Effects of rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits

Carol B Toris, Marsha A. McLaughlin, Douglas P. Dworak, Shan Fan, Shane J Havens, Gui Lin Zhan, Nicholas Horan, Ganesh Prasanna

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose: This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)355-364
Number of pages10
JournalJournal of Ocular Pharmacology and Therapeutics
Volume32
Issue number6
DOIs
StatePublished - Jul 1 2016

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rho-Associated Kinases
Aqueous Humor
Intraocular Pressure
Primates
Rabbits
Macaca
Y 27632
Glaucoma
Lasers
2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Ophthalmology
  • Pharmacology

Cite this

Effects of rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits. / Toris, Carol B; McLaughlin, Marsha A.; Dworak, Douglas P.; Fan, Shan; Havens, Shane J; Zhan, Gui Lin; Horan, Nicholas; Prasanna, Ganesh.

In: Journal of Ocular Pharmacology and Therapeutics, Vol. 32, No. 6, 01.07.2016, p. 355-364.

Research output: Contribution to journalArticle

Toris, Carol B ; McLaughlin, Marsha A. ; Dworak, Douglas P. ; Fan, Shan ; Havens, Shane J ; Zhan, Gui Lin ; Horan, Nicholas ; Prasanna, Ganesh. / Effects of rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits. In: Journal of Ocular Pharmacology and Therapeutics. 2016 ; Vol. 32, No. 6. pp. 355-364.
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abstract = "Purpose: This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics. Methods: 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. Results: 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. Conclusions: 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.",
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AU - Toris, Carol B

AU - McLaughlin, Marsha A.

AU - Dworak, Douglas P.

AU - Fan, Shan

AU - Havens, Shane J

AU - Zhan, Gui Lin

AU - Horan, Nicholas

AU - Prasanna, Ganesh

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N2 - Purpose: This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics. Methods: 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. Results: 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. Conclusions: 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.

AB - Purpose: This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics. Methods: 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. Results: 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. Conclusions: 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.

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