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Hong Liang, Christophe Baudouin, Phillipe Daull, Luisa Riancho, Jean-Sébastien Garrigue, Françoise Brignole-Baudouin; Ocular Safety Evaluation of Newly Developed Cyclosporine in Cationic Emulsion in an in vitro Corneal Wound Healing Model and in an Acute in vivo Rabbit Model. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2026.
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Topical preparation of cyclosporine (CsA) has been developed to treat dry eye while inducing side effects, such as allergy and irritation. The present study aims at evaluating the cytotoxicity profile of newly developed CsA in cationic emulsion (CEm) (a) in an in vitro corneal would healing model using human corneal epithelial (HCE) cells (b) and in an acute in vivo rabbit model.
Four CsA formulations were tested: 1) 0.05%CsA-0.005% cetalkonium chloride (CKC)-CEm, 2) 0.05%CsA-0.02% benzalkonium chloride (BAC)-CE, 3) 0.05%CsA-oil solvent excipient (Oi), commercial 0.05%CsA-Em (Restasis®). Phosphate buffered saline (PBS) was used as control. (a) A wound was created by scratching through a confluent HCE cell layer. Cytotoxicity, cell migration and proliferation were analyzed at 2, 24 and 72hours after a 30 min exposure to solutions diluted to 1/10; (b) The eye drops were applied to rabbit eyes 15 times at 5-min intervals, and the ocular surface structures were examined using slit-lamp and corneal in vivo confocal microscopy (IVCM).
(a) The in vitro study showed that CsA-BAC delayed corneal healing process by damaging dramatically the remaining HCE cells. The other solutions maintained a normal healing rate with a particular behavior for CsA-CKC that improves the healing process when compared to control. (b) CsA associated to BAC showed the highest toxicity by clinical observations and IVCM, inducing redness, chemosis with damaged corneal epithelium and inflammatory infiltration. CsA-Oi and CsA-Em induced moderate inflammatory cell infiltration around the conjunctiva-associated lymphoid tissue structures, and CsA-CKC showed the lowest toxicity with patterns similar to those of the control.
The combination of these in vitro and in vivo models evaluated the tolerance/cytotoxicity and the dynamic wound healing potential of CsA in different formulations. The CsA in cationic emulsion appeared to offer the best tolerance without delaying HCE healing. It will be of great interest to protect dry eye surface and improve long-term tolerance of CsA topical treatments.
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