title: Inflammation-mediated retinal edema in the rabbit is inhibited by topical nepafenac.
abstract: The purpose of this study was to evaluate the ability of the nonsteroidal anti-inflammatory drug nepafenac to prevent development of mitogen-induced pan-retinal edema following topical ocular application in the rabbit. Anesthetized Dutch Belted rabbits were injected intravitreally (30 microg/20 microL) with the mitogen concanavalin A to induce posterior segment inflammation and thickening (edema) of the retina. The Heidelberg Retina Tomograph was used to generate edema maps using custom software. Blood-retinal barrier breakdown was assessed by determining the protein concentration in vitreous humor, whereas analysis of PGE2 in vitreous humor was performed by radioimmunoassay. Inhibition of concanavalin A-induced retinal edema was assessed 72 h after initiation of topical treatment with nepafenac (0.1-1.0%, w/v), dexamethasone (0.1%), VOLTAREN (0.1%), or ACULAR (0.5%). Concanavalin A elicited marked increases in vitreal protein and PGE2 synthesis at 72 h postinjection. Retinal thickness was also increased by 32%, concomitant with the inflammatory response. Topical application of 0.5% nepafenac produced 65% reduction in retinal edema which was correlated with 62% inhibition of blood-retinal barrier breakdown. In a subsequent study, 0.5% nepafenac significantly inhibited (46%) blood-retinal barrier breakdown concomitant with near total suppression of PGE2 synthesis (96%). Neither Voltaren nor Acular inhibited accumulation of these markers of inflammation in the vitreous when tested in parallel. This study demonstrates that nepafenac exhibits superior pharmacodynamic properties in the posterior segment following topical ocular dosing, suggesting a unique therapeutic potential for a variety of conditions associated with retinal edema.
authors.affiliation: Ophthalmic Products Research, Alcon Research Ltd., Fort Worth, Texas 76134-2099, USA. mike.kapin@alconlabs.com
authors.forename: M A
authors.initials: MA
authors.lastname: Kapin
authors.forename: J M
authors.initials: JM
authors.lastname: Yanni
authors.forename: M T
authors.initials: MT
authors.lastname: Brady
authors.forename: T J
authors.initials: TJ
authors.lastname: McDonough
authors.forename: J G
authors.initials: JG
authors.lastname: Flanagan
authors.forename: M H
authors.initials: MH
authors.lastname: Rawji
authors.forename: D C
authors.initials: DC
authors.lastname: Dahlin
authors.forename: M E
authors.initials: ME
authors.lastname: Sanders
authors.forename: D A
authors.initials: DA
authors.lastname: Gamache
mesh_terms: D000287:Administration, Topical; D000818:Animals; D044482:Benzeneacetamides / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes; D003208:Concanavalin A; D004353:Drug Evaluation, Preclinical; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D010211:Papilledema / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D010599:Pharmacokinetics; D010648:Phenylacetates / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D011817:Rabbits; D012984:Software; D014018:Tissue Distribution; D014054:Tomography
chemical_list: D044482:Benzeneacetamides; D002250:Carbon Radioisotopes; D010648:Phenylacetates; C414203:nepafenac; D003208:Concanavalin A