MicroPulse™ transscleral cyclophotocoagulation in the treatment of canine glaucoma: Preliminary results (12 dogs).

OBJECTIVE: To describe the clinical application and effect of MicroPulse™ transscleral cyclophotocoagulation (MP-TSCPC) in dogs with glaucoma. ANIMALS STUDIED: Twelve dogs with primary (n = 8) or secondary (n = 4) glaucoma, aged 2-13 years (mean ± SD, 7.2 ± 3.8 years). PROCEDURES: MP-TSCPC was performed under sedation or general anesthesia. Laser duty cycle was 31.3%, laser power varied from 2000-2800 mW, and each hemisphere was treated for 90-180 seconds. The probe was applied to each quadrant in a "sweeping motion," sparing the 3 and 9 o'clock positions. RESULTS: The number of MP-TSCPC procedures per eye varied from 1 to 3 (1.4 ± 0.7). Intraocular pressure (IOP) was controlled (<25 mm Hg) in 11/12 dogs (92%) within 1-15 days post-operatively. The IOP control at 1 month and the duration between repeated procedures were significantly greater in eyes treated with high energy laser (2800 mW) compared to 2000-2500 mW. Long-term follow-up (315.3 ± 100.7 days) showed controlled IOP in 5/12 (42%) and vision retention in 4/8 (50%) dogs. In unsuccessful cases, loss of IOP control or vision loss occurred within 3-245 days (109.1 ± 93.7 days) and 28-261 days (114 ± 101.6 days), respectively, resulting in a salvage procedure in 6 dogs. Complications were as follows: corneal hypoesthesia (92%), anterior uveitis (67%), post-operative ocular hypertension (50%), neurotrophic corneal ulcer (25%), keratoconjunctivitis sicca (8%), and rubeosis iridis (8%). CONCLUSIONS: MP-TSCPC is a viable tool for managing canine glaucoma, although further studies are required to improve the long-term effect and reduce the complication rate.

Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

Comparison of topically administered 0.05% difluprednate and 1% prednisolone acetate for inhibition of aqueocentesis-induced breakdown of the blood-aqueous barrier in healthy dogs.

OBJECTIVE: To compare the efficacy of 0.05% difluprednate ophthalmic emulsion and 1% prednisolone acetate ophthalmic suspension for controlling aqueocentesis-induced breakdown of the blood-aqueous barrier in healthy dogs. ANIMALS: 34 healthy dogs. PROCEDURES: Dogs were allocated to 5 groups (6 to 8 dogs/group) to receive 0.05% difluprednate, 1% prednisolone acetate, or saline (0.9% NaCl) solution (control treatment) in both eyes 2 or 4 times daily. Eye drops were administered topically for 5 consecutive days. Anterior chamber paracentesis (aqueocentesis) was performed in 1 eye on the third day. Automated fluorophotometry was performed immediately before and 20 minutes and 24 and 48 hours after aqueocentesis. Relative fluorescence (RF), defined as fluorescence of the eye that had undergone aqueocentesis divided by fluorescence of the contralateral eye, was calculated to help control for variation among dogs. RESULTS: Mean RF was significantly lower at 24 hours after aqueocentesis in dogs treated twice daily with 0.05% difluprednate or 4 times daily with 1% prednisolone acetate than in dogs receiving the control treatment. At 48 hours after aqueocentesis, mean RF was significantly lower in dogs treated 4 times daily with 1% prednisolone acetate than in control dogs. Mean RF differed over time in dogs treated 4 times daily with 0.05% difluprednate but did not differ over time for any of the other treatments. CONCLUSIONS AND CLINICAL RELEVANCE: All 4 treatments were effective for reducing aqueocentesis-induced anterior uveitis in healthy dogs regardless of the drug or frequency of administration. Topical ophthalmic administration of 0.05% difluprednate may be a viable treatment option for dogs with anterior uveitis and warrants further study.

Fluorophotometric Assessment of Tear Volume and Turnover Rate in Healthy Dogs and Cats.

Purpose: The study establishes normative data of tear volume (TV) and tear turnover rate (TTR) in healthy dogs and cats, 2 species commonly used for translational research in ophthalmology. Methods: Thirty-six dogs and 24 cats were enrolled, encompassing a variety of breeds with diverse skull conformations (brachycephalic, mesocephalic, and dolichocephalic). Two microliters of 10% fluorescein were instilled onto the upper bulbar conjunctiva of both eyes, followed by tear collection with 2-µL capillary tubes at 0, 2, 4, 6, 10, 15, and 20 min. Fluorescein concentrations were measured with a computerized scanning ocular fluorophotometer. The TV and TTR were estimated based upon nonlinear mixed-effects analysis of fluorescein decay curves. Results: In dogs, median (interquartile range) TV, basal TTR (bTTR), and reflex TTR (rTTR) were 65.3 µL (42.3-87.9), 12.2%/min (3.7-22.1), and 50.0%/min (25.9-172.3), respectively. In cats, median (interquartile range) TV, bTTR, and rTTR were 32.1 µL (29.5-39.9), 10.9%/min (3.0-23.7), and 50.0%/min (28.4-89.4), respectively. Body weight (r = 0.44) and age (r = 0.30) were positively correlated (P ≤ 0.019) with TV in dogs. Age was negatively correlated (P ≤ 0.018) with TTR in dogs (r = -0.33) and cats (r = -0.24). However, TV and TTR were not associated with skull conformation in either species. Conclusions: Dogs have greater TV than cats but similar basal and rTTR. Tear parameters were impacted by body weight and age, but not by skull conformation. In both clinical and research settings, successive lacrimal tests should be spaced by ≥10 min to provide sufficient time for the tear film to replenish, as bTTR is ∼11%/min-12%/min in both species.

MG53 promotes corneal wound healing and mitigates fibrotic remodeling in rodents.

The cornea plays an important role in transmitting light and providing protection to the eye, but is susceptible to injury and infection. Standard treatments for corneal wounds include topical lubricants, antibiotics, bandage contact lens, and surgery. However, these measures are often ineffective. Here we show that MG53, a protein with an essential role in cell membrane repair, contributes to the corneal injury-repair process. Native MG53 is present in the corneal epithelia, tear film, and aqueous humor, suggesting its potential function in corneal homeostasis. Knockout of MG53 in mice causes impaired healing and regenerative capacity following injury. Exogenous recombinant human MG53 (rhMG53) protein protects the corneal epithelia against mechanical injury and enhances healing by promoting migration of corneal fibroblasts. Using in vivo alkaline-induced injury to the rat cornea, we show that rhMG53 promotes re-epithelialization and reduces post-injury fibrosis and vascularization. Finally, we show that rhMG53 modulates TGF-ß-mediated fibrotic remodeling associated with corneal injury. Overall, our data support the bi-functional role of MG53 in facilitating corneal healing and maintaining corneal transparency by reducing fibrosis and vascularization associated with corneal injuries.

Objective evaluation of the systemic effects of topical application of 1% atropine sulfate ophthalmic solution in healthy horses.

OBJECTIVE To determine the safety of topical administration of 1% atropine ophthalmic solution in healthy horses by objectively measuring gastrointestinal transit time. DESIGN Randomized, masked, controlled crossover study. ANIMALS 6 adult geldings. PROCEDURES Horses were randomly assigned (3/group) to first receive topical treatment of the left eye with 1% atropine or artificial tears solution; the right eye was left untreated. After 24 hours of treatment every 6 hours, 200 nontoxic beads were administered to each horse via nasogastric intubation and treatment frequency was decreased to every 12 hours for 4 more days. Pupillary light reflexes (PLRs), mydriasis, heart rate, fecal bead passage, abdominal girth measurements, auscultable gut sounds, fecal weight, and clinical signs of abdominal pain were monitored. Following a 4-week washout period, horses received the opposite treatment in the left eye and measurements were repeated. Serum atropine concentration (reflecting systemic absorption) was measured with an ELISA at various points after initial atropine administration. RESULTS No horse had subjective or objective evidence of colic or ileus at any monitoring point. Complete mydriasis of the left eye with absence of the PLR was identified in 5 horses within 6 hours and in all 6 horses within 12 hours after initial atropine administration. One horse had mydriasis with an absent PLR in the untreated eye by day 5 of atropine treatment. At no point was atropine detected in serum samples of any horse. CONCLUSIONS AND CLINICAL RELEVANCE Topical atropine application at clinically appropriate doses induced no evidence of ileus in healthy horses.