Intraocular Properties of Urokinase–derived Anti–angiogenic Å6 Peptide in Rabbits

Abstract

Abstract: : Purpose:To investigate the intraocular properties of an anti–angiogenic peptide, Å6, in rabbit eyes. Methods: A total of 70 eyes of New Zealand rabbits were used. For the toxicity study, 0.05 ml of 0.459 M or 0.148 M Å6 was injected intravitreally; right eyes received Å6, left eyes vehicle. Serial intraocular pressure, slit lamp and indirect ophthalmoscopy was performed. At 2 or 8 weeks, eyes were evaluated by fluorescein angiography, electroretinography and enucleated for histology. The pharmacokinetics of intravitreal Å6 (22.25 mg) and subtenon Å6 (139.0 mg) injection was studied. Results:There was no toxicity after 0.148 M Å6 injections. In 2 eyes with 0.459 M Å6, focal pigmentary change was observed in the area where the extremely hyperosmolar drug bolus directly contacted with the retina. Choroidal Å6, following intravitreal injection, remained therapeutic (>=10 mM) for 72 hours. The vitreous decay kinetics was linear with a half–life of 19.4 hours. Choroidal concentrations following subtenon injection were minimal. Conclusions:In normal rabbit eyes, there was no toxicity after intravitreal 0.148 M Å6 injection. Higher doses produce toxicity only if the drug is not dispersed after injection. More hydrophobic analogs of Å6 are likely to cross the retina more efficiently. On the other hand, in diseased eyes, in the area of CNV, the fluid content in edematous retina as well as the damage to the retina may permit higher concentrations to enter the choroid despite the polar nature of Å6. Further studies in eyes with retinal edema and damage are suggested.

Keywords: pharmacology • choroid: neovascularization • age–related macular degeneration