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Jeffrey W Kiel, Casey Kopczynski; Effect of AR-13324 on episcleral venous pressure (EVP) in Dutch Belted rabbits. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2900.
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AR-13324 is a new dual-action compound that is in clinical development for the treatment of glaucoma and ocular hypertension. It is both a Rho kinase (ROCK) inhibitor and norepinephrine transporter inhibitor that has been shown in a primate model to lower IOP through a dual mechanism of action, increasing trabecular outflow facility and decreasing aqueous production. The present study tested the hypothesis that AR-13324 also lowers IOP by reducing episcleral venous pressure.
In anesthetized Dutch Belted rabbits (n=6), we measured ear artery pressure (BP) and IOP by direct cannulation; carotid blood flow (BFcar) by transit time ultrasound, heart rate (HR) by a digital cardiotachometer, and EVP with a servo-null micropressure system. Animals were dosed with AR-13324 (0.04%, topical) once-daily for three days. On Day 3, measurements were obtained prior to dosing (Baseline) and for 3 hours following dosing of AR-13324. The data (mean +/- standard error) were analyzed by repeated measures ANOVA with Bonferroni post hoc testing.
Baseline values were: BP; 105 ± 3 mmHg, IOP; 34 ± 4 mmHg, EVP; 17 ± 2 mmHg, BFcar; 35 ± 1.1 ml/min, and HR; 337 ± 9 bpm. Three hours post dosing, IOP was reduced by 39 ± 7% (to 19 ± 2 mmHg, p<0.001) and EVP by 35 ± 4% (to 11 ± 1 mmHg, p<0.05). BP, BFcar and HR remained stable throughout the experiment.
AR-13324 lowered IOP and EVP significantly in Dutch Belted rabbits. At baseline, half of the measured IOP (34 mmHg) was attributable to EVP (17 mmHg), assuming the 1:1 correspondence between IOP and EVP in the Goldmann equation. At 3 hours post-dosing, the reduction in EVP caused by AR-13324 treatment accounted for 42% of the measured reduction in IOP. The remaining reduction in IOP achieved by AR-13324 is presumed to occur through increased outflow facility and decreased aqueous production, based upon previous mechanism of action studies in cynomolgus monkeys. Also noteworthy, the baseline values for BP, IOP and EVP in the Dutch Belted rabbit were markedly higher than previously reported for the New Zealand rabbit. We conclude that in the Dutch Belted rabbit model, AR-13324 lowers IOP in part through significant lowering of EVP.
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