Topical nepafenac inhibits ocular neovascularization.
OBJECTIVE
Topical nepafenac readily penetrates the cornea and is metabolized to amfenac, a potent cyclooxygenase (COX)-1 and COX-2 inhibitor. In this study, we tested the effect of topical nepafenac in three murine models of ocular neovascularization (NV).


METHODS
A masked trial was performed to compare the topical effects of vehicle with one of several concentrations of nepafenac (0.01%, 0.03%, 0.1%, or 0.5%), 0.1% diclofenac, or 0.5% ketorolac tromethamine in mice with oxygen-induced ischemic retinopathy, mice with choroidal NV (CNV) due to laser-induced rupture of Bruch's membrane, or transgenic mice with increased expression of vascular endothelial growth factor (VEGF) in photoreceptors (rho/VEGF transgenic mice).


RESULTS
Mice treated with 0.1% or 0.5% nepafenac had significantly less CNV and significant less ischemia-induced retinal NV than did vehicle-treated mice. Nepafenac also blunted the increase in VEGF mRNA in the retina induced by ischemia. In rho/VEGF transgenic mice, nepafenac failed to inhibit neovascularization. In additional studies, compared with vehicle-treated mice, mice treated with 0.1% or 0.03% nepafenac had significantly less CNV, whereas eyes treated with 0.1% diclofenac showed no significant difference. Mice treated with 0.5% ketorolac tromethamine for 14 days had high mortality, but when evaluated after 7 days of treatment showed no difference from mice treated with vehicle for 7 days.


CONCLUSIONS
Topical nepafenac inhibits CNV and ischemia-induced retinal neovascularization by decreasing production of VEGF. The absence of effect in rho/VEGF transgenic mice is consistent with this mechanism. Topical nepafenac may provide an effective new treatment for ocular neovascularization. The excellent corneal penetration of nepafenac certainly plays an important role in this effect. It is possible that other antiangiogenic agents are also amenable to topical application after formulations are identified that maximize their corneal penetration. Because of the many advantages of the topical route of delivery, this is a possible topic for exploration.
Takahashi
Kyoichi
K
Departments of Ophthalmology and Neuroscience, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-9277, USA.
Saishin
Yoshitsugu
Y
Saishin
Yumiko
Y
Mori
Keisuke
K
Ando
Akira
A
Yamamoto
Satoru
S
Oshima
Yuji
Y
Nambu
Hiroyuki
H
Melia
Michele B
MB
Bingaman
David P
DP
Campochiaro
Peter A
PA
D000287:Administration, Topical; D000818:Animals; D044482:Benzeneacetamides; D020256:Choroidal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D020911:Ketorolac Tromethamine / Q000008:administration & dosage / Q000627:therapeutic use; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009883:Ophthalmic Solutions; D010648:Phenylacetates / Q000008:administration & dosage / Q000627:therapeutic use*; D011355:Prodrugs; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger / Q000378:metabolism; D015861:Retinal Neovascularization / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D044482:Benzeneacetamides; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009883:Ophthalmic Solutions; D010648:Phenylacetates; D011355:Prodrugs; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C414203:nepafenac; D020911:Ketorolac Tromethamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse