Effects of Rho Kinase Inhibitors on Intraocular Pressure and Aqueous Humor Dynamics in Nonhuman Primates and Rabbits.
This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics.



IOPs of New Zealand albino rabbits with ocular normotension and cynomolgus macaques (nonhuman primate, NHP) with chronic unilateral laser-induced glaucoma were measured at baseline and periodically after a 9 a.m. dose of H-1152, Y-27632, or vehicle. In a separate group of NHPs, aqueous flow, outflow facility, uveoscleral outflow, and IOP were determined after treatment with Y-27632 or vehicle control.



Decreases in IOP were found in rabbits (n = 5) at 6 h after one dose of 2% Y-27632 (29%, P = 0.0002) or 1% H-1152 (35%, P = 0.0001), and in hypertensive eyes of NHPs (n = 7-9) at 3 h after one dose of 2% Y-27632 (35%, P = 0.005) or 1% H-1152 (51%, P = 0.0003). With 2 doses of 1% Y-27632 or vehicle in NHP hypertensive eyes (n = 12), significant drug effects were IOP reduction of 28% (P = 0.05) at 2.5 h after the second dose and increases in aqueous flow (36%; P = 0.013), uveoscleral outflow (59%, P = 0.008), and outflow facility (40%; P = 0.01). In normotensive eyes of the same animals, aqueous flow increased by 21% (P = 0.03). No significant change was found in any of the other parameters.



Y-27632 and H-1152 lower IOP in rabbits and hypertensive eyes of NHPs for at least 6 h after single doses. The Y-27632 effect on IOP in hypertensive NHP eyes is caused by increases in outflow facility and uveoscleral outflow. An increase in aqueous humor formation attenuates but does not prevent an IOP decrease.
1 Department of Ophthalmology and Visual Science, University of Nebraska Medical Center , Omaha, Nebraska.|2 Department of Ophthalmology and Visual Science, Case Western Reserve University , Cleveland, Ohio.
Carol B
CB
Toris
3 Alcon Laboratories , Fort Worth, Texas.
Marsha A
MA
McLaughlin
1 Department of Ophthalmology and Visual Science, University of Nebraska Medical Center , Omaha, Nebraska.
Douglas P
DP
Dworak
1 Department of Ophthalmology and Visual Science, University of Nebraska Medical Center , Omaha, Nebraska.
Shan
S
Fan
1 Department of Ophthalmology and Visual Science, University of Nebraska Medical Center , Omaha, Nebraska.
Shane
S
Havens
4 Xiamen Eye Centre, Xiamen University , Xiamne, China .
Gui-Lin
GL
Zhan
1 Department of Ophthalmology and Visual Science, University of Nebraska Medical Center , Omaha, Nebraska.
Nicholas
N
Horan
5 Department of Ophthalmology, Novartis Institutes for Biomedical Research (NIBR) , Cambridge, Massachusetts.
Ganesh
G
Prasanna
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001082:Aqueous Humor / Q000187:drug effects* / Q000378:metabolism; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D000577:Amides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases