Purchase this article with an account.
I. Falkenstein, L. Cheng, T.R. Jones, G. Lam, I. Kozak, A.M. Tammewar, W.R. Freeman; Intraocular Properties of Urokinase–Derived Antiangiogenic Å36 Peptide in Rabbits . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3884.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
It has been shown previously by our group that the urokinase–derived antiangiogenic peptide Å6 has the potential to be a successful treatment for choroidal neovascularization (CNV) in AMD (Koh & Freeman, JOPT, 2004), although the hydrophilic properties of Å6 would have to be addressed to enable satisfactory long–term intraocular treatment. Å36, a peptide designed to block urokinase plasminogen activator receptor and to be more lipophilic, inhibits cellular migration at IC50=100 nM level. We hypothesized that the lipophilic properties of Å36 would allow sustained vitreous drug level and good retinal penetration, which enable a single injection to be used as a long–term treatment.
The total of 50 New Zealand Red rabbits were used. To determine the highest non–toxic dose we utilized 0.05 ml of 20 mg/ml (1 mg), 6.5 mg/ml (0.3 mg) and 2 mg/ml (0.1 mg) of A36 injected intravitreally; fellow eyes were injected with 0.05ml of vehicle. Serial intraocular pressure measurements, slit lamp, color fundus photographs and indirect ophthalmoscopy were performed. At 2 and 12 weeks rabbits were evaluated by electroretinography, light microscopy and electron microscopy after scheduled sacrifice. The pharmacokinetics of the highest non–toxic intravitreal dose of Å36 (0.05 ml of 20 mg/ml) was also studied.
There was no toxicity observed in this study at any time point according to ERGs, IOPs, slit lamp exams and histopathological evaluations. The drug depo was present and slowly dissolved in the vitreous, with half of the drug visible at the 3–month point, yielding an approximate 6–month duration of action. The visible drug depo was confirmed to be an active drug by mass Spectrometry. The mean free vitreous drug level at one month was 560nM. The choroidal concentration of the drug during the first month varied, but remained above therapeutic concentration with average level of 500nM at one–month point.
Å36 is a new antiangiogenic drug with a novel mechanism of action. It has no toxicity in animal eyes and its intraocular properties are promising for the long–term treatment of CNV in wet macular degeneration as a single injection may be therapeutic for 6 months or longer. Further studies in the primate efficacy model of AMD are indicated, as the drug is species–specific.
This PDF is available to Subscribers Only