Kador Peter F, Blessing Karen, Randazzo James, Makita Jun, Wyman Milton
Laboratory of Ocular Therapeutics, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
J Ocul Pharmacol Ther. 2007 Apr;23(2):132-42. doi: 10.1089/jop.2006.0103.
Combretastatin A-4 (CA-4) is a vascular targeting agent known to rapidly shut off blood flow in new vessels and, as a result, regress neovascularization. In this pilot study, the ability of CA-4 to modify retinal neovascularization, which results in altered retinal vessel blood flow and retinal permeability, was evaluated in aphakic long-term galactose-fed beagles, an animal model that develops diabetes-like retinal neovascularization.
Two (2) groups of aphakic dogs, each group comprised of 4 galactose-fed dogs and 2 age-matched controls dogs, were utilized. Each group initially received the combretastatin A-4-phosphate prodrug (CA-4P) as either sub-Tenon's injections, administered at the corneoscleral junction, or intravitreal injections. Six (6) weeks after this treatment, all dogs also received systemic (intravenous) injections of CA-4P. Retinal vascular changes were monitored at 2-week intervals by fluorescein angiography.
All galactose-fed dogs demonstrated the presence of retinal neovascular lesions by fluorescein angiograms. Fluorescein leakage or perfusion through neovascular vessels was not altered by either sub-Tenon's, intravitreal, or systemic CA-4P administration. Whereas CA-4P was well tolerated by the healthy eyes of the control animals, its administration to some galactose-fed dogs was associated with corneal edema and increases in intraocular pressure following sub-Tenon's and intraocular injections.
Neovascularization in the galactose-fed dog progresses over a period of years, similar to that observed with clinical diabetic retinopathy. The failure of CA-4P to ameliorate neovascularization suggests that chronic, long-term administration may be required to destroy the slowly growing retinal endothelial cells.
康普瑞他汀A - 4（CA - 4）是一种血管靶向药物，已知其能迅速阻断新血管中的血流，从而使新生血管退化。在这项初步研究中，在无晶状体长期喂食半乳糖的比格犬（一种会发生类似糖尿病性视网膜新生血管形成的动物模型）中评估了CA - 4改变视网膜新生血管形成的能力，这种新生血管形成会导致视网膜血管血流和视网膜通透性改变。
使用两组无晶状体犬，每组由4只喂食半乳糖的犬和2只年龄匹配的对照犬组成。每组最初接受磷酸康普瑞他汀A - 4前药（CA - 4P），给药方式为在角膜巩膜交界处进行球周注射或玻璃体内注射。在该治疗6周后，所有犬还接受了CA - 4P的全身（静脉）注射。通过荧光素血管造影术每隔2周监测视网膜血管变化。
所有喂食半乳糖的犬通过荧光素血管造影显示存在视网膜新生血管病变。球周、玻璃体内或全身给予CA - 4P均未改变荧光素通过新生血管的渗漏或灌注情况。虽然对照动物的健康眼睛对CA - 4P耐受性良好，但对一些喂食半乳糖的犬进行球周和眼内注射后，出现了角膜水肿和眼压升高的情况。
喂食半乳糖的犬的新生血管形成过程持续数年，与临床糖尿病视网膜病变中观察到的情况相似。CA - 4P未能改善新生血管形成表明可能需要长期慢性给药才能破坏缓慢生长的视网膜内皮细胞。
