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VOL. 72 (3), 519-538, 2006 NEW PERSPECTIVES IN OCULAR PHARMACOLOGY...

When a wide range of concentrations of the dinucleotides were
used, it was possible to establish concentration-response curves
which permitted to calculate EC50 values for the diadenosine
polyphosphates. Ap4A presented an EC50 value of 2.76 µM, Ap5A a
value of 1.77 µM and Ap6A a value of 3.16 µM (14).

The ability of some diadenosine polyphosphates activating tear
production, is indicating that they can be considered as constitutive
activators of tear release being this mechanism independent from
the one that naturally control the main lachrymal glands (16).
Moreover, the topical application of some of these compounds such
as Ap4A, may be useful for the treatment of dry eye specially those
cases in which this pathology takes place with a lack of tear volume.

The design of new pharmacological compounds with nucleotidic
structure such as diquafosol aka INS365, brings interesting
expectations for dry eye treatment. This compound is a congener
of Ap4A (diuridine tetraphosphate, Up4U) and presents a similar
behaviour to the one observed for UTP or diadenosine
polyphosphates (22). This substance enhanced tear secretion even
after consecutive doses for several days as revealed by Schirmer
scores. Tear secretion was increased 5-15 min after the compound
application, and the effect persisted longer with solution of
diquafosol of 8.5%. The clinical trials performed with humans with
dry eye disease demonstrated good toleration in all the individuals
at all the doses assayed. Applications of 25 µL of 0.5%, 1%, 2%, and
5% w/v produced increased tear secretion in patients with mild to
moderate dry eye. All these results suggest the unequivocal utility of
this compound as a therapeutic agent for dry eye syndrome (23).

In a model of dry eye developed in rats, the topical application of
the dinucleotide Up4U (diquafosol) increased tear secretion, surface
health, and release of glycoproteins from goblet cells. These
interesting properties of this dinucleotide indicate the therapeutic
benefits of this compound for the treatment of dry eye (24).

Wound healing

The cornea is the most superficial part of the eye. This structure
is suitable of having different damages coming from the

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