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Hiroshi Nakamura, Jeffrey Dunmire, Vijaykumar Sutariya, Michael Hewit, Daniel Wehrung, Sulabh Patel, Ashim Mitra; Evaluation of Dose Effect of ALK-5 Inhibitor and Controlled Delivery with Novel Pentablock Polymer in Glaucoma Filtration Surgery. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4479.
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It was demonstrated that activin receptor-like kinase 5 (ALK-5) inhibitors are effective to improve filtering bleb survival after glaucoma filtration surgery (GFS) in the rabbit model. The purpose of this study is to evaluate the dose effect of the inhibitor, including drug concentration in blebs. In addition, a novel pentablock polymer was examined for controlled delivery of the inhibitor for GFS.
Tablets containing 2.5 (n=6), 5.0 (9), 10.0 (10) and 20.0 (6) mg of ALK-5 inhibitor were placed at the surgical site of GFS in the rabbit model. At post-surgical day 6, the filtering blebs were photographed and then collected. Reverse phase HPLC with UV detection was performed to measure the inhibitor concentration in the bleb. In order to investigate new controlled delivery of the inhibitor for GFS, thermoreversible gel consisting of a pentablock PEG-PCL-PLA-PCL-PEG polymer (25% w/v) containing the inhibitor at the concentration of 50 μg/μl was prepared. During rabbit GFS (n=3), 0.1 ml of the gel was injected into subconjunctival space at the surgical site after conjunctival sutures. Eyes were observed at least twice per week following surgery until the time of bleb failure. At the end of the observation period, the eyes were enucleated and fixed, and the blebs were histologically examined.
The concentration of ALK-5 inhibitor in the filtering bleb at day 6 was varied, and no statistical difference was observed among four different amounts of the inhibitor. On the other hand, the size of filtering bleb at day 6 was significantly larger with increasing amount of the inhibitor (p<0.05). In GFS using the inhibitor with thermoreversible gel, filtering blebs survived until day 14, 23 and 25, which is improved bleb survival compared to our previous data from GFS with tablets (12-19 days) containing the same amount of inhibitor. In two of 3 rabbits, backward flow of the gel into the anterior chamber was observed just after subconjunctival injection. In two of 3 rabbits, aqueous humor leakage from filtering blebs was observed at the end of post-surgical observation. In hematoxylin-eosin staining, a thinner conjunctival epithelium was observed.
The inhibitor amount in tablets did not affect its concentration in blebs but did affect the bleb size. The pentablock polymer may provide a novel controlled drug delivery system in GFS.
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