The future of canine glaucoma therapy.

Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO-VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP-lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.

Effects of propofol on intraocular pressure in premedicated and nonpremedicated dogs with and without glaucoma.

OBJECTIVE To establish a study cutoff for evidence of glaucoma on the basis of IOP measurements from a large population of healthy dogs and to assess the effects of IV propofol administration on IOPs in premedicated and nonpremedicated dogs with and without glaucoma defined by this method. DESIGN Prospective, descriptive study. ANIMALS 234 client-owned dogs. PROCEDURES IOPs measured in 113 healthy dogs (226 eyes) were used to calculate an IOP value indicative of glaucoma. The IOPs were measured in an additional 121 dogs (237 eyes) undergoing ophthalmic surgery. Midazolam-butorphanol was administered IV as preanesthetic medication to 15 and 87 dogs with and without glaucoma, respectively. A placebo (lactated Ringer solution) was administered IV to 8 and 11 dogs with and without glaucoma, respectively. Anesthesia of surgical patients was induced with propofol IV to effect. The IOPs and physiologic variables of interest were recorded before (baseline) and after preanesthetic medication or placebo administration and after propofol administration. RESULTS An IOP > 25 mm Hg was deemed indicative of glaucoma. Compared with baseline measurements, mean IOP was increased after propofol administration in nonpremedicated dogs without glaucoma and unchanged in nonpremedicated dogs with glaucoma. Propofol-associated increases in IOP were blunted in premedicated dogs without glaucoma; IOP in affected eyes of premedicated dogs with glaucoma was decreased after preanesthetic medication and after propofol administration. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that preexisting IOP influences the response to anesthetic drugs, and administration of preanesthetic medication with muscle-relaxing properties may blunt or reduce propofol-induced increases in IOP. Further research with a larger number of dogs is needed to confirm our results in dogs with glaucoma.

Topical KINOSTAT™ ameliorates the clinical development and progression of cataracts in dogs with diabetes mellitus.

OBJECTIVE: To determine whether topical administration of the aldose reductase inhibitor Kinostat™ can ameliorate the onset or progression of cataracts in dogs with naturally occurring diabetes mellitus (DM). MATERIALS AND METHODS: A randomized, prospective, double-masked placebo control pilot study was conducted with 40 dogs newly diagnosed with DM with no or minimal lens changes. Twenty-eight dogs received Kinostat™ and 12 dogs received placebo. PROCEDURES: Owners administered the agent into both eyes three times daily for 1 year and compliance was monitored with log sheets. Complete ophthalmic examinations were performed on dilated eyes at the time of enrollment and 1, 2, 3, 6, and 12 months into treatment. Cataract severity was assessed on a scale of 0-3. At 12 months, full bloodwork, including HbA1C and blood Kinostat™ levels were performed. RESULTS: After 12 months of treatment, the cataract score in the placebo group significantly increased with seven dogs (14 eyes) developing mature cataracts, two dogs (4 eyes) developing cortical opacities, and one dog (2 eyes) developing equatorial vacuoles with mild punctate cortical opacities. In contrast, the cataract score in the Kinostat™ treated dogs was significantly less with seven developing anterior equatorial vacuoles, two developing incipient anterior cortical cataracts, and four developing mature cataracts. In fact, the cataract scores of the Kinostat™ group at 12 months did not significantly increase from the score at the time of enrollment. The HbA1C values between the two groups after 12 months of treatment were similar, and no blood levels of Kinostat™ were found in any enrolled dog. CONCLUSION: The onset and/or progression of cataracts in dogs with DM can be significantly delayed by topical administration of Kinostat™.

The effect of phosphorylated Akt inhibition on posterior capsule opacification in an ex vivo canine model.

PURPOSE: To evaluate whether inhibition of phosphorylated Akt (pAkt) would reduce or prevent posterior capsule opacification (PCO) in an ex vivo canine lens capsule model. METHODS: Normal and cataractous lenses (n=6) were evaluated for pAkt via immunohistochemistry and immunoblotting. Primary cultures of lens epithelial cells (LEC) were exposed to ultraviolet light (UV) to induce pAkt. Cultures were then incubated in 0, 2.5, 5, or 10 µM (n=6) of a novel Akt inhibitor (AR-12) for either 8 or 24 h. Cultures were harvested and pAkt expression and telomerase activity examined by immunoblotting and telomeric repeat amplification protocol (TRAP)-enzyme linked immunosorbent assay (ELISA), respectively. Lens capsules were harvested post-sham cataract surgery and exposed to 0, 2.5, 5, 7.5, or 10 µM (n=8) of AR-12 for a total of 14 days treatment. Additional lens capsules (n=6) were exposed to 10 µM of AR-12 for 1 week followed by media alone for 1 week; or exposed to media alone for 1 week followed by 10 µM of AR-12 for 1 week. Histopathology and immunohistochemical staining were performed to evaluate PCO formation. Analysis of telomerase activity on the lens capsules was performed by TRAP-ELISA. RESULTS: pAkt protein expression was increased in clinical samples of canine cataracts compared to normal lenses. Following exposure to UV, cultures of LEC significantly (p<0.05) increased expression of pAkt and telomerase activity. Treatment with AR-12 for both 8 and 24 h following UV irradiation significantly (p<0.01) decreased pAkt expression. When UV-exposed LEC were allowed to recover in the presence of either 5.0 or 10.0 µM AR-12, there was a significant (p<0.05) decrease in telomerase activity. In the ex vivo model of PCO, within the region of the capsulorhexis, PCO inhibition was maximally achieved with 10 µM of AR-12. A significant decrease in LEC was noted on the posterior capsules containing 5.0, 7.5, and 10 µM AR-12 compared to the control capsules (p<0.01). Telomerase activity decreased in a dose-dependent manner. One week of treatment with 10 µM AR-12, immediately following capsule excision, was sufficient to inhibit PCO formation, while a delay in exposure to AR-12 after 1 week of media incubation alone did not prevent PCO formation. CONCLUSIONS: pAkt is known to have roles in cell survival, proliferation, and migration, and this study suggests its inhibition immediately following cataract surgery may be a useful approach to prevent PCO.