K. Keven Williams

Pupillary Response to Tropicamide in Patients with Alzheimer Disease

PURPOSE To determine whether pupillary responses to dilute tropicamide could be used as a diagnostic test for Alzheimer disease (AD). The authors also investigated whether concurrent use of an oral acetylcholinesterase inhibitor (tacrine) alters the pupillary response to dilute tropicamide in patients with AD, and whether pupillary responses to dilute tropicamide differ in young versus older control subjects. METHODS Pupillary diameter and area of both eyes were measured in light and darkness, at 10-minute intervals for 40 minutes after random instillation of 0.01% tropicamide to one eye. Four groups of subjects were studied: 9 patients with AD, 10 who were treated with tacrine, 11 older control subjects, and 10 young control subjects. RESULTS Mean change in anisocoria was not significantly different among groups at any of the measurement time points. Mean percent change in diameter of the treated eyes showed a trend toward faster maximum dilatation in the AD groups, but change in pupillary measurements did not identify individuals with AD. CONCLUSION Pupillary response to dilute tropicamide did not effectively distinguish individual patients with AD from young or older control subjects.

Evaluation of Effects of a Physiologic Artificial Tear on the Corneal Epithelial Barrier: Electrical Resistance and Carboxyfluorescein Permeability

Artificial tear solutions are widely used for relief of ocular surface irritation by patients with dry eye syndromes and by persons with ocular discomfort due to climatic conditions, air pollutants and various other causes. Although about 200,000 persons in the United States are classified as having a severe dry eye, nearly 5 million people report using dry eye protectants, resulting in the purchase of over 10 million units of ethical over-the-counter artificial tears worth nearly

The effects of moxifloxacin ophthalmic solution 0.5% or gatifloxacin ophthalmic solution 0.3% treatment on corneal wound healing in pigmented rabbits following anterior keratectomy

80 million dollars per year1. This has resulted in a highly competitive market for these products with at least 25 different solutions currently on the market in the United States2 and new ones appearing frequently.

Corneal diffusion and metabolism of 12 (R) -hydroxyeicosatetraenoic acid (12(R)HETE)

PURPOSE These studies examined corneal healing rates, Type-IV collagen and zonula occludens membrane-associated protein (ZO-1) expression, as well as aqueous PGE(2) and IL-1 beta concentrations in pigmented rabbits treated with either moxifloxacin 0.5%, gatifloxacin 0.3% or BSS following anterior keratectomy. METHODS Anterior keratectomy surgery was followed by topical administration with commercial ophthalmic formulations of either moxifloxacin or gatifloxacin or BSS (TID for 96 h). Images of the fluorescein-stained healing corneas were analyzed for wound area. At 48 or 96 h following surgery, aqueous humor samples were collected and analyzed for the inflammatory mediators PGE(2) and IL-1 beta using an ELISA. The corneas were subsequently evaluated using both scanning and transmission electron microscopy. In a second parallel study, corneas were evaluated at both 48 and 96 h for Type-IV collagen and ZO-1 expression using immunohistochemistry. RESULTS Fluorescein-stained corneal images at 96 h postsurgery demonstrated that 90% +/- 8% re-epithelialization for moxifloxacin, 81% +/- 14% for gatifloxacin, and 88 +/- 6% for BSS((R)) (P > 0.05). PGE(2 )levels in the aqueous humor of fluoroquinolone treated eyes were reduced at 48 h compared to BSS treated eyes. IL-1 beta was undetectable in all samples. No differences in Type-IV collagen or ZO-1 expression were observed between any treatment groups. There were no differences between groups in histological appearance or in ultrastructural healing processes. CONCLUSIONS These studies demonstrated that the commercial ophthalmic formulations of moxifloxacin and gatifloxacin were similar to each other in their effects on the levels of aqueous humor PGE(2) and rates of corneal wound re-epithelialization.

Comparison of wound healing in pigmented rabbits receiving moxifloxacin or gatifloxacin after creation of corneal flap or penetrating corneal incision

PURPOSE To quantify the corneal diffusion and metabolism of tritiated 12(R)-hydroxyeicosatetraenoic acid (12(R)HETE) in the in vitro-mounted rabbit cornea to determine if this compound or one of its metabolites can diffuse across the stroma to the corneal endothelium. METHODS The studies were performed in a Lucite block perfusion chamber by placing tritiated 12(R)HETE on the tear side of the cornea under the following conditions: (A) cornea completely intact (endothelium and epithelium present); (B) cornea with epithelium removed; and (C) cornea with both epithelium and endothelium removed. Radioactivity of 12(R)HETE and metabolites were measured in the different corneal layers and in the corneal perfusates using scintillation spectroscopy. 12(R)-hydroxyeicosatetraenoic and its metabolites were then quantified in the tissue perfusates using high performance liquid chromatography (HPLC) analysis. RESULTS 12(R)HETE is rapidly taken up and metabolized by the intact cornea to a number of more polar compounds including a metabolite which has spectral and retention time characteristics of 8(R)-hydroxyhexadecatrienoic acid (8(R)HHDTrE). Both 12(R)HETE and 8(R)HHDTrE can diffuse through the stroma to the endothelium. Corneas having the epithelium removed also allow diffusion of 12(R)HETE across the stroma; however, there is significantly less metabolism. When both the epithelium and endothelium are removed, 12(R)HETE is capable of diffusing across the stroma; however, there is little metabolism, which suggests that the majority of 12(R)HETE metabolism occurs in the epithelium and, to a lesser degree, in the endothelium and stroma. CONCLUSIONS 12(R)HETE and its metabolites are capable of diffusing from the epithelium through the cornea where they may adversely affect the endothelium.

Comparison of the effect of moxifloxacin and gatifloxacin on corneal epithelial wound healing in the rabbit model

Purpose: Corneal wound healing was compared with topical ocular applications of moxifloxacin ophthalmic solution 0.5%, gatifloxacin ophthalmic solution 0.3%, or BSS Sterile Irrigating Solution after a 6-mm penetrating corneal incision during a 1-week observation period or after creation of a corneal flap during a 3-week observation period. Methods: Fifteen pigmented rabbits were randomized into 3 test groups of 5 rabbits per group (group 1, moxifloxacin 0.5%; group 2, gatifloxacin 0.3%; group 3, BSS Sterile Irrigating Solution). All animals underwent surgery using a microkeratome to create a corneal flap approximately 8.5 mm in diameter and 160 μm deep in the right eye (OD). The animals were dosed 4 times a day with the appropriate test article for 7 days after surgery. Biomicroscopic examinations and postmortem histopathology were conducted to compare the different treatments. In a second study, 9 pigmented rabbits were divided into 3 test groups of 3 rabbits per group. Each animal underwent bilateral surgery to create a 6-mm linear, penetrating incision into the central cornea, using a diamond keratome. The wound was subsequently sutured, and the animals were treated bilaterally (topical ocular) for 7 days with moxifloxacin (3 times a day), gatifloxacin (4 times a day), or BSS Sterile Irrigating Solution (4 times a day). On day 7, the left eye (OS) of each animal was processed and analyzed using standard hematoxylin-eosin histopathology, whereas the right eye of each animal underwent processing and analysis using scanning and transmission electron microscopy. Corneas were examined to evaluate wound healing progress, including the epithelial plug, cellular infiltrates, and stromal precipitates. Results: For both the corneal flap and linear incision studies, no appreciable differences were noted between groups with regard to slit-lamp or histopathologic examinations. In the linear incision study, electron microscopy revealed normal remodeling processes in all treatment groups, with no evidence of abnormal electron densities of the basal epithelial cells, basement membrane, anchoring filaments, collagen fibrils, extracellular matrix, or stromal keratocytes. Conclusions: Results showed that moxifloxacin and gatifloxacin were not significantly different from BSS in their effects on corneal wound healing and corneal haze after creation of both superficial and penetrating corneal wounds.

The Effects of 12(R)Hete and Its Metabolite 8(R)HHDTre on Corneal Endothelial Function

Purpose: Corneal epithelial wound closure rates in rabbit eyes were compared after topical applications of moxifloxacin 0.5% ophthalmic solution, gatifloxacin 0.3% ophthalmic solution, and BSS Sterile Irrigating Solution. Methods: Thirty rabbits were divided into 3 randomization groups of 10 rabbits each. Animals in each randomization group were predosed 4 times a day with a different test article in each eye for 1 day before surgery. Group 1 animals received BSS in 1 eye and moxifloxacin in the other eye; group 2 animals received BSS in 1 eye and gatifloxacin in the other eye; and group 3 animals received moxifloxacin in 1 eye and gatifloxacin in the other eye, resulting in each test articles being administered to 20 eyes. Rabbits underwent a bilateral procedure to remove the full thickness of the central corneal epithelium within a 5-mm trephine mark. After wounding, the eyes were dosed 4 times a day with the same respective predose test articles, and epithelial wound closure was recorded using slit-lamp photography. The data were analyzed to determine the rate of wound closure. Results: The mean wound radius closure rate was 71.1 ± 11.7 μm/h for BSS-treated eyes, 67.6 ± 7.1 μm/h for moxifloxacin-treated eyes, and 65.9 ± 8.0 μm/h for gatifloxacin-treated eyes. Conclusions: The relative order of wound healing rates was BSS > moxifloxacin > gatifloxacin; however, differences between treatment groups were not considered significant.

Correlation of Histologic Corneal Endothelial Cell Counts With Specular Microscopic Cell Density

The purpose of this presentation is twofold: (1) to summarize our studies as to the direct effect of 12(R)HETE, 8(R)HHDTrE on the corneal endothelium, and (2) to illustrate the diffusion and metabolism of 12(R)HETE by the cornea. Our data has shown that 12(R)HETE causes corneal swelling in a dose-dependent manner when perfused directly to the corneal endothelium. As reported by Schwartzman et al, 12(R)HETE is one of the major cytochrome P450-dependent arachidonate metabolites of the corneal epithelium and is an endogenous inhibitor of Na+/K+ATPase. Contact lens-induced hypoxic stress has also been shown to stimulate the endogenous formation of 12(R)HETE by the corneal epithelium. This increased formation of 12(R)HETE was found to correlate to increased corneal thickness and to changes in the corneal endothelial structure.These results suggest that 12(R)HETE produced by the corneal epithelium might be capable of diffusing across the cornea and affecting endothelial function.