Effect of PF-04217329 a prodrug of a selective prostaglandin EP2 agonist on intraocular pressure in preclinical models of glaucoma

Prasanna, Ganesh; Carreiro, Samantha; Anderson, Scott; Gukasyan, Hovhannes J.; Sartnurak, Soisurin; Younis, Husam S.; Gale, David C.; Xiang, Cathie; Wells, Peter A.; Dinh, Dac M.; Almaden, Chau; Fortner, Jay H.; Toris, Carol B.; Niesman, Michael R.; Lafontaine, Jennifer; Krauss, Achim H.-P.

doi:10.1016/j.exer.2011.02.015

Cited by 53 publications

(47 citation statements)

References 20 publications

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“…15,16 Latanoprost, a prostaglandin (PG) F2a analogue, is the first F prostanoid (FP) receptor agonist approved for POAG treatment and is currently used as first-line therapy. 17 However, agonists of another prostanoid receptor, EP2, have also been shown to promote potent hypotensive effects in several animal models 18,19 and are currently in clinical development for the iovs.arvojournals.org j ISSN: 1552-5783 treatment of ocular hypertension (OHT). [20][21][22] The action of both FP and EP2 agonists seems to be mediated by an increased uveoscleral outflow pathway through activation of matrix metalloproteinases (MMP) and ECM remodeling.…”

Section: Methodsmentioning

confidence: 99%

Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells

Kalouche

Béguier

Bakria

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Prostaglandin F2a analogues are the first-line medication for the treatment of ocular hypertension (OHT), and prostanoid EP2 receptor agonists are under clinical development for this indication. The goal of this study was to investigate the effects of F prostanoid (FP) and EP2 receptor activation on the myofibroblast transition of primary trabecular meshwork (TM) cells, which could be a causal mechanism of TM dysfunction in glaucoma.METHODS. Human primary TM cells were treated with either latanoprost or butaprost and TGFb2. Trabecular meshwork contraction was measured in a three-dimensional (3D) TM cellpopulated collagen gel (CPCG) model. Expression of a-smooth muscle actin (a-SMA) and phosphorylation of myosin light chain (MLC) were determined by Western blot. Assembly of actin stress fibers and collagen deposition were evaluated by immunocytochemistry. Involvement of p38, extracellular signal-regulated kinase (ERK), and Rho-associated kinase (ROCK) pathways as well as matrix metalloproteinase activation was tested with specific inhibitors.RESULTS. In one source of validated adult TM cells, latanoprost induced cell contraction as observed by CPCG surface reduction and increased actin polymerization, a-SMA expression, and MLC phosphorylation, whereas butaprost inhibited TGF-b2-induced CPCG contraction, actin polymerization, and MLC phosphorylation. Both agonists inhibited TGF-b2-dependent collagen deposition. The latanoprost effects were mediated by p38 pathway.CONCLUSIONS. Latanoprost decreased TM collagen accumulation but promoted a contractile phenotype in a source of adult TM cells that could modulate the conventional outflow pathway. In contrast, butaprost attenuated both TM contraction and collagen deposition induced by TGF-b2, thereby inhibiting myofibroblast transition of TM cells. These results open new perspectives for the management of OHT.

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Section: Methodsmentioning

confidence: 99%

Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells

Kalouche

Béguier

Bakria

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…19 Each of the prostaglandins has a different binding profile from the FP and EP receptors and as a result, has differing effects on blood vessels, blood flow and hyperaemia. [20][21][22] Consequently, individual patients show varying responses to the range of prostaglandins that are available and changing these drugs can have an effect on efficacy and/or tolerability.…”

Section: Anton Hommermentioning

confidence: 99%

The Role of Preservative-free Therapies in the Treatment of Glaucoma

Baudouin¹,

Hommer²,

Konstas³

et al. 2013

European Ophthalmic Review

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“…Laboratory beagles of the Marshall strain are particularly passive and amenable to handling. Dogs have a relatively large eye (compared to rodents), allow tonometry without general anesthesia or sedation, and respond to most anti-glaucoma drug classes including adrenergics, cholinergics, beta-blockers, carbonic anhydrase inhibitors, prostaglandins, and cannabinoids [65,67,68,71,[86][87][88][89][90]. However, they have a larger cornea and anterior chamber than humans, greater housing requirements than rabbits, a need for continual acclimation/socialization to maintain acclimation to tonometry, and a diurnal curve in which IOP tends to decline over the course of the day.…”

Section: Dogs (Canis Lupus Familiaris)mentioning

confidence: 99%

Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

Miller

2013

Methods in Pharmacology and Toxicology

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A large number of factors are important in conducting anti-glaucoma drug efficacy studies. It is essential to have an understanding of aqueous humor dynamics and how the tonometer, tonometrist, and animal may affect IOP estimates. Additional critical considerations in the design of an anti-glaucoma drug efficacy studies include the following: (1) selecting the most appropriate species, (2) identifying the rate of nonresponders within the study population, (3) determining whether normotensive or glaucomatous animals should be used, and deciding (4) what secondary endpoints (if any) to include, and (5) whether one eye or both should be dosed. Anti-glaucoma drug efficacy studies have an acclimation phase in which the animal becomes conditioned to the procedures, a predose phase in which baseline data is collected, a dosing phase in which the drug is administered and IOP and possibly other endpoints are monitored, and a recovery phase in which IOP returns to predose values as the drug is washed out before another predose phase is started.

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Effect of PF-04217329 a prodrug of a selective prostaglandin EP2 agonist on intraocular pressure in preclinical models of glaucoma

Cited by 53 publications

References 20 publications

Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells

Activation of Prostaglandin FP and EP2 Receptors Differently Modulates Myofibroblast Transition in a Model of Adult Primary Human Trabecular Meshwork Cells

The Role of Preservative-free Therapies in the Treatment of Glaucoma

Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

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