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E. Budzynski, A. Shafiee, F. J. López, K. W. Ward; BOL-303242-X, a Selective Glucocorticoid Receptor Agonist (SEGRA), Offers a Better in vivo Side Effect Profile Than Dexamethasone on Intraocular Pressure Elevation in Normotensive Rabbits. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1468.
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BOL-303242-X is a Selective Glucocorticoid Receptor Agonist (SEGRA) currently of interest for the treatment of a variety of ocular diseases. SEGRAs may offer an improved clinical safety profile compared to steroids. In this study we evaluated the effect of BOL-303242-X on intraocular pressure (IOP) in normotensive rabbits compared to dexamethasone (DEX).
Rabbits were conditioned to morning IOP measurements with a pneumotonometer for two weeks (baseline IOP = 24.3 ± 1.8 mmHg) prior to dosing. After the conditioning period, animals were divided into five groups and the right eyes were treated topically four times per day with one of the following: PBS, DEX (0.5 mg), BOL-303242-X (0.05, 0.25, or 0.5 mg) for 30 days. IOP was measured three times per week between 7-10 am. Data were analyzed by a two-way ANOVA with repeated measures followed by the contrast procedure in JMP (SAS Institute; Cary, NC). In order to obtain an integrated response over time, the area under the curve (AUC) was calculated for each IOP time-profile using the trapezoidal rule. These data were then analyzed using one-way ANOVA followed by Dunnett’s test to compare differences between treatment groups versus the PBS-treated group.
DEX-treated animals showed significantly greater IOP on days 12-26 compared to PBS-treated animals. Rabbits treated with 0.05 mg BOL-303242-X showed no significant effect on IOP, whereas the rabbits treated with 0.25 mg BOL-303242-X showed significantly greater IOP than PBS on days 16, 18, 24, and 26, and at the highest dose tested IOP was greater than that of PBS-treated animals only on day 26. Evaluation of the integrated responses over time (AUC) revealed that no dose of BOL-303242-X changed IOP AUC (mm Hg•day) when compared to PBS treated animals. However, IOP AUC for DEX-treated animals was significantly greater than that of the PBS-treated group.
These data indicate that overall BOL-303242-X, a SEGRA, has a better safety profile than DEX and may therefore offer a better therapeutic index for conditions that may require chronic ocular treatment with GR agonists.
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