discovering dry eye
An Experimental Treatment Packs a Triple Punch
BY KELLY K. NICHOLS, OD, MPH, PHD

Inspire Pharmaceuticals, in collaboration with Allergan Inc. and Santen, has developed diquafosol tetrasodium (INS365) for treating dry eye disease. Final FDA decisions about this drug are expected in early 2004.  This column will summarize the mechanism of action and the treatment potential for diquafosol.

Figure 1. Ocular surface rehydration.

Activating P2Y₂ Receptors

Diquafosol is a P2Y₂ purinergic receptor agonist. It activates P2Y₂ receptors on the ocular surface, which stimulates the fluid pump mechanism of the accessory lacrimal glands on the conjunctival surface.

P2Y₂ agonists are also potent mucin secretagogues and stimulate goblet cell secretion of ocular mucins. Their ability to increase ocular lipid production (the outermost layer of the tear film) is less established, but in vitro experiments show that the receptor is present in the meibomian gland and that diquafosol induces lipid composition changes in cultured meibomian gland cells.

Diquafosol provides a rapid, receptor-mediated rehydration of the ocular surface through the coordinated production of salt, water, mucin and possibly lipid, thus restoring major tear film natural components (Figure 1).

	Figure 2. P2Y2 receptor in cell membrane.

How Diquafosol Works

Three suggested mechanisms of action for diquafosol are fluid transport, mucin secretion and lipid stimulation. Binding of diquafosol to P2Y₂ receptors increases intracellular calcium and activates chloride ion transport, driving fluid transport across the epithelial layer (Figure 2).

In rabbit conjunctival tissue, diquafosol increased the rate of serosal-to-mucosal fluid transport by about 50 percent (Li et al 2001) and increased cholesterol and phospholipid by 124 percent and 89 percent above basal, respectively (Wen et al 2002).

The results suggest that diquafosol may stimulate the formation of lipid-containing vesicles in meibocytes.

Indications and Usage

Diquafosol is an unpreserved, sterile, aqueous eye drop administered q.i.d for treating dry eye. Diquafosol's triple mechanism of action makes it an attractive treatment choice for dry eye.

Dr. Nichols is assistant professor of clinical optometry at The Ohio State University College of Optometry in the area of dry eye research. She served as an investigator for Inspire Pharmaceuticals INS365 clinical trial.