Effects of a Prostaglandin DP Receptor Agonist, AL-6598, on Aqueous Humor Dynamics in a Nonhuman Primate Model of Glaucoma

Abstract

This study examines, in 11 cynomolgus monkeys with unilateral laser-induced glaucoma, the ocular hypotensive mechanism of action of AL-6598, partial agonist at the DP and EP prostanoid receptors. In a crossover fashion, both eyes of each monkey were dosed twice daily with 25 microL of either AL-6598 0.01% or vehicle for 2 days and on the morning of the 3rd day. Measurements were made on day 3 of each treatment. Alternative treatments were separated by at least 2 weeks. Intraocular pressures (IOPs) were measured by pneumatonometry and aqueous flow and outflow facility by fluorophotometry. Uveoscleral outflow was calculated mathematically. In the normotensive eyes, compared to vehicle treatment, AL-6598 decreased IOP from 22.5 +/- 0.7 to 18.7 +/- 0.9 mmHg (P = 0.006), increased uveoscleral outflow from 0.47 +/- 0.17 to 1.22 +/- 0.17 microL/min (P = 0.03), and increased aqueous flow from 1.49 +/- 0.10 to 1.93 +/- 0.13 microL/min (P = 0.01). No measurement in AL-6598-treated hypertensive eyes was significantly different from vehicle treatment. It is concluded that AL-6598 reduces IOP by increasing uveoscleral outflow in normotensive eyes of ketamine-sedated monkeys, despite an increase in aqueous flow. This effect is different from that of PGD(2), which decreases aqueous flow, and of the selective DP receptor agonist, BW245C, which increases both outflow facility and uveoscleral outflow in addition to decreasing aqueous flow.

Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction

“…Trabecular outflow facility was unchanged following multiple topical treatments of monkeys with PGF 2α -isopropyl ester, 22 tafluprost, 62 and travoprost, 71 the DP receptor agonist AL-6598, 72 and EP receptor agonists butaprost 44 and 8-iso PGE 2 23 (Table 1). Exceptions do exist.…”

“…Multiple topical drops of agonists for FP receptors (tafluprost 62), DP receptors (AL-6598 72), and EP 2 receptors (butaprost 44 and 8-iso PGE 2 78) increased uveoscleral outflow in monkeys (Table 1). In contrast, one drop of the EP 4 agonist, 3,7-dithia PGE 1 , had no effect on uveoscleral outflow in monkeys 88.…”

“…11 Additionally aqueous flow increased during the day in monkeys treated with a DP agonist. 72 This effect does not contribute to any reduction in IOP but an increase in aqueous flow could be considered a healthy side-effect of topical PG analogs because aqueous humor carries essential nutrients and removes waste products, crucial for keeping the avascular tissues of the anterior segment healthy.…”

Prostanoid EP4Receptor Stimulation Produces Ocular Hypotension by a Mechanism That Does Not Appear to Involve Uveoscleral Outflow

“…To date, selective agonists for DP, EP 2 , and FP receptors all have been shown to reduce intraocular pressure (IOP) in nonhuman primates. [1][2][3][4][5][6][7] Of interest, the underlying mechanisms involved in ocular hypotension produced by DP, EP 2 , and FP receptor stimulation in nonhuman primates appear to exclusively involve increased uveoscleral outflow. 6 -11 This finding may be regarded as unexpected, as these receptors are not only discrete entities but do not couple with the same signal-transduction mechanisms.…”

Prolonged transgene expression with lentiviral vectors in the aqueous humor outflow pathway of non-human primates

“…The efficacy of glaucoma therapeutics has historically been well predicted using these two normotensive animal models, which provide good simulations of human ocular outflow anatomy and physiology (Zhan et al, 1992;Sagara et al, 1999;Wang et al, 1999Wang et al, , 2007Stjernschantz, 2001;Gabelt et al, 2003;Rasmussen and Kaufman, 2005;Toris et al, 2006). Although challenges remain, especially the identification of a therapeutic transgene(s), the potential clinical benefits of gene therapy for glaucoma are appealing.…”