Annals of RSCB Vol. XVII, Issue 12012 [629465]

Annals of RSCB Vol. XVII, Issue 1/2012

211 BENEFICIAL EFFECTS OF SELECTIVE CYCLOOXIGENASE-2
INHIBITOR ETORICOXIB IN PERIODONTITIS

C. Vlad 1, Daliborca Cristina Vlad 2,3 , Adina Bucur 4, Roxana Popescu 3,5 ,
V. Dumitra șcu 2,3

1DENTISSIMO DENTAL CARE S.R.L., TIMISOARA, ROMANIA;
VICTOR BABES UNIVERSITY OF MEDICINE AND PHARMACY TI MISOARA:
2DEPARTMENT OF PHARMACOLOGY; 4DEPARTMENT OF PUBLIC HEALTH;
3COUNTY EMERGENCY HOSPITAL No. 1 TIMISOARA, ROMANIA.

Summary
Adjunctive therapeutic strategies that modulate th e inflammatory mediators can play a
significant role in periodontal therapy. Periodonti tis has been reported to be associated with
coronary artery disease (CAD). In this prospective and controlled study, 132 eligible
postmenopausal women with chronic periodontitis wer e evaluated for 60 days. The
experimental group (66 patients) received once-dail y 60 mg of selective cyclooxygenase-2
(COX-2) inhibitor etoricoxib. The control group (66 patients) did not receive any anti-
inflammatory drugs, only periodontal maintenance th erapy. Plaque index (PI), probing
pocket depth (PPD) and bleeding on probing (BOP) we re monitored with an electronic
probe at baseline and after 30 days and 60 days. In flammatory mediators and lipid profiles
were comparatively evaluated at baseline and at the end of the study. Both groups displayed
clinical improvement in PPD, PI and BOP. They also showed statistically similar values
(p>0.05) of PPD reduction on day 30 (0.4 mm) and on day 60 (0.6 mm). At the baseline,
few deeper sites (> 7 mm) from etoricoxib group were responsible and mo st PPD reduction
was observed after 30 days (p<0.05).The etoricoxib treatment reduced median high-
sensitivity C-reactive protein (hs-CRP) by 22 perce nt (primary outcome (P = .02), and
increased the HDL-cholesterol level among women mor e than seven years postmenopausal.
Etoricoxib presents potential effect as an adjunct of periodontal disease treatment, but long-
term clinical trials are necessary to confirm its e fficacy.
Key words: periodontitis, inflammation, etoricoxib, C-reactive protein, periodontal status.

[anonimizat]

Introduction
Non-steroidal antiinflammatory
drugs (NSAIDs), sub-antimicrobial dose of
doxycycline and bisphosphonates or
combination of drugs have been
successfully used as an adjunct to non-
surgical mechanical periodontal therapy.
The results of host modulation studies have
shown that this approach may be a potential
target to reduce tissue destruction. NSAIDs
blockade the pro-inflammatory cytokines;
sub-dose of doxycycline blockades the
metalloproteinases and the bisphosphonates
blockade the osteoclast activity (Kirkwood
et al, 2007, de Queiroz et al, 2008). The basis of antiinflammatory drugs
in periodontal disease treatment is related to
the control of prostaglandin E 2 (PGE 2)
through the inhibition of cyclooxygenase-2
(COX-2) enzyme. Higher levels of PGE 2
are associated with increased gingival
inflammation and alveolar bone loss
(Noguchi&Ishikava, 2007, Reynolds et al ,
2007, Tripton et al , 2003).
Many reports have shown that
conventional NSAIDs may delay alveolar
bone healing, whereas the inhibitory effects
of COX-2-selective NSAIDs still lack
experimental and clinical evidence, even if
a diverse array of drugs has become

Annals of RSCB Vol. XVII, Issue 1/2012

212 available (table 1) (Dionne et al, 2001,
Holzhausen et al, 2002) . Etoricoxib (figure
1) is a nonsteroidal anti-inflammatory drug
that exhibits anti-inflammatory, antipyretic
and analgesic activities; doses are 60 to 120
mg/day, used for the treatment of
rheumatoid arthritis, osteoarthritis, chronic
low back pain, gout, and ankylosing
spondylitis. NCl
CH3SO O
CH3
Etoricoxib
Figure 1. Chemical structure of etoricoxib

Table 1. Classification of non-steroidal anti-inflammatory d rugs
Basic chemical structures Specific drugs

Salycilic acid derivates Aspirin
Sodium salycilate
Fenoprofen
Flurbiprofen
Ibuprofen
Naproxen
Ketoprofen

Heteroaryl acetic acids Diclofenac
Ketorolac
Tolmetin

Indole and indene acetic acids Etodolac
Indomethacin
Sulindac

Anthranilic acids (fenamates) Mefenamic acid
Meclofenamic acid
Tolfenamic acid

Enolic acids Meloxicam
Piroxicam
Phenylbutazone
Tenoxicam
Alkalones Nabumetone

Diarylheterocyclics (coxibs) Celecoxib
Valdecoxib
Etoricoxib
Others Nimesulide

The mechanism of action is due to
the inhibition of prostaglandin synthesis,
primarily via inhibition of cyclooxigenase-2
(COX-2), and at therapeutic concentrations
does not inhibit the cyclooxygenase-1
isoenzyme (Cepone et al, 2005 ).
There are few reports revealing the
effect of etoricoxib in periodontitis.
Azoubel and coworkers (2007) investigated
the effect of etoricoxib, a selective
cyclooxygenase-2 inhibitor, and
indomethacin, a non-selective
cyclooxygenase inhibitor, on experimental
periodontitis, and compared their
gastrointestinal side effects. Histopathology
of periodontium showed that etoricoxib and
indomethacin reduced inflammatory cell
infiltration, alveolar bone loss (ABL),
cementum and collagen fiber destruction.
Macroscopic and histopathological analysis
of gastric and intestinal mucosa
demonstrated that etoricoxib induces less
damage than indomethacin. Animals that
received indomethacin presented weight

Annals of RSCB Vol. XVII, Issue 1/2012

213 loss starting on the 7th day, and higher
mortality rate (58.3%) compared to
etoricoxib (0%). Treatment with etoricoxib,
even starting when ABL is detected,
reduces inflammation and cementum and
bone resorption, with fewer gastrointestinal
side effects.
The purpose of this study was to
evaluate a selective COX-2 inhibitor,
namely etoricoxib, as an adjunct for
periodontal disease treatment, using hs-
CRP and probing pocket depth (PPD) to
verify the inflammation reduction.

Material and methods
Study design and eligibility
criteria. One hundred thirty-two eligible
patients participated in this randomized,
prospective and controlled study, which
used parallel inter-subjects and a split-
mouth design. The patients with at least 20
teeth, ranging in age from 45-65 years, who
had two or more teeth with clinical
attachment loss (CAL) > 6 mm and one or
more sites with PPD > 5 mm were selected
according to the established periodontitis
criteria. Exclusion criteria were: presence of
systemic diseases gastric ulcer,
hypersensitivity to antiinflammatory drugs,
use of antibiotic, corticoids,
immunosuppressive drugs or any NSAIDs
within the past three months.
We recruited participants on a
rolling-admission basis between November
2010 and December 2011. Prior to
initiation, the purpose and design of study
was explained to patients and an informed
consent form was signed by every patient.
The patients were divided in two study
groups, of 66 patients each, as following:
the experimental group and the control
group.
The experimental group (66
patients) received once-daily 60 mg of
selective cyclooxygenase-2 (COX-2)
inhibitor etoricoxib for 60 days. The control
group (66 patients) did not receive any anti-
inflammatory drugs, only periodontal
maintenance therapy. Plaque index (PI),
probing pocket depth (PPD) and bleeding on probing (BOP) were monitored with an
electronic probe at baseline and after 30 and
60 days. Inflammatory mediators and lipid
profiles were comparatively evaluated at
baseline and at the end of the study.
Serum inflammatory mediator
analyses. Research assistants trained in
phlebotomy drew non-fasting blood
samples at baseline, one-month and two-
month appointments. Serum was obtained
using standard technique and stored at –
80˚C until analysis. We measured hs-CRP
by using a high-sensitivity enzyme-linked
immunosorbent assay (ELISA).
Lipid profile. In our clinical
chemistry laboratory we measured total
cholesterol, high-density lipoprotein (HDL)
cholesterol and trygliceride levels by using
standard techniques and reagents. Levels of
low-density lipoprotein (LDL) cholesterol
and very-low-density lipoprotein (VLDL)
cholesterol were based on results calculated
as follows: LDL cholesterol, total
cholesterol – (HDL cholesterol +
triglycerides: 5); VLDL cholesterol,
triglycerides: 5.
The sensitivity to detect lipids were
assay ranges of 3 to 800 mg per deciliter for
total cholesterol, 3 to 120 mg/dL for HDL
cholesterol and 4 to 1,000 mg/dL for
triglycerides.
Statistical analysis. Results were
expressed as mean and standard deviation.
Comparisons were made using the
Student’s test, and significance was
established at p<0.05. All statistical
analyses were performed using the SPSS
software package (version 6.0 for
Windows, SPSS Inc, Chicago, IL.).

Results
All 132 patients completed the
study, presenting 100% of medication
compliance, and no complain of adverse
reactions to the etoricoxib therapy.
Compliance was monitored at all exam
visits by the assessment of the amount of
medication taken from the original
prescription package.

Annals of RSCB Vol. XVII, Issue 1/2012

214 Baseline demographic
characteristics of the patients divided by
groups did not reveal any statistically
significant differences (p>0.05) between
groups regarding the evaluated parameters
at baseline (table 2).

Table 2. Baseline parameters for the
experimental and control group
Baseline
parameter Study group
(etoricoxib) Control
group
Age (yrs) 55± 3 55± 3
Age range 45-65 45-64
PPD (mm) 2.4±0.3 2.5±0.3
BOP% 25.6±10.3 23.6±11.3
PI% 58.6±23.5 59.6±25.5
Legend: PPD – probing pocket depth; BOP –
Bleeding on probing; PI – Plaque index.

The etoricoxib treatment reduced
median high-sensitivity C-reactive protein
(hs-CRP) by 22 percent (primary outcome
P = .02), and increased the HDL-cholesterol
level among women more than seven years
postmenopausal. The mean hs-CRP level at
baseline, did not differ significantly
between study groups (P=0.9). The
maximum baseline hs-CRP level was 10
mg/L. Data concerning the lipid profile,
revealed that mean HDL-cholesterol levels
were significantly higher in women more
than seven years post-menopausal (p<0.05).
Serum HDL-cholesterol levels increased
significantly 60 days of etoricoxib
treatment. Periodontal disease status was
determined using clinical criteria. Clinical
evaluation was based on full mouth plaque
index (PI), papillary bleeding index (PBI),
probing pocket depth (PPD) at six sites per
tooth and clinical attachment level (CAL) at
four sites per tooth. Both study groups
displayed clinical improvement in PD, PI
and BOP. They also showed statistically
similar values (p>0.05) of PD reduction on
day 30 (0.4 mm) and on day 60 (0.6 mm).
At the baseline, few deeper sites (> 7 mm)
from etoricoxib group were responsible and
most PD reduction was observed after 30
days (p<0.05) (table 3).
Table 3. Percentage reduction of probing
pocket depth in the experimental and control
group
. Probing
pocket depth Study group
(etoricoxib)
(%) Control
group (%)
PPD (<4 mm)
baseline 83.0 86.0
PPD (<4 mm)
30 days 87.0 89.0
PPD (<4 mm)
60 days 92.0 93.0
PPD (4-7 mm)
baseline 12.0 15.0
PPD (4-7 mm)
30 days 9.0 10.0
PPD (4-7 mm)
60 days 6.0 6.0
PPD (>7 mm)
baseline 1.5 1.5
PPD (>7 mm)
30 days 1.2 0.8
PPD (>7 mm)
60 days 0.4 0.6
Legend: PPD – probing pocket depth

Discussion
This short-term study evaluated the
effect of etoricoxib on the reduction of
probing pocket depth and on systemic
inflammation of periodontal disease.
Several recent studies have emphasized that
even moderately elevated CRP serum levels
are predictors of increased risk of
cardiovascular disease among apparently
healthy individuals (Ridker et al., 1997).
Chronic bacterial infections such as
periodontitis are one of the established risk
factors for moderately elevated CRP (Iade
et al., 2000). Previous studies have
demonstrated that CRP levels are higher in
periodontitis patients than in periodontally
healthy subjects and that serum CRP levels
are higher in patients with more severe
periodontitis (Saito et al., 2003).
CAD is an important clinical
sequela of menopause, and hs-CRP is a
robust risk factor. It was observed a limited
suggestive potential for the treatment of
deep periodontal pockets. Nevertheless, the
initial difference in PD reduction and the

Annals of RSCB Vol. XVII, Issue 1/2012

215 benefits on the deeper periodontal pockets
were insignificant after 30 days or longer.
Mean serum C-reactive protein level was
significantly lower in the experimental
group (8.9 mg/L), as compared to the
controlled group (5.9 mg/L) after 60 days
of etoricoxib treatment.
Clinical trials suggest that the
selective COX-2 inhibitor class of drugs (of
which etoricoxib is one) may be associated
with an increased risk of thrombotic events
(especially stroke). As the cardiovascular
risks of selective COX-2 inhibitors may
increase with dose and duration of
exposure, the shortest duration possible and
the lowest effective daily dose should be
used. Patients on long-term treatment
should be reviewed regularly, such as every
three months, with regards to efficacy, risk
factors and ongoing need for treatment
(Malmstrom et al., 2004).
Regarding NSAID efficacy period,
it has been shown that the inhibitory effect
of PGE 2 continues only during drug intake
phase and will end after drug therapy
cessation (Vadar et al., 2005).
In this short-term evaluation, PPD
and BOP presented significant
improvement during the observation period.
However, no differences were detected
between groups on day 30, which indicate
that mechanical therapy alone or combined
with etoricoxib can successfully reduce the
inflammation and promote pocket depth
reduction. Therefore, the extended use of
NSAIDs as an adjunctive therapy is not
essential to reduce gingival inflammation
and should be limited to the active phases
of periodontal disease.
One limitation of this study is the
lack of biochemical analyses of the gingival
crevicular fluid (GCF) and tissue biopsy.
Nevertheless, although PGs levels of the
patients were not measured in this
experiment, it seems like the present
findings are related to the mechanism of the
COX-2 inhibition will be supported by
further studies.

Conclusions
Etoricoxib used in low doses
reduced serum hs-CRP and increased HDL
cholesterol in postmenopausal women with
chronic periodontitis; it also improved the
plaque index (PI), probing pocket depth
(PPD) and bleeding on probing (BOP)
parameters.
Health condition should be carefully
evaluated before recommending etoricoxib
as an adjunct for clinical use.
Etoricoxib, as a selective COX-2
inhibitor, has a favorable safety profile and
represents an attractive new
pharmacological approach to managing
chronic systemic inflammation.

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