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Clavulanic acid: Wikis

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Clavulanic acid
Systematic (IUPAC) name
(2R,5R,Z)-3-(2-hydroxyethylidene)-
7-oxo-4-oxa-1-aza-bicyclo[3.2.0]
heptane-2-carboxylic acid
Identifiers
CAS number 58001-44-8
ATC code J01CR (combinations with penicillins)
PubChem 5280980
DrugBank APRD00049
ChemSpider 4444466
Chemical data
Formula C 8H9NO5  
Mol. mass 199.16
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability "well absorbed"
Metabolism hepatic (extensive)
Half life 1 hour
Excretion renal (30–40%)
Therapeutic considerations
Pregnancy cat. B (USA)
B1 (Aust)
Legal status Schedule 4 (Aust)
Routes oral, IV
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Clavulanic acid (rINN) (pronounced /klævjuːˌlænɨk ˈæsɨd/) is a beta-lactamase inhibitor (marketed by GlaxoSmithKline, formerly Beecham) combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete beta-lactamase, which otherwise inactivates most penicillins. In its most common form, the potassium salt potassium clavulanate is combined with amoxicillin (co-amoxiclav [brand name Augmentin] or the veterinary formulation Synulox from Pfizer, or [Clavulox]) or ticarcillin.

It is also under investigation as a NAALADase inhibitor with purported antidepressant and aphrodisiac properties, as in page 15 of this patent[1]. Clinical trials are underway on XR ("Serdaxin") and IR ("RX-10100", "Zoraxel") formulations by Rexahn in the US.[2]

Clavulanic acid is an example of a clavam.

Contents

Source

The name is derived from the Streptomyces clavuligerus, which produces clavulanic acid.[3][4]

Clavulanic acid is biosynthetically generated from the amino acid arginine and the sugar glyceraldehyde 3-phosphate.

History

Clavulanic acid was discovered around 1974/75 by British scientists working at the drug company Beecham. After several attempts, Beecham finally filed for US patent protection for the drug in 1981, and U.S. Patents 4,525,352, 4,529,720 and 4,560,552 were granted in 1985.

Mechanism of action

Clavulanic acid has negligible intrinsic antimicrobial activity, despite sharing the β-lactam ring that is characteristic of beta-lactam antibiotics. However, the similarity in chemical structure allows the molecule to act as a competitive inhibitor of beta-lactamases secreted by certain bacteria to confer resistance to beta-lactam antibiotics. This inhibition restores the antimicrobial activity of beta-lactam antibiotics against lactamase-secreting-resistant bacteria. Despite this, some bacterial strains that are even resistant to such combinations have emerged.

Adverse effects

The use of clavulanic acid with penicillins has been associated with an increased incidence of cholestatic jaundice and acute hepatitis during therapy or shortly after, particularly in men and those aged over 65 years. The associated jaundice is usually self-limiting and very rarely fatal.[5]

The UK Committee on Safety of Medicines (CSM) recommends that treatments such as amoxicillin/clavulanic acid preparations should be reserved for bacterial infections likely to be caused by amoxicillin-resistant β-lactamase-producing strains, and that treatment should not normally exceed 14 days.

Allergy has been reported.[6]

References

  1. ^ http://www.google.com/patents/pdf/Therapeutic_treatment_for_sexual_dysfunc.pdf?id=Lhl_AAAAEBAJ&output=pdf&sig=ACfU3U0ESWXC1lRCKxRbO4OD8h9FFa6LyQ
  2. ^ http://clinicaltrials.gov/ct2/results?term=rx-10100
  3. ^ Arulanantham H, Kershaw NJ, Hewitson KS, Hughes CE, Thirkettle JE, Schofield CJ (January 2006). "ORF17 from the clavulanic acid biosynthesis gene cluster catalyzes the ATP-dependent formation of N-glycyl-clavaminic acid". J. Biol. Chem. 281 (1): 279–87. doi:10.1074/jbc.M507711200. PMID 16251194. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=16251194.  
  4. ^ Tahlan K, Park HU, Wong A, Beatty PH, Jensen SE (March 2004). "Two sets of paralogous genes encode the enzymes involved in the early stages of clavulanic acid and clavam metabolite biosynthesis in Streptomyces clavuligerus". Antimicrob. Agents Chemother. 48 (3): 930–9. PMID 14982786. PMC 353097. http://aac.asm.org/cgi/pmidlookup?view=long&pmid=14982786.  
  5. ^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
  6. ^ Tortajada Girbés M, Ferrer Franco A, Gracia Antequera M, Clement Paredes A, García Muñoz E, Tallón Guerola M (2008). "Hypersensitivity to clavulanic acid in children". Allergol Immunopathol (Madr) 36 (5): 308–10. PMID 19080805. http://www.elsevier.es/revistas/0301-0546/36/308.  
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