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T. Saeki, H. Tsuruga, M. Aihara, M. Araie, K. Rittenhouse; Dose-Response Profile of PF-03187207 (PF-207) and Peak IOP Lowering Response Following Single Topical Administration to FP Receptor Knockout Mice vs. Wild Type Mice. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4064.
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To characterize the dose-response profile of PF-207 and peak IOP lowering response following single topical administration to mice and to compare PF-207 efficacy in FP receptor knockout mice (FPKO) mice vs. wild type mice.
Study 1: Serial dilutions of PF-207 were prepared and a single dose (3 µL) was administered to male C57BL/6 mice (n=8/dose). The dose-response curve for IOP lowering was assessed in C57BL/6 (wild type) mice measured 3 hr after dosing. Study 2: Male C57BL/6J mice or male FPKO mice, (10 weeks old n=10 per arm) were administered doses of FP-207 or latanoprost (3 µL of PF-207 (0.006%) or latanoprost (0.005%)) to one eye, and contralateral eye was untreated. Micro needle method was used to measure IOP between 21:00 and 24:00 (nocturnal) and between 4 and 7 minutes after initiation of anesthesia (ketamine/zylazine IP). IOP was then measured at 1, 2, 3, 6 hour after administration of test agent to treated eyes or untreated control eyes.
Study 1: Maximal IOP reduction (~17%) was achieved at the 0.006% dose of PF-207.There was a statistically significant dose related increase in IOP lowering response over the range of doses evaluated (0.00075, 0.0015, 0.003, 0.006%) vs. the lowest dose. Study 2: No significant difference was observed between PF-207 and latanoprost in the IOP response vs. time profiles for wild type pigmented mice. Latanoprost did not show IOP lowering activity in the FPKO mouse, as expected. In contrast PF-207 lowered IOP from 0.45-1.23 mmHg in FPKO mouse p = 0.025-0.036 (paired t tests, multiple experiments).
In the FPKO mouse model PF-207 was shown to reduce IOP in mice about ~1 mmHg whereas latanoprost was ineffective. The data support the view that NO donation by PF-207 is involved in lowering IOP.
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