Abstract
Purpose: :
Pazopanib is a potent multi-targeted tyrosine kinase inhibitor that blocks VEGF, PDGF, and c-kit (SCF) receptors. In this study, we sought to investigate the potential of topical pazopanib for treatment of diabetic macular edema (DME).
Methods: :
The effect of topically delivered pazopanib was tested on VEGF-induced vascular permeability by measuring the retina to lung leakage ratio (RLLR) and retina to renal leakage ratio (RRLR) of [3H]mannitol after intraocular injection of VEGF. The effect of topical pazopanib on VEGF-induced subretinal neovascularization (NV) was assessed in rhodopsin/VEGF (rho/VEGF) transgenic mice.
Results: :
Intraocular injection of VEGF caused significant increases in the RLLR (p=0.023) and RRLR (p=0.032), and oral administration of 40 mg/kg/day of pazopanib by gavage significantly reduced the RLLR (0.93 to 0.56, p=0.004) and the RRLR (0.56 to 0.31, p=0.004) in VEGF-injected eyes. After intraocular injection of VEGF in both eyes, topical administration of 10 mg/ml pazopanib 3 times a day to one eye significantly reduced RLLR (0.89 vs. 0.56, p=0.048) and albumin immunofluorescence compared to the fellow eye. Treatment of one eye of rho/VEGF mice with 10 mg/ml of pazopanib 3 times a day significantly reduced the mean area of subretinal NV compared to that in fellow eyes (0.0057 vs. 0.0026 mm2, p=0.020).
Conclusions: :
A 10 mg/ml pazopanib given by topical eye drops was able to suppress VEGF-induced leakage and NV suggesting a potential utility of this formulation in patients with DME.
Keywords: retinal neovascularization • diabetic retinopathy • vascular endothelial growth factor