode=&term=amlexanox |title=Amlexanox |date=2009 |work=MeSH |publisher=U.S. National Library of Medicine |access-date=12 February 2013}}</ref>
Not in use-->

<ref name=patent>{{cite patent |country=US |number=5362737 |status=patent |title=Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox |pubdate=1994-11-08 |inventor= Vora KR, Khandwala A, Smith CG |assign1=Chemex Pharmaceuticals, Inc.}}</ref>

<ref name=pubchem>{{cite web |url=https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?q=all&cid=2161#ec |title=Amlexanox |work=PubChem |publisher=U.S. National Library of Medicine |access-date=12 February 2013}}</ref>

<ref name=reilly_2013>{{cite journal | vauthors = Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, Rubin JR, Mowers J, White NM, Hochberg I, Downes M, Yu RT, Liddle C, Evans RM, Oh D, Li P, Olefsky JM, Saltiel AR | display-authors = 6 | title = An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice | journal = Nature Medicine | volume = 19 | issue = 3 | pages = 313–321 | date = March 2013 | pmid = 23396211 | pmc = 3594079 | doi = 10.1038/nm.3082 }}</ref>

<ref name=Chiang>{{cite journal | vauthors = Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, Ma JT, Zhou J, Qi N, Westcott D, Delproposto JB, Blackwell TS, Yull FE, Saltiel AR | display-authors = 6 | title = The protein kinase IKKepsilon regulates energy balance in obese mice | journal = Cell | volume = 138 | issue = 5 | pages = 961–975 | date = September 2009 | pmid = 19737522 | pmc = 2756060 | doi = 10.1016/j.cell.2009.06.046 }}</ref>

}}

{{Stomatological preparations}}
{{Drugs for obstructive airway diseases}}

[[Category:Anti-inflammatory agents]]
[[Category:Leukotriene antagonists]]
[[Category:Carboxylic acids]]
[[Category:Isopropyl compounds]]