Comparison of cyclooxygenase inhibitory activity and ocular anti-inflammatory effects of ketorolac tromethamine and bromfenac sodium.
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 E(2) (PGE(2)) 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 microg/kg lipopolysaccharide (LPS). In study animals, one eye was treated with 50 microL (+/-) ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50 microL buffered saline. In control animals, both eyes were treated with vehicle. All animals were treated twice: 2 hours and 1 hour before LPS.


METHODS
PGE(2) production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE(2) levels in vivo, measured by ELISA immunoassay.


RESULTS
Ketorolac was six times more active against COX-1 (IC(50) = 0.02 microM) than COX-2 (IC(50) = 0.12 microM) while bromfenac was approximately 32 times more active against COX-2 (IC(50) = 0.0066 microM) than COX-1 (IC(50) = 0.210 microM). In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE(2) 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.
Waterbury
L David
LD
Pacific BioLabs, Hercules, CA 94070, USA. David.Waterbury@alumni.uvm.edu
Silliman
David
D
Jolas
Thierry
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000627:therapeutic use; D001577:Benzophenones / Q000737:chemistry* / Q000627:therapeutic use; D001969:Bromobenzenes / Q000737:chemistry* / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000737:chemistry* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D005128:Eye Diseases / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D020911:Ketorolac Tromethamine / Q000737:chemistry* / Q000627:therapeutic use; D011817:Rabbits; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001577:Benzophenones; D001969:Bromobenzenes; D052246:Cyclooxygenase 2 Inhibitors; D011994:Recombinant Proteins; D020911:Ketorolac Tromethamine; C053083:bromfenac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2