FR122047, Selective Inhibitor of COX-1, Active in a Model of Lipopolysaccharide (LPS) Induced Ocular Inflammation in Rabbits

Abstract

Purpose: : FR-122047 (FR), a novel selective COX-1 inhibitor has been shown to have systemic analgesic and anti-inflammatory activity. The objective of this study is to determine if FR122047 is active by topical administration in LPS-induced ocular inflammation in rabbits.

Methods: : At hour 0, rabbits received either artificial tears (vehicle) in one eye, and FR122047, 0.1% suspension (FR) (50 µl) in the contralateral eye. Additional groups of 6 rabbits each received COX-1 inhibitors trans-resveratrol 0.1% (TR) (50 µl) or, COX-2 inhibitor -nimesulide 0.1% (50 µl), or COX-1 and COX-2 inhibitor ketorolac 0.40% (Acular^®; Allergan, Inc.; Irvine, CA) (50 µl). At hour 1, rabbits received intravenous injections of LPS (2.5 µg/kg) and fluorescein isothiocyanate (FITC)-dextran (30 mg/kg). At 90 minutes after LPS, aqueous samples were collected for analysis. Six additional rabbits received only FITC-dextran 90 minutes before sample collection. PGE₂ concentrations (immunoassay) and FITC-dextran (fluorometer) were determined in aqueous humor samples.

Results: : FR122017 (0.1% suspension) significantly reduced PGE₂ elevation (p = .0041, n =6, paired ‘t’ test, n =6) by 45% compared to the vehicle treated contralateral eye. The observed inhibition of PGE₂ was much greater than previously found with the selective COX-2 inhibitor nimesulide (0% inhibition), but less than observed with the mixed COX-1/COX-2 inhibitors ketorolac (>90% Inhibition). FR122017 did not affect FITC-dextran concentrations in aqueous humor (p = 0.96, 0% I); whereas the non-selective inhibitors-ketorolac resulted in a complete inhibition of FITC-dextran accumulation in the aqueous humor after LPS. The selective COX-2 inhibitor-nimesulide was completely inactive in suppressing FITC-dextran accumulation. Inefficacy of FR in reducing FITC-dextran leakage may be due to their poor penetration into iris-ciliary body.

Conclusions: : The inhibition of PGE₂ in aqueous humor by the selective COX-1 inhibitor -FR122047, and lack of activity by the COX-2 selective inhibitor- nimesulide suggests that the primary isoenzyme responsible for early inflammatory response to LPS is COX-1.This study was funded by an unrestricted educational grant from Allergan, Inc.

Keywords: inflammation • uveitis-clinical/animal model • anterior chamber