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K. M. Kengatharan, R. Lima e Silva, J. Yu, J. Hey, J. P. Cooke, P. Campochiaro; Topically Administered Mecamylamine (ATG-3) Penetrates to the Retina-Choroid and Reduces Laser-Induced Choroidal Neovascularization in C57BL/6J Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3424.
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To assess the efficacy and ocular bioavailability of topically administered mecamylamine (ATG-3, MEC), a non-selective nicotinic acetylcholine receptor (nAChR) antagonist with anti-angiogenic properties in a murine model of choroidal neovascularization (CNV).
In a masked experiment, 5 to 6 week-old female C57BL/6J mice were divided into 6 groups (9-10 animals/group); (1) vehicle b.i.d, (2) 0.1% MEC b.i.d and, (3) 1% MEC b.i.d; all sacrificed at 7d post injury, and (4) vehicle b.i.d, (5) 0.1% MEC b.i.d and, (3) 1% MEC b.i.d; all sacrificed at 14d post injury. At day 0, laser-photocoagulation-induced rupture of Bruch’s membrane was used to generate CNV (as per Lima e Silva, et al 2005) and treatment started. At 7d or 14d, mice were anesthetized and perfused with fluorescein-labeled dextran (2 x 106 average MW) and choroidal flat mounts were prepared. These were examined by fluorescence microscopy, images digitized and the area of each CNV lesion analyzed using image analysis software. In a separate experiment, mice were administered topically 3% MEC b.i.d, for 2 days and sacrificed on day 3 and the retina-choroid, plasma and red-blood cells (RBC) isolated for measurement of MEC by LC-MS-MS at 1, 3, 6 and 24h post single dose. Data are expressed as mean ± SEM. Statistical comparisons were made using one-way ANOVA with Bonferroni’s correction.
MEC given topically achieved micromolar level penetration into the retina-choroid (RC) with close to assay BLOQ levels observed in the plasma (P) or RBC at all time points assessed (ratios at 1hr; RC:P = 418.6; RC:RBC 565.5; P:RBC=1.3). These results suggest that topical delivery of MEC leads to significant penetration to the retina-choroid and reduction in CNV induced by laser-injury.
Topically delivered MEC, a non-selective nACh receptor antagonist, penetrates to the retina-choroid and reduces CNV in a mouse model of neovascular AMD.Reference: Lima e Silva R, et al., (2005). IOVS, Sep;46(9):3323-30.
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