ABSTRACT
Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months' storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.
Subject(s)
Capillary Permeability , Vascular Cell Adhesion Molecule-1 , Angiogenesis Inhibitors/pharmacology , Animals , Humans , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/genetics , Proto-Oncogene Proteins c-fos/metabolism , Rabbits , Rats , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Cell Adhesion Molecule-1/pharmacology , Vascular Endothelial Growth Factor A/metabolismABSTRACT
PURPOSE: To evaluate the safety and tolerability of a single intracameral administration of a combined mydriatic (tropicamide and phenylephrine) and anesthetic (lidocaine) formulation (Mydrane) with or without rinsing. SETTING: Iris Pharma, La Gaude, France. DESIGN: Experimental study. METHODS: Sixty pigmented rabbits received 100 µL or 200 µL of the combination product or a placebo (sodium chloride 0.9%) by intracameral injection. For the combination product, separate groups were included with and without rinsing after administration. From day 1 day to day 7, assessments included general clinical and ocular observations, pupil diameter measurements, corneal assessments, confocal microscopy, and electroretinography (ERG). Necropsy examinations were performed at study completion at day 8. RESULTS: Rapid mydriasis, stable 24 minutes after injection and returning to baseline levels by day 1, was induced in all groups that received the combination mydriatic and anesthetic drug. Rinsing had no effect. The combination product induced no adverse effects on the anterior or posterior segment of the eye (ie, no increased corneal thickness and endothelial cell loss, no abnormalities in ERG). Slitlamp examination showed slightly increased anterior chamber inflammation with rinsing in both the study group and placebo group. This observation was not confirmed by aqueous flare examination. No toxic effects of the products were found on histological evaluation. CONCLUSION: The combination mydriatic and anesthetic drug administered to pigmented rabbits as a single intracameral injection at volumes of 100 µL and 200 µL was well tolerated with no ocular adverse effects and no effect on the corneal endothelium.
