ar-12286 and Ocular-Hypertension

To evaluate the efficacy of rho-associated protein kinase inhibitor, AR-12286 topical solution, for its effect in eyes with exfoliation syndrome (XFS) and ocular hypertension (OHT) or exfoliative glaucoma (XFG) and examine any lasting effect on intraocular pressure (IOP) after discontinuation.. Prospective, double-masked, randomized, interventional study. Patients with XFS and OHT or XFG were enrolled. The study eyes were treated once daily with AR-12286, randomized to 0.5% or 0.7% for 24 weeks. Visits included baseline, 1, 4, and 12 weeks after drug initiation; at 12 weeks AR-12286 was discontinued for 1 week and was resumed at week 13. At the week 24 visit, AR-12286 was discontinued, and a final reexamination was performed at week 25.. Ten patients were treated. Mean baseline IOP was 25±2.4 mm Hg, mean IOP was reduced to 19.1±2.3 mm Hg at 1 week (P<0.001), 17.5±3.6 mm Hg at 4 weeks (P<0.001), and 17.4±3.6 mm Hg at 12 weeks (P<0.001), yielding an average IOP reduction of 23.6%, 30%, and 30.4%, respectively. At the week 13 visit, 1 week after the drug was discontinued, mean IOP increased to 21.6±5.4 mm Hg (P=0.06 compared with baseline visit). At week 24, the mean IOP was 21.8±7.8 mm Hg (P=0.2, and AR-12286 was discontinued). At week 25, the mean IOP was 21.3±5.3 mm Hg (P=0.06).. AR-12286 was well tolerated and provided statistically significant reduction in IOP in patients with XFS and OHT or XFG. This drug may represent an additional therapeutic paradigm for the treatment of XFG.

Topics: Administration, Topical; Aged; Aged, 80 and over; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Exfoliation Syndrome; Female; Follow-Up Studies; Glaucoma; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; rho-Associated Kinases; Treatment Outcome

To evaluate the ocular hypotensive efficacy of 0.05%, 0.1% and 0.25% AR-12286 Ophthalmic Solutions in patients diagnosed with ocular hypertension or glaucoma.. Parallel comparison, vehicle-controlled, double-masked, 3-week randomized clinical trial.. Subjects (n = 89) with elevated intraocular pressure (IOP) were assigned randomly to receive either 1 of 3 concentrations of AR-12286 or its vehicle. Dosing was once-daily in the morning for 7 days, then once-daily in the evening for 7 days, then twice daily for 7 days. Primary and secondary efficacy end points were mean IOP at each diurnal time point (8 am, 10 am, 12 pm, and 4 pm) and mean change in IOP from baseline, respectively.. All 3 concentrations of AR-12286 produced statistically and clinically significant reductions in mean IOP that were dose dependent, with peak effects occurring 2 to 4 hours after dosing. Mean IOP at peak effect ranged from 17.6 to 18.7 mm Hg (-6.8 to -4.4 mm Hg) for the 3 concentrations. The largest IOP reductions were produced by 0.25% AR-12286 after twice daily dosing (up to -6.8 mm Hg; 28%). The 0.25% concentration dosed once-daily in the evening produced highly significant IOP reductions throughout the following day (-5.4 to -4.2 mm Hg). The only adverse event of note was trace (+0.5) to moderate (+2) conjunctival hyperemia that was transient, typically lasting 4 hours or less. After once-daily evening dosing, hyperemia was seen in less than 10% of patients.. AR-12286 was well tolerated and provided clinically and statistically significant ocular hypotensive efficacy in patients with ocular hypertension and glaucoma.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; rho-Associated Kinases; Tonometry, Ocular; Treatment Outcome

We investigated mechanisms of reduction of intraocular pressure (IOP) by Rho kinase inhibitor AR-12286 in steroid-induced ocular hypertension (SIOH).. C57BL/6 mice (N = 56) were randomly divided into Saline, dexamethasone (DEX), DEX + AR-12286, and DEX-discontinuation (DEX-DC) groups. IOP was measured weekly during the first four weeks in all groups. Beginning at week 5, the DEX-DC group was followed without treatment until IOP returned to normal, and the other groups were treated as assigned with IOP measured every other day for another week. Fluorescent tracer was injected into the anterior chamber to visualize the outflow pattern in the trabecular meshwork (TM) and TM effective filtration area (EFA) was determined. Radial sections from both high- and low-tracer regions were processed for electron microscopy.. AR-12286 reduced IOP in SIOH mouse eyes in one day (P < 0.01). At the end of week 5, mean IOP in the DEX + AR-12286 group was ∼4 mm Hg lower than DEX group (P < 0.001) and ∼2 mm Hg lower than DEX-DC group (P < 0.05). After one-week AR-12286 treatment (P < 0.05) or five-week DC of DEX (P < 0.01), DEX-induced reduction of EFA was rescued and DEX-induced morphological changes in the TM were partially reversed.. AR-12286 reversed steroid-induced morphological changes in the TM and reduced EFA, which correlated with reduced IOP in SIOH eyes. AR-12286 reduced IOP elevation in SIOH eyes more effectively than discontinuing DEX treatment even when accompanied by continuous DEX treatment. Therefore Rho kinase inhibitors may lower SIOH in patients who rely on steroid treatment.

Topics: Animals; Glaucoma; Intraocular Pressure; Mice; Mice, Inbred C57BL; Ocular Hypertension; rho-Associated Kinases; Trabecular Meshwork