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

Within the above percentage, between 12% and 20% reduce
significantly the use of contact lenses because of the mentioned
discomfort. Most of the approaches to solve this problem lie in
changing the tear viscosity by the application of compounds
based on preparations containing carboxymethylcellulose,
hydroxypropylcellulose, or polyvinylalcohol. There are no good
pharmacological solutions available to restore normal tear film
properties.

Nucleotides are interesting compounds restoring the normality
in those individuals presenting ocular dryness. Nucleotides and
dinucleotides have been described in human and experimental
animal tears. The most representative ones are the diadenosine
polyphosphates, which are dinucleotides formed by two adenosines
linked by a variable number of phosphates which can fluctuate
between 2 and 7 (abbreviated as ApnA, n = 2-7) (13). These
dinucleotides have been described by means of high performance
liquid chromatography (HPLC) as presented in Figure 1A.
Diadenosine triphosphate, Ap3A, diadenosine tetraphosphate Ap4A
and diadenosine pentaphoshate Ap5A have been described in human
tears while Ap3A was absent in rabbit tears. The concentration
between human and rabbit tears were also different. While in
humans the concentrations of the dinucleotides are in the nanomolar
range in the animal it was in the micromolar one (14, 15).

One interesting point after demonstrating their presence in tears
is to understand where these dinucleotides come from. Experiments
performed in healthy human volunteers demonstrate that nucleotides
and dinucleotides are released from the ocular surface, probably
both cornea and conjunctiva by mechanical stress (16). It has been
demonstrated that an increase in the blinking frequency produces
an associated increase in the diadenosine polyphosphate tear
concentration. Although the molecular mechanism has not been
elucidated, it is possible, as occurs in the central nervous system,
that nucleotides are liberated from nerve terminals, but there is
evidence that nucleotides can be transported out of cells. Epithelial
cells (17, 18), and in particular ocular epithelial cells, use different
transport mechanisms as a regulated procedure for nucleotide
release. The ATP binding cassette (ABC) transporter, the cystic
fibrosis transmembrane conductance regulator (CFTR) or

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