William C. Hubbard

Acute effects of H-7 on ciliary epithelium and corneal endothelium in monkey eyes.

Purpose. Topical or intracameral administration of H-7 doubles outflow facility and reduces intraocular pressure in cynomolgus monkeys, by relaxing and expanding the trabecular meshwork (TM) and Schlemm’s canal (SC). Since H-7 may have anti-glaucoma potential, we determined its effects on the corneal endothelium and ciliary epithelium for safety considerations. Methods. Following topical H-7, aqueous humor flow (AHF), corneal endothelial transfer coefficient (k a) and anterior chamber (AC) entry of i.v. fluorescein were measured by fluorophotometry; AC aqueous protein concentration ([Protein] AC) was determined by Lowry assay; and corneal thickness and endothelial cell density and morphology were measured by ultrasonic pachymetry and specular microscopy respectively. Following intracameral H-7, specular and/or light and electron microscopy of the corneal endothelium or ciliary epithelium were performed. Results. Following unilateral topical H-7: (1) AHF and k a were essentially unchanged at 0.5–3.0, 3.5–6.0, and 0.5–6.0 hr, with an insignificant increase from 0.5–1.5 hr; (2) [Protein] AC was insignificantly increased at 1–1.5 hr but had returned to baseline by 2.5 hr; (3) entry of i.v. fluorescein into aqueous or cornea was modestly and transiently increased; (4) the central cornea thickened significantly at 1–2.5 hr, gradually returning to baseline 2.5 hr after H-7, while peripheral corneal thickness was less affected; (5) corneal endothelial cell borders became indistinct by 1 hr, but cell morphology was recovering by 3–5 hr and had completely returned to normal by 24 hr; (6) corneal endothelial cell density was unchanged at 5–24 hr. Following intracameral H-7, no significant changes were observed in corneal endothelial cell density or morphology by specular microscopy, nor in corneal endothelial or ciliary epithelial morphology by light and electron microscopy. Conclusions. A facility-effective intracameral dose of H-7 had no discernible structural effect on the corneal endothelium or ciliary epithelium. It is not yet clear whether carefully chosen topical doses of H-7 or analogues can enhance outflow facility without meaningfully affecting the cornea and ciliary processes.

Obstruction of Aqueous Humor Outflow by Cross-linked Polyacrylamide Microgels in Bovine, Monkey, and Human Eyes

PURPOSE Orcolon, a synthetic viscoelastic, may have contributed to refractory intraocular pressure (IOP) elevation after intracameral injection in some patients. Cross-linked polyacrylamide (microgels), an altered form of the polymer, was investigated as an etiologic candidate. METHODS Four adult rhesus monkeys underwent anterior chamber exchange with mock aqueous humor containing microgels in one eye and a vehicle in the other. Outflow facility (perfusion) and IOP (applanation) were determined before and at various times thereafter. Facility also was determined before and after microgel or vehicle infusion into organ-cultured individual human (n = 9) and paired calf (n = 6) anterior segments. Representative monkey and human eyes were examined by light and electron microscopy. RESULTS In the microgel-infused monkey eyes, IOP was consistently higher, by approximately 5 mmHg for approximately 1 month. In all three species, microgel infusion acutely decreased facility by approximately 50% to 80%. In the living monkeys where longer-term observation and retesting were possible, a facility reduction of approximately 40% to 50% persisted for at least 1 to 2 months, and rechallenge again produced an acute 80% facility decrease and subsequent 10-mmHg IOP rise. Results of electron microscopic examination in human and monkey eyes showed accumulation of microgels in the cribriform meshwork and beneath the inner wall of Schlemms canal, with no cellular alterations or inflammatory infiltrate. CONCLUSIONS Cross-linked polyacrylamide microgels can produce an acute and longstanding obstruction of trabecular drainage experimentally, and might therefore do so clinically.

The DP-Receptor Agonist SQ27986 Raises but Does Not Lower Intraocular Pressure in Ocular Normotensive Monkeys

rostaglandin (PG) D2 and the DP-receptor selective analog BW245C have been shown to lower intraocular pressure (IOP) in rabbits, monkeys, and man. In these experiments, the effects of the DP-receptor selective agonist SQ27986 on IOP, pupil diameter, and refractive error in ocular normotensive cynomolgus monkeys were tested. Single or repeated (three days of twice-daily) unilateral doses of SQ27986 produced a 2–6 mm Hg rise in IOP 15–120 min after administration, which was not followed by ocular hypotension. The SQ27986 had no effect on pupil diameter, refraction, or anterior segment biomicroscopic appearance. Although other DP-receptor agonists can lower IOP slightly in normotensive eyes and more substantially in hypertensive eyes by decreasing aqueous formation, the inability of SQ27986 to reduce IOP in our ocular normotensive monkeys suggests that DP-receptor stimulation does not increase uveoscleral outflow or play a major role in IOP reduction by other relatively nonselective prostaglandins such as PGF2α.