Page 166 - 80_01

Basilio
Colligris,
Jesús
Pintor

and
colleagues
confirmed
that
mapracorat
exerts
its
anti-­-inflammatory
effects,
at

least
in
part,
by
augmenting
MAPK
phosphatase-­-1
(MKP-­-1)
expression
(68).
The

compound
has
an
improved
side-­-effect
profile,
compared
to
classical

glucocorticoids.
On
the
other
hand
farther
research
is
necessary
due
to
reports
of

skin
atrophy
produced
in
some
patients
(69).
Bausch
&
Lomb
performed
Phase
II

studies
on
350
patients,
to
assess
the
safety
and
efficacy
of
0.3%,
2%
BOL-­-303242-­-
X
in
dry
eye
syndrome,
(ClinicalTrials.gov
Identifier:
NCT01163643)
from
July

2010
to
November
2012
but
did
not
publish
results.

AL43546

AL43546
is
an
ophthalmic
solution
developed
by
Alcon.
It
is
consisted
of

hydroxypropyl
guar
galactomannan
0.15%
or
0.25%
(Figure
10).
Guar

galactomannan
is
used
to
add
viscosity
to
artificial
tears.
In
September
2008
Alcon

started
a
Phase
II
clinical
pharmacological
study
of
AL-­-43546
ophthalmic

compound
in
subjects
with
shortened
tear
film
break
up
time,
to
study
the
lacrimal

fluid
condition
chronologically
after
a
single
dose
of
AL-­-43546
ophthalmic
solution

(ClinicalTrials.gov
Identifier:
NCT00760045)
(70).
The
results
were
not
published.

SIROLIMUS-­-RAPAMYCIN

Sirolimus
is
an
antibiotic
demonstrating
immunosuppressive
and
anti-­-
inflammatory
properties.
Its
mechanism
of
action
is
to
block
T-­-cell
activation
and

proliferation,
to
activate
p70
S6
kinase
and
to
inhibit
significantly
the
production

of
Th1
cytokines
(IFN
?,
IL-­-2
and
TNF)
(71).
Its
name
is
derived
from
a
native
word

from
Easter
Island,
Rapi
Nui
(Figure
11).
Santen
Pharmaceutical
is
working
with

subconjunctival
injections
of
sirolimus
as
a
mTOR
inhibitor
to
treat
dry
eye
(72).
It

is
reported
that
the
activation
of
rapamycinmTOR
signaling
mediates
nerve
growth

factor
(NGF)
inducing
cell
migration
(73).
From
December
2008
to
July
2010,

Santen
realized
a
Phase
II
dose-­-ranging
clinical
study
(ClinicalTrials.gov
Identifier:

NCT00814944)
to
assess
the
safety
and
efficacy
of
subconjunctival
injection
of

sirolimus
on
143
patients
with
dry
eye
in
a
controlled
adverse
environmental

(CAE)
model.
The
doses
applied
were
220,
440
and
880
micrograms
of
rapamycin.

The
results
indicated
that
sirolimus
is
safe
and
tolerable
with
no
systemic
adverse

events
noted,
demonstrating
bioactivity
as
immunomodulatory
and
corticosteroid-­-
sparing
agent.
It
is
proved
capable
to
reduce
vitreous
haze
and
cells,
improving

visual
acuity
(74).

162