Amlexanox

Amlexanox
Clinical data
Trade namesAphthasol
AHFS/Drugs.comMonograph
MedlinePlusa601017
Routes of
administration		Topical
ATC code
Pharmacokinetic data
Elimination half-life3.5 hours
ExcretionRenal (17%)
Identifiers
IUPAC name
  • 2-amino-7-isopropyl-5-oxo-5H-chromeno[2,3-b]pyridine-3-carboxylic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.230.878 Edit this at Wikidata
Chemical and physical data
FormulaC16H14N2O4
Molar mass298.298 g·mol−1
3D model (JSmol)
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) checkY
  • Key:SGRYPYWGNKJSDL-UHFFFAOYSA-N checkY
  (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, 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

Amlexanox synthesis:[14]

References

  1. ↑ "Amlexanox (Aphthasol®)". Archived from the original on 20 November 2013. Retrieved 20 November 2013.
  2. ↑ Gonsalves WC, Chi AC, Neville BW (February 2007). "Common oral lesions: Part I. Superficial mucosal lesions". Am Fam Physician. 75 (4): 501–7. PMID 17323710.
  3. 1 2 3 4 5 "Amlexanox". MedlinePlus. U.S. National Library of Medicine. February 2009. Retrieved 12 February 2013.
  4. 1 2 Plewa MC (March 2012). "Pediatric Aphthous Ulcers Treatment & Management". Medscape Reference. Medscape. Retrieved 14 February 2013.
  5. ↑ "Amlexanox". PubChem. U.S. National Library of Medicine. Retrieved 12 February 2013.
  6. 1 2 Bailey J, McCarthy C, Smith RF (October 2011). "Clinical inquiry. What is the most effective way to treat recurrent canker sores?". J Fam Pract. 60 (10): 621–32. PMID 21977491.
  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.
  8. 1 2 3 4 5 Bell J (2005). "Amlexanox for the treatment of recurrent aphthous ulcers". Clin Drug Investig. 25 (9): 555–66. doi:10.2165/00044011-200525090-00001. PMID 17532700.
  9. 1 2 3 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 (February 2013). "An inhibitor of the protein kinases TBK1 and IKK-ɛ improves obesity-related metabolic dysfunctions in mice". Nat. Med. 19 (3): 313–21. doi:10.1038/nm.3082. PMC 3594079. PMID 23396211.
  10. ↑ Oral, E. A., Reilly, S. M., Gomez, A. V., Meral, R., Butz, L., Ajluni, N., ... & Rus, D. (2017). Inhibition of IKKɛ and TBK1 improves glucose control in a subset of patients with type 2 diabetes. Cell Metabolism, 26(1), 157-170. doi:10.1016/j.cmet.2017.06.006
  11. ↑ US patent 5362737, Kakubhai R. Vora, Atul Khandwala, Charles G. Smith, "Methods of treating aphthous ulcers and other mucocutaneous disorders with amlexanox", published 1994-11-08, assigned to Chemex Pharmaceuticals, Inc.
  12. ↑ Kuteyi T, Okwundu CI (2012). Kuteyi, Teslim (ed.). "Topical treatments for HIV-related oral ulcers". Cochrane Database Syst Rev. 1: CD007975. doi:10.1002/14651858.CD007975.pub2. PMID 22258979.
  13. ↑ 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 (September 2009). "The protein kinase IKKepsilon regulates energy balance in obese mice". Cell. 138 (5): 961–75. 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. (1985). "Studies on Antianaphylactic Agents. 7. Synthesis of Antiallergic 5-Oxo-5H-\1]benzopyrano\2,3-b]pyridines". Journal of Medicinal Chemistry. 28 (5): 559–68. doi:10.1021/jm50001a005. PMID 3989816.
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