Page 169 - 80_01

Dry
eye
disease
compounds…

TOBRADEX

TobraDex
was
approved
by
FDA
as
dry
eye
treatment
in
1988.
TobraDex
is
a

combination
of
tobramycin
and
dexamethasone
(Figure
15).
Tobramycin
is
an

aminoglycoside
antibiotic-­-antibacterial
derived
from
streptomycestenebrarius
and

is
used
to
treat
various
types
of
eye
infections.
It
is
working
through
binding
to
a

site
on
the
bacterial
30S
and
50S
ribosome,
preventing
formation
of
the
70S

complex,
inhibiting
mRNA
to
be
translated
into
protein
(85).
Dexamethasone
is
a

potent
synthetic
member
of
the
glucocorticoid
class
of
steroid
drugs
used
to

reduce
the
inflammation
and
relieve
the
symptoms
of
the
inflammatory
eye
(86).

The
combination
of
tobramycin/dexamethasone
might
be
an
interesting
solution

for
dry
eye
problems
caused
by
inflammation
and
infection.
Lately
Alcon
is

evaluating
a
reformulation
of
TobraDex
decreasing
the
amount
of
the
steroid
(from

0.1%
to
0.05%)
adding
an
inactive
agent
(xanthan
gum),
to
stabilize
the

combination
and
to
deliver
more
of
each
drug
to
the
eye.
The
composition
provides

longer
ocular
retention
for
enhanced
ocular
bioavailability
of
tobramycin
and

dexamethasone
and
improved
suspension
of
dexamethasone
(87).
Alcon
executed

Phase
III
clinical
trials
(ClinicalTrials.gov
Identifier:
NCT00576251)
in
June
2007

for
TobraDex
ophthalmic
suspension,
containing
0.3%
of
tobramycin
and
0.05%

and
now
is
marketing
the
product
as
an
antibiotic
to
treat
bacterial
infections.

SYL1001

The
Spanish
biotechnology
company
Sylentis
is
developing
the
compound

SYL1001,
which
is
decreasing
the
pain
related
to
dry
eye
disease,
is
acting
by

targeting
the
TRPV1gene
expression
on
the
ocular
surface
(interference
RNA,

RNAi)
(84,
85).
This
is
an
interesting
approach
as
gene
silencing
is
an
attractive

aspect
avoiding
the
activity
of
some
proteins
by
inhibiting
its
synthesis.
In

November
2010
Sylentis
started
a
Phase
II
safety/efficacy
study
(ClinicalTrials.gov

Identifier:
NCT01776658)
on
patients
with
common
mild
to
moderate
dry
eye

symptoms
and
persistent
daily
symptoms
for
more
than
three
months.
The
study

is
still
ongoing
but
the
initial
results
are
very
promising.

R932348

Rigel
Pharmaceuticals
is
working
on
R932348
2,4-­-pyrimidinediamine,
a

small
JAK3
molecule
inhibitor,
as
a
possible
treatment
for
autoimmune
diseases

(Figure
16)
(88).
During
trials
it
was
observed
that
systemic
levels
of
IL-­-17,
IL-­-22,

IL-­-23,
and
TNF-­-a
were
significantly
lower
in
mice
receiving
the
compound,
and
T

165