Page 168 - 80_01

Basilio
Colligris,
Jesús
Pintor

colleagues
verified
that
DA-­-6034
at
concentrations
above
100
microM
increased

mucin-­-like
glycoprotein
levels
in
animal
models,
in
conjunctival
and
corneal

epithelial
cells
(79).
Furthermore
in
human
conjunctival
epithelial
cells,
DA-­-6034

treatment
in
doses
of
200
microM
increased
mucin
secretion
between
the
trans-­-
membrane
mucins
MUC1,
MUC2,
MUC4,
MUC5AC,
MUC5B,
and
MUC16
(79).
Seo

and
colleagues
investigated
the
inhibiting
effect
of
DA-­-6034
MMP-­-9
on

inflammatory
cytokines
and
the
activation
of
the
MAPK
signaling
pathway
on

rabbit
inflammation
models.
It
was
demonstrated
that
DA-­-6034
could
restore
tear

function
and
inhibit
inflammatory
responses
reducing
the
phosphorylation
of
Jun

N-­-terminal
kinase
(JNK)
and
p38
MAPK,
inhibiting
the
nuclear
factor
kappa
B
cells

(NF-­-kB)
activation
in
corneal
epithelial
cells
(80).
The
NF-­-?B
is
a
key
transcription

factor
pathway,
responsible
for
many
key
biological
processes,
such
as

inflammation,
apoptosis,
stress
response,
corneal
wound
healing,
and
angiogenesis

(81).
The
company
Dong-­-A
started
a
Phase
II
study
of
DA-­-6034
(ClinicalTrials.gov

Identifier:
NCT01670357)
in
January
2012
to
determine
the
efficacy
and
safety
of

3%
or
5%
DA-­-6034
eye
drops
on
150
patients
with
doses
of
one
drop/each
eye,

four
times/day,
for
four
weeks.

RX-­-10045

Resolvyx
Pharmaceuticals
developed
RX-­-10045
(Figure
14)
a
small
lipid

mediator
as
a
product
candidate
for
the
treatment
of
ocular
surface
and
anterior

segment
diseases
(82).
In
2010
Celtic
Therapeutics
and
Resolvyx
Pharmaceuticals

started
to
collaborate
in
the
development
of
the
compound.
RX-­-10045
is
a

synthetic
resolvin
E1
(RvE1)
analog
formulated
for
topical
application
treatment
of

eye
disease
as
a
potent
mediator
of
inflammatory
resolution,
endogenously

produced
by
the
human
body
from
omega-­-3
fatty
acid
(83).
In
pre-­-clinical
dry
eye

models,
RX-­-10045
has
demonstrated
potent
efficacy.
The
compound
successfully

completed
a
Phase
II
study
(ClinicalTrials.gov
Identifier:
NCT00799552)
in
dry
eye

patients
and
according
to
the
companies
it
demonstrated
significant
symptom

improvement
from
baseline
(as
assessed
in
subject
diaries),
and
performed

significantly
better
than
placebo
on
the
primary
endpoint
of
the
worst
symptom

score
with
a
75%
reduction
in
controlled
adverse
environment-­-induced
central

corneal
staining
from
baseline
(84).
RX-­-10045
was
evaluated
in
another
Phase
II

study
(ClinicalTrials.gov
Identifier:
NCT01675570)
from
August
2012
to
February

2013
on
150
patients
for
the
treatment
of
dry
eye
disease
but
the
results
are
not

yet
published.

164