Open Journal of Gastroenterology, 2013, 3, 72-77 OJGas
http://dx.doi.org/10.4236/ojgas.2013.31011 Published Online February 2013 (http://www.scirp.org/journal/ojgas/)
Anti free radical & anti inflammatory effect of rebamipide
in chronic gastritis
Marcellus Simadibrata1, Ari Fahrial Syam1, Aziz Rani1, Septelia Inawati Wanandi2, Achmad Fauzi1,
Murdani Abdullah1
1Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Depok, Indonesia
2Department of Biochemistry, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
Received 11 October 2012; revised 12 November 2012; accepted 19 November 2012
ABSTRACT
Background/Aim: Free radicals have a role in the
development of chronic gastritis. The aim of this
study to know the effect and efficacy of rebamipide
on free radicals in chronic gastritis. Method: Forty
five patients in the division gastroenterology Cipto
Mangunkusumo Hospital Jakarta 2009-2010 with
moderate and severe gastritis endoscopically were in-
cluded in this study. Before and after rebamipide
treatment the patient were performed endoscopical
examination and were taken 5 biopsies for histopa-
thological examination and free radicals (MDA &
Carbonyl Compound) examination. All patients were
given rebamipide 100 mg three times a day for 28
days. Data were analyzed with t test or wilcoxon
signed rank test. Exclusion: GERD, Peptic ulcer, PPI
treatment, NSAID consumption etc. The symptoms
were recorded on day-0 and day-28. The severity
symptoms were measured by VAS. Result: The mu-
cosal damage on day-0 was 2.268 ± 0.45 vs day-28 was
1.707 ± 0.78 (P < 0.001). The antrum neutrophil:
day-0: 0.12 ± 0.46 vs day-28: 0.10 ± 0.37 (P = 0.710)
and corpus neutrophil: day-0: 0.12 ± 0.40 vs day-28:
0.07 ± 0.26 (P = 0.421). The mean endoscopical mu-
cosal severity score was decreased significantly on day-
28 compared to day-0 (1.707 ± 0.78 vs 2.268 ± 0.45;
P < 0.05). The other histopathological appearances
between day-0 and day-28 were not different. Re-
bamipide can reduce the mean of MDA from 5.28 ±
3.54 on day-0 to 4.15 ± 2.71 on day-28 (P = 0.047).
The mean of carbonyl compound on day-0 was 4.14 ±
3.01 and on day-28 was 5.12 ± 2.71 (P = 0.642). Con-
clusion: Rebamipide significantly reduced the extend
of symptoms associated with chronic gastritis. The
improvement in symptoms was associated with the
decreased of endoscopic severity score and the mean
gastric mucosal malondialdehyde (MDA) significantly
but not the histopathologic appearance and carbonyl
compound.
Keywords: Rebamipide; Chronic Gastritis;
Histopathologic Severity; MDA; Carbonyl Compound
1. INTRODUCTION
Chronic gastritis is an inflammatory condition of the gas-
tric mucosa characterized by elementary lesions, whose
extent and distribution are related to their etiology and
host response.
Chronic gastritis has a multietiopathogenic factors with
dyspeptic syndrome. It is widely accepted that a major
underlying factor of this disorder is the generation of free
radicals. There is substantial evidence that oxygen de-
rived free radicals play an important role in the patho-
genesis of the injury of various tissues, including the
digestive system [1]. Furthermore, Helicobacter pylori
and non steroidal anti-inflammatory drug (NSAID) are
two major causes related to gastric injury. Helicobacter
pylori plays an important role in the induction of chronic
gastritis and has been accepted that there is a strong as-
sociation between Helicobacter pylori-associated gastri-
tis and gastric diseases including peptic ulcer and gastric
cancer.
Rebamipide is a gastro-protective drug used by pa-
tients suffering from gastric ailments and has been widely
used as an anti-gastritis and anti-ulcer agent in patients
with dyspepsia and gastroesophageal reflux diseases
(GERD) [2,3]. Rebamipide is classified as anti-inflam-
matory agent which will suppress inflammation process,
and as anti free-radical agent by inhibiting the release of
the free radical, superoxide (2) and also scavenge hy-
droxyl radical (OH−). Rebamipide is one of the most
commonly used gastro protective agents in East Asia and
had been widely proven that the drug exhibits preventive
effects in gastric mucosa by increasing endogenous pros-
taglandin or by suppressing oxygen free-radicals as well
as increasing blood flow. Unlike in Western countries,
gastric atrophy is more prominent in Asia, which indi-
cates that mucosal protection is more important than
O

M. Simadibrata et al. / Open Journal of Gastroenterology 3 (2013) 72-77 73
mono antiacid therapy.
Helicobacter pylori eradication therapy in patients
with functional dyspepsia, gastritis, and gastro esophag-
eal reflux disease remains controversial. Therefore, the
therapeutic strategy without H. pylori eradication therapy
is needed for these symptomatic patients [4,5]. Pre-clini-
cal studies have indicated that rebamipide contributes to
the enhancement of the defense mechanism in gastric
mucosa, which results from increasing gastric mucus and
the stimulation of the production of endogenous pros-
taglandins without gastric acid suppression. Rebamipide
is known to suppress gastric mucosal inflammation, which
is thought to be related to its activity in the inhibition of
superoxide anion production from neutrophils and scav-
enging hydroxyl radicals, and in inhibiting interleukin-8
production. Rebamipide appears to be a suitable drug for
the treatment of chronic gastritis patients whose symp-
toms and inflammation in gastric mucosa are not im-
proved by acid-suppressive agents [6,7].
The aim of this study was to evaluate the efficacy and
safety of rebamipide for the relief of dyspeptic symptoms
due to free radicals and inflammation, and also the im-
provement in endoscopic and histological appearances in
patients suffering from chronic gastritis in Indonesia.
2. MATERIALS AND METHODS
2.1. Patients
Patients with chronic gastritis by evaluating endoscopic
and histological biopsy and with dyspeptic symptoms
were enrolled in this study.
Written informed consent was obtained from all par-
ticipants.
The protocol was approved by the Ethics Committee
of the Faculty of Medicine, University of Indonesia.
At screening, upper gastrointestinal endoscopy was
performed in all patients so that the presence of endo-
scopic and histological features of chronic mucosal in-
flammation could be confirmed. Helicobacter pylori was
evaluated by histology and/or rapid urease test.
Patients might also have other symptoms, including
stomach heaviness, abdominal fullness, poor appetite,
and diarrhea.
Exclusion criteria were: 1) patients who are treated
with drugs that may induce gastritis or ulcer or may af-
fect the evaluation before enrolled (NSAIDs, teprenone,
sucralfate, PPIs, H2RAs, antibiotics, mesalazine); 2)
chronic alcoholism; 3) drug abuser; 4) contraindicated
for endoscopic examination; 5) erosive or ulcerative
esophagitis; 6) peptic ulcer; 7) pyloric stenosis; 8) active
gastrointestinal bleeding; 9) major absorption disorder;
10) history of gastric surgery; 11) renal disorder (creatinine
> 2 mg/dL); 12) liver diseases; 13) hematologic disorder;
14) suffering from congestive gastropathy due to liver
cirrhosis; 15) congestive heart disease; 16) pregnancy or
breast feeding; 17) hypersensitive to rebamipide.
Patients who are under treatment of PPIs or H2RAs
should undergo wash-out period at least 1 week before
enrolled to the study. Only antacid is allowed during the
wash-out period.
2.2. Study Design
The study was carried out as an open, non-randomized
and single group treatment clinical trial performed in Dr.
Cipto Mangunkusumo General Hospital, Jakarta, Indo-
nesia between October 2007 and February 2010.
Patients orally received an open-labeled treatment of
rebamipide 100 mg three times a day for 4 weeks. Re-
bamipide used in the current study was an original drug
(Mucosta).
3. EVALUATIONS
3.1. Endpoints
At the end of study, the patients were examined on the
basis of their dyspepsia symptoms. Endoscopy was per-
formed to compare endoscopic score and grading of
chronic gastritis on day-0 and day-28.
The primary endpoint of this study was to assess the
efficacy of rebamipide in reducing gastric mucosal
damage due to free radicals and inflammation. The free
radicals were measured accordingly to the malondial-
dehyde and dicarbonyl compound levels in biochemis-
try assessment while the latter were measured by the
level of mononuclear inflammatory cells and polymer-
phonuclear neutrophil activity in the laboratory evalua-
tion. The secondary endpoint was to confirm the im-
provement of dyspeptic symptoms which were measured
using the visual analogue scale of the Updated Sydney
System [8].
3.2. Clinical Assessments
A visual analogue scale-based standard questionnaire
was used to investigate and to access the dyspepsia
symptoms, such as epigastric pain, nausea, vomiting, ano-
rexia, bloating, belching and early satiety. All of these
symptoms were rated by patients using a visual analogue
scale from 0, none, to 10, worst symptom in day-0, day-7
and day-28 observation.
3.3. Endoscopic Evaluation
The endoscopic appearance of the mucosa was observed
and photographed with a video-endoscope. Endoscopic
score was expressed in terms of the local endoscopic
criteria for evaluation of gastritis and gastric mucosal
lesion (Department of Gastroenterology, Cipto Mangun-
kusumo General Hospital, Faculty of Medicine, Univer-

M. Simadibrata et al. / Open Journal of Gastroenterology 3 (2013) 72-77 74
sity of Indonesia). Endoscopic was performed before and
after treatment (day-0 and day-28) by 4 endoscopists.
The endoscopic score was expressed from score 0 to
score 3: score 0 = no hyperaemia or erosion (normal),
score 1 = mild hyperaemia or mild erosion (mild gastri-
tis), score 2 = mild hyperaemia with moderate erosion or
moderate hyperaemia with mild erosion or moderate hy-
peraemia with moderate erosion (moderate gastritis),
score 3 = severe hyperaemia or severe hyperaemia with
mild erosion or severe hyperaemia with moderate erosion
or severe hyperaemia with severe erosion or moderate
hyperaemia with severe erosion or mild hyperaemia with
severe erosion (severe gastritis).
3.4. Laboratory and Histological Evaluation
During endoscopy, two mucosal biopsy specimens were
taken from each of two sites, the corpus and antrum.
Giemsa stains for identification of Helicobacter pylori.
All specimens were graded for gastritis according to the
Updated Sydney System for chronic mononuclear in-
flammatory cells, polymorphonuclear neutrophil activity,
and Helicobacter pylori density. Inflammation and neu-
trophil activity were classified and graded into four cate-
gories: absent, mild, moderate and severe. All the biopsy
specimens were reviewed by a pathologist. Hematologic
screening such as haemoglobin, erythrocyte, leukocyte,
neutrophil, eosinophil, monocytes, lymphocytes, serum
creatinine, blood urea nitrogen, AST, ALT, bilirubin
were done at day-0 and day-28. Biochemistry assessment
(malondialdehyde and dicarbonyl compound) were done
at day-0 and day-28.
3.5. Safety Assessment
Patients who are under treatment of PPIs or H2RAs
should undergo wash-out period at least 1 week before
enrolled to the study. Only antacid is allowed during the
wash-out period.
Any complaint, adverse drug reaction or adverse events
during the study will be recorded in the safety report
form in the case study report form.
3.6. Statistical Analysis
The data was analyzed with STATA version 9.0. Shapiro
wilk normality test was used to describe the data. Then
the data was analyzed with dependent t-test or Wilcoxon
match paired signed rank test. Statistical significance
was defined at the P < 0.05 level.
4. RESULTS
Forty five patients diagnosed with chronic gastritis were
enrolled and completed the study. All patients were proven
to have dyspeptic symptoms and features of chronic gas-
tritis by endoscopy and histology.
There was a significantly improvement of epigastric
pain score on day 28 and day 7 after rebamipide com-
pared to day-0 (P < 0.05). The score of nausea, anorexia,
bloating, belching and early satiety score on day 28 and
day 7 after rebamipide was also improved significantly
compared to day 0 (P < 0.05). There was no significant
improvement of the vomiting score on day 28 or day 7
after rebamipide compared to day 0 (see Table 1).
The mean gastric mucosal malondialdehyde (MDA)
was decreased significantly on day-28 rebamipide com-
pared to day-0 and the mean gastric mucosal dicarbonyl
compound (CC) was slightly increased on day-28 re-
bamipide compared to day-0 but not significant (see Ta-
ble 2 and Figure 1). The endoscopic mucosal severity
score on day-28 was improved significantly compared to
day-0 (see Table 2).
Histological features of chronic gastritis according to
the updated Sydney system are summarized in Table 2,
Figures 2 and 3.
The degree of activity of chronic mononuclear inflam-
matory cells in both corpus and antrum was higher than
polymorphonuclear neutrophil activity in the same area
(corpus 1.39 ± 0.54 vs 0.12 ± 0.40; antrum 1.41 ± 0.59 vs
0.12 ± 0.46). There were no differences in mononuclear
Table 1. The score of dyspeptic symptom.
Dyspeptic symptom Mean ± SD P
Epigastric pain
‐ Day-0
‐ Day-7
‐ Day-28
4.15 ± 2.70
3.00 ± 2.95
2.00 ± 2.67
0.006
0.003
Nausea
‐ Day-0
‐ Day-7
‐ Day-28
3.80 ± 2.99
2.09 ± 2.43
1.71 ± 2.21
0.001
0.003
Vomiting
‐ Day-0
‐ Day-7
‐ Day-28
1.68 ± 2.63
1.28 ± 2.58
0.97 ± 2.16
0.387
0.137
Anorexia
‐ Day-0
‐ Day-7
‐ Day-28
3.43 ± 3.35
2.52 ± 2.65
1.94 ± 2.61
0.033
0.001
Bloating
‐ Day-0
‐ Day-7
‐ Day-28
5.19 ± 3.45
2.53 ± 3.13
3.96 ± 3.42
0.001
0.001
Belching
‐ Day-0
‐ Day-7
‐ Day-28
4.74 ± 2.83
3.59 ± 2.79
2.51 ± 2.60
0.001
0.001
Early satiety
‐ Day-0
‐ Day-7
‐ Day-28
4.83 ± 3.08
3.95 ± 2.82
3.35 ± 3.09
0.001
0.001

M. Simadibrata et al. / Open Journal of Gastroenterology 3 (2013) 72-77 75
Table 2. The result of free radical and endoscopic examination.
Va ri ab le Per protocol
(n = 45)
Univariate: Day-0 Day-28 P
Mean malondialdehyde
(MDA) 5.28 ± 3.54 4.15 ± 2.710.047
Mean dicarbonyl
compound (CC) 4.14 ± 3.01 5.12 ± 2.710.642
Endoscopic mucosal
severity score 2.268 ± 0.45 1.707 ± 0.780.001
P<0.05 P>0.05
5.28
4.15 4.14
5.12
Figure 1. Biochemistry assessment.
1.41
0.12 0.15 0.15 0.10
1.49
0.10 0.10
0.24
0.15
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Mono nucl ear 
cells
Neutrophyl HpyloriAtrophy Metaplasia
intestinal
Da y‐0
Da y‐28
P>0.05
Figure 2. Histopathology assessment of the gastric antrum.
1.38
0.12 0.07 0.10 0.15
1.41
0.07
0.15 0.15 0.10
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Mono nucl ear
cells
Neutrophyl HpyloriAtrophy Metaplasia
intestinal
Da y‐0
Da y‐28
P>0.05
P>0.05
Figure 3. Histopathology assessment of the gastric corpus.
cell infiltration and neutrophil activity between corpus
and antrum on day-0 and day-28 (P > 0.05). The density
of H. pylori colonization in the corpus at day-0 was
lower than in the antrum, with no significant differences
before and after treatment (P > 0.05). There were no sig-
nificant changes in atrophy and intestinal metaplasia
between corpus and antrum of the stomach before and
after treatment (P > 0.05) (See Table 3).
Table 3. Histopathological score.
Histopathology Mean score SD P
Antrum mononuclear cell
‐ Day-0
‐ Day-28
1.41
1.49
0.59
0.55 0.372
Corpus mononuclear cell
‐ Day-0
‐ Day-28
1.38
1.41
0.54
0.50 0.800
Antrum neutrophil
‐ Day-0
‐ Day-28
0.12
0.10
0.46
0.37 0.710
Corpus neutrophil
‐ Day-0
‐ Day-28
0.12
0.07
0.40
0.26 0.421
Antrum H. pylor i
‐ Day-0
‐ Day-28
0.15
0.10
0.48
0.37 0.323
Corpus H. pylori
‐ Day-0
‐ Day-28
0.07
0.15
0.26
0.48 0.262
Antrum atrophy
‐ Day-0
‐ Day-28
0.15
0.24
0.36
0.49
0.253
Corpus atrophy
‐ Day-0
‐ Day-28
0.10
0.15
0.30
0.42 0.486
Antrum intestinal metaplasia
‐ Day-0
‐ Day-28
0.10
0.15
0.30
0.36
0.323
Corpus intestinal metaplasia
‐ Day-0
‐ Day-28
0.15
0.10
0.48
0.30
0.534
5. DISCUSSION
Rebamipide, a gastro-protective agent, has been used
clinically for the treatment of acute gastritis and peptic
ulcer [9,10].
One of the major roles of rebamipide
[2-(4chlorobenzoylamino)-3[2(1H)-quinolonin-4-yl] pro-
pionic acid], is to stimulate the generation of endogenous
prostaglandins in the gastric mucosa and it has been re-
ported to facilitate and accelerate ulcer healing.
Depending on the extensive published studies in vitro
or in vivo, this clinical trial represents a reliable result of
rebamipide on chronic gastritis. Open-label design had
been chosen in this study, because this was a pilot study
only and further trials involving larger sample size and
longer observation/treatment period with well-controlled
and randomized trials are needed.
Rebamipide shows satisfied chronic gastritis-associ-
ated symptom attenuation with 4 weeks therapy. Though
symptom scores are sometimes subjective and vary be-
tween studies, they may provide direct evidence in clini-
cal trials. Rebamipide showed a better effect on symptom
attenuation, including epigastric pain, nausea, anorexia,
bloating, belching, and early satiety at day-7 and day-28

M. Simadibrata et al. / Open Journal of Gastroenterology 3 (2013) 72-77 76
compared with day-0 (P < 0.05). While symptom of vo-
mitus was not improved at day-7 and day-28 compared
to day 0 (P > 0.05). Chitapanarux et al. and Miwa et al.
showed that rebamipide can improve the score of dys-
pepsia symptoms [5,11]. Rebamipide may have an effect
on Nitric oxide (NO), and improve these functional
symptoms including bloating, belching etc. It has been
proven that Nitric oxide (NO) plays multiple roles in
inflammation and was found to be an essential mediator
of the maintenance of resting blood flow of the gastric
mucosa.
The most frequent characteristic of the patients with
gastritis was men 51.1%. The mean age of patients in
this study was 42.73 ± 11.52 years. The mean Body
Mass Index (BMI) of the patients in this study was 22.69
± 4.45. Jeffery et al. [12] found that chronic gastritis,
gastric ulceration and atrophy and Helicobacter pylori
infection is associated with low body mass index (BMI).
There was a significant improvement of endoscopic
mucosal severity score on day-28 compared to day-0
(1.707 ± 0.78 vs 2.268 ± 0.45; P < 0.05).
The mean gastric mucosal malondialdehyde (MDA)
was decreased significantly on day-28 compared to day-0
(P < 0.05). So, in this study, malondialdehyde (MDA)
was measured and this result may show relationship be-
tween these values and improvement of gastric mucosa.
Du et al. [13] also showed the improvement of endo-
scopy scores and gastric mucosa appearances and a sig-
nificant reduction of malondialdehyde (MDA) after ad-
ministration of rebamipide in chronic erosive gastritis.
Everett et al. [14] also described the levels of malon-
dialdehyde in the gastric mucosa in relationship with
lipid peroxidation and Helicobacter pylori infection.
The mean gastric mucosal dicarbonyl compound was
slightly increased on day-28 compared to day-0 but not
significant (P > 0.05).
Although there was a non-significant small increase in
dicarbonyl compound levels from day-0 to day-28 after
rebamipide therapy, the level on day-28 was not signifi-
cantly affecting the effectiveness of rebamipide. This
may be explained by other effects of infection that com-
pensate for increased dicarbonyl compound levels, such
as carbonyl reactions with proteins including not only
lipid peroxidation reactions but also other physiological
oxidative stress reactions [15].
In histopathologic assessment, our study demonstrated
that the degree of histological gastritis was not different
between the corpus and the antrum. There were no sig-
nificant changes in the histopathologic examination on
day-28 compared to day-0 (P > 0.05). There were no
significant changes in atrophy and intestinal metaplasia
between corpus and antrum of the stomach as well (P >
0.05). Chitapanarux et al. [5] has demonstrated that treat-
ment with rebamipide for 8 weeks not only significantly
improved the dyspepsia symptoms (epigastralgia, stom-
ach heaviness, abdominal fullness, poor appetite and
diarrhea) but also promoted the healing of both endo-
scopic and histological features of chronic gastritis. The
differences of these results to our study may be related to
the short term observation period of the treatment dura-
tion.
The anti-free radicals and anti-inflammatory properties
of rebamipide in chronic gastritis had been proven in
some studies and this is only a pilot study with a rela-
tively small sample size and short term observation pe-
riod to the treatment duration.
Importantly, no serious adverse event was reported
during the study period. The data in the current study
indicates the safety of rebamipide.
6. CONCLUSIONS
In conclusion, rebamipide was effective in healing gas-
tritis and significantly reduced the extend of symptoms
associated with chronic gastritis. The improvement in
symptoms was associated with the decreased of endo-
scopic severity score and the mean gastric mucosal
malondialdehyde (MDA) significantly but not the histo-
pathologic appearance and carbonyl compound.
The main shortcoming of this pilot study is the rela-
tively small sample size and short term observation pe-
riod to the treatment duration.
7. SUGGESTION
Regarding the relatively small sample size and short term
of observation period, further longer duration, well-con-
trolled and randomized trials are warranted in the future.
8. ACKNOWLEDGEMENTS
The authors would like to greatly thank Aan Santi and Indri Rizkiyani
for their help and assistance in this study. The authors also thank the
endoscopic nurses in Cipto Mangun kusumo Hospital for their assis-
tance as well. Credit should also go to P. T. Otsuka Indonesia for sup-
porting and providing the drugs for the study.
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