A phase II trial of a transmucosal herbal patch
for the treatment of gingivitis
John Grbic, Isaiah Wexler, Romi Celenti, Jaclyn
Altman and Aron Saffer
J Am Dent Assoc 2011;142;1168-1175
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RESEARCH
A phase II trial of a transmucosal herbal
patch for the treatment of gingivitis
John Grbic, DMD, MS, MMSc; Isaiah Wexler, MD, PhD; Romi Celenti, MS;
Jaclyn Altman, DDS, MS, FRCD(C); Aron Saffer, DDS, MS
I
AB STRACT
Background. Systemic treatments for gingivitis frequently are
inadequate for controlling specific sites of severe gingival inflammation. The authors conducted a study to test site-specific therapy
using a transmucosal herbal periodontal patch (THPP) that was
impregnated with plant extracts reported to reduce inflammatory
response.
Methods. The study was a single-center, randomized, placebocontrolled, double-masked, longitudinal phase II trial involving participants with clinically diagnosed gingivitis. Participants who were
enrolled in the study received either THPPs or placebo patches (PP)
for three days. The authors evaluated gingival inflammation visually using the gingival index (GI) and by measuring gingival crevicular fluid ß-glucuronidase (BG) enzymatic activity at baseline (day
one) and on days two, four, eight and 15.
Results. The authors randomly assigned 53 participants to
receive the THPP or the PP. Participants who received the THPPs
had a greater reduction in mean GI scores than did those who
received the PPs. This finding was significant on days four and 15.
The percentage of participants whose GI scores decreased by one or
more was higher among those receiving the THPP than among
those receiving the PP, as assessed on days four and 15. The
average decrease in BG levels (fluorescence units) for participants
receiving the THPP was significantly greater on days four and
eight than they were for those receiving the PP. No serious adverse
events were associated with the use of the THPP.
Conclusions. Topical treatment by means of the THPP may be
effective and safe in reducing topical gingival inflammation. Further
studies are needed to confirm these findings and determine the best
method for administering the THPP and the appropriate dosing.
Clinical Implications. Site-specific treatment of gingival
inflammation is feasible and could be used as an adjunct for systemic therapeutic interventions.
Key Words. Gingival diseases; gingival crevicular fluid; herbal
medicine; anti-inflammatory agents.
JADA 2011;142(10):1168-1175.
Dr. Grbic is a professor of clinical dental medicine, and the director, Division of Oral Biology, Section of Oral and Diagnostic Sciences, Columbia University
College of Dental Medicine, Box 20, 630 W. 168th St., New York, New York 10032, e-mail “[email protected]”. Address reprint requests to Dr. Grbic.
Dr. Wexler is an associate professor, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem.
Ms. Celenti is a senior research associate, Section of Oral and Diagnostic Sciences, Columbia University College of Dental Medicine, New York City.
Dr. Altman is an associate in dentistry, Faculty of Dentistry, University of Toronto.
Dr. Saffer is the senior vice president for research and development, Izun Pharmaceuticals, New York City.
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nflammatory periodontal disease is a common disorder associated with significant morbidity. Gingivitis, the milder
form of periodontal disease, has a
prevalence of 50 to 90 percent, and
more than 80 percent of people older
than 65 years who live in the United
States have periodontal disease.1-4
Untreated periodontal disease can
cause tooth loss and has been associated with accelerated atherosclerosis, diabetic complications and
adverse pregnancy outcomes.5-10
Periodontal disease is a result of
the chronic inflammatory response to
bacterial biofilm.5,11-13 Periodontal
pathogens trigger a chronic inflammatory response that includes elevated levels of enzymes such as metalloproteases, elastases and collagenases, which can lead to dysregulated tissue repair with subsequent
breakdown of connective tissue.14-19
In addition, the level of gingival
inflammation may not be homogeneous, and, therefore, specific areas
of severe gingivitis may benefit from
targeted therapy designed to treat
localized severe inflammation.20
We conducted a phase II trial to
test the efficacy and safety of a
transmucosal herbal periodontal
patch (THPP) developed by Izun
Pharmaceuticals (New York City)
that was impregnated with plant
extracts. The THPP included extracts derived from the herbs Cen-
RESEARCH
tella asiatica (gotu kola), Echinacea purpurea
and Sambucus nigra (elderberry). Extracts from
these plants have antioxidant and immunomodulatory activity that might reduce the inflammatory response, and preliminary results of studies
have shown that these extracts have the potential to reduce the inflammatory component of
periodontal disease.21-25 The proprietary transmucosal patch system (the THPP) covers the
inflamed gingiva and allows direct contact of the
extracts with the gingiva. The specific aim of our
investigation was to determine whether a THPP
applied in a site-specific manner could reduce
gingival inflammation at the targeted location.
METHODS
ABBREVIATION KEY. BG: ß-glucuronidase. GCF: Gingival crevicular fluid. GI: Gingival index. PP: Placebo
patch. THPP: Transmucosal herbal periodontal patch.
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We designed our investigation to be a singlecenter, randomized, placebo-controlled, doublemasked, longitudinal study involving participants who had clinically diagnosed gingivitis.
We conducted the study at the dental clinic of the
Columbia University College of Dental Medicine,
New York City. The institutional review board of
Columbia-Presbyterian Medical Center, New
York City, approved the study. We obtained
informed consent from all participants enrolled
in the study. The study received investigational
new drug approval from the U.S. Food and Drug
Administration.
We included in our study male and female
patients from the ages of 18 to 65 years who had
a minimum of three posterior teeth in both maxillary quadrants. Participants had to have a
mean gingival index (GI) score of greater than
1.0, which we determined by using Löe and Silness’26 methods regarding the maxillary posterior teeth (premolars and molars but not third
molars). We excluded patients from the study if
they had known allergies to any of the components of the patch; were pregnant or nursing;
were receiving hormonal therapies, antibiotic
agents or anti-inflammatory agents; had systemic conditions such as diabetes; or had severe
periodontal disease as indicated by having
probing depths of 7 millimeters or more on maxillary posterior teeth, excluding third molars.
Study protocol. We randomly assigned participants who met the inclusion criteria to receive
either a THPP or a placebo patch (PP), which
had an identical delivery system but was not
impregnated with any plant extracts. We also
randomly assigned the site of patch placement,
either the left or right maxillary quadrant.
The treatment intervention took place across
three days. Each patch was placed on the buccal
gingivae between the two most posterior maxillary teeth. A total of five patches were applied to
the same treatment site. On day one, the clinical investigator (J.A.) applied the first patch,
and the participant subsequently applied two
additional patches at home. We instructed the
participant to apply one patch on day two and
one patch on day three.
To determine the efficacy of site-specific treatment of gingival inflammation, we obtained GI
scores at the site of application. For the primary
site, the clinical investigator assessed both sides
of the interproximal space (distobuccal aspect of
the proximal tooth and mesiobuccal aspect of the
posterior tooth). The secondary sites included the
mesiogingival surface of the anterior tooth and
the posterior surface of the distal tooth surrounding the primary site. The clinical investigator conducted all the GI assessments. The clinical investigator was trained and monitored
periodically by the principal investigator (J.G.) to
ensure that the GI measurements were consistent
over time, thus reducing intraobserver variability.
The principal investigator, who observed the
scoring process in selected cases to ensure that
the process remained consistent throughout the
study, monitored the intraobserver variability.
We used gingival crevicular fluid (GCF) to
analyze inflammatory markers. The clinical
investigator collected the GCF from the mesiobuccal aspect of the most posterior tooth in the
quadrant in which the patch was placed. Evaluations that included a clinical examination and
obtaining GI scores and samples of GCF took
place on days one (baseline), two, four, eight and
15. At these visits, we asked participants about
adverse events and their subjective impressions
regarding the patches.
We designed the study to be a crossover
study. Participants who received the THPPs in
phase one received the PPs in phase two and
vice versa. Phase two was to begin on day 15, as
we expected that participants’ GI scores would
return to the baseline level by day 15. When we
analyzed the data from phase two, we noted
that participants’ GI scores had not returned to
their baseline levels and that the groups from
phase one and phase two were not equivalent in
terms of their baseline GI scores at the start of
phase two. For this reason, we report efficacy
data from phase one only.
Adverse events monitoring. One of the
goals of the study was to assess the safety of the
THPP. We recorded adverse events on the basis
of participants’ reports or observer determina-
RESEARCH
TABLE 1
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We evaluated study results using
a
per-protocol
analysis of data
Demographic characteristics of the study
because this was a proof-of-principle
population in phase one.
investigation conducted to determine
if the efficacy of the THPP was suffiCHARACTERISTIC
TOTAL
TRANSMUCOSAL
PLACEBO
(N = 53)
HERBAL
PATCH
cient to justify future studies. We
PERIODONTAL
(n = 26)
used parametric to analyze changes
PATCH (n = 27)
in the GI scores and the GCF BG
Age (Years [Mean
33.1 ± 8.4
33.8 ± 8.6
32.4 ± 8.2
levels (fluorescence units). Data
± Standard Deviation])
(20.6-60.0)
(23.6-60.0)
(20.6-52.6)
met the conditions for normalcy as
(Range [Years])
determined by a goodness-of-fit
Sex (% Male)
45
44
46
(Kolmogorov-Smirnov) test. EvaluRace (No.)
ating the mean GI scores as a paraWhite
13
7
6
metric statistic, we used the paired
African American
5
2
3
t test (day X compared with baseline)
Asian
10
6
4
or independent t test (THPP versus
Hispanic
20
9
11
PP). We performed a covariate
Other
5
3
2
analysis and used baseline mean GI
tion. We present safety data for both phases.
values and changes in mean GI scores as the
Analytic procedures. The protocol for
covariates. For BG, we performed a covariate
obtaining GCF and measuring its ß-glucuronidase
analysis and used baseline BG values and the
(BG) enzymatic activity has been described and
change in BG levels as covariates. In evaluating
validated.27 After we removed all supragingival
response rates to treatment, we used the
plaque, we introduced precut filter paper strips
Cochran-Mantel-Haenszel test for significance to
into the gingival sulcus from the mesiobuccal
determine the frequency of response at the site
aspect until we felt mild resistance. We angled
of patch application to specific treatments and
the strips to meet at the midpoint of the mesial
used baseline GI scores as the reference. We
surface and held them in place for 30 seconds.
compared the response rate with the PP after
After we used a calibrated Periotron 8000
controlling for the contralateral (nonpatch) side.
(Smithtown, N.Y.) to determine the fluid volume,
We defined response as an improvement of GI
we placed the strip containing GCF into a microscore increase of 1 or more.
centrifuge tube containing 50 microliters of
RESULTS
sterile phosphate-buffered saline (0.02 molars of
phosphate, 0.15 M of sodium chloride, pH 7.5,
The planned enrollment for the study was 50 parcontaining 0.05 percent Tween 20 [phosphateticipants. We enrolled 53 participants, and 50
buffered saline with Tween, Fisher Scientific,
completed the study with evaluable data. The
Fair Lawn, N.J.]). We determined the BG
demographic characteristics of the study populaactivity of the GCF immediately or assayed it
tion are shown in Table 1. We found no significant
after freezing, because activity of this enzyme
differences between participants assigned to the
can be retained for extended periods when the
THPP and PP groups in phase one of the study.
sample has been frozen.
We dropped three participants from the study
Statistical analysis. The primary outcome
(two for noncompliance and one because of an
measures of our study were the decrease in
unrelated injury that precluded continuation in
the trial). There were no protocol deviations
mean GI scores comparing the THPP with the
during the course of the study.
PP and the safety of the THPP. Secondary outMean GI scores. Use of both the THPP and
come measures included response to treatment
the PP in phase one led to decreased mean GI
and BG levels. For decrease in mean GI scores,
scores at the patch site at days two, four and
which was the measure of efficacy, we powered
eight compared with at baseline (Figure 1). Parthe study so it would detect an effect size of
ticipants who received the THPPs also had
30 percent between the THPP and the PP, which
decreased mean GI scores on day 15 compared
we considered a significant clinical response. On
with at baseline. When comparing the THPP
the basis of the results of previous studies, we
with the PP, the participants who received the
estimated a standard deviation of 0.5 for the GI
THPPs had a significantly greater decrease in
score so that each cohort required 20 participants (assuming an α of .05 and a ß of .80). On
mean GI scores than did those who received the
the basis of this power analysis, we recruited 25
PP at days four and 15. The data indicated that
THPP use decreased mean GI scores beginning
participants per group.
RESEARCH
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PERCENTAGE OF SITES WITH
IMPROVED GINGIVAL INDEX
SCORES
DECREASE IN MEAN GINGIVAL
INDEX SCORES
24 hours after application of the
–0.5
patch, an effect that lasted
*
throughout the study. In com–0.4
*
parison, use of the PP appeared to
–0.3
have a variable effect with a mild
decrease of GI scores after 24
–0.2
hours, which then returned to
–0.1
close to the baseline scores at day
four. At day eight, there was
0
another decrease in GI scores,
0.1
which once again returned to close
0.2
to baseline at day 15 (Figure 1).
2
4
8
15
We conducted analysis of covariDAY
ance (ANCOVA) to determine the
influence of the baseline scores on
THPP
PP
the decrease of mean GI scores at
Figure 1. Decrease in mean gingival index score during the course of the study. Error
the primary site. We conducted a
bars represent standard error of the mean. *: P < .05. THPP: Transmucosal herbal
two-way parametric analysis of
periodontal patch. PP: Placebo patch.
variance for each time point. As we
expected, the baseline score was
45
correlated with the change in the
GI scores at each time point. Even
*
after factoring in the baseline
effect (which reflected the severity
*
35
of the disease), the use of the
THPP on both day four and day 15
resulted in a significant decrease
in GI scores (P = .013 for day four
25
and P = .037 on day 15).
We also evaluated the percentage of participants who had a positive clinical response to use of the
15
2
4
8
15
THPP compared with those who
had a positive response to the use
DAY
of PP. When we defined a response
THPP
PP
as a primary site improvement of
a score of 1 or greater in the GI
Figure 2. Clinical response to treatment. Response was defined as a decrease of 1 or
from baseline (for example,
greater in gingival index score at the primary site. *: P < .05. THPP: Transmucosal
decreasing from a GI score of 3 to
herbal periodontal patch. PP: Placebo patch.
2), we found that a significantly
phase two (which took place on day 15) comgreater number of participants responded posipared with the participants who initially
tively to the use of the THPP as compared with
received the PPs.
those who responded positively to the use of the
Efficacy of GCF BG levels. In phase one,
PP at day four (Figure 2). Specifically, 38 percent
we measured the BG level in the GCF for THPP
of those who received the THPPs responded posand PP groups at the site on which the patch
itively compared with 22 percent of those who
was applied (Table 2). Participants receiving the
received the PP (P = .036). Likewise, the THPP
THPP had significantly lower BG levels on days
outperformed the PP at day 15 (P = .014). These
two, four and eight compared with the baseline
data, which are similar to the pattern we saw
levels. When we compared the decrease in BG
with mean GI scores, demonstrate both the early
level between the two groups, we found signifionset and retained effect of the use of the THPP.
cant differences on days four and eight (P = .048
Results from phase two of our crossover study
and P = .040, respectively).
did not show differences between the THPP and
To determine the separate contributions of the
PP groups. It is likely that the retained effect of
use of the THPP and baseline scores (that is, the
the THPP may have biased the results, as the
level of inflammation) with the decrease in BG
participants who initially received the THPPs
levels, we conducted ANCOVA by using baseline
had a lower overall mean GI score at baseline in
RESEARCH
TABLE 2
Decrease in BG* levels at patch placement site.
THPP†
DAY
PP‡
SEM
DIFFERENCE IN
MEAN
PERCENTAGE
CHANGE FROM
BASELINE§
t TEST
(P VALUE)
62.2
4.1
—
—
25
60.6
5.0
−18.7
.220
4.6
24
54.8
4.4
−26.4
.048
47.3
4.0
22
58.2
5.3
−30.4
.040
54.2
5.6
25
54.7
6.1
2.8
.910
No.¶
Mean#
SEM**
No.
Mean
1
(Baseline)
27
67.1
5.5
26
2
27
56.2
4.9
4
25
47.9
8
26
15
24
*
†
‡
§
TABLE 3
Analysis of covariance of the primary site
ß-glucuronidase levels.
DISCUSSION
In this single-center, randomized,
placebo-controlled, doublemasked, longitudinal phase II
DAY
DIFFERENCE IN MEAN ß-GLUCURONIDASE
P VALUES FOR THE
LEVELS OF THE TRANSMUCOSAL HERBAL
EFFECTS
trial, we found that a three-day
PERIODONTAL PATCH AND THE PLACEBO
application of a transmucosal
PATCH*†
patch containing plant extracts
Mean (95 Percent Confidence Interval)
Treatment Baseline
reduced gingival inflammation.
−6.6 (−19.4-6.3)
2
.311
.001
THPP use decreased mean GI
−9.1 (−21.9-3.6)
4
.156
.068
scores beginning at 24 hours, and
−12.3 (−25.7-1.1)
the mean GI scores remained
8
.071
.322
decreased throughout the 15-day
0.17
(−16.4-16.7)
15
.983
.207
observation period. Mean GI
* When considering baseline levels as a covariate.
scores at the site of the THPP
† A negative value implies that the transmucosal herbal periodontal patch group had a
greater decrease in mean ß-glucuronidase levels (fluorescence units) from baseline
were decreased significantly on
than did the placebo patch group.
days four and 15 compared with
those at the site of the PP. A
BG levels as a continuous covariate. The results
higher percentage of sites receiving the THPP
of the analysis of covariance show that baseline
had a decreased GI score compared with those
BG levels had their greatest impact on subreceiving the PP, and this finding was statistisequent BG levels on day four but less so on day
cally significant on days four and 15 of phase
eight. In contrast, use of the THPP was the
one of the study. The adverse events that could
major contributor to the reduction of BG levels
be attributed to use of the THPP, such as taste
on day eight (Table 3).
perversion and application site reactions, were
Safety. We evaluated the safety of the THPP
tolerated by the participants.
during both phases of the trial. We did not
In our study, the decrease in mean GI scores
observe any serious adverse events (adverse
for the THPP was consistent throughout the
events for which the participant had to be hospistudy. For the PP, however, there also was a
talized) in participants receiving the THPP or
noticeable reduction in mean GI scores on day
the PP during either phase of the study. In
eight compared with the baseline scores (Figure
terms of total adverse events, 32.1 percent (17 of
1). A probable explanation for this finding was
53) of the participants who received the THPPs
that participants improved their oral hygiene
had at least one adverse event that may have
after patch treatment was stopped on day three,
been related to the study drug (total of 21
causing participants receiving both the THPP
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BG: ß-glucuronidase.
THPP: Transmucosal herbal periodontal patch.
PP: Placebo patch.
Mean percentage decrease in BG levels (fluorescence units) from baseline in the THPP group minus
the mean percentage change in BG levels from baseline in the PP group. A negative value implies that
the THPP group had a greater mean percentage decrease in the BG level from baseline than did the
PP group.
¶ No.: Number of participants in the group at the time point at which the BG level was obtained.
# Mean: The mean BG level at each time point.
** SEM: Standard error of the mean for the BG level at each time point.
events). All of these
adverse events were
mild. We found no differences in terms of
the frequency or type
of adverse events that
were related to either
sex or race of the participants. A more detailed analysis of adverse events for both
phases of our study is
shown in Table 4. The
most frequent adverse event associated with use of the
THPP or the PP was
taste perversion, followed by application
site reaction, accidental injury and
headache.
RESEARCH
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TABLE 4
and the PP to have
similar improvements
Adverse events associated with the transmucosal
in GI scores at day
herbal periodontal patch and the placebo patch
eight. This placebo
effect was short lived,
for both phases of the study.
as the GI scores of the
ADVERSE EVENT
TRANSMUCOSAL
PLACEBO PATCH
TOTAL (NO. [%])
participants who
HERBAL
(N = 53) (NO. [%])
received the PP
PERIODONTAL
PATCH (N = 53)
returned to levels
(NO. [%])
closer to the baseline
Accidental
Injury
2 (3.8)
3 (5.7)
5 (9.4)
levels, and the participants who received
Headache
3 (5.7)
1 (1.9)
4 (7.5)
the THPP had signifiBack Pain
1 (1.9)
0 (0.0)
1 (1.9)
cantly decreased GI
Anorexia
1 (1.9)
0 (0.0)
1 (1.9)
scores at day 15.
Dry Mouth
0 (0.0)
1 (1.9)
1 (1.9)
We used GCF BG
Dyspepsia
1 (1.9)
0 (0.0)
1 (1.9)
levels as an indeNausea
1 (1.9)
0 (0.0)
1 (1.9)
pendent measure of
the inflammatory
Nausea, Vomiting or Both
1 (1.9)
1 (1.9)
2 (3.8)
response. Whereas GI
Increased Salivation
0 (0.0)
2 (3.8)
2 (3.8)
scores and response
Ulcer Mouth
0 (0.0)
1 (1.9)
1 (1.9)
rates are subjective
Increased Cough
1 (1.9)
0 (0.0)
1 (1.9)
and relate to the
Nasopharyngitis
0
(0.0)
1
(1.9)
1 (1.9)
visual appearance of
the gingiva, the level
Pharyngitis
1 (1.9)
0 (0.0)
1 (1.9)
of GCF BG enzymatic
Application Site Reaction
3 (5.7)
2 (3.8)
5 (9.4)
activity is a more
Taste Perversion
6 (11.3)
5 (9.4)
11 (20.8)
objective measureDysmenorrhea
1 (1.9)
0 (0.0)
1 (1.9)
ment. The GCF BG
level reflects the
this area rather than in the buccal or lingual
quantity of polymorphonuclear leukocytes found
aspects of the gingiva.
in the sulcus and may be a more accurate assessWe expected that participants would return
ment of inflammation found in the periodontal
to their baseline statuses on day 15 of the study
sulcus than are clinical signs of inflammation
(12 days after receiving the last patch applicasuch as tissue erythema and bleeding.27 GCF BG
levels were significantly lower in participants
tion). On day 15, those receiving the THPP had
who received the THPPs than in those who
reduced mean GI scores compared with both
received the PPs on days four and eight (Table 2).
baseline scores and those of participants
When we factored in baseline BG levels as a
receiving the PP (Figure 1). For this reason, it
covariate, we found that the effect of THPP use
would not have been valid for us to draw any
approached significance on day eight (P = .071
conclusions from phase two of the study, as the
for the THPP compared with P = .322 for basetwo treatment groups were not comparable at
line BG levels) (Table 3). On day 15, the GCF BG
day 15. The data suggest that participants who
levels returned to baseline in participants who
initially received the THPPs had a lasting
received the THPPs, although the mean GI
improved effect even after discontinuing the use
scores at this time point still were improved sigof the THPP.
nificantly compared with the baseline GI scores
Our study had several strengths and limita(Figure 1). One explanation for the lack of a temtions. In terms of strengths, we performed
poral association between BG levels and GI
ANCOVA, the results of which demonstrated
scores is that the BG measures neutrophil influx
that the major factor contributing to the
to the sulcus, which may be a better measure of
improved status of the participants’ receiving
deep sulcular inflammation than is the level of
the THPP was the patch and not the degree of
surface erythema, which reflects the level of
severity of disease, as reflected by baseline GI
superficial inflammation of the sulcus as
scores. In addition, we confirmed the efficacy of
assessed by GI. In addition, since we collected
treatment using the THPP in reducing inflamGCF from the intraproximal area, BG levels may
mation by using both clinical and laboratory
be more indicative of the level of inflammation in
measures of gingival inflammation.
RESEARCH
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lients needs to be determined.
The use of pharmaceutical agents to reduce
inflammation is limited by their associated side
effects and contraindications in the presence of
comorbid conditions. The clinical value of the
THPP is that it interrupts the cycle of inflammation across the short term, allowing for adequate
oral hygiene measures on the part of the patient.
In the long term, periodic therapy with a THPP
may be able to control the destructive aspects of
inflammation and prevent future recurrence.
The results of our study present proof of concept that targeted treatment of specific sites of
gingival inflammation by means of the THPP is
effective. Site-specific therapy is an important
adjunct to standard treatment of gingival inflammation, since conventional treatment often fails
to reduce gingival inflammation at refractory
sites. The results of large interventional studies
determining if periodontitis is a risk factor for
premature birth have shown a significant incidence of refractory bleeding on probing after
standard periodontal treatment.37,38 Even after
intensive interventions, clinical and biochemical
markers of periodontal disease remain elevated,
indicating significant residual disease.39 The
THPP is designed to target these refractory sites.
CONCLUSIONS
Topical treatment by means of the THPP may
be an effective and safe method of reducing topical gingival inflammation. Further studies are
needed to confirm these findings and determine
the best method for administering the THPP, as
well as the appropriate dosing. ■
Disclosure. Dr. Grbic is a consultant to Izun Pharmaceuticals,
New York City. Dr. Saffer is a cofounder and the senior vice president
for research and development, Izun Pharmaceuticals, New York City.
Dr. Saffer helped design the study.
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2. Albandar JM. Global risk factors and risk indicators for periodontal diseases. Periodontol 2000 2002;29:177-206.
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periodontitis in the USA in decline? Periodontol 2000 2009;50:13-24.
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The limitations of our study were related to
the crossover design. Initially, we chose a crossover design because we thought its results would
provide more information regarding safety and
efficacy, while providing an additional level of
control for participant variability. Underlying the
basis of the control study was the expectation
that the effects of the THPP would be short-lived
so that participants could start phase two immediately after conclusion of phase one (on day 15).
This turned out not to be the case, as there still
were significant differences between the two
groups on day 15. In future studies, either the
trial should be limited to a single phase with
more participants or a washout period should be
built into the study design.
In our study, we tested specific plant extracts
embedded in an easily applied patch. The THPP
contained plant extracts derived from Centella
asiatica, Echinacea purpurea and Sambucus
nigra. These three herbs have shown antioxidant and immunomodulatory activity that can
reduce the inflammatory component of gingivitis and improve wound healing. C. asiatica
is known for its healing properties, especially
with regard to wound healing and microangiopathy.28-30 The natural anti-inflammatory
properties of Centella have been found to reduce
levels of BG activity, which often is elevated at
sites of inflammation, including sites with gingivitis.31 E. purpurea is one of the most widely
used medicinal herbs. The compounds derived
from E. purpurea have immunomodulatory
effects related to proinflammatory interleukins,
interferon-γ and tumor necrosis factor-α.22,25,32
S. nigra inhibits the proinflammatory properties of bacteria commonly found in periodontitis.21
An at least partial, and even possibly a major,
contribution to the effect of the THPP is the
mechanical effect of the patch. The oral environment is an important factor in sustaining gingivitis. Transmucosal patches may act as a barrier to microorganisms, or they may absorb
inflammatory mediators, as has been shown in
other wound-care products.33,34 Our data comparing the PP with the THPP (Figure 1) showed
that the PP also reduced gingival inflammation
when compared with baseline, suggesting that
the patch itself reduces gingival inflammation
to some degree in relation to baseline mean GI
scores. This effect, in part, most likely is due to
the classic placebo effect seen in periodontal
treatment studies.35,36 It appears, however, that
there also is an additive or even synergistic
effect resulting from the use of the THPP.
Whether the plant extracts in the THPP serve
as anti-inflammatory agents or as simple emol-
RESEARCH
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systemic inflammatory responses to periodontal therapy (published
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