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C. Ghosn, Y. Li, W. Orilla, T. Lin, L. Wheeler, S. Whitcup, J. Burke; Dexamethasone in an Intravitreal Drug Delivery System (Posurdex®) Decreases Levels of Inflammatory Mediators in a Model of Experimental Uveitis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5632.
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The treatment of uveitis with oral corticosteroids is associated with systemic side effects that may be avoided with intravitreal dosing using a sustained-release biodegradable drug delivery system. This study evaluated the efficacy of dexamethasone in an intravitreal drug delivery system (DexDDS) on suppressing cytokines and chemokines that are up-regulated in experimental uveitis in rabbits.
Uveitis was induced by an intracameral injection of 20ug Mycobacterium Tuberculosis (Mbt) in one eye of 18 rabbits pre-immunized 20 days previously with 2 subcutaneous doses of 10mg Mbt. Four days after disease induction, animals were dosed with either intravitreal DexDDS 700 ug (n=12) or a 22-gauge sham injection (n=6). The primary evaluation was at 3 weeks and consisted of assessments of anterior chamber cells with a slit-lamp using a standard grading scale (0-4+) and corneal thickness with the Visante anterior segment OCT (Topcon). The iris ciliary body (ICB) was also assayed for 89 chemokines/cytokines from the human Multi-Analyte Profiles® antigen panel using the Luminex assay (Rules-Based Medicine, Austin, TX). All data are expressed as mean ± SD. An unpaired Student’s ‘t’ test was used to compare Sham and DexDDS groups.
At 3 weeks, DexDDS reduced anterior chamber inflammatory cell scores by 52 ± 7 % relative to the sham group; mean AC cell scores were 1.9 ± 0.3 and 4.0 ± 0 for DexDDS and Sham, respectively (p<0.05). In addition, corneal thickness was significantly lower in DexDDS-treated animals: DexDDS: 406 ± 111 um; Sham: 802 ± 73 um (p<0.05). Normal cornea thickness was 353 ± 14 um. Ten chemokines/cytokines were up-regulated 3 fold or greater in the ICB of the sham group compared to naïve eyes: BDNF, CD40, IL-1 beta, IL-8, MIP-1alpha, MIP-1beta, MMP-2, RANTES, VCAM-1, and VEGF. Increases ranged from 3X for MIP-1 alpha (<2.6 ± 0 pg/ml to 7.2 ± 3.1 pg/ml) to 1488X for RANTES (1.8 ± 1.9 pg/ml to 2.7 ± 0.74 ng/ml). VEGF was increased 4X: 11 ± 1.6 pg/ml to 45 ± 17 pg/ml. DexDDS significantly reduced the ICB levels of all 10 mediators by 33% - 88%.
DexDDS significantly reduced intraocular inflammation in experimental uveitis.
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