cp-544326 and Ocular-Hypertension

To assess the effect of topical taprenepag isopropyl on each layer of the cornea by confocal microscopy.. Thirty-two ocular hypertensive or glaucoma patients were randomized into a 2-period, crossover study of 14 days of 0.1% taprenepag alone and in unfixed combination with 0.005% latanoprost (combination therapy). Baseline and sequential slit-lamp biomicroscopy, fluorescein staining, central ultrasonic pachymetry, and confocal microscopy were performed. Confocal images were analyzed for the density of the central superficial and basal epithelium, midstromal keratocytes, and endothelium, as well as endothelial coefficient of variation and percentage of hexagonal cells, and reflectivity of anterior stromal and midstromal layers.. Corneal staining increased from baseline, reaching a peak at day 13 (69% and 63% of subjects treated with monotherapy and combination therapy, respectively), which resolved by day 35. A statistically significant increase in mean corneal thickness for both eyes and both treatments occurred on days 7 and 13 (range, 20-27 μm; P < 0.001) but recovered (≤ 6 μm) by day 35. No statistically significant changes were observed in the basal epithelial, midstromal, or endothelial cells. Mean ratio of average reflectivity of anterior stroma to midstroma increased on days 13 and 35 in period 1 for each treatment (range, 1.2-1.9; P < 0.001), and this increase persisted during period 2.. Anterior stromal reflectivity may remain increased even when biomicroscopic and confocal images of corneal layers remain normal or have recovered after topical taprenepag. This subclinical measure may be useful to detect a persistent adverse effect of a topical agent on the cornea.

Topics: Acetates; Administration, Topical; Aged; Aged, 80 and over; Cell Count; Corneal Diseases; Corneal Keratocytes; Corneal Pachymetry; Corneal Stroma; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Endothelium, Corneal; Epithelium, Corneal; Glaucoma, Open-Angle; Humans; Latanoprost; Microscopy, Confocal; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic; Receptors, Prostaglandin E, EP2 Subtype; Refraction, Ocular; Sulfonamides; Visual Acuity

To evaluate the safety of escalating doses of taprenepag isopropyl (PF-04217329), a selective EP(2) receptor agonist administered as a topical ophthalmic solution, versus its vehicle (Stage I), and dose-response of taprenepag isopropyl alone and in unfixed combination with latanoprost ophthalmic solution 0.005% versus latanoprost alone (Stage II).. Randomized, vehicle- and active-controlled, double-masked, two-stage, dose-finding trial in primary open-angle glaucoma (POAG) or ocular hypertension; first taprenepag isopropyl study in patients (NCT00572455). Study eye: 26 mmHg ≤ intraocular pressure (IOP) <36 mmHg at 8 am and 22 mmHg ≤ IOP <36 mmHg at 10 am, 1 pm, 4 pm. Stage I: 3 cohorts (total n = 67) received 1 drop of taprenepag isopropyl unit dose formulation qPM/eye for 14 days: low dose: 0.0025%, 0.005%, vehicle; middle dose: 0.01%, 0.015%, vehicle; high dose: 0.02%, 0.03%, vehicle. Stage II: 7 groups (total n = 250) received 1 drop of taprenepag isopropyl multidose formulation qPM/eye for 28 days: 0.005%, 0.01%, 0.015% monotherapy; each in unfixed combination with latanoprost 0.005%, or latanoprost monotherapy.. mean change in diurnal IOP, baseline to last visit; adverse events.. Stage I at day 14: statistically significantly greater IOP reductions were observed at all taprenepag isopropyl doses versus vehicle. Stage II at day 28: statistically significantly greater IOP reductions were observed at all doses of the unfixed combination versus latanoprost monotherapy. At least 1 treatment-emergent adverse event reported for 29/67 (43.3%) subjects in Stage I and 158/250 (63.2%) in Stage II.. Taprenepag isopropyl significantly reduces IOP in POAG and ocular hypertension. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. As demonstrated in this report, the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications.

Topics: Acetates; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Latanoprost; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Prostaglandins F, Synthetic; Receptors, Prostaglandin E, EP2 Subtype; Sulfonamides; Treatment Outcome