The PDE4 Inhibitor Cilomilast Inhibits Corneal Staining and Normalizes Tear Film Parameters in Animal Models of Dry Eye

Abstract

Purpose: : Phosphodiesterase type 4 (PDE4) inhibitors prevent catalysis of intracellular cAMP in multiple cell types. With respect to dry eye therapy, relevant consequences of elevated cAMP include anti-inflammatory and pro-secretory effects. Cilomilast is a potent and selective PDE4 inhibitor which inhibits inflammatory cell activation and cytokine secretion. Cilomilast was evaluated for topical ocular efficacy in several models of dry eye disease.

Methods: : Dry eye was induced in Wistar rats by systemic administration of scopolamine through subcutaneous osmotic pumps and housing in an environmental chamber. Corneal staining was measured by digital image analysis of fluorescein-stained corneas in vivo. Dry eye was induced in NZW rabbits by direct lacrimal gland injection of concanavalin A. Corneal staining was measured by uptake of methylene blue dye. Sex hormone deficiency was induced in female Lewis rats by ovariectomy at 2 weeks of age. Tear fluorescein clearance and total tear protein concentration were measured in vivo. Tear secretion in rats was measured by the phenol red thread test. Human corneal epithelial cells (CEPI-17) in culture were stimulated with hyperosmolar media and cytokine secretion was measured by ELISA.

Results: : In both the rat and rabbit models of dry eye, cilomilast (BID) provided steroid-equivalent inhibition of corneal staining at concentrations of 0.001 to 0.1% w/v. Topical administration of 0.05% cilomilast normalized tear protein concentrations and tear clearance in sex steroid-deficient rats. Cilomilast significantly increased tear secretion above vehicle from 10 min to 4 hrs after topical administration in normal rats. Topical 0.05% cilomilast (BID) also normalized tear secretion in dry eye rats. Cilomilast inhibited hyperosmolarity-induced TNF secretion in CEPI cells (EC₅₀ = 450 nM).

Conclusions: : Topical administration of the anti-inflammatory and pro-secretory selective PDE4 inhibitor cilomilast suppressed corneal staining and normalized tear secretion, clearance, and protein concentration in animal models of dry eye. Pro-secretory effects of cilomilast did not exhibit tachyphylaxis. Anti-inflammatory efficacy was equivalent to dexamethasone. These data support the utility of selective PDE4 inhibitors such as cilomilast in the topical treatment of dry eye.

Keywords: cornea: tears/tear film/dry eye