Efficacy of treatment with rebamipide for endoscopic submucosal dissection-induced ulcers

Abstract

To prospectively compare the healing rates of endoscopic submucosal dissection (ESD)-induced ulcers treated with either a proton-pump inhibitor (PPI) or rebamipide.
We examined 90 patients with early gastric cancer who had undergone ESD. All patients were administered an intravenous infusion of the PPI lansoprazole (20 mg) every 12 h for 2 d, followed by oral administration of lansoprazole (30 mg/d, 5 d). After 7-d treatment, the patients were randomly assigned to 2 groups and received either lansoprazole (30 mg/d orally, n = 45; PPI group) or rebamipide (300 mg orally, three times a day; n = 45; rebamipide group). At 4 and 8 wk after ESD, the ulcer outcomes in the 2 groups were compared.
No significant differences were noted in patient age, underlying disease, tumor location, Helicobacter pylori infection rate, or ESD-induced ulcer size between the 2 groups. At both 4 and 8 wk, the healing rates of ESD-induced ulcers were similar in the PPI-treated and the rebamipide-treated patients (4 wk: PPI, 27.2%; rebamipide, 33.3%; P = 0.5341; 8 wk: PPI, 90.9%; rebamipide, 93.3%; P = 0.6710). At 8 wk, the rates of granulation lesions following ulcer healing were significantly higher in the PPI-treated group (13.6%) than in the rebamipide-treated group (0.0%; P = 0.0103). Ulcer-related symptoms were similar in the 2 treatment groups at 8 wk. The medication cost of 8-wk treatment with the PPI was 10945 yen vs 4889 yen for rebamipide. No ulcer bleeding or complications due to the drugs were observed in either treatment group.
The healing rate of ESD-induced ulcers was similar with rebamipide or PPI treatment; however, rebamipide treatment is more cost-effective and prevents granulation lesions following ulcer healing.

Full text

5706 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
Efcacy of treatment with rebamipide for endoscopic
submucosal dissection-induced ulcers
Masaki Takayama, Shigenaga Matsui, Masanori Kawasaki, Yutaka Asakuma, Toshiharu Sakurai,
Hiroshi Kashida, Masatoshi Kudo
Masaki Takayama, Shigenaga Matsui, Masanori Kawasaki,
Yutaka Asakuma, Toshiharu Sakurai, Hiroshi Kashida, Ma-
satoshi Kudo, Department of Gastroenterology and Hepatology,
Kinki University, Osaka 589-8511, Japan
Author contributions: Takayama M and Matsui S contributed
equally to this work; Takayama M, Matsui S, Kawasaki M,
Asakuma Y, Sakurai T, Kashida H and Kudo M designed the
research; Takayama M and Matsui S performed the research;
Takayama M and Matsui S analyzed the data; Takayama M wrote
the paper.
Correspondence to: Masaki Takayama, MD, Department of
Gastroenterology and Hepatology, Kinki University, 377-2 Ohno-
Higashi, Osaka-Sayama, Osaka 589-8511,
Japan. masaki0742@yahoo.co.jp
Telephone: +81-72-3660221 Fax: +81-72-3672880
Received: June 9, 2013 Revised: July 25, 2013
Accepted: August 8, 2013
Published online: September 14, 2013
Abstract
AIM: To prospectively compare the healing rates of
endoscopic submucosal dissection (ESD)-induced ulcers
treated with either a proton-pump inhibitor (PPI) or re-
bamipide.
METHODS: We examined 90 patients with early gas-
tric cancer who had undergone ESD. All patients were
administered an intravenous infusion of the PPI lan-
soprazole (20 mg) every 12 h for 2 d, followed by oral
administration of lansoprazole (30 mg/d, 5 d). After
7-d treatment, the patients were randomly assigned
to 2 groups and received either lansoprazole (30 mg/d
orally,
n
= 45; PPI group) or rebamipide (300 mg oral-
ly, three times a day;
n
= 45; rebamipide group). At 4
and 8 wk after ESD, the ulcer outcomes in the 2 groups
were compared.
RESULTS: No significant differences were noted
in patient age, underlying disease, tumor location,
Helicobacter pylori
infection rate, or ESD-induced ulcer
size between the 2 groups. At both 4 and 8 wk, the
healing rates of ESD-induced ulcers were similar in the
PPI-treated and the rebamipide-treated patients (4 wk:
PPI, 27.2%; rebamipide, 33.3%;
P
= 0.5341; 8 wk:
PPI, 90.9%; rebamipide, 93.3%;
P
= 0.6710). At 8 wk,
the rates of granulation lesions following ulcer heal-
ing were significantly higher in the PPI-treated group
(13.6%) than in the rebamipide-treated group (0.0%;
P
= 0.0103). Ulcer-related symptoms were similar in the
2 treatment groups at 8 wk. The medication cost of 8-wk
treatment with the PPI was 10945 yen
vs
4889 yen for
rebamipide. No ulcer bleeding or complications due to
the drugs were observed in either treatment group.
CONCLUSION: The healing rate of ESD-induced ulcers
was similar with rebamipide or PPI treatment; however,
rebamipide treatment is more cost-effective and pre-
vents granulation lesions following ulcer healing.
© 2013 Baishideng. All rights reserved.
Key words: Early gastric cancer; Rebamipide; Endo-
scopic submucosal dissection; Gastric ulcer; Proton-
pump inhibitor
Core tip: In this prospective randomized, parallel-con-
trolled study, we demonstrated that rebamipide mono-
therapy was as effective as proton-pump inhibitor (PPI)
in the healing of endoscopic submucosal dissection-in-
duced ulcers, regardless of the location of the resected
cancer, the degree of atrophic gastritis, or the presence
of
Helicobacter pylori
infection. In addition, rebamipide
treatment is more cost-effective and results in a better
quality of ulcer healing compared with the PPI lanso-
prazole.
Takayama M, Matsui S, Kawasaki M, Asakuma Y, Sakurai T,
Kashida H, Kudo M. Efficacy of treatment with rebamipide
for endoscopic submucosal dissection-induced ulcers. World J
Gastroenterol 2013; 19(34): 5706-5712 Available from: URL:
BRIEF ARTICLE
Online Submissions: http://www.wjgnet.com/esps/
wjg@wjgnet.com
doi:10.3748/wjg.v19.i34.5706
World J Gastroenterol 2013 September 14; 19(34): 5706-5712
ISSN 1007-9327 (print) ISSN 2219-2840 (online)
© 2013 Baishideng. All rights reserved.

http://www.wjgnet.com/1007-9327/full/v19/i34/5706.htm DOI:
http://dx.doi.org/10.3748/wjg.v19.i34.5706
INTRODUCTION
Endoscopic mucosal resection (EMR) is a well-estab-
lished curative treatment for gastric neoplasms, such as
early gastric cancer confined to the mucosa. However,
EMR, performed using conventional techniques such as
strip biopsy or cap EMR, does not always achieve en bloc
resection. Thus, endoscopic submucosal dissection (ESD)
has become the preferred treatment method. Compared
with EMR, ESD facilitates the collection of larger speci-
mens, regardless of lesion size or location, resulting in a
higher rate of en bloc and histologically complete resec-
tion. Moreover, the rate of local recurrence of tumors
after ESD may be lower than that after conventional
EMR[1]. However, the iatrogenic ulcer that develops as a
result of ESD is large, and requires a considerably longer
healing time compared to that resulting from conven-
tional EMR.
Proton-pump inhibitors (PPIs) are the most effective
medications for the treatment of ESD-induced ulcers.
However, studies have shown that PPI monotherapy
does not heal the ESD-induced ulcers sufciently within
4 wk[2-6]. Increased understanding of the mucosal defense
system has prompted the development of mucopro-
tective agents for clinical use in Japan. The efficacy of
combination treatment involving PPIs and the mucopro-
tective agent rebamipide in the early treatment of ESD-
induced ulcers and in the prevention of relapse of such
disorders has been clearly indicated[2-5].
Rebamipide [2-(4-chlorobenzoylamino)-3-[2-(1H)-
quinolinon-4-yl]-propionic acid), a novel mucosal-
protective and ulcer-healing drug, is widely prescribed in
East Asia. Previous studies have indicated that rebamip-
ide is effective in the treatment of gastric ulcers as well
as decreasing the recurrence rate, without affecting the
Helicobacter pylori infection status of the patients[7-12]. In
addition, previous randomized-controlled studies have
also found that rebamipide can prevent the formation of
peptic ulcers induced by the administration of nonsteroi-
dal anti-inammatory drugs (NSAIDs) and can suppress
the mucosal inammation associated with chronic erosive
gastritis[13,14]. However, to our knowledge, no reports on
the use of rebamipide for the treatment of ESD-induced
ulcers have been published.
In the present study, we have prospectively evaluated
the efcacy of rebamipide monotherapy in comparison
to PPI monotherapy for the treatment of iatrogenic ul-
cers resulting from ESD for early gastric cancers.
MATERIALS AND METHODS
Patients
We examined 90 consecutive patients with early gastric
cancer who had been treated with ESD at Kinki Univer-
sity Hospital between February 2011 and January 2013.
The study protocol was approved by the Kinki University
Ethics Committee, and all participants provided written
informed consent before undergoing ESD. In addition,
the study was registered at the University Hospital Medi-
cal Information Network 000005134. All patients with
early gastric cancer, including well-differentiated or mod-
erately differentiated adenocarcinoma, were included in
the study. The exclusion criteria were as follows: (1) cur-
rent use of other anti-ulcer drugs, aspirin, NSAIDs, or
prednisolone; (2) treatment with anti-coagulative agents;
or (3) previous endoscopic treatment or surgery.
ESD procedure
ESD was performed with an insulation-tipped knife
(KD-610L; Olympus Medical Systems, Tokyo, Japan)
and a flush knife (BTDK2618JB; Fujifilm Medical Sys-
tem, Tokyo, Japan). The electrosurgical unit used was A
VIO-300D (ERBE). The injection solutions contained
glycerin with 1% indigo carmine dye and, depending on
the tumor location, hyaluronic acid sodium (0.4%) was
also added. The ulcers that developed after ESD were
carefully examined endoscopically, and any visible vessels
were heat-coagulated by using hot biopsy forceps (KD-
410LR; Olympus Medical Systems). Thereafter, the re-
sected specimens were stretched, pinned at on a rubber
plate, and measured.
Study design
The design of this single-center, open-label, prospective,
randomized, parallel-controlled study is illustrated in Fig-
ure 1.
After ESD, all patients were administered an intrave-
nous infusion of lansoprazole (20 mg; Takepron; Takeda
Pharmaceutical, Osaka, Japan) every 12 h for 2 d, and
received oral lansoprazole (30 mg/d) for 5 d. On post-
operative day 7, the patients were randomly assigned to 2
groups and received either lansoprazole at a dose of 30
mg/d orally (PPI group; n = 45), or rebamipide (Mucosta;
Otsuka Pharmaceutical Co., Tokyo, Japan) at a dose of
300 mg orally, 3 times a day (n = 45) for 8 wk. The pri-
mary endpoint was endoscopically documented ulcer
healing; complete healing was defined as regression to
the S-stage on the Sakita and Miwa scale[23]. Moreover, we
evaluated the healing rates of atrophic gastritis based on
the Kimura and Takemoto classification[24], in the pres-
ence or absence of Helicobacter pylori (H. pylori) infection.
We also compared the response of ulcers in relation to
their locations in the stomach (lower, middle, or upper).
The secondary endpoint was the ulcer reduction ratio,
which was compared according to the ulcer location. For
calculation of the ratio, we determined the maximum
diameters of the ulcers and the diameters perpendicular
to the maximum diameters, which were measured using
a bendable endoscopic measuring device (M2-3; Olym-
pus Corp., Tokyo, Japan). Moreover, we determined the
ulcer size (maximal diameter × diameter perpendicular
to the maximal diameter). At 4 and 8 wk after ESD, the
healing and reduction rates for the ulcers were compared
between the 2 groups. In addition, at 8 wk after ESD, we
5707 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers

evaluated the scar status of the ESD-induced ulcers ac-
cording to the Quality of Ulcer Healing (QOUH).
Statistical analysis
Patient baseline characteristics and ulcer reduction ratios
were compared using Pearson’s
χ
2 test or Student’s t-test.
Pearson’s
χ
2 test was also used to compare the healing
rates of the ESD-induced ulcers and for the evaluation
of the scar status of the ESD-induced ulcers according to
the QOUH. Statistical signicance was dened as P < 0.05.
RESULTS
Table 1 shows the patient characteristics of the 2 treat-
ment groups. No signicant differences were noted be-
tween the groups with regard to age; gender; tumor loca-
tion; tumor size; histologic classification; ESD-induced
ulcer size; glandular atrophy; history of disease; and the
rates of H. pylori infection, smoking, drinking alcohol, or
the presence of complicated disease or intestinal meta-
plasia. One patient was excluded from the PPI group
because histologic examination of the resected specimen
5708 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
POD 0 1 2 7 56/d
2
8
PPI: Lansoprazole 30 mg/d
Rebamipide 300 mg/d
PPI
div.
PPI
ESD
Endscopy
Figure 1 Study design. After ESD, all patients were administered an intravenous infusion of lansoprazole (20 mg; Takepron; Takeda Pharmaceutical, Osaka, Japan)
every 12 h for 2 d, and received oral lansoprazole (30 mg/d) for 5 d. On postoperative day 7, the patients were randomly assigned to 2 groups and received either
lansoprazole at a dose of 30 mg/d orally (PPI group; n = 45), or rebamipide (Mucosta; Otsuka Pharmaceutical Co., Tokyo, Japan) at a dose of 300 mg orally, 3 times a
day (n = 45) for 8 wk. ESD: Endoscopic submucosal dissection; PPIs: Proton-pump inhibitors; div.: Drip intravenous infusion; POD: Postoperative days.
Table 1 Patient characteristics
Lansoprazole group
(
n
= 45)
Rebamipide group
(
n
= 45)
P
-value
Age (yr)
(mean ± SD, median)
70 ± 7.8, 72 67 ± 8.0, 67 0.0930
Gender (M/F) 36/9 31/14 0.2269
H. pylori-infection 86.7% 84.4% 0.7643
Smoker 31.1% 33.3% 0.8215
Drinking alcohol 46.7% 42.2% 0.6714
History of disease 46.7% 31.1% 0.1301
Complicated disease 71.1% 71.1% 1.0000
Location of tumors 0.1620
Low 23 16
Middle 17 26
Upper 5 3
Tumor size 0.4986
> 20 (mm) 13 16
≤ 20 (mm) 32 29
Histologic classication 0.6939
Tub1 41 42
Tub2 4 3
Dissected size
(mean ± SD, mm)
30.5 ± 7.8 30.6 ± 6.4 0.9413
Dissected area
(mean ± SD, mm2)
687.9 ± 393.1.7 712.3 ± 298.6 0.7417
Glandular atrophy 0.3167
C-1 0 0
C-2 3 2
C-3 11 14
O-1 19 13
O-2 12 13
O-3 0 3
CandO 0.6547
C 14 16
O 31 29
Intestinal metaplasia 71.1% 68.9% 0.8181
Figure 2 Flow chart of study participants. ESD: Endoscopic submucosal
dissection.
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers
H. pylori: Helicobacter pylori; M/F: Male/female.
Enrollment (
n
= 90)
ESD (
n
= 90)
Randomization (
n
= 90)
Lansoprazole group (
n
= 45) Rebamipide group (
n
= 45)
Excluded (
n
= 1)
Deep submucosal
invasion surgery
Analyzed (
n
= 44) Analyzed (
n
= 45)

5709 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
respectively) and in the PPI group (97.2% and 99.9%, re-
spectively) (Figure 4). These ratios were not inuenced by
the locations of the ulcers in the stomach (low, middle,
and upper).
Quality of ulcer healing and adverse events
Six patients in the PPI group developed unusual gastric
lesions, which comprised an overgrowth of granulation
tissue at the ulcer site. At 8 wk, the proportion of pa-
tients who developed a at scar in the rebamipide group
(100%) was found to be signicantly higher than that in
the PPI group (86.3%; P = 0.0103) (Figure 5). No ulcer
bleeding or complications related to the drugs used after
ESD were observed in any of the study subjects.
DISCUSSION
Some authors have repor ted that the combination
therapy involving PPI and rebamipide is superior to PPI
monotherapy in the healing of ESD-induced ulcers[2-5];
however, to our knowledge, no reports on the efficacy
of rebamipide for the treatment of ESD-induced ulcers
indicated deep submucosal invasion (depth ≥ 500 μm;
SM2 invasion). Hence, 44 patients in the PPI group and
45 in the rebamipide group constituted the final study
cohort (Figure 2).
Ulcer responses
The rates of ulcer healing (regression to S-stage) were
not signicantly different between the PPI group (27.2%)
and the rebamipide group (33.3%) at 4 wk (P = 0.5341)
or at 8 wk (90.9% for the PPI group and 93.3% for the
rebamipide group; P = 0.6710) (Figure 3A). Moreover, at
4 and 8 wk, the healing rates were not signicantly differ-
ent between the treatment groups with regard to ulcer lo-
cation (low, middle, or upper stomach; Figure 3B) or with
regard to the presence of absence of H. pylori infection
(Figure 3C). In addition, at 4 and 8 wk, the healing rates
of atrophic gastritis (closed or open type) were similar in
the 2 treatment groups (Figure 3D).
Reduction ratios of ESD-induced ulcers
The reduction ratios of ESD-induced ulcers were similar
at 4 and 8 wk in the rebamipide group (98.0% and 99.9%,
100
80
60
40
20
0
%
P
= 0.6710
Pearson's
χ
2 test
P
= 0.5341
27.2% 33.3%
90.9% 93.3%
4 wk 8 wk
PPI (
n
= 44)
RM (
n
= 45)
Figure 3 Rates of healing in both groups. A: The rates of healing to S stage in both groups; B: The rates of healing to S stage in both groups according to resected
location. L: Low stomach, M: Middle stomach; U: Upper stomach. C: The rates of healing to S stage in both groups. 1Helicobacter pylori (H. pylori) positive 2H. pylori
negative. D: The rates of healing to S stage in both groups in atrophic gastritis. 3Closed type; 4Open type. RM: Rebamipide.
100
80
60
40
20
0
%
P
= 0.6771
Pearson's
χ
2 test
P
= 0.4475
26.1%
L M U L M U L M U L M U
4 wk 8 wk
PPI (
n
= 44)
RM (
n
= 45)
P
= 0.5127
25.0%
40.0%
37.5% 34.6%
P
= 0.2059
0.0%
P
= 0.4272
82.6%
100% 100%
87.5%
96.2%
100%
100
80
60
40
20
0
%
Pearson's
χ
2 test
P
= 0.62161
28.9%
4 wk 8 wk
PPI (
n
= 44)
RM (
n
= 45)
34.2%
16.7%
28.6%
92.1% 92.1%
83.3%
100%
P
= 0.61152
P
= 1.00001
P
= 0.26092
100
80
60
40
20
0
%
4 wk 8 wk
P
= 0.63183
P
= 0.76884
Pearson's
χ
2 test
P
= 0.69383
28.6%
P
= 0.19554
25.0% 26.7%
37.9%
85.7% 93.8% 93.3% 93.1%
PPI (
n
= 44)
RM (
n
= 45)
DC
BA
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers

5710 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
have been published. In this prospective randomized,
parallel-controlled study, we demonstrated that rebamip-
ide monotherapy was as effective as PPI in the healing
of ESD-induced ulcers, regardless of the location of the
resected cancer, the degree of atrophic gastritis, or the
presence of H. pylori infection.
Although the response of post-ESD ulcers to PPIs
and rebamipide may be similar, the mechanisms of ac-
tion of these drugs are different. PPIs decrease gastric
acid production, whereas rebamipide stimulates the
production of prostaglandins[19], epidermal growth fac-
tor[12,20], and nitric oxide[21], and decreases the level of
oxygen-free radicals[22]. These mucosal protective actions
of rebamipide appear to promote ulcer healing. Fujiwara
et al[3] showed that 8 wk of PPI and rebamipide treat-
ment was particularly effective for patients with severe
atrophic gastritis, classied as O-3. Severe atrophic gas-
tritis may result in the formation of a low-acid environ-
ment in the stomach; therefore, acid-suppressive agents
such as PPI alone may have a limited effect. However,
rebamipide can be effective in this environment because
of its different mechanism of action. We believe that
this is a contributing factor to the similar efcacies ob-
served between PPIs and rebamipide regardless of the
degree of atrophic gastritis.
Previous studies have reported that various mecha-
nisms are involved in the effects of rebamipide on H.
pylori-positive atrophic gastritis; these include prevention
of adhesion of the bacteria to gastric epithelial cells, and
inhibition of H. pylori-induced secretion of prostaglan-
din E2 from neutrophils and interleukin-8 expression in
gastric epithelial cells[25-28]. Terano et al[15] indicated that
the treatment of gastric ulcers with rebamipide promotes
ulcer healing regardless of the success or failure of H.
pylori eradication therapy, and Higuchi et al showed that
rebamipide prevents the recurrence of gastric ulcers
without affecting the H. pylori infection status[10]. In the
present study, PPI and rebamipide appeared to aid in ul-
cer healing without affecting the H. pylori infection status.
Moreover, we noted that the proportion of patients
who developed a at scar at the ulcer site was signicant-
ly higher in the rebamipide group than in the PPI group.
Thus, rebamipide appears to be more effective than PPIs
in improving the QOUH. In animal studies, rebamipide
was found to improve the QOUH by increasing the level
of prostaglandin E2 and decreasing the levels of malo-
ndialdehyde and interleukin-8 in the gastric mucosa[16].
In the present study, the unusual elevated gastric lesions
that were observed following ulcer healing could not be
easily characterized as benign granulation tissue or a ma-
lignant recurrence without performing a biopsy (Figure
6). Therefore, we believe that improvement in QOUH is
essential for preventing the occurrence of mucosal pro-
trusion due to the growth of granulation tissue.
The most frequent complication that occurs after en-
doscopic therapy is bleeding, and the rate of intraopera-
tive bleeding is signicantly higher with ESD than with
EMR. Jeong et al[17] reported that PPIs may be more effec-
tive than histamine H2 inhibitors in preventing bleeding
after ESD by promoting a more rapid healing of these
large iatrogenic ulcers[17]. Moreover, Uedo et al[18] indicated
that therapy with PPI was more effective than treatment
100
80
60
40
20
0
%
4 wk 8 wk
Pearson's
χ
2 test
P
= 0.3404
97.2%
PPI (
n
= 44)
RM (
n
= 45)
98.0% 99.9% 99.9%
P
= 0.4887
Figure 4 Reduction ratio of the endoscopic submuco sal dissec tion-
induced ulcers in both groups. PPI: Proton-pump inhibitor; RM: Rebamipide.
100
80
60
40
20
0
%
8 wk
Pearson's
χ
2 test
P
= 0.0103
86.3%
PPI (
n
= 44)
RM (
n
= 45)
100%
Figure 5 Proportion of patients who developed a at scar after ulcer heal-
ing in both groups. PPI: Proton-pump inhibitor; RM: Rebamipide.
Figure 6 At 8 wk, granulation lesions following ulcer healing in the pro-
ton-pump inhibitors treated group.
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers

5711 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
with histamine H2 inhibitors in preventing delayed bleed-
ing from ulcers induced by ESD. However, in the present
study, no post-ESD bleeding or complications related to
the drugs used were noted in the patients receiving re-
bamipide or PPI treatment; moreover, the ratio of ulcer
reduction was at least 90% in both groups at 8 wk after
initiation of therapy. Thus, our ndings indicated that the
rate of intraoperative bleeding was not signicantly dif-
ferent between both the groups.
In addition, in the present study, we found that treat-
ment with rebamipide was more cost-effective than treat-
ment with the PPI lansoprazole. The cost of the 56-d
treatment course was 4889 yen for rebamipide and 10945
yen for lansoprazole, which is a difference of 44.7%. This
high difference in cost may be a factor in determining
which medication to prescribe in the treatment of ESD-
induced ulcers.
In conclusion, rebamipide monotherapy was equiva-
lent to treatment with a PPI (lansoprazole) in the healing
of ulcers induced by ESD for early gastric cancer. The
similarity in the treatment efcacy was observed irrespec-
tive of the presence of H. pylori infection, the severity
of atrophic gastritis, or the locations of the ulcers in the
stomach. However, rebamipide therapy also resulted in
a more favorable QOUH compared with that obtained
by PPI treatment. Moreover, the treatment involving
rebamipide was more cost-effective compared to the
treatment with the PPI lansoprazole for the treatment of
ESD-induced ulcers.
ACKNOWLEDGMENTS
The authors wish to thank Otsuka Pharmaceutical Co.,
Ltd. for providing the drugs for the study.
COMMENTS
Background
Endoscopic submucosal dissection (ESD) is useful for treating early gastric
cancer. The articial ulcer that is generated after ESD is large, and needs a
considerably longer healing time compared with conventional endoscopic mu-
cosal resection (EMR). Rebamipide is one of the mucoprotective antiulcer drug,
and is widely employed treatment of gastric ulcer in Japan.
Research frontiers
Previous studies have shown that the combination therapy involving proton
pump inhibitor (PPI) and rebamipide is superior to PPI monotherapy in the
healing of ESD-induced ulcers; however, to people knowledge, no reports on
the efcacy of rebamipide for the treatment of ESD-induced ulcers have been
published. Therefore, the authors prospectively investigated differences in heal-
ing of ESD-induced ulcers according to treatment with PPI or rebamipide only.
Innovations and breakthroughs
In this prospective randomized, parallel-controlled study, the authors demon-
strated that rebamipide monotherapy was as effective as PPI in the healing
of endoscopic submucosal dissection-induced ulcers. In addition, rebamipide
treatment was more cost-effective and resulted in a better quality of ulcer heal-
ing compared to the PPI lansoprazole treatment.
Applications
This article suggests that the healing rate of ESD-induced ulcers was similar
with rebamipide or PPI treatment; however, rebamipide treatment is more cost-
effective and prevents granulation lesions following ulcer healing. However, it
is a small study, therefore, a prospective multicenter study with a large sample
size should be performed to assess the efcacy of treatment with rebamipide
for endoscopic submucosal dissection-induced ulcers.
Terminology
ESD is a well-established curative treatment for early gastric cancer. ESD fa-
cilitates the collection of larger specimens, regardless of lesion size or location,
resulting in a higher rate of en bloc and histologically complete resection. How-
ever, the iatrogenic ulcer that develops as a result of ESD is large, and requires
a considerably longer healing time compared to that resulting from conventional
EMR. Rebamipide is a novel mucosal-protective and ulcer-healing drug that
has been widely prescribed in East Asia. Rebamipide stimulates the production
of prostaglandins, epidermal growth factor, and nitric oxide, and decreases the
level of oxygen-free radicals. These mucosal protective actions of rebamipide
appear to promote ulcer healing.
Peer review
This paper is well written. The clinical results are appropriately described.
The authors present the Efcacy of treatment with rebamipide for endoscopic
submucosal dissection-induced ulcers. The data indicate the healing rate of
ESD-induced ulcers was similar with rebamipide or PPI treatment; however,
rebamipide treatment is more cost-effective and prevents granulation lesions
following ulcer healing.
REFERENCES
1 Oka S, Tanaka S, Kaneko I, Mouri R, Hirata M, Kawamura T,
Yoshihara M, Chayama K. Advantage of endoscopic submu-
cosal dissection compared with EMR for early gastric cancer.
Gastrointest Endosc 2006; 64: 877-883 [PMID: 17140890 DOI:
10.1016/j.gie.2006.03.932]
2 Kato T, Araki H, Onogi F, Ibuka T, Sugiyama A, Tomita E,
Nagaki M, Moriwaki H. Clinical trial: rebamipide promotes
gastric ulcer healing by proton pump inhibitor after endo-
scopic submucosal dissection--a randomized controlled
study. J Gastroenterol 2010; 45: 285-290 [PMID: 19957195 DOI:
10.1007/s00535-009-0157-0]
3 Fujiwara S, Morita Y, Toyonaga T, Kawakami F, Itoh T, Yo-
shida M, Kutsumi H, Azuma T. A randomized controlled
trial of rebamipide plus rabeprazole for the healing of arti-
ficial ulcers after endoscopic submucosal dissection. J Gas-
troenterol 2011; 46: 595-602 [PMID: 21359522 DOI: 10.1007/
s00535-011-0372-3]
4 Kobayashi M, Takeuchi M, Hashimoto S, Mizuno K, Sato Y,
Narisawa R, Aoyagi Y. Contributing factors to gastric ulcer
healing after endoscopic submucosal dissection including the
promoting effect of rebamipide. Dig Dis Sci 2012; 57: 119-126
[PMID: 21842241 DOI: 10.1007/s10620-011-1850-4]
5 Shin WG, Kim SJ, Choi MH, Kim KO, Jang HJ, Park CH,
Baek IH, Kim KH, Baik GH, Kae SH, Kim JH, Kim HY. Can
rebamipide and proton pump inhibitor combination therapy
promote the healing of endoscopic submucosal dissection-
induced ulcers? A randomized, prospective, multicenter
study. Gastrointest Endosc 2012; 75: 739-747 [PMID: 22281110
DOI: 10.1016/j.gie.2011.11.004]
6 Asakuma Y, Kudo M, Matsui S, Okada M, Kawasaki M,
Umehara Y, Ichikawa T, Kitai S. Comparison of an ecabet so-
dium and proton pump inhibitor (PPI) combination therapy
with PPI alone in the treatment of endoscopic submucosal
dissection (ESD)--induced ulcers in early gastric cancer: pro-
spective randomized study. Hepatogastroenterology 2009; 56:
1270-1273 [PMID: 19950775]
7 Yamasaki K, Kanbe T, Chijiwa T, Ishiyama H, Morita S.
Gastric mucosal protection by OPC-12759, a novel antiulcer
compound, in the rat. Eur J Pharmacol 1987; 142: 23-29 [PMID:
3480223]
8 Ogino K, Hobara T, Ishiyama H, Yamasaki K, Kobayashi H,
Izumi Y, Oka S. Antiulcer mechanism of action of rebamip-
ide, a novel antiulcer compound, on diethyldithiocarbamate-
induced antral gastric ulcers in rats. Eur J Pharmacol 1992; 212:
9-13 [PMID: 1313372]
9 Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi
K. Rebamipide, novel prostaglandin-inducer accelerates
COMMENTS
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers

5712 September 14, 2013
|
Volume 19
|
Issue 34
|
WJG
|
www.wjgnet.com
healing and reduces relapse of acetic acid-induced rat gas-
tric ulcer. Comparison with cimetidine. Dig Dis Sci 1995; 40:
2469-2472 [PMID: 7587834]
10 Higuchi K, Arakawa T, Nebiki H, Uchida T, Fujiwara Y,
Ando K, Yamasaki K, Takaishi O, Fukuda T, Kobayashi K,
Kuroki T. Rebamipide prevents recurrence of gastric ulcers
without affecting Helicobacter pylori status. Dig Dis Sci 1998;
43: 99S-106S [PMID: 9753234]
11 Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A. Re-
bamipide: overview of its mechanisms of action and efcacy
in mucosal protection and ulcer healing. Dig Dis Sci 1998; 43:
5S-13S [PMID: 9753220]
12 Tarnawski A, Arakawa T, Kobayashi K. Rebamipide treat-
ment activates epidermal growth factor and its receptor ex-
pression in normal and ulcerated gastric mucosa in rats: one
mechanism for its ulcer healing action? Dig Dis Sci 1998; 43:
90S-98S [PMID: 9753233]
13 Park SH, Cho CS, Lee OY, Jun JB, Lin SR, Zhou LY, Yuan
YZ, Li ZS, Hou XH, Zhao HC, Kachintorn U, Kositchaiwat C,
Lertkupinit C. Comparison of Prevention of NSAID-Induced
Gastrointestinal Complications by Rebamipide and Misopro-
stol: A Randomized, Multicenter, Controlled Trial-STORM
STUDY. J Clin Biochem Nutr 2007; 40: 148-155 [PMID: 18188417
DOI: 10.3164/jcbn.40.148]
14 Du Y, Li Z, Zhan X, Chen J, Gao J, Gong Y, Ren J, He L, Zhang
Z, Guo X, Wu J, Tian Z, Shi R, Jiang B, Fang D, Li Y. Anti-
inammatory effects of rebamipide according to Helicobacter
pylori status in patients with chronic erosive gastritis: a
randomized sucralfate-controlled multicenter trial in China-
STARS study. Dig Dis Sci 2008; 53: 2886-2895 [PMID: 18288617
DOI: 10.1007/s10620-007-0180-z]
15 Terano A, Arakawa T, Sugiyama T, Suzuki H, Joh T, Yo-
shikawa T, Higuchi K, Haruma K, Murakami K, Kobayashi
K. Rebamipide, a gastro-protective and anti-inflammatory
drug, promotes gastric ulcer healing following eradication
therapy for Helicobacter pylori in a Japanese population: a
randomized, double-blind, placebo-controlled trial. J Gas-
troenterol 2007; 42: 690-693 [PMID: 17701133 DOI: 10.1007/
s00535-007-2076-2]
16 Qi Z, Jie L, Haixia C, Xiaoying Z. Effect of rebamipide on
quality of peptic ulcer healing in rat. Dig Dis Sci 2009; 54:
1876-1883 [PMID: 19082723 DOI: 10.1007/s10620-008-0577-3]
17 Jeong HK, Park CH, Jun CH, Lee GH, Kim HI, Kim HS, Choi
SK, Rew JS. A prospective randomized trial of either famoti-
dine or pantoprazole for the prevention of bleeding after
endoscopic submucosal dissection. J Korean Med Sci 2007; 22:
1055-1059 [PMID: 18162722 DOI: 10.3346/jkms.2007.22.6.1055]
18 Uedo N, Takeuchi Y, Yamada T, Ishihara R, Ogiyama H,
Yamamoto S, Kato M, Tatsumi K, Masuda E, Tamai C, Yama-
moto S, Higashino K, Iishi H, Tatsuta M. Effect of a proton
pump inhibitor or an H2-receptor antagonist on prevention of
bleeding from ulcer after endoscopic submucosal dissection of
early gastric cancer: a prospective randomized controlled trial.
Am J Gastroenterol 2007; 102: 1610-1616 [PMID: 17403076 DOI:
10.1111/j.1572-0241.2007.01197.x]
19 Kleine A, Kluge S, Peskar BM. Stimulation of prostaglandin
biosynthesis mediates gastroprotective effect of rebamipide in
rats. Dig Dis Sci 1993; 38: 1441-1449 [PMID: 8393757]
20 Tarnawski AS, Chai J, Pai R, Chiou SK. Rebamipide activates
genes encoding angiogenic growth factors and Cox2 and
stimulates angiogenesis: a key to its ulcer healing action? Dig
Dis Sci 2004; 49: 202-209 [PMID: 15104358]
21 Takaishi O, Arakawa T, Yamasaki K, Fujiwara Y, Uchida T,
Tominaga K, Watanabe T, Higuchi K, Fukuda T, Kobayashi
K, Kuroki T. Protective effect of rebamipide against ammonia-
induced gastric mucosal lesions. Dig Dis Sci 1998; 43: 78S-82S
[PMID: 9753231]
22 Naito Y, Yoshikawa T, Tanigawa T, Sakurai K, Yamasaki
K, Uchida M, Kondo M. Hydroxyl radical scavenging by
rebamipide and related compounds: electron paramagnetic
resonance study. Free Radic Biol Med 1995; 18: 117-123 [PMID:
7896165]
23 Sakita T, Fukushima H. Endoscopic diagnosis. In: Yoshitoshi
Y, editor. Ulcer of the stomach and duodenum. Tokyo: Nan-
kodo, 1971: 198-208
24 Kimura K, Takemoto T. An endoscopic recognition of the
atrophic border and its signicance in chronic gastritis. Endos-
copy 1969; 3: 87-97
25 Hayashi S, Sugiyama T, Amano K, Isogai H, Isogai E, Aihara
M, Kikuchi M, Asaka M, Yokota K, Oguma K, Fujii N, Hirai Y.
Effect of rebamipide, a novel antiulcer agent, on Helicobacter
pylori adhesion to gastric epithelial cells. Antimicrob Agents
Chemother 1998; 42: 1895-1899 [PMID: 9687380]
26 Azuma T, Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Dojo M,
Yamazaki Y, Higashi H, Hatakeyama M. The effects of cure
of Helicobacter pylori infection on the signal transduction of
gastric epithelial cells. Aliment Pharmacol Ther 2003; 18 Suppl 1:
39-44 [PMID: 12925139 DOI: 10.1046/j.1365-2036.18.s1.2.x]
27 Yoshida N, Ishikawa T, Ichiishi E, Yoshida Y, Hanashiro
K, Kuchide M, Uchiyama K, Kokura S, Ichikawa H, Naito
Y, Yamamura Y, Okanoue T, Yoshikawa T. The effect of re-
bamipide on Helicobacter pylori extract-mediated changes of
gene expression in gastric epithelial cells. Aliment Pharmacol
Ther 2003; 18 Suppl 1: 63-75 [PMID: 12925142 DOI: 10.1046/
j.1365-2036.18.s1.7.x]
28 Kim JS, Kim JM, Jung HC, Song IS. The effect of rebamipide
on the expression of proinammatory mediators and apopto-
sis in human neutrophils by Helicobacter pylori water-soluble
surface proteins. Aliment Pharmacol Ther 2003; 18 Suppl 1:
45-54 [PMID: 12925140 DOI: 10.1046/j.1365-2036.18.s1.1.x]
P- Reviewers Mizukami K, Naito Y S- Editor Zhai HH
L- Editor Cant MR E- Editor Zhang DN
Takayama M
et al
. Treatment with rebamipide for ESD-induced ulcers

Baishideng Publishing Group Co., Limited © 2013 Baishideng. All rights reserved.
Published by Baishideng Publishing Group Co., Limited
Flat C, 23/F., Lucky Plaza,
315-321 Lockhart Road, Wan Chai, Hong Kong, China
Fax: +852-65557188
Telephone: +852-31779906
E-mail: bpgoffice@wjgnet.com
http://www.wjgnet.com
I S S N 1 0 0 7 - 9 3 2 7
9 7 7 1 0 07 9 3 2 0 45
3 4