Phase 2 Randomized Clinical Study of a Rho Kinase Inhibitor, K-115, in Primary Open-Angle Glaucoma and Ocular Hypertension

Tanihara, Hidenobu; Inoue, Toshihiro; Yamamoto, Tetsuya; Kuwayama, Yasuaki; Abe, Haruki; Araie, Makoto

doi:10.1016/j.ajo.2013.05.016

Cited by 171 publications

(145 citation statements)

References 9 publications

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“…33 Ripasudil is the first ophthalmic solution approved for the treatment of glaucoma and ocular hypertension in Japan; in 2014, it became available in an eye drop form to increase the outflow of the aqueous humor. [34][35][36] In addition, oral ripasudil protects RGCs after optic nerve injury by suppressing oxidative stress via Nox1 downregulation, 37 but there are few reports about its neuroprotective effects. In the present study, we found that topical ripasudil prevents glaucomatous retinal degeneration in EAAC1 KO mice by stimulating an IOP-independent pathway, in addition to IOPdependent pathways.…”

mentioning

confidence: 99%

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Akaiwa

Namekata

Azuchi

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. Topical administration (5 lL/day) of two different concentrations of ripasudil (0.4% and 2%) were applied to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, the measurement of intraocular pressure (IOP), and histopathology analyses were performed at 5, 8, and 12 weeks old. Retrograde labeling of retinal ganglion cells (RGCs), immunoblot, and immunohistochemical analyses of phosphorylated p38 mitogen-activated protein kinase (MAPK) in the retina were performed at 8 weeks old.RESULTS. Topical ripasudil ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old. Ripasudil reduced IOP and strongly suppressed the phosphorylation of p38 MAPK that stimulates RGC death in EAAC1 KO mice.CONCLUSIONS. These results suggest that, in addition to IOP reduction, ripasudil prevents glaucomatous retinal degeneration by neuroprotection, which is achieved by suppressing celldeath signaling pathways.

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confidence: 99%

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Akaiwa

Namekata

Azuchi

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…In completed clinical trials, twice daily application of 0.4 % ripasudil proved to be safe and effective from the viewpoint of lowering the IOP [52][53][54]. Furthermore, an 8 week study (with four hundred and thirteen patients) pointed out that ripasudil has additional pressure-lowering effects when combined with betablockers or prostaglandin analogues [55].…”

Section: Recent Status Of Rock Inhibitors In Clinical Applicationmentioning

confidence: 99%

ROCK inhibitors in ocular disease

Halasz

Townes‐Anderson

2016

ADMET DMPK

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“…Phase 2 clinical study results have recently been published for another selective Rho kinase inhibitor, K-115, from Kowa. 24 In patients with elevated IOP, twicedaily dosing of 0.4% K-115 achieved IOP reductions of 3.1-4.5 mmHg. A 65% incidence of transient, mild hyperemia was reported for this concentration.…”

Section: Rho Kinase Inhibitors In Glaucomamentioning

confidence: 99%

Emerging glaucoma therapeutics

Santra¹,

Munshi²

2015

Int J Basic Clin Pharmacol

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Glaucoma is a frequent, pathophysiologically heterogeneous ophthalmologic condition characterized by a typical visual field loss pattern from peripheral to central. As a chronic progressive optic neuropathy, it can lead to severe disability and blindness. Glaucoma is classified according to whether it is congenital or acquired. It is further sub-divided into open-angle or closed-angle, depending on how the aqueous outflow is impaired. Glaucoma is usually associated with an increase in intraocular pressure (IOP) above the normal value, which is usually estimated at 21 mm Hg (mean 15.5, range 10-21). Patients with statistically normal IOP who develop the characteristic changes associated with openangle glaucoma are said to have low tension or normal pressure glaucoma. Finally, primary or secondary types are identified depending on the presence of underlying contributory factors. The pathophysiology of glaucoma is not fully understood till date. The trabecular outflow pathway is the primary draining tissue for the aqueous humor in the eye. It consists of 3 structures, the trabecular meshwork (TM), juxtacanalicular tissue, and Schlemm's canal. In a healthy eye, IOP is maintained within a narrow range through dynamic regulation of trabecular outflow resistance. In a glaucomatous eye, elevated IOP is due to an abnormally high resistance to outflow in the trabecular outflow pathway.1 The causes of increased outflow resistance are not fully understood, but it has been hypothesized to involve an increase in the contractile tone and stiffness of the TM and changes in extracellular matrix composition and/or a change in the conductance of Schlemm's canal (Figures 1 and 2).2 There is a significant need for glaucoma drugs that specifically target the physiologic cause of elevated IOP and thereby enhance trabecular outflow. Currently, the management of glaucoma is focused on controlling the IOP by pharmacological and surgical measures to avoid these consequences. The tissues of the trabecular outflow pathway are avascular and rely on the aqueous humor to supply nutrients, growth factors, and antioxidants. The most widely prescribed glaucoma drugs, ABSTRACTThe purpose of this review was to discuss the major recent advances in the field of ophthalmology, particularly as it pertains to glaucoma. We reviewed literature using MEDLINE and PubMed databases with the following search terms: "glaucoma," "melatonin," "trabecular outflow pathway," "adenosine," "rho kinase," "norepinephrine," and "matrix metalloproteinases." We also reviewed pertinent references from articles found in this search. We looked at various studies concerning the clinical trials of glaucoma therapeutics, and therapeutic potential of putative ocular drug delivery systems in glaucoma. Challenges of assuring safety and efficacy of the newer medicines and techniques are pertinent in this regard. However, more research is needed to better elucidate the mechanism of various investigational drug products and drug delivery devices in glaucoma.

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Phase 2 Randomized Clinical Study of a Rho Kinase Inhibitor, K-115, in Primary Open-Angle Glaucoma and Ocular Hypertension

Cited by 171 publications

References 9 publications

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

Topical Ripasudil Suppresses Retinal Ganglion Cell Death in a Mouse Model of Normal Tension Glaucoma

ROCK inhibitors in ocular disease

Emerging glaucoma therapeutics

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