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Stimulatory action on secretion of tear fluid including mucin: A single dose administration of diquafosol sodium into the eyes of normal animals (rabbits and rats) promoted tear fluid secretion and mucin secretion from the conjunctival cells.
A single dose administration of diquafosol sodium into the eyes of dry eye model rats promoted tear fluid secretion. Repeated dose administration increased mucin contents in the conjunctival tissues.
Stimulatory action on mucin production in corneal epithelial cells: Diquafosol sodium stimulated gene expression and protein production of membrane-associated mucin in corneal epithelial cells.
Improvement of corneal epithelial damage: Repeated dose administration of diquafosol sodium 6 times daily for 4 weeks improved corneal epithelial damage in rat dry eye model in a dose-dependent manner, and exhibited the maximal effect at the concentration of 1% or higher. Repeated dose of 1% diquafosol sodium for 2 weeks exhibited the maximal improvement effect when daily administration exceeded 6 times.
Clinical Studies: Late phase II study (Randomized, double-masked comparative study using a placebo ophthalmic solution as a control drug): In the late phase II study in patients with dry eye, DIQUAS (in 93 patients including 16 patients with Sjogren's syndrome) significantly lowered fluorescein staining scores* in the cornea and rose bengal staining scores* in the cornea and conjunctiva compared to a placebo ophthalmic solution (as a control drug in 93 patients including 23 patients with Sjogren's syndrome). (See Table 1 and Table 2.)
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Click on icon to see table/diagram/imagePhase III study (Randomized, double-masked comparative study using 0.1% purified sodium hyaluronate ophthalmic solution as a control drug): In the phase III study in patients with dry eye, DIQUAS (in 144 patients including 36 patients with Sjogren's syndrome) equivalently lowered fluorescein staining scores* in the cornea and significantly lowered rose bengal staining scores* in the cornea and conjunctiva compared to a 0.1% purified sodium hyaluronate ophthalmic solution (as a control drug in 142 patients including 32 patients with Sjogren's syndrome). (See Table 3 and Table 4.)
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Click on icon to see table/diagram/imageLong-term administration study (Phase III): In a long-term administration study in patients with dry eye (in 244 patients including 9 patients with Sjogren's syndrome and 2 patients with Stevens-Johnson syndrome), the group under DIQUAS administration exhibited lower fluorescein staining scores* in the cornea and rose bengal staining scores* in the cornea and conjunctiva throughout the 52 weeks administration period, and longer continued effect compared to those before administration.
* Scoring method in the clinical studies: In the fluorescein staining, severity of a corneal damage was graded on a nine-point scale by scoring the fluorescein staining intensity at 3 sites (superior, middle and inferior) which were individually graded from 0 to 3 points. In the rose bengal staining, severity of a corneal and conjunctival damage was graded on a 15-point scale by scoring the rose bengal staining intensity at 5 sites (superior, middle and inferior sites of the cornea, and nasal and temporal conjunctiva) which were individually graded from 0 to 3 points.
Pharmacokinetics: Plasma concentrations: After topical administration of diquafosol sodium solution either at concentrations of 0.3%, 1%, 3% or 5% to the eye of healthy adult volunteers one drop, once daily for one day, 6 times daily for one day or 6 times daily for 7 days, the plasma concentrations of diquafosol sodium and its metabolites were measured. Those of diquafosol sodium were below the lower limit of quantitation (2ng/mL) at every time point in all of the volunteers. Its metabolites (UTP, UDP, UMP and uridine) did not affect physiological concentrations derived from the endogenous components. (Note: The approved concentration of this product is 3%.)
Ocular tissue distribution in animals (Rabbits): Following a single topical administration of 3% 14C-diquafosol sodium ophthalmic solution to rabbit eyes, the radioactivity was distributed in the extraocular tissues including the conjunctiva and cornea, and reached the maximum radioactive concentrations in the cornea and conjunctiva at 5 minutes after administration. Thereafter, the radioactivity reduced to 4 to 30% of the maximum concentrations at 24 hours after administration.
Metabolism (Human in vitro): In vitro metabolism reaction using human plasma and human liver microsome demonstrated that diquafosol sodium was rapidly metabolized, and UMP, uridine and uracil were produced.
(Rabbits): At 30 minutes after instillation of 3% 14C-diquafosol sodium ophthalmic solution to rabbit eyes, diquafosol sodium was hardly detected in the ocular tissues, and instead UTP, UDP, UMP, uridine and uracil were detected.
