Amlexanox

Amlexanox
Clinical data
Trade names	Aphthasol
AHFS/Drugs.com	Monograph
MedlinePlus	a601017
Routes of; administration	Topical
ATC code	A01AD07 (WHO) R03DX01 (WHO);
Pharmacokinetic data
Elimination half-life	3.5 hours
Excretion	Renal (17%)
Identifiers
	IUPAC name 2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid;
CAS Number	68302-57-8 ;
PubChem CID	2161;
IUPHAR/BPS	7113;
DrugBank	DB01025 ;
ChemSpider	2076 ;
UNII	BRL1C2459K;
KEGG	D01828 ;
ChEBI	CHEBI:31205 ;
ChEMBL	ChEMBL1096 ;
CompTox Dashboard (EPA)	DTXSID2022595 ;
ECHA InfoCard	100.230.878
Chemical and physical data
Formula	C16H14N2O4
Molar mass	298.298 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES O=C1c3cc(ccc3Oc2nc(c(cc12)C(=O)O)N)C(C)C;
	InChI InChI=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) ; Key:SGRYPYWGNKJSDL-UHFFFAOYSA-N ;
	(verify)

Amlexanox (trade name Aphthasol) is an anti-inflammatory antiallergic immunomodulator used to treat recurrent aphthous ulcers (canker sores), and (in Japan) several inflammatory conditions. This drug has been discontinued in the U.S.^[1]

Medical uses

Amlexanox is the active ingredient in a common topical treatment for recurrent aphthous ulcers of the mouth (canker sores),^[2] reducing both healing time^[3] and pain.^[4] Amlexanox 5% paste is well tolerated,^[5] and is typically applied four times per day directly on the ulcers.^[3] A 2011 review found it to be the most effective treatment of the eight treatments investigated for recurrent canker sores.^[6] It is also used to treat ulcers associated with Behçet disease.^[7]

In Japan, it is used to treat bronchial asthma, allergic rhinitis and conjunctivitis.^[8]

Contraindications

The drug is contraindicated in those with known allergies to it.^[3]

Adverse effects

Amlexanox may cause a slightly painful stinging or burning sensation, nausea or diarrhea.^[3]

Mechanism of action

Its mechanism of action is not well-determined, but it might inhibit inflammation by inhibiting the release of histamine and leukotrienes.^[8] It has been shown to selectively inhibit TBK1 and IKK-ε, producing reversible weight loss and improved insulin sensitivity, reduced inflammation and attenuated hepatic steatosis without affecting food intake in obese mice.^[9] It produced a statistically significant reduction in glycated hemoglobin and fructosamine in obese patients with type 2 diabetes and nonalcoholic fatty liver disease^[10]

Chemistry

The chemical itself is an odorless, white to yellowish-white powder.^[8]

The 5% preparation for patient use is an adherent beige paste,^[3]^[8] and it is also available in some countries as a tablet that adheres to the ulcer in the mouth.^[4]

Pharmacokinetics

Amlexanox applied to an aphthous ulcer is largely absorbed through the gastrointestinal tract; an insignificant amount enters the bloodstream through the ulcer itself. After a single 100 mg dose, mean maximum serum concentration occurs 2.4 +/- 0.9 hours after application, with a half-life of elimination (through urine) of 3.5 +/- 1.1 hours. With multiple daily applications (four doses per day), steady state serum levels occur after one week, with no accumulation occurring after four weeks.^[8]

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.^[11]

Society and culture

Economics

A 2011 review found a one-week supply of amlexanox 5% paste to cost $30.^[6]

Research

A review found that, as of July 2011^[update], robust studies investigating its effectiveness alongside other canker sore treatments were still needed.^[12]

Because it is an inhibitor of the protein kinases TBK1 and IKK-ε,^[9] which are implicated in the etiology of type II diabetes and obesity,^[13] amlexanox may be a candidate for human clinical trials testing in relation to these diseases.^[9]

Synthesis

References

^ "Amlexanox (Aphthasol®)". Archived from the original on 20 November 2013. Retrieved 20 November 2013.
^ Gonsalves WC, Chi AC, Neville BW (February 2007). "Common oral lesions: Part I. Superficial mucosal lesions". American Family Physician. 75 (4): 501–507. PMID 17323710.
^ ^a ^b ^c ^d ^e "Amlexanox". MedlinePlus. U.S. National Library of Medicine. February 2009. Retrieved 12 February 2013.
^ ^a ^b Plewa MC (March 2012). "Pediatric Aphthous Ulcers Treatment & Management". Medscape Reference. Medscape. Retrieved 14 February 2013.
^ "Amlexanox". PubChem. U.S. National Library of Medicine. Retrieved 12 February 2013.
^ ^a ^b Bailey J, McCarthy C, Smith RF (October 2011). "Clinical inquiry. What is the most effective way to treat recurrent canker sores?". The Journal of Family Practice. 60 (10): 621–632. PMID 21977491.
^ Yousefi M, Ferringer T, Lee S, Bang D (July 2012). "Dermatologic Aspects of Behcet Disease Treatment & Management". Medscape Reference. Medscape. Retrieved 14 February 2013.
^ ^a ^b ^c ^d ^e Bell J (2005). "Amlexanox for the treatment of recurrent aphthous ulcers". Clinical Drug Investigation. 25 (9): 555–566. doi:10.2165/00044011-200525090-00001. PMID 17532700. S2CID 24492356.
^ ^a ^b ^c Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, et al. (March 2013). "An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice". Nature Medicine. 19 (3): 313–321. doi:10.1038/nm.3082. PMC 3594079. PMID 23396211.
^ Oral EA, Reilly SM, Gomez AV, Meral R, Butz L, Ajluni N, et al. (July 2017). "Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes". Cell Metabolism. 26 (1): 157–170.e7. doi:10.1016/j.cmet.2017.06.006. PMC 5663294. PMID 28683283.
^ US patent 5362737, Vora KR, Khandwala A, Smith CG, "Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox", published 1994-11-08, assigned to Chemex Pharmaceuticals, Inc.
^ Kuteyi T, Okwundu CI (January 2012). Kuteyi T (ed.). "Topical treatments for HIV-related oral ulcers". The Cochrane Database of Systematic Reviews. 1: CD007975. doi:10.1002/14651858.CD007975.pub2. PMID 22258979.
^ Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, et al. (September 2009). "The protein kinase IKKepsilon regulates energy balance in obese mice". Cell. 138 (5): 961–975. doi:10.1016/j.cell.2009.06.046. PMC 2756060. PMID 19737522.
^ Nohara A, Ishiguro T, Ukawa K, Sugihara H, Maki Y, Sanno Y (May 1985). "Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines". Journal of Medicinal Chemistry. 28 (5): 559–568. doi:10.1021/jm50001a005. PMID 3989816.

[1] "Amlexanox (Aphthasol®)". Archived from the original on 20 November 2013. Retrieved 20 November 2013.

[gonsalves_2007-2] Gonsalves WC, Chi AC, Neville BW (February 2007). "Common oral lesions: Part I. Superficial mucosal lesions". American Family Physician. 75 (4): 501–507. PMID 17323710.

[medline_2009-3] "Amlexanox". MedlinePlus. U.S. National Library of Medicine. February 2009. Retrieved 12 February 2013.

[medscape_aphthous_2012-4] Plewa MC (March 2012). "Pediatric Aphthous Ulcers Treatment & Management". Medscape Reference. Medscape. Retrieved 14 February 2013.

[pubchem-5] "Amlexanox". PubChem. U.S. National Library of Medicine. Retrieved 12 February 2013.

[bailey_2011-6] Bailey J, McCarthy C, Smith RF (October 2011). "Clinical inquiry. What is the most effective way to treat recurrent canker sores?". The Journal of Family Practice. 60 (10): 621–632. PMID 21977491.

[medscape_behcet_2012-7] Yousefi M, Ferringer T, Lee S, Bang D (July 2012). "Dermatologic Aspects of Behcet Disease Treatment & Management". Medscape Reference. Medscape. Retrieved 14 February 2013.

[bell_2005-8] Bell J (2005). "Amlexanox for the treatment of recurrent aphthous ulcers". Clinical Drug Investigation. 25 (9): 555–566. doi:10.2165/00044011-200525090-00001. PMID 17532700. S2CID 24492356.

[reilly_2013-9] Reilly SM, Chiang SH, Decker SJ, Chang L, Uhm M, Larsen MJ, et al. (March 2013). "An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice". Nature Medicine. 19 (3): 313–321. doi:10.1038/nm.3082. PMC 3594079. PMID 23396211.

[pmid28683283-10] Oral EA, Reilly SM, Gomez AV, Meral R, Butz L, Ajluni N, et al. (July 2017). "Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes". Cell Metabolism. 26 (1): 157–170.e7. doi:10.1016/j.cmet.2017.06.006. PMC 5663294. PMID 28683283.

[patent-11] US patent 5362737, Vora KR, Khandwala A, Smith CG, "Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox", published 1994-11-08, assigned to Chemex Pharmaceuticals, Inc.

[kuteyi_2012-12] Kuteyi T, Okwundu CI (January 2012). Kuteyi T (ed.). "Topical treatments for HIV-related oral ulcers". The Cochrane Database of Systematic Reviews. 1: CD007975. doi:10.1002/14651858.CD007975.pub2. PMID 22258979.

[Chiang-13] Chiang SH, Bazuine M, Lumeng CN, Geletka LM, Mowers J, White NM, et al. (September 2009). "The protein kinase IKKepsilon regulates energy balance in obese mice". Cell. 138 (5): 961–975. doi:10.1016/j.cell.2009.06.046. PMC 2756060. PMID 19737522.

[14] Nohara A, Ishiguro T, Ukawa K, Sugihara H, Maki Y, Sanno Y (May 1985). "Studies on antianaphylactic agents. 7. Synthesis of antiallergic 5-oxo-5H-[1]benzopyrano[2,3-b]pyridines". Journal of Medicinal Chemistry. 28 (5): 559–568. doi:10.1021/jm50001a005. PMID 3989816.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]