Takeshi Matsugi

Selective prostaglandin D2 receptor stimulation elicits ocular hypotensive effects in rabbits and cats

The effects of the selective prostaglandin D2 (DP) receptor agonists, 572C85 ((+/-)-5-(3-carboxypropylthio)-1-(2-cyclohexyl-2-hydroxyethyl- amino)hexahydrocyclopenta(d)imidazol-2(1H)-one) and 192C86 ((+/-)-5-(3-carboxypropylthio)-1-(2-cyclohexyl-2-hydroxyethylidene - amino)-3-ethylhexahydrocyclopenta(d)imidazol-2(1H)-one), were determined on intraocular pressure regulation in rabbits and cats. 572C85 (50 micrograms) in rabbits maximally lowered intraocular pressure by 4.3 mm Hg, and significantly for 4 h compared to control. In cats 572C85 had a similar effect. 192C86 (50 micrograms) reduced intraocular pressure by 2.8 mm Hg for 2 h in rabbits. Following exposure to the specific DP receptor antagonist, BW A868C ((+/-)-3-benzyl-5-(6-carboxyhexyl)-1-(2-cyclohexyl-2-hydroxyethylamin o)- hydantoin; 50 micrograms), which had no effect on intraocular pressure by itself, 572C85 (50 micrograms) did not reduce intraocular pressure in rabbits and cats. The intraocular pressure lowering effect of the mixed DP and EP receptor agonist, BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)-hydantoin; 50 micrograms), in cats was suppressed by only 64% by BW A868C (50 micrograms). These results clearly show that the DP receptors in rabbit and cat eyes are involved in intraocular pressure regulation. However, under baseline conditions DP receptor activity does not contribute to this regulation.

Effects of bunazosin hydrochloride on ciliary muscle constriction and matrix metalloproteinase activities.

Purpose:To clarify the mechanism by which bunazosin hydrochloride (BZ), a selective &agr;1-adrenoceptor antagonist, increases uveoscleral outflow. Methods:The effects of BZ on matrix metalloproteinase (MMP) activities in cultured monkey ciliary muscle cells, and on phenylephrine hydrochloride-induced constriction in bovine ciliary muscles, were examined. Also, the possible additive ocular hypotensive effects of BZ and latanoprost (LP) were evaluated in ocular normotensive monkeys. Results:Although BZ at 10−7 to 10−5 M did not increase MMP-2, -3, and -9 activities in the culture medium of ciliary muscle cells, BZ at 10−7 to 10−5 M inhibited phenylephrine hydrochloride-induced constriction in ciliary muscles. The maximal reduction in intraocular pressure of concomitant administration of BZ and LP was greater than that of BZ alone and tended to be greater than that of LP alone. Conclusion: These findings, in normotensive monkeys, indicate that the mechanism whereby BZ increases uveoscleral outflow is independent of an effect on MMPs and is partly due to relaxation of the ciliary muscle. This effect is different from that of LP, which might help to explain the finding that topical concomitant administration of BZ and LP increased AUC(0–6h) value (IOP reduction) to 201% and 145% of BZ and LP given alone, respectively.

Oxidative Stress in Retinal Diseases

1Department of Molecular and Cellular Pharmacology, Pharmacogenomics and Pharmacoinformatics, Mie University Graduate School of Medicine, Mie 514-8507, Japan 2Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan 3Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan 4Department of Ophthalmology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea 5Non-Clinical Research, Santen Pharmaceutical Co. Ltd., Osaka 530-8552, Japan

Pharmacologic Characterization of Omidenepag Isopropyl, a Novel Selective EP2 Receptor Agonist, as an Ocular Hypotensive Agent

Purpose The objective of this study was to investigate the pharmacologic characteristics of omidenepag isopropyl (OMDI), a compound developed as a novel intraocular pressure (IOP)-lowering agent, with better IOP control and fewer side effects than other prostanoid receptor agonists such as prostaglandin F receptor (FP) agonists. Methods Binding activities of OMDI and its hydrolyzed form, omidenepag (OMD), to human recombinant prostanoid receptors (DP1-2, EP1-4, FP, and IP) were evaluated. Based on these binding assays, the agonistic activities of OMDI and OMD were further evaluated using cultured cells expressing selected prostanoid receptors. The pharmacokinetics of OMDI after topical administration was assessed in rabbits by measurement of the concentrations of both OMDI and OMD in aqueous humor. The ocular hypotensive effect of OMDI was evaluated in ocular normotensive rabbits, dogs, and both ocular normotensive and hypertensive monkeys. Results OMD was determined to be a selective EP2 receptor agonist. OMDI weakly bound to EP1; however, the agonistic activity of OMDI to this receptor was not demonstrated in the functional assay. After topical administration of OMDI, OMD was detected in aqueous humor whereas OMDI was not detectable. OMDI significantly lowered IOP in both ocular normotensive and hypertensive animals. The significant ocular hypotensive effects of OMDI were demonstrated by both single and repeated dosing, and its effective duration suggests sufficient efficacy by once-daily dosing. Conclusions These studies demonstrated that OMDI is hydrolyzed in the eye to OMD, an EP2 receptor agonist, with a significant ocular hypotensive effect in both ocular normotensive and hypertensive animal models.

Effects of Ocular Hypotensive Agents on Circadian Rhythms of Intraocular Pressure in Rabbits as Measured by Telemetry System

PurposeTo establish a telemetry system for measuring intraocular pressure (IOP) in rabbits and to evaluate the effects of topical application of ocular hypotensive agents on the circadian rhythm of IOP.Subjects and MethodsWe developed a telemetry system in rabbits housed under a 12-hour light-dark cycle (light and dark phases: 7:00∼19:00, 19:00∼7:00, respectively). The IOP resulting from a single topical application of ocular hypo-tensive agents was measured by telemetry during the light phase and the dark phase.ResultsThe values measured by the telemetry system were positively correlated to the value of the anterior chamber pressure measured by a transducer in a range from 5 to 50 mmHg (r = 0.987). A single topical application of timolol maleate (0.5%), dorzolamide hydrochloride (1%), and dipivefrine hydrochloride (0.1%) caused no significant reduction in IOP in the light phase, but they did in the dark phase. A single topical application of bunazosin hydrochloride (0.01% or 0.1%) had significant ocular hypotensive effects in both phases.ConclusionThese findings indicate that the different effects of ocular hypotensive agents on circadian rhythms of IOP can be measured by a telemetry system. Telemetry may be useful for evaluation of ocular hypotensive agents and the circadian rhythm of IOP. Nippon Ganka Gakkai Zasshi (J Jpn Ophthalmol Soc 107:513–518, 2003)