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J. Hood, N. Umeda, P. Campochiaro, S. Yee, K. Barrett, G. Noronha, R. Soll; Topical Administration of Tg100801, a Multi–Targeted Tyrosine Kinase Prodrug, Inhibits Choroidal Neovascularization in Mice . Invest. Ophthalmol. Vis. Sci. 2006;47(13):5184.
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Vascular leakage and angiogenesis are common underlying etiologies in the pathophysiology of choroidal neovascularization (CNV), PDR & DME. As such, agents that prevent vascular leakage and angiogenesis may have significant utility in the treatment of these diseases. Antagonists of vascular endothelial growth factor (VEGF) have shown benefit in patients with CNV or DME, but require repeated intraocular injections. Also, while VEGF is an important target for these diseases, it is not the only target. In this study, topical administration of a multi–targeted tyrosine kinase inhibitor was tested in a mouse model of CNV.
Enzymatic analysis of TG100572 or its prodrug, TG100801, was performed using recombinant human enzymes and standard methods. After rupture of Bruch’s membrane with laser photocoagulation, C57BL/6 mice were treated with eyedrops containing TG100801 three times a day for 14 days, and then the area of CNV at rupture sites was measured on choroidal flat mounts by image analysis.
TG100572 potently inhibited tyrosine kinases critical for ocular vasoproliferative diseases including VEGFR, PDGFR and Src. Topical administration to the cornea of a solution of 5 mg/ml of TG100801 three time a day for 14 days caused a 40% reduction in the area of CNV at rupture sites compared to that the untreated fellow eye or the eyes of control mice treated with vehicle (p<0.05 by linear mixed model).
These data suggest that topically administered TG100801 inhibits multiple kinases involved in the complex etiology of ocular diseases and has potential as a new, noninvasive suppressive therapy for CNV.
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