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; Zhan, G.; Horan, Nicholas; Prasanna, Ganesh

doi:10.1089/jop.2015.0116

Cited by 21 publications

(21 citation statements)

References 36 publications

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“…Unlike in vivo conditions, however, this model cannot evaluate the impact of aqueous humor production, normal ciliary body tone, episcleral venous pressure, or uveoscleral outflow, which has recently been reported to increase with treatment of Rho kinase inhibitor Y-27632 in monkey eyes. 60 Since we were not able to evaluate netarsudil's effects on aqueous humor production, its function as a NET inhibitor was not investigated in this study. In addition, since the episcleral venous pressure is zero in enucleated eyes, compared to approximately 7 mm Hg in the in vivo condition, 61 the 15-mm-Hg pressure we used for perfusion produced a relatively higher pressure gradient across the TM than is typical for normotensive eyes.…”

Section: Discussionmentioning

confidence: 99%

Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms

Ren

et al. 2016

Invest. Ophthalmol. Vis. Sci.

135

115

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PurposeNetarsudil is a Rho kinase/norepinephrine transporter inhibitor currently in phase 3 clinical development for glaucoma treatment. We investigated the effects of its active metabolite, netarsudil-M1, on outflow facility (C), outflow hydrodynamics, and morphology of the conventional outflow pathway in enucleated human eyes.MethodsPaired human eyes (n = 5) were perfused with either 0.3 μM netarsudil-M1 or vehicle solution at constant pressure (15 mm Hg). After 3 hours, fluorescent microspheres were added to perfusion media to trace the outflow patterns before perfusion-fixation. The percentage effective filtration length (PEFL) was calculated from the measured lengths of tracer distribution in the trabecular meshwork (TM), episcleral veins (ESVs), and along the inner wall (IW) of Schlemm's canal after global and confocal imaging. Morphologic changes along the trabecular outflow pathway were investigated by confocal, light, and electron microscopy.ResultsPerfusion with netarsudil-M1 significantly increased C when compared to baseline (51%, P < 0.01) and to paired controls (102%, P < 0.01), as well as significantly increased PEFL in both IW (P < 0.05) and ESVs (P < 0.01). In treated eyes, PEFL was significantly higher in ESVs than in the IW (P < 0.01) and was associated with increased cross-sectional area of ESVs (P < 0.01). Percentage effective filtration length in ESVs positively correlated with the percentage change in C (R2 = 0.58, P = 0.01). A significant increase in juxtacanalicular connective tissue (JCT) thickness (P < 0.05) was found in treated eyes compared to controls.ConclusionsNetarsudil acutely increased C by expansion of the JCT and dilating the ESVs, which led to redistribution of aqueous outflow through a larger area of the IW and ESVs.

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Section: Discussionmentioning

confidence: 99%

Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms

Ren

et al. 2016

Invest. Ophthalmol. Vis. Sci.

135

115

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“…The AHD methods were similar to those described previously. 32,33 The study was performed according to the schedule described in Fig. 2.…”

Section: Ahd Studymentioning

confidence: 99%

“…48 When dosed for multiple days, it increases uveoscleral outflow. 48 Rho kinase inhibitors mainly improve outflow facility, 33,49 although an effect on P ev 50 and uveoscleral outflow 33 also contribute to its IOP-lowering effect. We previously confirmed the adjunctive IOP-lowering effect of OMDI in animal models.…”

Section: Figmentioning

confidence: 99%

Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys

Fuwa

Toris

Fan

et al. 2018

Journal of Ocular Pharmacology and Therapeutics

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“…IOP was measured noninvasively 31 by using an Alcon computerized pneumatonometer after the application of a drop of 0.1% proparacaine to anesthetize the cornea. IOP readings were taken before (baseline, 0 hours) and after dosing with vehicle or drug from 0.5 to 6 hours and again at 24 and 48 hours postdose.…”

Section: Ocular and Systemic Exposure Assessments In Rabbits And Systmentioning

confidence: 99%

“…31 Dosing was either done during the daytime (8 AM) or nighttime (8 PM), where indicated. IOP was stably elevated in the monkeys, following a unilateral laser-induced trabeculoplasty of the TM tissue up to a 3258 axis, and scarring of 90% of the tissue left 10% of TM tissue intact.…”

Section: Measurement Of Iop Inmentioning

confidence: 99%

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

Prasanna

Ferrara

Adams

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. METHODS.Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.RESULTS. sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8-to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.CONCLUSIONS. MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOPlowering drugs in glaucoma patients could be further determined in clinical studies.Keywords: soluble guanylate cyclase, monkey model of glaucoma, IOP, ODQ, cGMP, glaucoma T he estimated number of glaucoma cases globally is over 60 million, and primary open angle glaucoma accounts for >70% of the total cases. In the United States alone, over 120,000 patients are blind from this disease, accounting for 9% to 12% of all cases of blindness.1 Lowering of intraocular pressure (IOP) is the current gold standard for reducing visual field (VF) loss in glaucoma. However, up to 45% of patients who achieved an IOP-lowering target of 25% to 30% (6 to 8 mm Hg) from baseline IOP by medical treatment continued to show progressive VF loss. Every 1 mm Hg higher mean IOP in the follow-up period was associated with 13% higher risk of progressive VF loss for the study population, whereas each mm Hg reduction was associated with a 10% reduction in disease progression. Rhopressa and latanoprost, which lowered IOP by 1 to 3 mm Hg greater than the monotherapy comparators over 3 months of dosing in patients with glaucoma.5 IOP lowering via the NO/ cGMP signaling pathway is also well known. This is a key pathway in several physiologic processes, including platelet inhibition, smooth muscle relaxation, and neurotransmission. NO is the endogenous ligand of soluble guanylate cyclase (sGC). Binding of NO to the heme domain of sGC results in sGC activation and production ...

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Effects of Rho Kinase Inhibitors on Intraocular Pressure and Aqueous Humor Dynamics in Nonhuman Primates and Rabbits

Cited by 21 publications

References 36 publications

Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms

Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms

Effects of a Novel Selective EP2 Receptor Agonist, Omidenepag Isopropyl, on Aqueous Humor Dynamics in Laser-Induced Ocular Hypertensive Monkeys

A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing

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