December 2002
Volume 43, Issue 13
Free
ARVO Annual Meeting Abstract  |   December 2002
Studies of the Effect and Mechanism of Action of Topical Nepafenac in a Rat Model of ROP
Author Affiliations & Notes
  • JS Penn
    Ophthalmology and Visual Sciences Vanderbilt Univ School of Med Nashville TN
  • X Qi
    Ophthalmology and Visual Sciences Vanderbilt Univ School of Med Nashville TN
  • PA Percinel
    Ophthalmology and Visual Sciences Vanderbilt Univ School of Med Nashville TN
  • VS Rajaratnam
    Ophthalmology and Visual Sciences Vanderbilt Univ School of Med Nashville TN
  • DP Bingaman
    Retina/Degenerative Diseases Alcon Laboratories Inc Fort Worth TX
  • Footnotes
    Commercial Relationships    J.S. Penn, Alcon Laboratories, Inc. F, C; X. Qi, None; P.A. Percinel, None; V.S. Rajaratnam, None; D.P. Bingaman, Alcon Laboratories, Inc. E. Grant Identification: EY07533, RPB Challenge Grant, Alcon Labs, Inc.
Investigative Ophthalmology & Visual Science December 2002, Vol.43, 2741. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to authenticated users only.
      Sign In or Create an Account ×
    • Get Citation

      JS Penn, X Qi, PA Percinel, VS Rajaratnam, DP Bingaman; Studies of the Effect and Mechanism of Action of Topical Nepafenac in a Rat Model of ROP . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2741.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Abstract: : Purpose: To investigate the angiostatic potential of Nepafenac, or 2-amino-3-benzoylbenzeneacetamide, and its mechanism of action using well-established in vitro and in vivo systems. As a prodrug, the topical NSAID Nepafenac has rapid corneal penetration, and it is metabolized to a potent cyclo-oxygenase (COX I & II) inhibitor, AL-6295A. Methods: Bovine retinal microvascular endothelial cells (BRMEC) were used at 6th passage in VEGF-stimulated proliferation and tube formation assays. In addition, preretinal neovascularization (NV) was produced in rat pups maintained from birth in a variable oxygen atmosphere for 14 days and then removed to room air for up to 6 days before euthanasia (Penn et al, 2001; IOVS, 42:283-290). Starting 1 day prior to removal to room air, some rats received topical QID OU delivery of 0.1% Nepafenac or vehicle (0.5% carbopol, 2.4% mannitol, 0.1% tyloxapol in water). Retinas were harvested at 1, 2, 4, and 6 days post-exposure for retinal VEGF measurement by ELISA. In other rats, topical QID OU delivery of 0.1% Nepafenac, vehicle, or two marketed NSAIDs, 0.5% ketorolac tomethamine or 0.1% diclofenac, was administered from P14-19. Retinas were harvested at P20 for assessment of preretinal NV. Results: Nepafenac showed no significant effect on VEGF-stimulated BRMEC proliferation or tube formation at concentrations between 0.1-10µM. Its metabolite, AL-6295A, significantly inhibited both proliferation and tube formation in a potent, dose-dependent manner. In the rat ROP model, 0.1% Nepafenac caused a 56% inhibition of preretinal NV (p = 0.0292) as compared to vehicle, and the two marketed NSAIDs had no effect. Topical ocular delivery of 0.1% Nepafenac marginally inhibited retinal VEGF protein levels only at P18 (p = 0.0498). Conclusion: COX activity is suspected to provide regulation of angiogenesis in colon cancer and Alzheimer's disease. This is the first evidence of COX inhibition preventing ocular angiogenesis in an animal model. Our VEGF ELISA results suggest that the mechanism by which Nepafenac/AL-6295A inhibits NV is primarily downstream of VEGF, but additional experiments are in progress to further elucidate the link between COX activity and ischemia-induced preretinal NV. Nepafenac is formulated for topical ocular delivery, which restricts its angiostatic action to the eye and may eliminate the systemic toxicity that has limited the clinical utility of other antiangiogenic agents.

Keywords: 566 retinal neovascularization • 572 retinopathy of prematurity • 614 vascular cells 
×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×