Subconjunctivally implanted micro-osmotic pumps for continuous ocular treatment in horses.

OBJECTIVE: To evaluate the feasibility of using a subconjunctivally implanted micro-osmotic pump for continuous delivery of medication to the eyes of horses- during a 7-day period. ANIMALS: 4 healthy adult horses. PROCEDURE: With horses restrained in a standing position, micro-osmotic pumps were implanted subconjunctivally in each eye for 7 days. The treatment eye received an atropine-loaded micro-osmotic pump (100 microl of 1.5% atropine), and the contralateral eye received a sterile saline-loaded pump (100 microl of 0.9% NaCl) as a control treatment. Pupil size was measured at 12-hour intervals until values returned to baseline. RESULTS: The micro-osmotic pumps were tolerated and did not migrate or become dislodged. During the 7-day treatment period, pupils were significantly larger in the eyes implanted with atropine-loaded pumps, compared with saline-implanted control eyes. CONCLUSIONS AND CLINICAL RELEVANCE: Micro-osmotic pumps were implanted and removed easily from standing horses and were not associated with complications during the 7-day treatment period. Therefore, subconjunctivally implanted micro-osmotic pumps can potentially be used when treating ophthalmic disease in horses.

Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKCbeta inhibition with LY333531.

OBJECTIVE: The authors tested the antiangiogenic properties of an orally administered protein kinase-Cbeta inhibitor, LY333531, in a pig model of preretinal neovascularization caused by retinal branch vein occlusion to determine the effectiveness of this therapy in preventing intraocular neovascularization from an ischemic stimulus. METHODS: In 20 eyes of 10 pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from an argon laser with green light. Five animals received 1 mg/kg LY333531 daily in two oral doses, and five animals were untreated. The eyes were followed clinically for 12 weeks with ophthalmoscopy, fundus photography, and fluorescein angiography. A standardized grading system permitted masked assessment of disc proliferations using stereo fundus photographs. After the pigs were killed, all neovascularization was confirmed histopathologically in a masked fashion and a final grade was assigned to each eye. The Mann-Whitney test was used for statistical analysis of the median values of the unpaired data between the two eyes of each animal (data were rounded up). RESULTS: Significant inhibition of neovascularization was observed in eyes from animals treated with the study drug (P = 0.03). Although some of the treated eyes demonstrated no clinically evident new vessels, histopathologic and photographic analysis demonstrated fine new vessels on the optic disc in all eyes (mean grade 1.9). All the untreated eyes developed clinically evident neovascularization (mean grade 3.1). The oral drug was well tolerated, and no side effects were documented. CONCLUSIONS: A specific protein kinase-Cbeta inhibitor, LY333531, effectively inhibited preretinal and optic nerve head neovascularization in the pig model of branch retinal vein occlusion. This was consistent with the known pathways of signal transduction by growth factors in activated cells and suggested that inhibition of this key regulatory isozyme is effective in the treatment of ischemia-mediated neovascular diseases.

Insulin-like growth factor-1 retinal microangiopathy in the pig eye.

OBJECTIVE: Human recombinant insulin-like growth factor-1 (hrIGF-1), a ubiquitous angiogenic growth factor, was injected into the vitreous cavity of pigs to investigate the clinical and histopathologic consequences of supraphysiologic levels of this angiogenic growth factor on the retinal vasculature. DESIGN: Young male pigs were injected with 600 microg hrIGF-1 into the vitreous cavity and were observed with serial examinations by ophthalmoscopy, fundus photography, and fluorescein angiography for varying periods up to 6 months. In a separate set of experiments, a dose-response relation was explored in animals injected with varying doses of IGF-1. MAIN OUTCOME MEASURES: Histopathologic analysis included light and transmission electron microscopy and modified elastase digestion. Quantitative morphometric measurements were made of capillary basement membrane thickness and endothelial cell and pericyte densities of the retinal capillaries. RESULTS: Early clinical features of IGF-1-injected eyes included marked arteriolar tortuosity, vitreitis, and retinal vessel and optic nerve head vascular fluorescein leakage. By 4 weeks, hyperfluorescent dots consistent with microaneurysms appeared and increased in number until 8 weeks postinjection. Clinical findings did not change appreciably after 8 weeks. Elastase digestion showed microaneurysms of the retinal capillaries and no ischemia or pericyte ghosts. Quantitative analysis of the digested specimens showed increased endothelial density by 1 month after injection (P < 0.05). Transmission electron microscopic cross-sections of capillaries showed significant basement membrane thickening by 3 months (P < 0.05). Lower doses of IGF-1 showed fewer clinical and histopathologic changes, and no significant changes were noted with a single 6 microg injection. Suspending hrIGF-1 in acidic buffer produced less intraocular inflammation than use of bovine serum albumin at neutral pH. CONCLUSIONS: A single intravitreous injection of a large dose of hrIGF-1 produces a retinal microangiopathy that has a prolonged time of onset and remains stable from 2 to 6 months after injection. Some aspects of this angiopathy resemble diabetic retinopathy, suggesting growth factor effects in the morphologic vascular changes of diabetes.

Inhibition of preretinal and optic nerve head neovascularization in pigs by intravitreal triamcinolone acetonide.

PURPOSE: The authors tested the antiangiogenic properties of intravitreally administered triamcionolone acetonide in a pig model of preretinal neovascularization to determine the effectiveness of this therapy in preventing neovascularization. METHODS: In 14 eyes of seven pigs, branch retinal vein occlusions were created in a standardized manner using photodynamic thrombosis with rose bengal dye and thermal burns from the argon green laser. Intravitreal injection of approximately 4 mg of triamcinolone acetonide was performed in one eye of each animal, and eyes were followed clinically for 12 weeks with ophthalmoscopy and fundus photography. A standardized grading system was developed to permit masked assessment of disc proliferations from fundus stereophotographs. After death, all neovascularization was confirmed histopathologically and a final grade was assigned to each eye. Statistical analysis employed use of a nonparametric test of the paired data. RESULTS: Significant inhibition of neovascularization was observed in triamcinolone-treated eyes (P = 0.0156). Although none of the steroid-injected eyes demonstrated clinically evident new vessels, histopathologic and photographic analysis results demonstrated fine new vessels on the optic disc in four eyes. In all of the untreated eyes, neovascularization of a moderate (II) to high (III to IV) grade developed. CONCLUSIONS: Intravitreal triamcinolone acetonide effectively inhibited preretinal and optic nerve head neovascularization in the pig model. The grading system used permitted masked assessment of outcome and paired analysis allowed a conclusion to be drawn from a relatively small number of eyes. The mechanisms by which triamcinolone acetonide inhibits neovascularization remain to be elucidated.