Digestive Diseases and Sciences, Vol. 47, No. 4 (April 2002), pp.

862– 867 (© 2002)

Long-Term Rebamipide Therapy Improves

Helicobacter pylori-Associated
Chronic Gastritis
K. HARUMA, MD,* M. ITO, MD,†‡ S. KIDO, MD,† N. MANABE, MD,† Y. KITADAI, MD,†
M. SUMII, MD,† S. TANAKA, MD,† M. YOSHIHARA, MD,†‡ and K. CHAYAMA, MD†

We investigated an antiinflammatory effect of rebamipide {2-(4-chlorobenzoylamino)-3-

[2(1H)-quinolinon-4-yl] propionic acid}, a gastroprotective agent, in H. pylori-associated
gastritis. Eighty-six patients with H. pylori-positive chronic gastritis were enrolled: 53 were
treated with rebamipide (300 mg daily for 12 months) and 33 served as controls. Significant
decreases in mononuclear cell infiltration into the antrum and corpus were noted in the
rebamipide treatment group (before vs after, 1.42 ⫾ 0.15 vs 1.02 ⫾ 0.15; P ⬍ 0.01 and 1.60 ⫾
0.15 vs 1.21 ⫾ 0.14; P ⬍ 0.05, respectively). Levels of infiltrating neutrophil were also
decreased in the antrum (before vs after, 0.98 ⫾ 0.14 vs 0.70 ⫾ 0.13; P ⬍ 0.05) and were
associated with a decrease in iNOS production. Sera from patients treated with rebamipide
showed a significant decrease in gastrin (276.3 ⫾ 58.3 pg/ml vs 173.0 ⫾ 34.2 pg/ml; P ⬍ 0.05),
whereas no change was observed in the control group. These suggest that long-term
rebamipide treatment improved histologic gastritis and decreased serum gastrin levels in H.
pylori-associated gastritis.

KEY WORDS: rebamipide; H. pylori; gastritis; iNOS.

Helicobacter pylori plays an important role in the
induction of chronic gastritis (1). It has been accepted
that there is a strong association between H. pylori-
associated gastritis and gastric diseases including pep-
tic ulcer and gastric cancer (2– 4). Therefore, it is
important to investigate the pathogenesis of chronic
gastritis for developing methods to control the occur-
rence of gastric diseases.
Rebamipide {2-(4-chlorobenzoylamino)-3-[2(1H)-
quinolinon-4-yl] propionic acid} is used in East Asian
countries as a gastroprotective agent for the treat-
Manuscript received June 28, 2001; revised manuscript received
November 2, 2001; accepted November 23, 2001.
From the *Division of Gastroenterology II, Department of In-
ternal Medicine, Kawasaki Medical School, Kurashiki, Japan; and
†First Department of Internal Medicine and ‡Health Service Cen-
ter, Hiroshima University School of Medicine, Hiroshima, Japan.
Address for reprint requests: Dr. Ken Haruma, Division of
Gastroenterology II, Department of Internal Medicine, Kawasaki
Medical School, 577 Matsushima Kurashiki, 701-0192, Japan.
ment of acute gastritis, including gastritis induced by
nonsteroidal antiinflammatory drugs, and peptic ul-
cers (5, 6). Recent in vitro studies have demonstrated
the antiinflammatory effect of rebamipide on gastric
mucosal cells. Rebamipide suppresses activation of
neutrophils induced by H. pylori and protects gastric
epithelial cell (7). Production of free radicals by ac-
tivated neutrophils is also inhibited by rebamipide
(8).
Increased mucosal levels of various cytokines in-
cluding IL-1, -6, -8 and tumor necrosis factor
(TNF)-␣ play critical roles in the pathogenesis of H.
pylori-associated gastritis (9, 10). Production of IL-8
by epithelial cells stimulated by H. pylori infection is a
crucial factor in H. pylori-induced gastritis (11–13).
Rebamipide has been reported to decrease levels of
various cytokines including IL-8 in vitro (14). In ad-
dition, we showed that expression of IL-8 is dramat-

862 Digestive Diseases and Sciences, Vol. 47, No. 4 (April 2002)
0163-2116/02/0400-0862/0 © 2002 Plenum Publishing Corporation
EFFECT OF REBAMIPIDE ON GASTRITIS
TABLE 1. CLINICAL FEATURES
Rebamipide group (N ⫽ 53)
Age [yr, mean (range)]
Sex (men/women)
Serum PG (pg/ml, mean ⫾ SE)
PG I/II (mean ⫾ SE)
ically suppressed by short-term treatment with re-
bamipide in patients with H. pylori-associated gastritis
(15).
Many clinical studies have demonstrated that re-
bamipide accelerates ulcer healing and prevents ulcer
recurrence (5, 6). No report, however, has discussed
whether rebamipide administration can improve
chronic gastritis. We studied the effect of rebamipide
on chronic gastritis in humans. Severity of gastritis
was assessed histologically before and after long-term
treatment with rebamipide. Serum gastrin and pep-
sinogen levels were measured in the same subjects.
Moreover, the production of inducible nitric oxide
synthase (iNOS), which is induced by H. pylori infec-
tion and is closely associated with gastric carcinogen-
esis, was investigated.
MATERIALS AND METHODS
Patients. This study was performed in a prospective and
open-randomized manner. Eighty-six patients with dyspep-
sia were included, and all gave informed consent. All pa-
tients were positive for H. pylori as determined by CLO-test,
Giemsa staining, [13C]urea breath test or serum IgG anti-
bodies against H. pylori (Amrad). No patient who had
undergone gastrectomy or was taking H2 blocker/proton
pump inhibitors was included in the study. Endoscopic
examination showed that no localized lesion was present in
any patient. Patients were requested to visit the hospital
every four weeks and were randomized to treatment. We
excluded data of patients who dropped out of the study or
who were lost to follow up. A few patients needed other
treatment within 12 months and were also excluded from
the study. After diagnosis of H. pylori infection, 53 patients
(32 men/21 women, mean age 60.9 years) were treated with
300 mg rebamipide daily for 12 months, and 33 patients (17
men/16 women, mean age 59.0 years) were followed up
without medication. We found no significant side effects of
rebamipide. Prior to and 12 months after treatment, routine
endoscopic examination was performed on each patient;
five biopsy specimens were obtained: three from the antrum
and two from the corpus. The degree of gastritis was deter-
mined from hematoxylin and eosin (HE)-stained sections
and scored on a scale of 0 to 3 according to the updated
Sydney system (16).
Serum Gastrin and Pepsinogens. Fasting serum was col-
lected from all patients. The samples were centrifuged
immediately at 4°C and stored at ⫺20°C until use. Serum
concentrations of serum gastrin and pepsinogens were de-
termined by radioimmunoassay (Dainabot, Tokyo, Japan).
Digestive Diseases and Sciences, Vol. 47, No. 4 (April 2002)
OF REBAMIPIDE AND CONTROL GROUP
Control group (N ⫽ 33)
60.9 (36–82) 59.0 (39–78)
32/21 17/16
276.3 ⫾ 58.3 223.4 ⫾ 78.1
3.21 ⫾ 0.28 3.11 ⫾ 0.45
Immunohistochemistry. Immunohistochemical analysis
was performed as we have described previously (17). Four-
micron sections of formalin-fixed paraffin-embedded tissues
were deparaffinized and hydrated. After treatment with
pepsin (Biomeda, Foster City, California, USA) for 10 min,
endogenous peroxidase was quenched with 3% H2O2 in
methanol for 10 min followed by a phosphate-buffered
saline (PBS) rinse. Nonspecific binding was blocked by a
20-min incubation with PBS containing 1.5% normal goat
serum. Sections were then incubated with a polyclonal
antibody against human iNOS (diluted 1/500 with PBS;
Santa Cruz Biotechnology, California, USA) overnight at
4°C. A biotin-labeled secondary antibody (anti-rabbit IgG
sheep antibody) was applied and incubated for 30 min at
room temperature and followed by ABC procedure (Dako).
The sections were developed with DAB chromogen
(Merck, Darmstadt, Germany), counterstained with May-
er’s hematoxylin, dehydrated, and mounted.
Grading for iNOS. Immunoreactivity was graded on a
scale of 0 to 3 (0, no stained cells; 1, a few stained cells; 2,
a moderate number of stained cells; 3, most cells stained) as
described previously (18). Two investigators independently
scored the slides without information regarding the pa-
tients. Only clear cytoplasmic stainings in inflammatory
cells were judged as positive.
Statistics. Results are reported as mean ⫾ standard error
(SE). Statistical analysis was performed by paired t-test with
StatView software (SAS Institute Inc., Cary, North Caro-
lina, USA). P ⬍ 0.05 was considered statistically signifi-
cant.
RESULTS
Changes in Histologic Features of Gastritis by
Long-Term Treatment with Rebamipide. Clinical
features of patients are given in Table 1; no differ-
ence was seen between the two groups. Changes in
the histologic features of gastritis are summarized
in Table 2. In the rebamipide-treatment group,
infiltration by mononuclear cells was decreased sig-
nificantly after 12 months of rebamipide therapy,
but no significant difference was found in the con-
trol group. Neutrophil infiltration in the antrum
also improved after rebamipide therapy. The
grades of atrophy before and after the therapy,
however, did not differ in either groups.
Serum Gastrin and Pepsinogens. Fasting levels of
serum gastrin decreased significantly after long-term
rebamipide therapy (before, 276.3 ⫾ 58.3 pg/ml; af-
863
 HARUMA ET AL

TABLE 2. CHANGES IN HISTOLOGIC STATUS OF GASTRITIS WITH LONG-TERM REBAMIPIDE THERAPY

Rebamipide group (N ⫽ 53) Control group (N ⫽ 33)

Before After Before After

Mononuclear cell infiltration

Corpus 1.60 ⫾ 0.15* 1.21 ⫾ 0.14* 1.52 ⫾ 0.21 1.48 ⫾ 0.21
Antrum 1.42 ⫾ 0.15† 1.02 ⫾ 0.15† 1.92 ⫾ 0.16 1.74 ⫾ 0.19
Neutrophil infiltration
Corpus 1.18 ⫾ 0.17 0.98 ⫾ 0.15 1.03 ⫾ 0.17 1.29 ⫾ 0.19
Antrum 0.98 ⫾ 0.14* 0.70 ⫾ 0.13* 1.13 ⫾ 0.14 1.11 ⫾ 0.17
Atrophy
Corpus 1.51 ⫾ 0.14 1.59 ⫾ 0.14 1.52 ⫾ 0.18 1.48 ⫾ 0.18
Antrum 2.17 ⫾ 0.13 2.17 ⫾ 0.13 1.89 ⫾ 0.14 1.64 ⫾ 0.14
*P ⬍ 0.05.
†P ⬍ 0.01.

ter, 173.0 ⫾ 34.2 pg/ml; P ⬍ 0.01; Figure 1), whereas DISCUSSION

no significant difference was found in the control
H. pylori is involved in the pathogenesis of gastritis,
group (before, 223.4 ⫾ 78.1 pg/ml; after, 226.6 ⫾ 94.6
peptic ulcer, and gastric cancer (1– 4), and atrophic
pg/ml). However, the serum pepsinogen I/II ratio was
gastritis is found primarily in patients with H. pylori
not altered in the rebamipide group (before, 3.21 ⫾
infection (1). This suggests that H. pylori plays a
0.28; after, 3.22 ⫾ 0.28; Figure 2) or the control group
critical role in the promotion of atrophic gastritis,
(before, 3.11 ⫾ 0.45; after, 2.96 ⫾ 0.44).
which is a risk factor for gastric cancer (2– 4). Epide-
Production of iNOS. A significant decrease in the
miological studies have indicated that infection with
iNOS score was observed after long-term rebamipide
H. pylori is a risk factor for gastric cancer, and the
therapy in both the antrum (before, 1.07 ⫾ 0.21; after,
World Health Organization classified this infection as
0.37 ⫾ 0.15; P ⬍ 0.05; Figure 3) and the corpus
a definite biological carcinogen in 1994 (19, 20).
(before, 1.23 ⫾ 0.25; after, 0.32 ⫾ 0.15; P ⬍ 0.01).
Therefore, eradication of H. pylori should reduce the
No significant difference was found in the control
frequency of atrophic gastritis and contribute to can-
group in the antrum (before, 1.19 ⫾ 0.20; after,
cer prevention.
1.09 ⫾ 0.24) or the corpus (before, 0.95 ⫾ 0.17; after,
Rebamipide, a gastroprotective agent, has been
0.84 ⫾ 0.19). The iNOS immunoreactivity was mainly
used clinically for treatment of acute gastritis and
detected primarily in the cytoplasm of inflammatory
peptic ulcer (5, 6). In vitro studies have demonstrated
cells including the neutrophils, lymphocytes and mac-
that rebamipide suppresses the production of several
rophages (Figure 4).
cytokines and free radicals that play an important role

Fig 1. Effect of rebamipide on serum levels of gastrin. Serum
gastrin levels were measured by RIA in patients treated with
rebamipide (A) and in controls (B). Sera were collected prior to
the start of therapy (left) and after 12 months of therapy (right).
**P ⬍ 0.01. NS, not significant.
Fig 2. Effect of rebamipide on pepsinogen I/II levels. Serum pep-
sinogen levels were measured by RIA in patients treated with
rebamipide (A) and in controls (B). Sera were collected prior to
the start of therapy (left) and after 12 months of therapy (right).
NS, not significant.

864 Digestive Diseases and Sciences, Vol. 47, No. 4 (April 2002)
EFFECT OF REBAMIPIDE ON GASTRITIS

Fig 3. Effect of rebamipide on iNOS production. Production of iNOS was investigated by

immunohistochemical analysis. All specimens were scored as described in Materials and Methods
section. The results are shown as mean ⫾ SE in the patients treated with rebamipide (A) and in
controls (B). Biopsy specimens were collected from the antrum and the corpus prior to the start of
therapy (left) and after 12 months of therapy (right). *P ⬍ 0.05. **P ⬍ 0.01. NS, not significant.

in H. pylori-associated gastritis (7, 8). However, no
reported studies have investigated the effect of re-
bamipide on chronic gastritis in humans. In the
present study, we demonstrated that rebamipide im-
proved gastritis induced by H. pylori infection in vivo.
Improvement of histologic gastritis might be one of
the important mechanisms of rebamipide to protect
human gastric mucosa.
A recent study has demonstrated that H. pylori
attaches to gastric epithelial cells and injects patho-
genic proteins into the epithelial cells (21). Intracel-
lular cascades are stimulated by these events, leading
to expression of NF-␬B and IL-8 (21). IL-8 expression
by epithelial cells is a critical event caused by CagA-
positive H. pylori infection (11). Cag A protein is
commonly expressed in H. pylori strains in Japan (22).
In a previous study, rebamipide therapy (300 mg/day
for two weeks) dramatically decreased mucosal levels
of IL-8 protein (15). In our 53 patients with long-term
treatment of rebamipide, the status of H. pylori infec-
tion was unaffected by long-term rebamipide therapy
(data not shown). Therefore, after H. pylori attaches
to epithelial cells, rebamipide might block the events
upstream of IL-8 production by the gastric mucosa
and improve histologic gastritis. It has been believed
that eradication of H. pylori may be necessary for
improvement of H. pylori-associated gastritis. Long-
term rebamipide therapy should be considered for
patients in whom successful H. pylori eradication
could not be obtained to improve gastritis.
It is thought that the atrophic changes associated
with chronic gastritis are reversible. We have previ-
ously reported improvement in histologic atrophy in
some patients after H. pylori eradication (23). How-
ever, we did not observe improvement in atrophy
after 12 months of treatment with rebamipide alone.
Pepsinogen I/II ratios were also unaffected by rebam-
ipide therapy. We have followed some patients
treated with rebamipide for more than five years, but
we have found no obvious improvement in atrophy.
Serum levels of gastrin were decreased by long-
term administration of rebamipide. This suggests that
rebamipide may improve not only histologic but also
functional abnormalities caused by H. pylori infection.
The reason for the alteration of gastrin level is not
clear because we could not demonstrate an improve-
ment in atrophy in the corpus histologically and se-
rologically. Acid secretion is controlled by some lym-
phokines, including IL-1, which inhibits the acid
secretion of parietal cells. We examined the level of
IL-1 by enzyme-linked immunosorbent assay and con-
firmed that rebamipide does not affect the IL-1 level
in gastric mucosa (data not shown). The most likely
mechanism of normalizing gastrin levels is the escape
from controls of some lymphokines (except for IL-1)
by improvement of histologic gastritis. Next, we have
to evaluate acid output in the present cases and
confirm whether rebamipide can improve acid output
or not.
It has been proposed that reactive oxygen and

Digestive Diseases and Sciences, Vol. 47, No. 4 (April 2002) 865
 HARUMA ET AL

(18). In addition, in the present patients, we have

confirmed the simultaneous expression of iNOS and
nitrotyrosine. The production of iNOS, primarily by
inflammatory cells, was strongly suppressed by long-
term rebamipide therapy, indicating that rebamipide
may be useful for the prevention of gastric cancer in
high risk subjects when H. pylori eradication is not
possible. In vitro studies have demonstrated that re-
bamipide decreases the oxidative stress increased by
H. pylori infection, supporting our present result (29).
In conclusion, long-term rebamipide therapy is an
effective treatment for chronic gastritis associated
with H. pylori infection, and it may improve gastric
function. Further studies are needed to assess im-
provement of clinical symptoms and possible indica-
tions for use of rebamipide in patients with functional
dyspepsia.

Fig 4. Immunohistochemical staining of iNOS. Expression of iNOS
was determined by immunohistochemical staining. Paraffin-
embedded sections were obtained from gastric biopsies of a 56-
year-old female before (A) and after administration (B) of rebam-
ipide. Positive signals were found primarily in the cytoplasm of
mononuclear cells in the section of pre-administration of rebam-
ipide. (⫻120).
nitrogen species play roles in carcinogenesis (24).
Reactive nitrogen species derived from nitric oxide
are generated by iNOS in a variety of cell types,
including activated macrophages and neutrophils
(25). Increased activity of iNOS has been observed in
patients with chronic gastritis and gastric cancer (26,
27). Recent studies have shown that H. pylori infec-
tion leads to formation of nitrotyrosine, which may
contribute to DNA damage and apoptosis in the
gastric mucosa (28). It is likely that iNOS expression
is associated closely with gastric carcinogenesis. As we
have previously reported, iNOS expression does not
simply correlate with the degree of inflammation and
10. Noach LA, Bosma NB, Jansen J, Hoek FJ, van Deventer SJ,
H. pylori status (18). Expressions of iNOS and nitro-
tyrosine were significantly higher in the gastric cancer
patients than in H. pylori-positive noncancer patients
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