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P.F. Kador, K. Blessing, M. Wyman; The Results of Combretastatin in Galactose-Fed Dogs With Diabetes-Like Proliferative Retinopathy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):558.
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Purpose: Combretastatin A-4 (CA4P) is a vascular targeting agent that has been reported to be capable of destroying newly formed capillary endothelial cells in growing vessels. The net effect of this drug has been to rapidly shut off blood flow in newly growing vessels and, as a result, regress neovascularization. The purpose of this study was to determine whether retinal neovascularization which results in altered retinal vessel blood flow and retinal permeability in the long-term galactose-fed dog can be halted with CA4P. Methods: All experiments conform to the ARVO Resolution on the Use of Animals in Research and NIH ACUC Guidelines. Eight beagles fed 30% galactose diet for 80-104 months and four age-matched control dogs were surgically made aphakic. Following recovery the dogs were divided into two groups each containing 4 galactose-fed dogs and 2 age-matched controls dogs with each group receiving CA4P either as sub-Tenon’s injections administered at the corneoscleral junction or intravitreal injections. Six weeks after initial CA4P treatment all dogs also received systemic (IV) injections of CA4P. The extent of neovascularization and affect of CA4P administration were monitored by fluorescein angiography and color and monochromatic fundus photography at 2-week intervals. Results: Although CA4P was well tolerated by the healthy eyes of the control animals its administration to galactose-fed dogs was associated with corneal edema and increases in IOP after sub-Tenon’s and intraocular injections. All galactose-fed dogs demonstrated retinal neovascular lesions and these were not ameliorated by either sub-Tenon’s, intravitreal or systemic CA4P administration. Conclusions: Neovascularization in this animal model progresses over a period of years similar to that observed clinically. The failure of CA4P to ameliorate neovascularization suggests that chronic, long-term administration is required to destroy the slowly growing retinal endothelial cells.
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