Rimexolone dose–dependently inhibits corneal staining and increases tear breakup time in a rabbit model of lacrimal gland inflammation–induced dry eye

Abstract

Abstract: : Purpose:To determine the efficacy of the anti–inflammatory corticosteroid rimexolone in a rabbit model of dry eye. Methods:In vitro, rimexolone was evaluated for the ability to inhibit proinflammatory cytokine secretion from human corneal epithelial cells exposed to hypertonic media. In the in vivo disease model, lacrimal gland inflammation was elicited in rabbits following injection with the T–lymphocyte mitogen Concanavalin A (Con A) and clinically relevant signs of dry eye, tear breakup time (TBUT) and corneal epithelial cell integrity were subsequently assessed. TBUT was monitored daily using sodium fluorescein and corneal injury was determined by spectrophotometric quantitation of the uptake of methylene blue dye. Rimexolone and other test drugs were administered topically as indicated for each study. Results:Rimexolone was equipotent (IC₅₀ = <10nM) with dexamethasone in inhibiting hyperosmolar media–stimulated secretion of IL–1ß, IL–6, IL–8 and TNFα by human corneal epithelial cells in vitro. In vivo, rimexolone significantly increased TBUT and prevented corneal injury when administered topically to rabbits at concentrations ranging from 0.005%, w/v to 0.1%, w/v. Baseline TBUT was approximately one full minute in normal rabbits as well as in animals injected in the lacrimal gland with saline. In contrast, TBUT in vehicle treated animals was less than five seconds within one day of lacrimal gland injection with Con A. Topical ocular treatment with rimexolone dose–dependently restored TBUT toward baseline with significant efficacy achieved at the lowest concentration tested, 0.005%, w/v. Topical ocular treatment with rimexolone also dose–dependently inhibited corneal staining, with greater than 50% inhibition of dye uptake achieved over a 0.01%–0.1% rimexolone concentration range. Rimexolone was prophylactically and therapeutically effective in the rabbit dry eye model. Rimexolone was optimally effective at 0.1%, w/v and, at this concentration, was superior in efficacy to 0.2% loteprednol etabonate. Conclusions:The preclincal studies suggest that rimexolone may be effective in treating ocular surface inflammation associated dry eye at low concentrations, thereby maximizing its therapeutic index.

Keywords: cornea: tears/tear film/dry eye • inflammation • corticosteroids