The effects of nepafenac and amfenac on retinal angiogenesis.
OBJECTIVE
Nepafenac is a potent NSAID that rapidly penetrates the eye following topical ocular administration. In the eye, nepafenac is converted to amfenac, which has unique time-dependent inhibitory properties for COX-1 and COX-2. The purpose of the present study was to investigate the capacity of amfenac to inhibit discrete aspects of the angiogenic cascade in vitro, and to test the efficacy of amfenac and nepafenac in vivo, using the rat OIR model.


METHODS
Müller cells were treated with amfenac, celecoxib (COX-2), or SC-560 (COX-1), and hypoxia-induced VEGF and PGE(2) assessed. Endothelial cells were treated with amfenac, celecoxib, or SC-560, and VEGF-induced proliferation and tube formation assessed. Rat pups were subjected to OIR, received intravitreal injections of amfenac, celecoxib, or SC-560, and neovascularization (NV), prostanoid production, and VEGF assessed. Other OIR-exposed pups were treated with topical nepafenac, ketorolac, or diclofenac, and inhibition of NV assessed.


RESULTS
Amfenac treatment failed to inhibit hypoxia-induced VEGF production. Amfenac treatment significantly inhibited VEGF-induced tube formation and proliferation by EC. Amfenac treatment significantly reduced retinal prostanoid production and NV in OIR. Nepafenac treatment significantly reduced retinal NV in OIR; ketorolac and diclofenac had no effect.


CONCLUSIONS
Nepafenac and amfenac inhibit OIR more effectively than the commercially available topical and injectable NSAIDs used in this study. Our data suggests there are COX-dependent and COX-independent mechanisms by which amfenac inhibits OIR. Because it is bioavailable to the posterior segment following topical delivery, nepafenac appears to be a promising advancement in the development of therapies for neovascular eye diseases.
Yanni
Susan E
SE
Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, 8000 Medical Center East, Nashville, TN 37232-8808, USA. susan.e.yanni@vanderbilt.edu
Clark
Monika L
ML
Yang
Rong
R
Bingaman
David P
DP
Penn
John S
JS
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D044482:Benzeneacetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D010100:Oxygen / Q000009:adverse effects; D010648:Phenylacetates / Q000494:pharmacology / Q000627:therapeutic use*; D011453:Prostaglandins / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000166:cytology; D015861:Retinal Neovascularization / Q000139:chemically induced / Q000188:drug therapy*; D012171:Retinal Vessels / Q000166:cytology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D044482:Benzeneacetamides; D016861:Cyclooxygenase Inhibitors; D010648:Phenylacetates; D011453:Prostaglandins; D011720:Pyrazoles; C115461:SC 560; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C414203:nepafenac; C014285:amfenac; D000068579:Celecoxib; D015232:Dinoprostone; D010100:Oxygen