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Kazufumi Nagai, Shinsaku Yamane, Kazumi Moriyuki, Tomohiro Karakawa, Shintaro Nakao, Tsutomu Shiroya, Yutaka Shichino; Comparative IOP lowering from single dose studies of latanoprost, timolol and ONO-9054 in Dogs and Monkeys. Invest. Ophthalmol. Vis. Sci. 2013;54(15):1986.
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ONO-9054 (Ono Pharmaceuticals, Osaka Japan) is a novel prodrug compound. ONO-9054 is an isopropyl ester derivative of the free acid ONO-AG-367 that has been classified as a dual FP/EP3 agonist that may be effective in lowering intraocular pressure in humans. The purpose of this study was to investigate the effect of ONO-9054 on IOP in normotensive dogs and monkeys following a single ocular administration compared with that produced by latanoprost (a prostaglandin FP receptor agonist), timolol (a beta-adrenergic receptor antagonist) and a fixed combination of latanoprost / timolol.
IOP lowering effects of ONO-9054 (1, 3 and 10 µg/mL), latanoprost (50 µg/mL), timolol (5000 µg/mL) and a fixed latanoprost / timolol combination were examined in male beagle dogs. IOP was measured before and at 2, 4, 6, 8, and 24 hours after administration with an applanation pneumatonometer. In a second study the IOP lowering effect of ONO-9054 (0.1, 0.3, 1, 3, 10, 30 µg/mL) and latanoprost (50 µg/mL) were examined in male cynomolgus monkeys. The IOPs were measured before and at 4, 8, 12, 24, 48, 72 and 96 hours after administration. Compounds were administered topically in a 30 µL volume once into the right eye.
In dogs, ONO-9054 lowered IOP in a dose-dependent manner, and the reduction of IOP persisted for at least 24 hours after administration. ONO-9054 at 3 µg/mL or more showed a more potent and longer-lasting reduction of IOP than latanoprost, ONO-9054 at 10 µg/mL showed more potent and longer-lasting reduction of IOP than the fixed latanoprost / timolol combination. In monkeys, ONO-9054 lowered IOP in a dose-dependent manner, and the reduction of IOP at 3 and 10 µg/mL was observed for up to 48 hours after administration and IOP at 30 µg/mL persisted for up to 72 hours after administration. The IOP reduction of ONO-9054 at 1 µg/mL was comparable to that of latanoprost and showed more potent and longer-lasting IOP-reducing effects at concentrations of 3 µg/mL or more.
The IOP-lowering effects of the FP/EP3 agonist ONO-9054 were more potent and longer-lasting than those produced by an FP receptor agonist, a beta-adrenergic receptor antagonist and a fixed combination FP agonist/beta-adrenergic antagonist. These results suggest that ONO-9054 should be considered further in clinical trials in patients with elevated intraocular pressure due to glaucoma.
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