Profile of netarsudil ophthalmic solution and its potential in the treatment of open-angle glaucoma: evidence to date

Dasso, Lily; Al-Khaled, Tala; Sonty, Sriram; Aref, Ahmad A.

doi:10.2147/opth.s154001

Cited by 42 publications

(39 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The association between the spread distribution, multiple roles, and few pharmacological agents has hindered the use of Rho proteins and downstream pathways as therapeutic targets. Despite the accumulated knowledge and previous clinical trials in different fields, including the cardiovascular system, the only marketed drug in the United States containing a ROCK inhibitor, named netarsudil, is an ophthalmic solution indicated for glaucoma [191]. Ripasudil has similar uses in Japan [192].…”

Section: Final Remarks and Conclusionmentioning

confidence: 99%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

View full text Add to dashboard Cite

Sepsis and septic shock are associated with acute and sustained impairment in the function of the cardiovascular system, kidneys, lungs, liver, and brain, among others. Despite the significant advances in prevention and treatment, sepsis and septic shock sepsis remain global health problems with elevated mortality rates. Rho proteins can interact with a considerable number of targets, directly affecting cellular contractility, actin filament assembly and growing, cell motility and migration, cytoskeleton rearrangement, and actin polymerization, physiological functions that are intensively impaired during inflammatory conditions, such as the one that occurs in sepsis. In the last few decades, Rho proteins and their downstream pathways have been investigated in sepsis-associated experimental models. The most frequently used experimental design included the exposure to bacterial lipopolysaccharide (LPS), in both in vitro and in vivo approaches, but experiments using the cecal ligation and puncture (CLP) model of sepsis have also been performed. The findings described in this review indicate that Rho proteins, mainly RhoA and Rac1, are associated with the development of crucial sepsis-associated dysfunction in different systems and cells, including the endothelium, vessels, and heart. Notably, the data found in the literature suggest that either the inhibition or activation of Rho proteins and associated pathways might be desirable in sepsis and septic shock, accordingly with the cellular system evaluated. This review included the main findings, relevance, and limitations of the current knowledge connecting Rho proteins and sepsis-associated experimental models.

show abstract

Section: Final Remarks and Conclusionmentioning

confidence: 99%

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Hahmeyer

Silva-Santos

2021

Cells

View full text Add to dashboard Cite

show abstract

“…In the United States, only the recently approved Rhoassociated kinase (ROCK) inhibitor netarsudil 21 directly aims at the stiffened HTM to increase AH outflow via cell/tissue relaxation [22][23][24][25][26] . However, various adverse events at the ocular surface in some patients have been reported during the drug's brief window of availability [27][28][29] , raising concerns over its routine use. This highlights the clear unmet need for new/improved POAG treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling

Bagué

Kirschner

et al. 2020

Preprint

View full text Add to dashboard Cite

PurposeAbnormal human trabecular meshwork (HTM) cell function and extracellular matrix (ECM) remodeling contribute to HTM stiffening in primary open-angle glaucoma (POAG). Most current cellular HTM model systems do not sufficiently replicate the complex native three dimensional (3D) cell-ECM interface, which makes them less than ideal to investigate POAG pathology. Tissue-engineered protein-based hydrogels are ideally positioned to overcome shortcomings of current models. Here, we report a novel biomimetic HTM hydrogel and test its utility as a POAG disease model.MethodsHTM hydrogels were engineered by mixing normal donor-derived HTM cells with collagen type I, elastin-like polypeptide and hyaluronic acid, each containing photoactive functional groups, followed by UV light-activated free-radical crosslinking. Glaucomatous conditions were induced with dexamethasone (DEX), and therapeutic effects of the Rho-associated kinase (ROCK) inhibitor Y27632 on cytoskeletal organization and tissue-level function, contingent on HTM cell-ECM interactions, were assessed.ResultsDEX exposure increased HTM hydrogel contractility, f-actin and alpha smooth muscle actin abundance and rearrangement, ECM remodeling, and fibronectin and collagen type IV deposition, all contributing to HTM hydrogel condensation and stiffening consistent with recent data from normal vs. glaucomatous HTM tissue. Y27632 treatment produced precisely the opposite effects and attenuated the DEX-induced pathologic changes, resulting in HTM hydrogel relaxation and softening.ConclusionsWe have developed a biomimetic HTM hydrogel model for detailed investigation of 3D cell-ECM interactions under normal and simulated glaucomatous conditions. Its bidirectional responsiveness to pharmaceutical challenge and rescue suggests promising potential to serve as screening platform for new POAG treatments with focus on HTM biomechanics.

show abstract

“…In 2017, netarsudil (Aerie Pharmaceuticals, Durham, NC, USA) was approved by the US Food and Drug Administration for the reduction of IOP in eyes with primary openangle glaucoma (POAG) or ocular hypertension (OHT) [2]. Netarsudil is a Rho kinase inhibitor, which is believed to lower IOP through up to three distinct mechanisms of action: increasing trabecular outflow, reducing aqueous formation, and reducing episcleral venous pressure (EVP) [3,4].…”

Section: Introductionmentioning

confidence: 99%

Effects of Netarsudil and Latanoprost Alone and in Fixed Combination on Corneal Endothelium and Corneal Thickness: Post-Hoc Analysis of MERCURY-2

et al. 2020

View full text Add to dashboard Cite

Introduction: To describe the changes in endothelial cell density (ECD), the coefficient of variation (CV), the percentage of hexagonal cells (%HEX), and central corneal thickness (CCT) following 3 months of therapy with netarsudil 0.02%/latanoprost 0.005% fixed combination, and to compare these changes with those seen with netarsudil 0.02% or latanoprost 0.005% in eyes with ocular hypertension or open-angle glaucoma. Methods: A subset of subjects enrolled in a Phase 3 evaluation of the intraocular pressurelowering efficacy and safety of netarsudil 0.02%/latanoprost 0.005% fixed combination once daily (QD) versus each of its individual components underwent corneal endothelial cell imaging by specular microscopy and ultrasound pachymetry at baseline and following 3 months of therapy. Images were evaluated in masked fashion at an independent reading center. Changes from baseline to 3 months in ECD, CV, %HEX, and CCT were compared between treatment groups. Results: Data from 415 subjects obtained at both baseline and Month 3 were included in this post hoc analysis. Changes from baseline to Month 3 in ECD, CV, and %HEX were clinically insignificant in all three groups, and the changes in the netarsudil/latanoprost fixed combination group demonstrated no statistical difference from those seen in the netarsudil and latanoprost groups. Mean CCT decreased more in the fixed combination group (-6.4 lm) than in either the netarsudil group (-3.3 lm, p = 0.0248) or the latanoprost group (-1.2 lm, p \ 0.0001). Conclusions: Netarsudil 0.2%/latanoprost 0.005% fixed combination QD for 3 months in eyes with ocular hypertension or open-angle glaucoma had no clinically significant effects on endothelial cell density or morphology. The significant decrease in CCT in the fixed combination group compared to the two individual component groups may indicate that the potential effects of each drug on CCT are additive, although the magnitude of the observed effects is likely of negligible clinical significance. Clinicaltrials.gov Identifier: NCT02674854.

show abstract

Profile of netarsudil ophthalmic solution and its potential in the treatment of open-angle glaucoma: evidence to date

Cited by 42 publications

References 33 publications

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

Rho-Proteins and Downstream Pathways as Potential Targets in Sepsis and Septic Shock: What Have We Learned from Basic Research

A tissue-engineered human trabecular meshwork hydrogel for advanced glaucoma disease modeling

Effects of Netarsudil and Latanoprost Alone and in Fixed Combination on Corneal Endothelium and Corneal Thickness: Post-Hoc Analysis of MERCURY-2

Contact Info

Product

Resources

About