Delivery of SAR 1118 to the retina via ophthalmic drops and its effectiveness in a rat streptozotocin (STZ) model of diabetic retinopathy (DR)

<div><p style="color: #4aa564;">Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5198-204. doi: 10.1167/iovs.09-5144. Epub 2010 May 5.</p><p><b>ABSTRACT</b></p><p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">PURPOSE: To determine the pharmacokinetics of SAR 1118, a small-molecule antagonist of leukocyte function-associated antigen (LFA)-1, after administration of ophthalmic drops in normal rats, and to determine its pharmacologic activity by assessing the inhibition of retinal leukostasis and vascular leakiness in a streptozotocin (STZ)-induced diabetic retinopathy model.</p><p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">METHODS: The ocular pharmacokinetics of SAR 1118 were studied in rats after a single topical dose of (14)C-SAR 1118 (1 mg/eye; 40 μCi; 15.5 μL). SAR 1118 concentration time profiles in plasma and ocular tissues were quantified by liquid scintillation counting (LSC). The pharmacologic activity of SAR 1118 eye drops administered thrice daily for 2 months at 1% (0.3 mg/eye/d) and 5% (1.5 mg/eye/d) was assessed in an STZ-induced diabetic rat model by determining retinal leukostasis and blood-retinal barrier breakdown. Diabetic rats treated with periocularly administered celecoxib microparticles served as the positive control, and vehicle-treated rats served as the negative control.</p><p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">RESULTS: A single dose of 6.5% (14)C-radiolabeled SAR 1118 ophthalmic drops delivered retinal drug levels greater than 1 μM in less than 30 minutes and sustained levels greater than 100 nM for 8 hours. SAR 1118 eye drops significantly reduced leukostasis and blood-retinal barrier breakdown in a dose-dependent manner.</p><p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">CONCLUSIONS: SAR 1118 ophthalmic drops administered thrice daily deliver therapeutic levels of SAR 1118 in the retina and can alleviate the retinal complications associated with diabetes.</p><p style="color: lightgray">PMID:<a href="https://pubmed.ncbi.nlm.nih.gov/20445119/?utm_source=curl&utm_medium=rss&utm_content=1VUFS2KU_hFtBW8JwQk072MHYZ5gxZFnBkRHVr5WgfOlmKiMcV&ff=20231127175201&v=2.17.9.post6+86293ac">20445119</a> | PMC:<a href="https://www.ncbi.nlm.nih.gov/pmc/PMC3066602/?utm_source=curl&utm_medium=rss&utm_content=1VUFS2KU_hFtBW8JwQk072MHYZ5gxZFnBkRHVr5WgfOlmKiMcV&ff=20231127175201&v=2.17.9.post6+86293ac">PMC3066602</a> | DOI:<a href=https://doi.org/10.1167/iovs.09-5144>10.1167/iovs.09-5144</a></p></div>