A double-dummy, double-blind, placebo-controlled phase III study comparing the efficacy and efficiency of miconazole chewing gum with a known drug (Brentan gel) and a placebo in patients with oral candidosis


Bastian, H.Lehmann.; Rindum, J.; Lindeberg, H.

Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics 98(4): 423-428

2004


The purpose was to compare the therapeutic effect, the required overall treatment duration, and patients' subjective perception of treatment of candidosis with miconazole chewing gum 20 mg/piece (3.6 mg released) and 2% Brentan gel 2.5 g (50 mg released), both administered 4 times daily. Randomly selected patients (chewing gum: 96; gel: 28; placebo 16) were seen at baseline and at 4 and 6 weeks. They were evaluated clinically and with culture and cytology assays. There was no significant difference between the 2 drugs after 6 weeks, but miconazole released in small doses from chewing gum was at least as effective as a larger gel dose. Both active drugs demonstrated efficiency and efficacy (P=1.9%). The hypothesis of equal proportions was rejected (P=.0001). Patients preferred the chewing gum. There was a statistically significant difference in patient preference for the chewing gum treatment. The chewing gum medication is clinically promising.

A
double-dummy,
double-blind,
placebo-controlled
phase
III
study
comparing
the
efficacy
and
efficiency
of
miconazole
chewing
gum
with
a
known
drug
(Brentan
®
gel)
and
a
placebo
in
patients
with
oral
candidosis
Henning
Lehmann
Bastian,
DDS,
a
Judith
Rindum,
DDS,
b
and
Henning
Lindeberg,
DMSci,
PhD,
DDS,
MD,
c
Odense,
Copenhagen,
and
Aarhus,
Denmark
ODENSE
UNIVERSITY
HOSPITAL,
RIGSHOSPITALET,
AND
AARHUS
UNIVERSITY
Objective.
The
purpose
was
to
compare
the
therapeutic
effect,
the
required
overall
treatment
duration,
and
patients'
subjective
perception
of
treatment
of
candidosis
with
miconazole
chewing
gum
20
mg/piece
(3.6
mg
released)
and
2%
Brentan
®
gel
2.5
g
(50
mg
released),
both
administered
4
times
daily.
Study
design.
Randomly
selected
patients
(chewing
gum:
96;
gel:
28;
placebo
16)
were
seen
at
baseline
and
at
4
and
6
weeks.
They
were
evaluated
clinically
and
with
culture
and
cytology
assays.
Results.
There
was
no
significant
difference
between
the
2
drugs
after
6
weeks,
but
miconazole
released
in
small
doses
from
chewing
gum
was
at
least
as
effective
as
a
larger
gel
dose.
Both
active
drugs
demonstrated
efficiency
and
efficacy
(P
=
1.9%).
The
hypothesis
of
equal
proportions
was
rejected
(P
=
.0001).
Patients
preferred
the
chewing
gum.
There
was
a
statistically
significant
difference
in
patient
preference
for
the
chewing
gum
treatment.
Conclusion.
The
chewing
gum
medication
is
clinically
promising.
(Oral
Surg
Oral
Med
Oral
Pathol
Oral
Radio!
Endod
2004;98:423-8)
Oral
candidosis
may
be
treated
in
various
ways
and
by
different
routes,
eg
intravenously
(amphotericin),
per-
orally
(fluconazole,
ketoconazole,
etc.)
and
by
means
of
lozenge
(clotrinazole,
nystatin),
rinse
(nystatin),
and
gel.
The
treatment
time
with
intravenous
and
peroral
treatment
is
short;
for
lozenge,
rinse,
and
gel
it
is
ap-
proximately
4-6
weeks.
The
first
2
treatments
are
rela-
tively
expensive;
lozenge,
rinse,
and
gel
are
relatively
cheap.
The
standard
antifungal
drug
regimen
for
oral
candidosis
in
Europe
consists
of
topical
administration
of
either
polyenes
or
imidazoles.
Miconazole
is
an
imid-
azole
derivative
and
the
second
of
the
azole
derivatives
introduced
as
a
routine
regimen.
Miconazole,
in
its
various
formulations
(mixture,
lozenges,
or
gel)
for
local
use,
is
an
effective
antimycotic
drug
for
treating
oral
can-
didosis.
1.2
Interest
has
centered
on
the
development
of
drugs
yielding
high
oral
concentrations
of
antimycotics
for
protracted
periods
after
application.
Previous
trials
have
'Associate
Professor,
Department
of
Oral
and
Maxillofacial
Surgery,
Odense
University
Hospital.
b
Specialist
in
Oral
and
Maxillofacial
Surgery,
Rigshospitalet,
Copenhagen.
`Associate
Professor,
Department
of
Oral
Pathology,
Aarhus
University.
Received
for
publication
Apr
28,
2003;
returned
for
revision
Jun
25,
2003;
accepted
for
publication
Dec
15,
2003.
1079-2104/$
-
see
front
matter
©
2004
Elsevier
Inc.
All
rights
reserved.
doi:10.1016/j.tripleo.2003.12.028
demonstrated
that
healthy
subjects
may
obtain
such
long-lasting
efficient
saliva
concentrations
of
anti-
mycotics
by
using
chewing
gum.
3
Miconazole
has
a
pKa
value
in
water
of
6.7
4
and
hence
a
low
water
solubility,
which
hampers
its
release
from
chewing
gum
formulations
when
incorporated
by
conventional
methods.
However,
the
addition
of
sur-
factants
ensures
the
release
of
a
therapeutic
amount
of
miconazole
as
demonstrated
in
an
in
vitro study
by
Pedersen
and
Rassing.
5
In
a
pilot
study,
Rindum
et
al
b
examined
32
patients
with
oral
candidosis
caused
by
Candida,
predominantly
C
albicans.
The
results
of
this
pilot
study
indicated
that
miconazole
released
in
small
doses
from
chewing
gum
is
as
effective
as
a
larger
dose
dispensed
in
an
oral
gel.
The
results
also
indicated
that
treatment
with
miconazole
dispensed
either
in
chewing
gum
or
in
oral
gel
should
last
more
than
3
weeks,
but not
necessarily
6
weeks.
Finally,
the
patients
participating
in
this
study
described
chewing
gum
as
a
pleasant
medicament.
It
is
a
discrete
means
of
taking
drugs;
thus
it
helps
prevent
patient
stigmatization.
Furthermore,
this
form
of
medicament
is
easy
to
apply.
This
double-dummy,
double-blind,
placebo-con-
trolled
phase
DI
study
aimed
to
test
a
new
formulation
designed
to
improve
the
stability
of
the
chewing
gum.
The
study
was
planned
as
a
bioequivalence
study,
but
it
was
not
relevant
to
measure
the
plasma
concentration
because
of
the
local
nature
of
the
treatment
performed,
and
the
study
is,
therefore,
in
reality
an
efficacy
and
efficiency
study.
The
specific
aims
were
to
compare
the
therapeutic
effect
(bioequivalence),
the
required
overall
423
0000E
424
Bastian,
Rindum,
and
Lindeberg
October
2004
Table
I.
Patients
included
in
the
study
Group
Treatment
Number
of
patients
Placebo
Placebo
gum
+
placebo
gel
13
Active
gum
Active
gum
+
placebo
gel
62
Active
gel
Placebo
gum
+
active
gel
31
treatment
duration,
and
patients'
subjective
perception
of
treatment
of
candidosis
with
miconazole
chewing
gum
20
mg/piece
(3.6
mg
released)
and
2%
Brentan
®
gel
2.5
g
(50
mg
released),
both
administered
4
times
daily.
MATERIALS
AND
METHODS
Patients
The
study
was
originally
planned
to
include
160
patients
(all
over
18
years
of
age)
suffering
from
verified
oral
candidosis,
divided
into
3
groups:
16
placebo,
96
active
gum,
and
48
active
gel.
These
sample
size
calculations
were
based
on
a
previous
study.
4
Patients
were
subjected
to
a
prescreening
visit
to
establish
if
they
met
the
inclusion
criteria
of
objective
pathological
con-
dition
and
positive
cytologic
and
mycologic
tests.
One
week
later,
the
patients
attended
a
screening
visit
where
the
subjective
and
objective
symptoms
and
signs
were
registered,
new
laboratory
tests
were
made
and
medi-
cation
was
dispensed.
A
total
of
106
patients
met
the
inclusion
criteria
and
they
were
divided
into
3
groups
(Table
I).
All
patients
had
to
use
gel
and
chewing
gum
as
prescribed
below.
All
patients
attended
visits
4
and
6
weeks
after
screening.
Drug
products
and
their
use
Miconazole
chewing
gum
20
mg/piece
(Fertin
Pharma
A/S,
Denmark)
was
tested
against
oral
miconazole
gel
2%
(Brentan
®
gel;
Janssenpharma
A/S).
Furthermore,
a
placebo
chewing
gum
(Fertin
Pharma
A/S)
and
a
placebo
gel,
(Janssenpharma
A/S)
were
used
in
the
test.
One
piece
of
chewing gum
(placebo
or
active)
was
chewed
for
30
minutes
and
then
spit
out.
Subsequently,
2.5
ml
gel
(active
or
placebo)
corresponding
to
half
a
measuring
spoon
was
dispersed
and
kept
in
the
oral
cavity
for
2
minutes.
The
patients
did
so
4
times
a
day.
One
piece
of
chewing
gum
containing
20
mg
of
mi-
conazole
released
approximately
3.6
mg
of
miconazole
(unpublished
data).
Study
design
The
trial
was
carried
out
as
a
double-blind,
placebo-
controlled
phase
III
study
according
to
the
double-
dummy
principle.
The
study
was
performed
as
a
multicentre
trial
with
the
participation
of
3
Danish
centres.
Based
on
previous
study
results,
a
6-week
period
of
treatment
was
chosen.
Researchers
checked
up
on
the
therapeutic
effect
at
follow-up
examinations
4
and
6
weeks
after
treatment
start.
However,
17
randomly
selected
persons
receiving
active
treatment
were
exam-
ined
once
a
week.
A
Drug
Accountability
Form
was
used
to
register
patient
compliance.
The
effect
of
the
treatment
was
evaluated
clinically,
mycologically,
and
cytologi-
cally.
The
study
was
approved
by
the
regional
ethics
committee
ICF03-001/95.
Clinical
investigation
The
effect
was
evaluated
clinically
by
comparing
the
symptoms
and
clinical
presentations
(stinging/burning
sensation,
excoriation,
changed
taste
sensation)
after
4
and
6
weeks
of
treatment
with
the
symptoms
experienced
before
treatment
initiation,
7
except
for
the
17
persons
who
were
examined
weekly.
Mycologic
investigation
The
effect
of
the
treatments
was
evaluated
by
comparing
the
results
of
cultivation
4
weeks
and
6
weeks
after
treatment
with
the
results
of
cultivation
immediately
before
initiating
the
treatment
and
by
comparing
the
cultivation
results
within
the
3
treatment
groups.
Yeast
cells
were
cultivated
by
means
of
the
imprint
method
described
by
Arendorf
and
Walker."
A
quadrangular
sterile
polyester
sponge
(2.5
X
2.5
cm,
produced
individually)
was
immersed
into
Sabouraud's
substrate
and
placed
on
affected
mucosa
for
60
seconds.
The
sponge
was
subsequently
pressed
lightly
onto
a
Sabouraud
agar
plate,
where
it
was
left
for
the
first
8
hours
of
48
hours'
incubation
at
37°C.
After
the
in-
cubation,
the
following
registrations
were
made:
00
=
no
colonies;
01
=
colonies.
'
11
For
the
17
patients
selected
for
weekly
follow-up
examinations,
colonies
were
counted
according
to
the
following
graduation:
02
=
<10
colonies/plate;
03
=
10-100
colonies/plate;
04
=
>100
colonies/plate;
05
=
confluent
growth.
Cytologic
investigation
Scrapings
from
inflamed
mucosa
were
obtained
before
treatment
start
and
after
4
and
6
weeks
of
treatment.
The
scrapings
were
performed
with
a
wooden
spatula,
and
the
material
was
then
transferred
to
microscope
slides.
The
preparations
were
fixed
with
Spray
Cyte
Fixative
®
(Hassellunden;
Smorum,
Denmark)
and
coloured
ac-
cording
to
the
periodic
acid-Schiff
method
(PAS).
The
preparations
were
subjected
to
microexamination
for
identification
of
yeast
cells
by
the
presence
of
blasto-
spores
or
hyphae/pseudohyphae.
The
following
regis-
trations
were
made:
00
=
no
bastospores
or
hyphae;
01
=
blastospores
or
hyphae.
For
the
17
patients
selected
for
weekly
follow-up
examinations,
blastospores
and
hyphae
were
counted
according
to
the
following
0000E
Volume
98,
Number
4
graduation:
02
=
<5
blastospores
or
hyphae/prepara-
tions;
03
=
5-10
blastospores
or
hyphae/preparations;
04
=
>10
blastospores
or
hyphae/preparation.
The
ef-
fect
of
the
treatments
was
evaluated
by
comparing
the
results
of
the
microscopy
at
the
time
of
each
follow-up
examination
after
treatment
with
the
result
of
the
microscopy
immediately
before
initiating
the
treatment
and
by
comparing
the
results
of
the
microscopies
performed
within
the
3
treatment
groups.
Side
effects
The
side
effects
were
evaluated
at
each
follow-up
examination.
The
patients
were
asked
directly
whether
they
had
experienced
any
inconveniences
in
connection
with
the
treatment,
and
the
various
inconvenience
types
were
registered.
The
side
effects
were
discussed
with
the
patient,
and
the
treatment
could
be
discontinued
at
any
time
at
the
patient's
request.
Acceptability
On
termination
of
the
study,
each
group
of
patients
was
invited
directly
according
to
a
set
question
template
to
provide
an
evaluation
of
the
2
types
of
treatment
(Table
II).
Statistics
Spadille
A/S
performed
data
management
and
made
the
statistical
analysis
plan
based
on
the
final
protocol.
Trial
data
were
to
be
collected
by
the
investigator
performing
the
trial.
The
investigator
had
to
ensure
that
the
data
registered
on
the
case
record
forms
(CRFs)
were
correct
and
legible.
Statistical
analyses
were
performed
on
all
patients
(intention
to
treat
population).
Primary
analysis
Bioequivalence
was
investigated
by
computing
90%
confidence
intervals
(CIs)
of
the
difference
in
recovery
rates
after
6
weeks
between
the
2
active
treatments
and
by
comparing
these
data
with
the
equivalence
criteria.
Also,
comparisons
in
pairs
were
made
among
the
3
groups.
The
P-values
were
corrected
for
multiplicity
using
Tukey-Kramer
corrections.
12
Secondary
analyses
The
same
analyses
were
made
on
the
recovery
rates
after
4
weeks
of
treatment.
Visual
analog
scale
measure-
ments
were
analysed
to
detect
differences
between
the
groups
using
an
exact
permutation
test.
A
supplementary
chi-square
analysis
was
made
on
the
patients'
treatment
preference.
13
Bastian,
Rindum,
and
Lindeberg
425
Table
II.
Acceptability
Active
gel
Active
chewing
gum
Placebo
Number
of
patients
Acceptability
31
(N
=
31)
N
(%)
62
(N
=
55)
N
(%)
13
(N
=
11)
N
(%)
Prefers
chewing
gum
21
(67.7)
37
(67.3)
8
(72.7)
Prefers
gel
6
(19.4)
15
(27.3)
2
(18.2)
No
difference
4
(12.9)
3
(5.5)
1
(9.1)
Reasons
for
preferring
chewing
gum
(N
=
21)
(N
=
37)
(N
=
8)
N
(%)
N
(%)
N
(%)
Easier
to
apply
13
(61.9)
23
(62.2)
4
(50.0)
Fewer
side
effects
5
(23.8)
10
(27.0)
2
(25.0)
Other
3
(14.3)
4
(10.8)
2
(25.0)
Reasons
for
preferring
gel
(N
=
6)
(N
=
15)
(N
=
2)
N
(%)
N
(%)
N
(%)
Easier
to
apply
5
(83.3)
9
(60.0)
2
(100.0)
Fewer
side
effects
3
(20.0)
Other
1
(16.7)
3
(20.0)
RESULTS
Preliminary
screening
There
was
no
significant
difference
among
the
3
groups
at
the
time
of
preliminary
screening.
Women
and
smokers
dominated
the
study,
which
is
fully
com-
patible
with
the
literature.
All
3
groups
included
pa-
tients
also
harbouring
other
oral
mucosal illnesses
than
oral
candidosis
and
patients
using
partial
plates.
Both
active
groups
included
patients
using
local
ste-
roid
inhalators.
The
group
treated
with
active
chewing
gum
included
patients
treated
with
systemic
antibiot-
ics.
The
group
treated
with
active
chewing
gum
seemed
to
contain
an
excess
of
patients
using
partial
plates,
using
steroid
inhalators,
having
received
systemic
antibiotic
treatment,
or
suffering
from
other
oral
muco-
sal
illnesses
besides
the
candida.
The
group
treated
with
active
gel
contained
an
excess
of
smokers.
Treatment
effect
There
were
no
clinically
significant
differences
among
the
groups.
Stinging
and
burning
sensations
were
the
most
frequent
subjective
symptom
in
all
3
groups.
Most
patients
in
all
3
groups
had
lesions
in
more
than
one
location.
Treatment
reduced
stinging
and
burning
already
after
only
4
weeks
of
treatment
in
all
3
groups,
but
most
noticeably
in
the
active
groups.
After
6
weeks
of
treatment,
these
symptoms
were
further
reduced
in
the
group
treated
with
active
gel,
but
a
small
increase
from
week
4
to
week
6
was
observed
in
the
group
treated
with
active
chewing gum
where
the
most
frequent
location
of
the
lesions
was
the
tongue.
The
chronically
erythema-
tous
type
of
Candida
was
the
most
frequently
observed
lesion.
Both
treatment
groups experienced
a
mycologic
and
cytologic
therapeutic
effect
after
4
weeks
as
well
as
1
.0
12
0.8
_o
0.7
0.6
0.5
0
0.4
at
0.9
a)
U)
0
0
0000E
426
Bastian,
Rindum,
and
Lindeberg
October
2004
----
-------
---____
------
-----
e-
--
-,1-,„
_
---------
x
to
0.3
0.2
C
a)
a_
0.1
0
.
0
1
2
3
4
5
Week
Plot:
)oo(
active
gel
n(0)=29
n(4)=27
n(6)=28
000
placebo
n(0)=13
n(4)=9
n(6)=9
OEM
active
gum
n(0)=61
n(4)=52
n(9)=49
Fig
1.
Culture
score
in
all
three
groups
after
4
and
6
weeks.
6
after
6
weeks
of
treatment
(Fig
1).
We
observed
no
significant
difference
between
the
2
treatment
groups,
but
there
was
a
marked
difference
between
the
placebo
group
and
the
treatment
groups
and
between
the
placebo
group
and
each
of
the
treatment
groups.
No
mycologic
difference
was
observed
between
4
weeks
and
6
weeks
of
gel
treatment,
but
chewing
gum
treatment
seemed
to
provide
a
small
gain
from
week
4
to
week
6.
The
cytologic
investigation
confirmed
this
finding.
Side
effects
All
treatment
groups
were
treated
with
both
gel
and
chewing
gum.
The
side
effects
of
gel
or
chewing
gum
therapy
were
not
of
a
magnitude
requiring
that
they
should
be
reported
to
The
National
Board
of
Health,
the
Regional
Ethics
Committee,
or
the
company
supplying
the
medicine.
Acceptability
Overall,
68%
of
the
patients
preferred
the
chewing
gum.
In
all
3
groups,
most
of
the
patients
preferred
chewing
gum
treatment.
Compliance
The
comments
in
the
CRF
showed
that
some
patients
did
not
take
the
trial
drug
as
prescribed.
The
drug
accountability
data
were
therefore
further
studied
after
the
project
had
been
concluded.
Hence,
these
data
were
not
subjected
to
any
kind
of
validation.
The
statistical
analysis
rests
on
patients
completing
6
weeks
of
treat-
ment.
From
these
data,
it
can
be
concluded
that
there
was
no
difference
between
the
gel
and
gum
with
regard
to
compliance.
Statistical
analysis
The
patients
were
considered
cured
when
they
were
free
of
symptoms
and
clinical
signs,
culture,
and
cytology
were
negative.
The
results
of
the
primary
statistical
analysis
showed
that
the
equivalence
criterion
(-20;
20)
was
not
satisfied
at
the
90%
CI
(-8.61;
30.04).
Thus,
it
was
not
possible
to
demonstrate
bioequivalence
between
the
2
active
treatments
after
6
weeks
of
treatment.
However,
it
should
be
noted
that
chewing
gum
had
a
better
cure
rate
than
gel,
even
if
the
difference
0000E
Volume
98,
Number
4
Bastian,
Rindum,
and
Lindeberg
427
Table
III.
Cured
patients
Active
chewing
Active Active
Active
chewing
Active
gellchewing
gum
gel
Placebo
gellplacebo
gum/placebo
gum
(N)
(%)
(N)
(%)
(N)
(%)
P
(for
equality
P
(for
equality
P
(90%
CI
of
cure
rates)
of
cure
rates)
for
difference)
Results
after
6
weeks
28
(57.14%)
13
(46.43%)
0
(0%)
P
=
.015
P
=
.002
(-8.61;30.04)
P
=
.477
Results
after
4
weeks
23
(44.23%)
13
(48.15%)
1
(11.11%)
P
=
.062
P
=
.076
(-23.32;15.48)
P
=
.814
between
the
2
regimens
fell
short
of
statistical
signifi-
cance
in
the
present
clinical
trial
(Table
III).
The
comparison
in
pairs
between
active
chewing
gum
versus
placebo
and
active
gel
versus
placebo
shows
a
statistically
significant
difference
at
the
1.9%
level.
This
result
shows
that
both
active
treatments
have
a
therapeutic
effect.
Bioequivalence
between
the
2
active
treatments
after
4
weeks
of
treatment
has
not
been
demonstrated,
as
the
90%
CI
for
difference
in
cure
rate
(-23.32;
15.48)
did
not
satisfy
the
equivalence
criterion.
Paired
comparison
after
4
weeks
showed
no
statistically
significant
difference
between
the
active
treatments
or
between
each
of
the
active
treatments
and
placebo.
It
should
be
noted,
however,
that
the
P-values
were
low
when
comparing
each
of
the
active
treatments
with
placebo.
Recovery
rates
were
low
after
6
weeks
of
treatment.
The
patient
groups
examined
once
a
week
were
too
small
for
any
conclusions
to
be
drawn
with
regard
to
differences
in
cure
rates
or
treatment
times.
A
chi-square
test
for
equal
proportions
was
made
to
analyse
the
difference
in
preference
between
gum
and
gel.
The
hypothesis
of
equal
proportions
was
rejected
(P
=
.0001).
Hence,
there
was
a
statistically
significant
difference
in
patients'
preference
for
the
chewing
gum
treat-
ment.
DISCUSSION
We
did
not
demonstrate
a
significant
difference
between
the
cure
rates
of
the
2
treatments,
and
the
estimated
cure
rates
(57.14%
for
chewing
gum,
46.43%
for
gel)
were
considerably
lower
than
rates
reported
in
previous
pilot
studies.
2
'
6
The
most
frequently
encoun-
tered
Candida
infection
was
chronically
erythematous
Candida,
which
is
compatible
with
the
predominance
of
smokers
among
the
patients
and
which
confirms
reports
in
extant
literature.
8
In
general,
the
compliance
was
low.
We
suspect
that
patients
experiencing
a
treatment
effect
towards
the
end
of
the
study
period
did
not
take
the
medication
as
prescribed.
Hence,
CRF
comments
showed
that
several
patients
failed
to
take
their
medicine
as
prescribed,
presumably
because
6
weeks
is
a
long
time
to
take
medicine,
particularly
4
times
a
day.
Furthermore,
patients
may
forget
to
take
their
medicine
when
subjective
symptoms,
if
any,
fail
to
appear,
although
this
does
not
necessarily
mean
that
clinical
or
laboratory
cure
has
been
obtained.
We
were
surprised
to
learn that
a
low
dose
of
active
substance
in
chewing
gum
was
at
least
as
effective
as
a
larger
dose
administered
as
a
gel.
We
ascribe
this
beneficial
effect
to
the
slow
release
obtained
with
gum,
causing
the
active
substance
to
be
dispensed
over
a
longer
time,
perhaps
combined
with
a
mechanical
effect
of
chewing
favouring
the
contact
between
the
miconazole
and
the
fungi.
The
chewing
gum
was
compared
to
the
gel
because
it
is
a
very
common
standard
treatment
in
Europe.
In
a
new
study
it
could
be
very
interesting
to
increase
the
topical
doses
in
the
chewing
gum
to
reduce
the
treatment
time.
There
is
no
doubt
that
the
long
treatment
time
has
pro-
duced
a
significant
compliance
problem
because
it
has
greatly
reduced
many
patients'
acceptance
of
this
kind
of
treatment.
CONCLUSION
Based
on
the
present
clinical
study,
the
following
conclusions
were
made.
It
was
not
possible
to
show
statistical
bioequivalence
between
miconazole
dispensed
as
chewing
gum
and
miconazole
dispensed
as
gel.
After
6
weeks
of
treatment,
the
cure
rate
for
patients
treated
with
miconazole
chewing
gum
was
at
least
as
high
as
that
for
patients
treated
with
miconazole
gel.
Miconazole
released
in
small
doses
(3.6
mg)
from
chewing
gum
is
at
least
as
effective
as
a
larger
dose
in
the
form
of
oral
gel
(50
mg).
The
preferred
treatment
method
was
the
chewing
gum.
The
main
reason
for
choosing
chewing gum
was
that
it
was
easier
to
use
and
had
fewer
adverse
events.
The
treatment
time
for
chewing
gum
should
be
at
least
6
weeks.
REFERENCES
1.
Odds
FC.
Candida
and
candidosis.
2nd
ed.
London:
Bailliere
Tindall;
1988.
2.
Lamey
PI,
Samaranayake
LP.
Oral
candidosis:
2.
Diagnosis
and
management.
Dent
Update
1988;15:328-31.
3.
Pedersen
M.
Tyggegummi
som
lwgemiddelfotm.
Kobenhavn:
Licentiatafhandling;
1990.
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October
2004
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Peeters
J.
Determination
of
ionization
constants
in
mixed
aqueous
solvents
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varying
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by
a
single
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J
Phann
Sci
1978;127:67.
5.
Pedersen
M,
Rassing
MR.
Miconazole
chewing
gum
as
a
drug
delivery
system
test
of
release
promoting
additives.
Drug
Dev
Ind
Phann
1991;17:411-20.
6.
Rindum
JR,
Holmstrup
P,
Pedersen
M,
Rassing
MR,
Stoltze
K.
Miconazole
chewing
gum
for
treatment
of
chronic
oral
candidosis.
Scand
J
Dent
Res
1993;6:386-90.
7.
Hohnstrup
P,
Axe11
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Classification
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clinical
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of
oral
yeast
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Acta
Odontol
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Arendorf
TM,
Walker
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in
health
and
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Arendorf
TM,
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The
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and
intraoral
distri-
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albicans
in
man.
Arch
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10.
Kreger-van
Rij.
The
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a
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Amster-
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11.
Haley
LD,
Callaway
CS.
Laboratory
methods
in
medical
mycology.
Atlanta:
US
Centers
for
Disease
Control;
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12.
Hochberg
Y,
Tamhane
AC.
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New
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Wiley;
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p.
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Hollander
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Wolfe
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Reprint
requests:
Henning
Lehmann
Bastian
Department
of
Oral
and
Maxillofacial
Surgery
Odense
University
Hospital
Sdr.
Boulevard
DK-5000
Odense
C
Denmark
henning.lehmann@ouh.fyns-amt.dk
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