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Sodium hyaluronate eyedrops in the treatment of dry eyes

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Several studies in the past have attempted to demonstrate the efficacy of sodium hyaluronate in the treatment of dry eyes. However, results have been conflicting and a definite conclusion has not yet been reached. This study recruited a larger group of patients and has incorporated for the first time both fluorescein and rose bengal staining in the evaluation of the epithelium. Eighteen albino rabbit corneas were used in a basic animal study to demonstrate the efficacy of sodium hyaluronate by comparing the effects on the rate of epithelial healing. The optimal concentration to be used in the clinical trial was determined from the results of the basic study. In the clinical study 104 patients with dry eye syndrome were enrolled in a double masked controlled clinical trial. Patients received sodium hyaluronate drops in one eye and control medication in the other eye for 4 weeks. Grading of subjective symptoms and clinical examinations were performed at 2 and 4 weeks. In the animal study sodium hyaluronate at concentrations of 0.1% and 0.5% significantly accelerated the recovery time of iodine vapour induced corneal erosions (p < 0.01). In the clinical study no statistical significance was observed in the improvement of subjective symptoms or rose bengal staining, while fluorescein scores significantly improved in eyes receiving sodium hyaluronate (p = 0.0001) at 4 weeks. Sodium hyaluronate drops applied in six daily doses could not be demonstrated to offer advantages over conventional tear supplies in the improvement of subjective symptoms, but may play a role in maintaining a healthy corneal epithelium.
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British
Joumnal
of
Ophthalmology
1995;
79:
1007-101
1
Sodium
hyaluronate
eyedrops
in
the
treatment
of
dry
eyes
Shigeto
Shimmura,
Masafumi
Ono,
Kazumi
Shinozaki,
Ikuko
Toda,
Etsuko
Takamura,
Yukihiko
Mashima,
Kazuo
Tsubota
Abstract
Background-Several
studies
in
the
past
have
attempted
to
demonstrate
the
efficacy
of
sodium
hyaluronate
in
the
treatment
of
dry
eyes.
However,
results
have
been
conflicting
and
a
definite
con-
clusion
has
not
yet
been
reached.
This
study
recruited
a
larger
group
of
patients
and
has
incorporated
for
the
first
time
both
fluorescein
and
rose
bengal
staining
in
the
evaluation
of
the
epithelium.
Methods-Eighteen
albino rabbit
corneas
were
used
in
a
basic
animal
study
to
demonstrate
the
efficacy
of
sodium
hyaluronate
by
comparing
the
effects
on
the
rate
of
epithelial
healing.
The
optimal
concentration
to
be
used
in
the
clinical
trial
was
determined
from
the
results
of
the
basic
study.
In
the
clinical
study
104
patients
with
dry
eye
syndrome
were
enrolled
in
a
double
masked
controlled
clinical
trial.
Patients
received
sodium
hyaluronate
drops
in
one
eye
and
control
medication
in
the
other
eye
for
4
weeks.
Grading
of
subjective
symptoms
and
clinical
exmnations
were
performed
at
2
and
4
weeks.
Results-In
the
animal
study
sodium
hyaluronate
at
concentrations
of
0-1%
and
0*5%
significantly
accelerated
the
recovery
time
of
iodine
vapour
induced
corneal
erosions
(p<
0-01).
In
the
clinical
study
no
statistical
significance
was
observed
in
the
improvement
of
subjective
symptoms
or
rose
bengal
staining,
while
fluorescein
scores
significantly
improved
in
eyes
receiving
sodium
hyaluronate
(p=0.0001)
at
4
weeks.
Conclusion-Sodium
hyaluronate
drops
applied
in
six
daily
doses
could
not
be
demonstrated
to
offer
advantages
over
conventional
tear
supplies
in
the
improve-
ment
of
subjective
symptoms,
but
may
play
a
role
in
maintaining
a
healthy
corneal
epithelium.
(Br_J
Ophthalmol
1995;
79:
1007-101
1)
Sodium
hyaluronate
is
a
glycosaminoglycan
found
in
significant
amounts
in
synovial
fluid
and
the
vitreous
humour.
Owing
to
the
large
number
of
negative
charges
on
the
molecule,
sodium
hyaluronate
is
capable
of
holding
large
quantities
of
water,
and
thus
lubricating
surrounding
structures.
Previous
studies
have
evaluated
the
efficacy
of
sodium
hyaluronate
as
a
tear
replacement
in
the
treatment
of
dry
eyes
with
varying
results.'
Controlled
double
masked
studies
by
Limberg4
and
Nelson5
showed
no
significant
advantage
compared
with
chondroitin
sulphate
or
polyvinyl
alcohol,
while
Sand6
concluded
that
sodium
hya-
luronate
was
effective
in
another
double
masked
trial.
This
discrepancy
may
be
due
to
factors
such
as
differences
in
severity
of
dry
eyes,
variation
of
examination
techniques,
or
frequency
of
application.
The
relatively
small
number
of
patients
enrolled
(20
to
30
cases
in
each
study)
may
have
contributed
to
statistical
variation.
However,
certain
properties
of
sodium
hyaluronate
such
as
long
ocular
surface
residence
time7
and
increased
tear
evaporation
from
the
ocular
surface
following
application8
make
sodium
hyaluronate
a
promising
agent
that
merits
a
more
extensive
study.
In
order
to
provide
additional
evidence
for
the
effectiveness
of
sodium
hyaluronate,
we
first
conducted
an
in
vivo
study
using
rabbits
to
demonstrate
the
effects
of
sodium
hyaluronate
on
experimentally
induced
corneal
epithelial
lesions,
followed
by
a
multicentred,
controlled
double
masked
clinical
trial
of
sodium
hyaluronate
in
the
treatment
of
kerato-
conjunctival
lesions
in
dry
eyes.
We
adopted
a
study
design
in
which
sodium
hyaluronate
and
placebo
were
applied
concurrently
in
different
eyes
of
the
same
patient
in
order
to
minimise
differences
in
study
conditions.
This
minimises
temporal
factors
that
come
into
play
when
comparing
eyedrops
applied
during
different
time
periods.
This
study
focused
primarily
on
fluorescein
staining
as
well
as
rose
bengal
staining.
Both
fluorescein
and
rose
bengal
are
of
the
hydroxy-
xanthene
dye
family,
with
rose
bengal
having
extra
halide
derivatives
within
the
molecule
accounting
for
its
larger
molecular
weight
and
shift
in
spectroscopic
absorption
wavelength.
Feenstra
and
Tseng9
reviewed
how
fluorescein
and
rose
bengal
have
slightly
different
staining
properties.
Although
the
consensus
is
that
rose
bengal
stains
non-viable
cells
and
mucous
strands,
it
has
been
demonstrated
to
stain
viable
cells
in
vitro
but,
in
vivo,
is
blocked
by
tear
component
proteins
and
polymers
such
as
carboxymethylcellulose.
On
the
other
hand,
fluorescein
lacks
this
ability
to
be
blocked
by
tear
constituents,
and
diffuses
rapidly
into
the
stroma
where
cell
to
cell
junctions
are
dis-
rupted.
The
clinical
implications
of
each
dye,
as
summarised
by
Feenstra
and
Tseng,
are
that
fluorescein
staining
is
promoted
by
disruption
of
cell-cell
junctions,
and
rose
bengal
staining
is
due
to
insufficient
protection
of
the
pre-
ocular
tear
film,
both
in
terms
of
decreased
tear
components
and
abnormal
surface
epithelial
cells.
The
different
staining
properties
of
each
Department
of
Ophthalmology,
Keio
University
School
of
Medicine,
Tokyo,
Japan
S
Shimmura
Y
Mashima
Department
of
Ophthalmology,
Minami-Tama
Hospital,
Tokyo,
Japan
M
Ono
Department
of
Ophthalmology,
Tokyo
Women's
Medical
College,Tokyo,
Japan
K
Shinozaki
E
Takamura
Department
of
Ophthalmology,
Tokyo
Dental
College,
Chiba,
Japan
I
Toda
K
Tsubota
Correspondence
to:
Shigeto
Shimmura,
MD,
Department
of
Ophthalmology,
Keio
University
School
of
Medicine,
Shinanomachi
35,
Shinjuku,
Tokyo,
Japan.
Accepted
for
publication
18
July
1995
1007
Shimmura,
Ono,
Shinozaki,
Toda,
Takamura,
Mashima,
Tsubota
dye
may
prove
effective
in
differentiating
the
pathological
condition
of
the
corneal
epithe-
lium.
Micropipettes
were
used
to
apply
fluo-
rescein
and
rose
bengal
in
order
to
standardise
the
amount
of
applied
dye
as
much
as
possible.
Material
and
methods
BASIC
STUDY
Eighteen
corneas
of
nine
male
albino
rabbits
weighing
2
to
3
kg
were
used
in
the
study.
Test
medication
consisted
of
01%
and
05%
sodium
hyaluronate,
while
the
vehicle
of
the
solution
(phosphate
buffer,
pH
7
35)
served
as
a
control.
Corneas
were
divided
into
four
groups:
two
groups
receiving
sodium
hyaluronate
in
concentrations
mentioned
above
(n=4
and
5
respectively),
one
group
receiving
the
vehicle
(n=4)
serving
as
control,
and
one
untreated
group
(n=
5).
Corneal
erosions
were
made
according
to
Parkinson
and
Schuchard10
using
iodine
vapour.
In
brief,
rabbits
were
put
under
general
anaesthesia
by
pentobarbitone
fol-
lowed
by
topical
administration
of
oxybupro-
caine.
A
7
mm
glass
tube
with
a
glass
wool
plug
containing
iodine
crystals
was
gently
applied
to
the
central
cornea
for
3-5
minutes.
Round
corneal
erosions
appeared
approximately
4
hours
after
exposure
to
iodine
vapour.
Corneas
were
stained
with
fluorescein,
and
the
area
of
epithelial
erosions
was
quantita-
tively
calculated
using
a
digitiser
(Cosmozone
1S,
Nikon
Inc,
Tokyo,
Japan).
After
initial
evaluation
at
4
hours,
50
,ll
of
0
1%,
0
5%
sodium
hyaluronate,
and
control
were
applied
four
times
daily
at
2
hour
intervals
for
2
days.
Evaluation
of
the
wounded
cornea
was
done
at
22,
28,
and
34
hours.
Statistical
analysis
was
performed
by
the
one
way
ANOVA
and
Duncan's
tests.
CLINICAL
STUDY
The
clinical
study
was
conducted
at
eight
major
medical
centres
by
18
dry
eye
specialists
during
a
period
of
9
months
between
September
1991
to
May
1992.
A
total
of
104
patients
with
dry
eye
syndrome
(including
Sjogren's
syndrome)
were
enrolled.
Dry
eye
was
diagnosed
accord-
ing
to
Toda
et
al."
In
brief,
patients
with
(1)
dry
eye
related
symptoms,
(2)
positive
staining
with
either
fluorescein
or
rose
bengal,
and
(3)
tear
break
up
time
less
than
5
seconds
or
a
Schirmer
test
value
of
less
than
5
mm
were
diagnosed
as
having
dry
eyes.
Sjogren's
syn-
drome
was
diagnosed
according
to
the
criteria
proposed
by
Fox
et
al,
12
where
patients
positive
in
three
or
more
of
the
following
four
criteria
were
diagnosed
as
having
Sjogren's
syndrome:
(1)
dry
eye,
(
2)
xerostomia,
(3)
lymphocytic
infiltrates
on
minor
salivary
gland
biopsy,
and
(4)
serological
evidence
(positive
rheumatoid
factor
or
positive
antinuclear
antibody
or
posi-
tive
SS-A
or
SS-B
antibody).
The
criteria
for
dry
eye
in
this
case
are
somewhat
different
from
the
original
criteria
for
keratoconjunctivitis
sicca
(KCS)
proposed
by
Fox
et
al
on
two
points:
(1)
the
presence
of
symptoms
is
not
questioned
in
the
original
paper,
and
(2)
patients
with
Schirmer
values
in
the
normal
range,
but
with
tear
break
up
times
of
less
than
5
seconds
were
included.
All
patients
gave
their
informed
consent
before
enlisting
in
the
study.
In
addition
to
the
diagnosis
of
dry
eye,
patients
eligible
for
the
study
were
required
to
have
a
rose
bengal
score
of
greater
than
3
(on
a
scale
of
0
to
21).
This
was
to
exclude
very
mild
cases
where
statistical
comparisons
of
staining
scores
would
not
be
possible.
Patients
with
infectious
extraocular
disease,
corneal
epithelial
disorders
associated
with
diabetes
mellitus,
and
neurotrophic
ker-
atitis
were
excluded
from
the
study.
Patients
with
overt
asymmetrical
staining
patterns
at
the
time
of
initial
examination
were
also
excluded.
The
test
medication
used
was
a
preservative-
free
0
1%
sodium
hyaluronate
solution
(1
X
106
Da)
bottled
in
a
single
dose
disposable
con-
tainer.
The
vehicle
for
the
solution,
consisting
of
the
same
agents
as
the
test
solution
exclud-
ing
sodium
hyaluronate
(25
mM
phosphate
buffered
saline,
pH
7
36),
was
used
as
control.
Identical
disposable
containers
were
used
so
that
discrimination
between
solutions
was
difficult.
The
study
was
conducted
in
a
double
blind,
controlled fashion
in
which
each
patient
received
the
sodium
hyaluronate
eyedrops
in
one
eye,
and
the
vehicle
in
the
other.
The
eye
to
receive
sodium
hyaluronate
in
each
patient
was
randomly
selected
by
a
designated
study
controller.
Before
participating
in
the
study,
patients
were
required
to
'wash
out'
their
eyes
for
2
weeks
with
a
conventional
preservative-free
artificial
tear
solution
(Soft
Santear,
an
iso-
tonic
NaCl,
KCI
solution
with
1%
boric
acid,
pH
7-0-8-0,
Santen
Pharmaceuticals,
Osaka
Japan),
applied
six
times
a
day.
After
this
2
week
period,
patients
were
examined
and
interviewed
to
grade
subjective
symptoms
such
as
foreign
body
sensation,
pain,
burning,
and
itching
on
a
scale
of
0
to
5
(see
Table
1
for
list
of
symptoms).
Fluorescein
and
rose
bengal
staining,
as
well
as
tear
break
up
time
were
observed
according
to
Toda
and
Tsubotal3
by
instilling
2
,ul
of
a
1%
fluorescein-1%
rose
ben-
gal
solution
by
micropipette
(Fig
1).
Micropipettes
were
used
in
order
to
obtain
Table
1
Improvement
in
symptoms
(SD)
in
91
patients
after
4
weeks
0
1%
Sodium
hyaluronate
Control
Asthenopia
-0
55
(0
90)
-0-46
(0
89)
Dry
eye
sensation
-0-69
(1-04)
-0-65
(1-16)
Foreign
body
sensation
-0-67
(1.10)
-0-56
(1-07)
Pain
-0-40
(1-00)
-0-41
(1
10)
Blurred
vision
-0
43
(0
80)*
-0
30
(0
84)
Photophobia
-0
34
(0
82)
-0-31
(0
85)
Redness
-0
43
(0
99)
-0-52
(1-02)
Discharge
--0-24
(0
81)
-014
(080)
Heavy
lids
-0-40
(1-06)
-0
35
(0
98)
General
discomfort
-0
59
(1-14)
-0-46
(1-10)
Difficulty
in
awakening
-0-14
(0
85)
-0-13
(0-79)
Epiphora
-0-10
(0
62)
-0
07
(0
44)
Itchy
sensation
-0-04
(0-82)
+0
01
(0-81)
Hot
sensation
-0-08
(0-97)
-0
03
(0
90)
Minus
sign
indicates
decrease
(improvement)
in
grading
score.
*p=0-0627
(Wilcoxon's
signed
rank
test),
p>0
1
for
all
other
examinations.
1008
Sodium
hyaluronate
eyedrops
in
the
treatment
of
dry
eyes
Figure
1
Slit-lamp
photograph
folowing
application
of
2
,ul
of
%fluorescein-1%
rose
bengal
solution
by
micropipette.
consistent
volumes
and
concentrations
of
dye
so
that
staining
scores
were
not
influenced
by
the
staining
habits
of
different
physicians.
Staining
was
graded
on
a
scale
of
0
to
3
for
each
section
of
cornea
and
conjunctiva
as
in
Figure
2,
followed
by
a
photograph
and/or
detailed
sketch.
Comeal
debris,
meibomitis,
conjunctivitis,
and
conjunctival
injection
were
graded
on
a
scale
of
0
to
4.
Schirmer
test
and
tear
clearance
were
observed
simultaneously
according
to
Ono
et
al,4
5
minutes
after
instil-
ling
10
[lI
of
a
0-5%
fluorescein-0-1%
oxy-
buprocaine
solution
by
micropipette.
Tear
clearance
was
evaluated
by
the
colour
of
the
Schirmer
strip
stained
by
residual
fluorescein
in
the
conjunctival
sac.
Schirmer
strips
stained
with
known
concentrations
of
fluorescein
were
compared
with
the
Schirmer
strip
of
the
patient
to
determine
qualitatively
the
amount
of
fluorescein
remaining
after
5
minutes.
The
Schirmer
test
with
nasal
stimulationl5
was
per-
formed
on
selected
patients.
Following
prelim-
inary
examinations,
patients
were
supplied
with
two
sets
of
eyedrops
in
single
use
dispos-
able
containers
with
labels
indicating
the
eye
to
be
treated.
Neither
the
patient
nor
the
physi-
cian
knew
of
the
contents.
Information
con-
cerning
which
eye
to
receive
sodium
hyaluronate
and
which
eye
to
receive
control
in
Rose
bengal
staining
Fluorescein
staining
Figure
2
Anterior
segment
sectioning
for
staining
scores.
Each
compartment
was
graded
on
a
scale
of
0
(no
staining)
to
3
(intense
staining).
Rose
bengal:
(1)
superior
palpebral
conjunctiva,
(2)
and
(6)
nasal
and
temporal
bulbar
conjunctiva,
(3)
superior
cornea,
(4)
mid
cornea,
(5)
infenor
cornea,
(7)
inferor
palpebral
conjunctiva.
Fluorescein:
(1)
superior
cornea,
(2)
mid
cornea,
(3)
inferior
cornea.
each
patient
was
sealed
in
an
envelope,
kept
under
guard
by
the
study
controller,
and
left
unopened
until
the
study
was
over.
Patients
were
asked
to
use
the
designated
eyedrops
in
each
eye
six
times
daily
at
3
hour
intervals
for
4
weeks.
Patients
were
equipped
with
digital
wrist
watches
with
preset
alarms
indicating
time
of
eyedrop
application.
Compliance
was
determined
by
counting
the
number
of
empty
containers
collected
upon
each
visit.
Grading
of
subjective
symptoms
and
objective
findings
was
repeated
at
2
weeks
and
at
the
end
of
the
study.
Wilcoxon's
signed
rank
test
was
used
to
analyse
differences
in
efficacy
between
each
test
medication.
Analysis
was
done
in
the
entire
group
as
a
whole,
and
in
subgroups
of
patients
with
the
Sjogren's
syndrome
and
patients
with
non-Sjogren
dry
eye.'6
Results
BASIC
STUDY
Each
group
demonstrated
a
linear
reduction
in
erosion
size
as
shown
in
Figure
3.
The
time
required
for
50%
recovery
in
erosion
size
was
significantly
shorter
in
groups
receiving
01%
and
0
5°/
sodium
hyaluronate
(18
hours)
com-
pared
with
the
untreated
group,
or
the
group
receiving
vehicle
alone
(30
hours).
The
accel-
erating
effect
of
sodium
hyaluronate
was
observed
up
to
22
hours
after
erosion
of
the
epithelium.
Between
22
hours
and
34
hours,
the
healing
rates
in
each
group
were
similar,
but
wound
area
was
significantly
smaller
in
both
concentrations
of
sodium
hyaluronate
compared
with
control
and
the
untreated
group.
No
significant
difference
was
observed
between
0-1%
and
0
5%
sodium
hyaluronate
in
both
healing
rate
and
wound
area,
and
therefore
01%
was
chosen
as
the
final
con-
centration
to
be
used
in
the
clinical
trial.
CLINICAL
STUDY
Of
the
104
patients
enrolled
in
the
study,
91
patients
successfully
completed
the
trial
and
were
eligible
for
statistical
analysis.
Among
the
13
dropout
patients,
two
patients
developed
signs
of
allergic
conjunctivitis,
one
discon-
tinued
treatment
because
of
exacerbation
of
symptoms,
and
the
remainder
were
disquali-
fied
because
of
non-compliance
of
dose
or
period
not
related
to
symptoms
or
side
effects.
Non-compliance
was
mainly
the
result
of
a
lack
of
understanding
of
the
protocol
such
as
omitting
to
apply
drops,
or
failure
to
visit
clinics
on
the
appointed
dates.
Compliance
of
dose
was
confirmed
by
counting
the
number
of
empty
and
untouched
containers
collected
at
each
visit.
No
statistically
significant
difference
was
observed
between
any
of
the
subjective
symp-
toms
under
study
in
terms
of
improvement
in
grading
scores
(Table
1).
There
was
a
trend
towards
improvement
in
blurring
of
vision
in
eyes
receiving
sodium
hyaluronate
(p=0.063).
The
absolute
score
value
for
foreign
body
sensation
at
4
weeks
was
less
in
sodium
1009
Shimmura,
Ono,
Shinozaki,
Toda,
Takamura,
Mashima,
Tsubota
N
40
E
0
*O5%
HA
=30L
20
0
4
22
28
34
Time
following
exposure
to
iodine
vapour
(hours)
Figure
3
Wound
size
(mean
(SD))
folowing
application
of
sodium
hyaluronate
drops
and
controL
Wound
size
improved
significantly
earlier
in
groups
receiving
0
1%
and
05%
sodium
hyaluronate.
No
signifcant
difference
was
observed
between
each
concentration
of
sodium
hyaluronate.
HA=sodium
hyaluromate.
hyaluronate
treated
eyes
in
the
Sjogren
group
(1-67
(SD
0.20)
versus
1-97
(SD
0-21))
and
the
entire
group
(1'20
(SD
0-12)
versus
1X36
(SD
0d13))
with
statistical
significance;
how-
ever,
when
comparing
improvement
(differ-
ence
in
score
before
and
after
treatment)
the
difference
was
not
significant.
Neither
of
the
test
medications
was
overwhelmingly
preferred
over
the
other
in
a
questionnaire
completed
by
participants
at
the
end
of
the
study.
Fluorescein
staining
scores
significantly
decreased
in
eyes
receiving
sodium
hyaluronate
(average
decrease
1
46
(SD
2
08))
compared
with
eyes
receiving
control
at
4
weeks
(average
decrease
0
54
(SD
1-89))
(p=0.0001).
No
statistically
significant
differ-
ence
was
observed
in
rose
bengal
staining,
tear
break
up
time,
Schirmer
scores,
or
tear
clear-
ance.
Similar
results
were
obtained
in
both
the
Sjogren
group
and
the
non-Sjogren
dry
eye
group
when
analysed
separately
(Table
2).
Discussion
Although
previous
studies
have
demonstrated
greater
subjective
improvements
in
eyes
receiv-
ing
sodium
hyaluronate
drops,
our
study
failed
to
demonstrate
any
significant
difference
com-
pared
with
the
control
except
for
a
trend
in
improvement
in
blurred
vision
and
foreign
body
sensation.
The
grading
scores
for
symp-
toms
improved
in
both
eyes
in
the
majority
of
cases.
This
may
be
due
to
the
therapeutic
effects
of
the
placebo
vehicle
itself,
as
well
as
the
difficulty
patients
may
have
experienced
in
grading
symptoms
in
each
eye
separately.
In
other
words,
symptomatic
relief
or
deteriora-
tion
in
one
eye
invariably
affected
judgment
of
symptoms
in
the
other
eye.
The
use
of
a
five
point
scale
for
symptoms
as
well
as
the
long
list
Table
2
Improvement
in
staining
score
(SD)
after
4
weeks
No
of
patients
Stain
0-1%
HA
Control
p
Value
Total
91
Rosebengal
-1-27(1-84)
-1
19
(209)
0-8955
Fluorescein
-1-46
(2
08)
-0
54
(1-89)
0-0001
Non-Sj6gren's
Rose
bengal
-1-36
(1-77)
-1-49
(2
08)
0-6926
syndrome
55
Fluorescein
-1-40
(2
29)
-0-58
(2
08)
0
0049
Sj6gren's
Rose
bengal
-1-14
(1-97)
-0-72
(2
05)
0-5643
syndrome
36
Fluorescein
-1-56
(1-73)
-0
47
(1-58)
0-0005
HA=sodium
hyaluronate.
Minus
sign
indicates
decrease
in
staining
score.
Statistical
analysis
by
Wilcoxon's
signed
rank
test.
of
relatively
non-specific
symptoms
under
study
may
have
been
an
excess
burden
for
the
patients,
which
may
have
affected
their
con-
centration
and
keenness.
The
trends
observed
in
the
study
suggest
that
a
more
extensive
study
focusing
on
fewer
symptoms
may
be
worthwhile.
To
our
surprise,
fluorescein
staining
scores
significantly
improved
in
eyes
receiving
sodium
hyaluronate
drops,
while
no
significant
differ-
ence
was
observed
in
rose
bengal
scores.
Based
on
the
observations
made
by
Feenstra
and
Tseng9
as
reviewed
in
the
introduction
to
this
paper,
the
lack
of
improvement
in
rose
bengal
scores
suggests
that
sodium
hyaluronate
drdps
in
quantities
used
in
the
study
(six
drops
per
day)
may
not
be
sufficient
to
stabilise
the
pre-
ocular
tear
film.
The
half
life
of
0-2%
sodium
hyaluronate
applied
to
the
ocular
surface
is
reported
to
be
approximately
321
seconds,7
and
thus
a
more
frequent
dose
may
be
more
effective.
However,
the
improvement
in
fluo-
rescein
scores
indicates
that
sodium
hyaluronate
may
improve
cell
to
cell
adhesions
between
corneal
epithelial
cells,
since
fluores-
cein
staining
is
exaggerated
by
rapid
diffusion
into
the
stroma
through
disruptions
in
cell
to
cell
junctions.9
Pflugfelder
et
al
17
have
suggested
the
possi-
bility
that
squamous
metaplasia
of
the
con-
junctiva
in
patients
with
Sjogren's
syndrome
may
be
a
primary
feature
of
the
disease
in
addi-
tion
to
tear
deficiency.
The
fact
that
sodium
hyaluronate
in
six
daily
doses
improved
fluo-
rescein
scores
in
the
Sjogren
group
may
be
a
promising
sign
that
sodium
hyaluronate
can
be
used
to
treat
conditions
caused
by
factors
other
than
desiccation.
Results
of
the
preliminary
study
on
rabbits
also
confirmed
that
sodium
hyaluronate
drops
have
an
accelerating
effect
on
epithelial
wound
healing
in
vivo.
The
mechanism
by
which
sodium
hyaluronate
enhances
epithelial
wound
healing
has
not
yet
been
clarified.
Fibronectin
is
known
to
promote
epithelial
wound
healing
by
chemotactic
and
haptotactic
effects
on
epithelial
cells.1820
Inoue
and
Katakami2l
reported
that
sodium
hyaluronate
promotes
cell
proliferation,
which
may
contribute
to
the
wound
healing
effects
of
sodium
hyaluronate.
Nishida
et
al
22have
demonstrated
that
sodium
hyaluronate
stimulates
comeal
epithelial
migra-
tion
in
rabbit
organ
cultures,
which
was
not
affected
by
the
addition
of
antisera
against
fibronectin
or
epithelial
growth
factor.
The
effects
of
sodium
hyaluronate
on
the
epithelium
may
be
caused
by
different
factors
from
those
of
fibronectin
and
epithelial
growth
factor.
The
possible
existence
of
sodium
hyaluronate
bind-
ing
sites
in
the
epithelium
has
been
suggested.22
Previous
reports
have
demonstrated
improvements
in
rose
bengal
staining
with
the
use
of
sodium
hyaluronate
drops.2
5
6
This
dis-
crepancy
with
our
results
may
be
due
to
differ-
ences
in
scoring
methods,
the
manner
in
which
dyes
were
applied,
or
the
number
of
patients
involved.
Certain
limitations
in
our
study
design
can
also
be
pointed
out.
Different
climatic
conditions
among
the
eight
centres
may
have
contributed
to
variability.
Although
1010
Sodium
hyaluronate
eyedrops
in
the
treatment
of
dry
eyes
outpatient
clinics
were
all
run
during
the
morning,
variation
in
the
interval
between
clinical
evaluation
and
the
last
drop
applied
may
have
affected
results.
However,
the
rela-
tively
large
number
of
patients
(n=
104)
enrolled
in
this
double
blind
study,
excellent
patient
compliance,
and
the
use
of
micropipettes
to
apply
precise
amounts
of
dye
have
assured
maximal
standardisation
in
such
a
clinical
situation.
Sodium
hyaluronate
drops
presented
with
very
few
complications.
Two
patients
devel-
oped
signs
of
allergic
conjunctivitis,
and
only
one
patient
had
to
discontinue
the
trial
owing
to
exacerbation
of
symptoms.
This
patient
was
treated
with
her
original
prescription
of
frequently
applied
tear
supplies
to
alleviate
symptoms.
Sodium
hyaluronate
drops
alone
in
six
daily
doses
may
not
adequately
improve
subjective
symptoms
associated
with
dry
eye,
but
may
play
a
role
in
maintaining
a
healthy
corneal
epithelium.
Drops
applied
more
frequently,
or
in
conjunction
with
conventional
tear
replace-
ments,
may
offer
effective
treatment
of
patients
with
dry
eyes.
1
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FM,
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M,
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1011
... Six treatment arms found improvement in conjunctival impression cytology (CIC) measures (Iester et al. 2000;Aragona et al. 2002a;Sanchez et al. 2010;Hwang et al. 2014;Liu et al. 2015), while one found some CIC measures to be improved and others not (Nelson & Farris 1988) The nine HA treatment arms in the eight placebo-controlled trials comparing HA treatment with either saline or vehicle are presented in Table 2. All but one treatment arm found improvement in at least one subjective or objective measure (Sand et al. 1989;Shimmura et al. 1995;Condon et al. 1999;Aragona et al. 2002b;Vogel et al. 2010;Baeyens et al. 2012;L opez-de la Rosa et al. 2017;Pinto-Fraga et al. 2017). Three of nine treatment arms showed statistically significant subjective improvement (Condon et al. 1999;Vogel et al. 2010;Pinto-Fraga et al. 2017), one of nine found improvement in some and no change in other subjective measures (Baeyens et al. 2012), and five of nine arms found no change in subjective measures (Sand et al. 1989;Shimmura et al. 1995;Aragona et al. 2002b;L opez-de la Rosa et al. 2017). ...
... All but one treatment arm found improvement in at least one subjective or objective measure (Sand et al. 1989;Shimmura et al. 1995;Condon et al. 1999;Aragona et al. 2002b;Vogel et al. 2010;Baeyens et al. 2012;L opez-de la Rosa et al. 2017;Pinto-Fraga et al. 2017). Three of nine treatment arms showed statistically significant subjective improvement (Condon et al. 1999;Vogel et al. 2010;Pinto-Fraga et al. 2017), one of nine found improvement in some and no change in other subjective measures (Baeyens et al. 2012), and five of nine arms found no change in subjective measures (Sand et al. 1989;Shimmura et al. 1995;Aragona et al. 2002b;L opez-de la Rosa et al. 2017). Three of seven treatment arms found improvement in TBUT (Sand et al. 1989;Baeyens et al. 2012;L opezde la Rosa et al. 2017). ...
... Five of nine treatment arms found improvement in OSS (Sand et al. 1989;Condon et al. 1999;Vogel et al. 2010;Baeyens et al. 2012;Pinto-Fraga et al. 2017). One of nine treatment arm found improvement in some but not all OSS measures (Shimmura et al. 1995). Only two of eight treatment arms found improvement in Schirmer's test (Condon et al. 1999;Baeyens et al. 2012). ...
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Dry eye disease (DED) is a highly prevalent and debilitating condition affecting several hundred million people worldwide. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan commonly used in the treatment of DED. This review aims to critically evaluate the literature on the safety and efficacy of artificial tears containing HA used in DED treatment. Literature searches were conducted in PubMed, including MEDLINE, and in Embase via Ovid with the search term: “(hyaluronic acid OR hyaluronan OR hyaluronate) AND (dry eye OR sicca)”. A total of 53 clinical trials are included in this review, including eight placebo‐controlled trials. Hyaluronic acid concentrations ranged from 0.1% to 0.4%. Studies lasted up to 3 months. A broad spectrum of DED types and severities was represented in the reviewed literature. No major complications or adverse events were reported. Artificial tears containing 0.1% to 0.4% HA were effective at improving both signs and symptoms of DED. Two major gaps in the literature have been identified: 1. no study investigated the ideal drop frequency for HA‐containing eyedrops, and 2. insufficient evidence was presented to recommend any specific HA formulation over another. Future investigations assessing the optimal drop frequency for different concentrations and molecular weights of HA, different drop formulations, including tonicity, and accounting for DED severity and aetiology are essential for an evidence‐based, individualized approach to DED treatment.
... Since the concentration of HA is not a property that reflects molecular weight, it cannot be stated that a high concentration of HA preparation is superior for water binding. Therefore, it is not theoretically accurate to suggest that a low concentration of HA is appropriate for mild dry eye, and a high concentration of HA is better in severe dry eye [30,33]. ...
... Therefore, these improvements at 8 weeks suggest that a combination treatment promoted ocular surface cohesion more effectively than 0.15% HA or 0.3% HA. Our results agree with previous clinical studies, which report that HAcontaining eye drops stimulate corneal epithelial healing [14,33]. ...
Article
PurposeWe report the clinical efficacy of sequential applications of 0.3% and 0.15% unpreserved hyaluronic acid (HA) for the treatment of dry eye disease (DED).Study designRandomized clinical trial.Methods Patients over 19 years of age with DED level 2 or higher, corneal fluorescein staining (CFS) score > 1, and tear break-up time (TBUT) < 10 s were included. Seventy-six patients were randomly assigned to the 0.15% HA group, 0.3% HA group, or combination group. Each group applied two drops of 0.15% or 0.3% HA, or a single drop of both 0.3% and 0.15% HA. Patients were evaluated using the ocular surface disease index (OSDI), CFS and conjunctival fluorescein stain score, TBUT, and blurring/discomfort after application at baseline, 4 weeks, and 8 weeks.ResultsThe combination group had the greatest improvement in CFS score from baseline to 8 weeks, compared with the 0.15% and 0.3% HA group (p < 0.001). The combined CFS-OSDI responder rates of the combination group (CFS score = 0 and OSDI ≥ 50% improvement at 8 weeks) were significantly higher than those of the 0.15% and 0.3% groups (p = 0.037). At 4 and 8 weeks, blurring after application in both the 0.3% and combination groups was significantly higher than in the 0.15% group, despite no difference between the 0.3% and combination groups. There were no differences in CFS and conjunctival staining score, TBUT, or OSDI within the three groups at baseline, 4 weeks, and 8 weeks.Conclusions Sequential application of 0.3% and 0.15% HA improved symptoms/signs in moderate to severe DED patients.
... 16,17 Corneal fluorescein staining was performed with 2% unpreserved sodium fluorescein solution. Grading of corneal fluorescein staining was based on the Expanded National Eye Institute/Industry Workshop Corneal Fluorescein Staining Scale and methods modified from Lemp (1995) 18 and Shimmura et al (1995). 19 A conjunctival redness scale was modified from Efron et al (2001). ...