Pre–Clinical Studies of OPC–12759 Ophthalmic Suspension for Dry Eye Treatment

Abstract

Abstract: : Purpose: OPC–12759 is a novel quinolinone derivative synthesized by Otsuka Pharmaceutical Company, Ltd., Japan. In these pre–clinical studies, we investigate the pharmacological effect of OPC–12759 and its usefulness as a therapeutic agent for dry eye treatment. Methods: In vivo studies; OPC–12759 ophthalmic suspension was instilled 6 times per day for about 14 days to normal or N–acetylcysteine (NAC)–treated rabbits to evaluate the following parameters. 1) Mucin content in the cornea and conjunctiva (Alcian blue binding method) 2) PAS–positive cell density of the conjunctiva (impression cytology method) 3) Therapeutic effect on corneal and conjunctival damage in NAC–treated eyes (Rose bengal scores). In vitro studies; HCECs were cultured with or without OPC–12759, then secreted and cell–associated mucin contents were measured by the combined methods of gel filtration and enzyme–linked lectin assay (ELLA) and the expression of mucin gene in cultured HCECs was determined by RT–PCR. Results: Topical application of OPC–12759 significantly increased the corneal and conjunctival mucin contents in normal and NAC–treated eyes and conjunctival PAS–positive cell density in normal eyes. One % OPC–12759 significantly decreased the Rose bengal scores of the cornea and conjunctiva in NAC–treated eyes. OPC–12759 increased the mucin contents of the secreted and cell–associated mucin from/in cultured HCECs in a concentration–dependent manner. The gene expression levels of MUC1 and MUC4 in cultured HCECs were up–regulated by 10^–5M OPC–12759. Conclusions: OPC–12759 increased the amount of mucin contents in the ocular surface due to its effect on corneal epithelial cells and conjunctival PAS–positive cells, and improved ocular surface damage. For corneal epithelial cells, it directly increased secreted and membrane–spanning mucin contents. Therefore, OPC–12759 may be of therapeutic value in the treatment of dry eye patients by increasing the mucin contents in the ocular surface.

Keywords: cornea: surface mucins • cornea: tears/tear film/dry eye • drug toxicity/drug effects