Amlexanox

Last updated
Amlexanox
Amlexanox.svg
Clinical data
Trade names Aphthasol
AHFS/Drugs.com Monograph
MedlinePlus a601017
Routes of
administration
Topical
ATC code
Pharmacokinetic data
Elimination half-life 3.5 hours
Excretion Renal (17%)
Identifiers
  • 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 InfoCard 100.230.878 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H14N2O4
Molar mass 298.298 g·mol−1
3D model (JSmol)
  • O=C1c3cc(ccc3Oc2nc(c(cc12)C(=O)O)N)C(C)C
  • 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) Yes check.svgY
  • Key:SGRYPYWGNKJSDL-UHFFFAOYSA-N Yes check.svgY
   (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]

Contents

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: Amlexanoxsynthesis.png
Amlexanox synthesis:

Related Research Articles

Sodium dodecyl sulfate (SDS) or sodium lauryl sulfate (SLS), sometimes written sodium laurilsulfate, is an organic compound with the formula CH3(CH2)11OSO3Na and structure H3C(CH2)11−O−S(=O)2−ONa+. It is an anionic surfactant used in many cleaning and hygiene products. This compound is the sodium salt of the 12-carbon organosulfate. Its hydrocarbon tail combined with a polar "headgroup" give the compound amphiphilic properties that make it useful as a detergent. SDS is also component of mixtures produced from inexpensive coconut and palm oils. SDS is a common component of many domestic cleaning, personal hygiene and cosmetic, pharmaceutical, and food products, as well as of industrial and commercial cleaning and product formulations.

<span class="mw-page-title-main">Mouth ulcer</span> Sore which occurs on the mucous membrane of the oral cavity

A mouth ulcer (aphtha) is an ulcer that occurs on the mucous membrane of the oral cavity. Mouth ulcers are very common, occurring in association with many diseases and by many different mechanisms, but usually there is no serious underlying cause. Rarely, a mouth ulcer that does not heal may be a sign of oral cancer. These ulcers may form individually or multiple ulcers may appear at once. Once formed, an ulcer may be maintained by inflammation and/or secondary infection.

<span class="mw-page-title-main">GSK-3</span> Class of enzymes

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, glycogen synthase (GS), GSK-3 has since been identified as a protein kinase for over 100 different proteins in a variety of different pathways. In mammals, including humans, GSK-3 exists in two isozymes encoded by two homologous genes GSK-3α (GSK3A) and GSK-3β (GSK3B). GSK-3 has been the subject of much research since it has been implicated in a number of diseases, including type 2 diabetes, Alzheimer's disease, inflammation, cancer, addiction and bipolar disorder.

<span class="mw-page-title-main">Aphthous stomatitis</span> Common condition involving ulceration of the oral mucosa.

Aphthous stomatitis, or recurrent aphthous stomatitis (RAS), is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term canker sore is also used, mainly in North America, although it may also refer to other types of mouth ulcers. The cause is not completely understood but involves a T cell-mediated immune response triggered by a variety of factors which may include nutritional deficiencies, local trauma, stress, hormonal influences, allergies, genetic predisposition, certain foods, dehydration, some food additives, or some hygienic chemical additives like SDS.

<span class="mw-page-title-main">Stomatitis</span> Medical condition

Stomatitis is inflammation of the mouth and lips. It refers to any inflammatory process affecting the mucous membranes of the mouth and lips, with or without oral ulceration.

<span class="mw-page-title-main">Herpetic gingivostomatitis</span> Medical condition

Gingivostomatitis is a combination of gingivitis and stomatitis, or an inflammation of the oral mucosa and gingiva. Herpetic gingivostomatitis is often the initial presentation during the first ("primary") herpes simplex infection. It is of greater severity than herpes labialis which is often the subsequent presentations. Primary herpetic gingivostomatitis is the most common viral infection of the mouth.

A protein kinase inhibitor (PKI) is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function.

A genital ulcer is an open sore located on the genital area, which includes the vulva, penis, perianal region, or anus. Genital ulcers are most commonly caused by infectious agents. However, this is not always the case, as a genital ulcer may have noninfectious causes as well.

<span class="mw-page-title-main">IKK2</span> Protein-coding gene in the species Homo sapiens

IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB gene.

The IκB kinase is an enzyme complex that is involved in propagating the cellular response to inflammation.

<span class="mw-page-title-main">CHUK</span> Protein-coding gene in the species Homo sapiens

Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.

<span class="mw-page-title-main">Sulfonated phenolics/sulfuric acid</span> Medication

Sulfonated phenolics/sulfuric acid liquid topical agent that is used in the treatment of ulcerating oral mucosal lesions and minor oral abrasions.

<span class="mw-page-title-main">TANK-binding kinase 1</span> Protein-coding gene in the species Homo sapiens

TBK1 is an enzyme with kinase activity. Specifically, it is a serine / threonine protein kinase. It is encoded by the TBK1 gene in humans. This kinase is mainly known for its role in innate immunity antiviral response. However, TBK1 also regulates cell proliferation, apoptosis, autophagy, and anti-tumor immunity. Insufficient regulation of TBK1 activity leads to autoimmune, neurodegenerative diseases or tumorigenesis.

<span class="mw-page-title-main">IKBKE</span> Protein-coding gene in the species Homo sapiens

Inhibitor of nuclear factor kappa-B kinase subunit epsilon also known as I-kappa-B kinase epsilon or IKK-epsilon is an enzyme that in humans is encoded by the IKBKE gene.

CankerMelts is a non-prescription over-the-counter medication produced by Orahealth Corporation, located in Bellevue, Washington. CankerMelts are used to treat canker sores and other trauma-based mouth ailments. The product's active ingredient is Glycyrrhiza extract (GX), which comes from the root of the licorice plant. GX is thought to have pain relieving, anti-inflammatory, and anti-bacterial properties.

<span class="mw-page-title-main">Behçet's disease</span> Inflammatory disorder

Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the eye, and arthritis. The sores can last from a few days, up to a week or more. Less commonly there may be inflammation of the brain or spinal cord, blood clots, aneurysms, or blindness. Often, the symptoms come and go.

<span class="mw-page-title-main">Celastrol</span> Chemical compound

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Oral manifestations of systematic disease are signs and symptoms of disease occurring elsewhere in the body detected in the oral cavity and oral secretions. High blood sugar can be detected by sampling saliva. Saliva sampling may be a non-invasive way to detect changes in the gut microbiome and changes in systemic disease. Another example is tertiary syphilis, where changes to teeth can occur. Syphilis infection can be associated with longitudinal furrows of the tongue.

<span class="mw-page-title-main">Hagit Eldar-Finkelman</span> Israeli biochemist

Hagit Eldar-Finkelman is an Israeli scientist and a principal investigator of an active research laboratory at the Sackler School of Medicine at Tel Aviv University. Eldar-Finkelman’s research is focused on the signal transduction field and drug development targeting protein kinases. She is well known for her pioneering work on the functions of GSK-3 and its contribution to diabetes and other pathogenies, including depressive behavior, Alzheimer’s diseases, and Huntington’s diseases. Novel findings also include the unique evolution of GSK-3 isozymes. Eldar-Finkelman is a leading figure in developing novel substrate competitive inhibitors (SCIs) for GSK-3 with significant benefits as drug candidates.

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". American Family Physician. 75 (4): 501–507. 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?". The Journal of Family Practice. 60 (10): 621–632. 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". Clinical Drug Investigation. 25 (9): 555–566. doi:10.2165/00044011-200525090-00001. PMID   17532700. S2CID   24492356.
  9. 1 2 3 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.
  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.
  11. USpatent 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.
  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.
  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.