Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium

Author: Waterbury L. David   Silliman David   Jolas Thierry  

Publisher: Informa Healthcare

ISSN: 1473-4877

Source: Current Medical Research and Opinion, Vol.22, Iss.6, 2006-06, pp. : 1133-1140

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Abstract

Objective: To compare the cyclooxygenase (COX) activity and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketorolac tromethamine (ketorolac) and bromfenac sodium (bromfenac).Methods: Cyclooxygenase activity and selectivity was determined in vitro by measuring prostaglandin E2 (PGE2) production following incubation of varying concentrations of NSAID with human recombinant COX-1 or COX-2 and arachidonic acid. Anti-inflammatory effects were evaluated in a rabbit model in which an ocular inflammatory response was induced by intravenous injection of 10 μg/kg lipopolysaccharide (LPS). In study animals, one eye was treated with 50 μL (+/−) ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50 μL buffered saline. In control animals, both eyes were treated with vehicle. All animals were treated twice: 2 hours and 1 hour before LPS.Main outcome measures: PGE2 production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE2 levels in vivo, measured by ELISA immunoassay.Results: Ketorolac was six times more active against COX-1 (IC50 = 0.02 μM) than COX-2 (IC50 = 0.12 μM) while bromfenac was ≈ 32 times more active against COX-2 (IC50 = 0.0066 μM) than COX-1 (IC50 = 0.210 μM). In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE2 production in the anterior chamber of treated eyes. There was also a 79% inhibition (p < 0.001) of FITC-dextran leakage in the contralateral eyes of bromfenac-treated rabbits, and a 22.5% inhibition (not statistically significant) in the contralateral eyes of ketorolac-treated rabbits.Conclusions: Ketorolac is relatively COX-1 selective while bromfenac is potently selective for COX-2 over COX-1. In the animal model, both ketorolac 0.4% and bromfenac 0.09% demonstrated maximal anti-inflammatory activity in treated eyes. Only bromfenac 0.09% had a significant effect on the contralateral eye, suggesting possible systemic absorption of this drug.