• Gastroesophageal reflux disease
• Mucosal protection
• Peptic ulcer
• Rebamipide
• Treatment

• ZnO nanoparticles
• bioavailability
• foliar application
• iron
• maize
• selenium
• zinc

• Comorbidities
• FDA approved NSAIDs
• Non-selective NSAIDs
• current guidelines for OA management
• efficacy and safety of NSAIDs
• selective COX-2

• Humans
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Osteoarthritis/drug therapy
• Osteoarthritis/chemically induced
• Comorbidity
• Risk Factors

• Amlexanox
• Dologel CT
• Oral ulcers
• Rebamipide
• Recurrent aphthous stomatitis

• Indian Council of Medical Research

• Anti-inflammatory agents, non-steroidal
• Gastrointestinal diseases
• Proton pump inhibitors
• Rebamipide
• Small bowel injury

• Humans
• Pilot Projects
• Ulcer/chemically induced
• Ulcer/drug therapy
• Alanine/adverse effects
• Intestinal Diseases
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects

• the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)

• fecal microbiota transplantation
• gut microbiota
• non-steroidal anti-inflammatory drug enteropathy
• probiotics
• proton pump inhibitors
• toll-like receptor 4

• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Gastrointestinal Microbiome
• Humans
• Intestinal Diseases/chemically induced
• Intestinal Mucosa
• Microbiota
• Probiotics

To contrast the effect of rebamipide with proton pump inhibitors (PPIs) versus PPIs alone for the treatment of endoscopic submucosal dissection (ESD-) induced ulcers.

PubMed, Embase, the Cochrane library, the WanFang database, and China National Knowledge Infrastructure (CNKI) were searched to identify studies that met the inclusion criteria.

Nine randomized controlled trials (RCTs) were recognized, including 1170 patients. In general, rebamipide plus PPIs acted better than PPIs alone against ESD-induced ulcers at four weeks (RR = 1.42, 95% CI: 1.13-1.78, P = 0.003) but showed no significant differences at eight weeks (RR = 1.03, 95% CI: 0.97-1.10, P = 0.315). The use of rebamipide plus PPIs was superior to PPIs alone for ESD-induced ulcers greater than 20 mm in size (20-40 mm: RR = 1.98, 95% CI: 1.22-3.23, P = 0.006; >40 mm: RR = 5.14, 95% CI: 1.49-17.74, P = 0.010). In addition, rebamipide plus PPI therapy was discovered to be significantly more effective than PPIs alone for lower ESD-induced ulcers (RR = 1.82, 95% CI: 1.04-3.20, P = 0.037). There were no significant differences between the treatment groups with the ulcer reduction rate.

Evidences now available show rebamipide plus PPIs is practical for protecting against ESD-induced ulcers at four weeks but not at eight weeks, especially large ulcers (>20 mm). However, we still need more high-quality RCTs in the future to supplement our conclusions.

• Enteropathy
• Innate immunity
• Low-dose aspirin
• Misoprostol
• Non-steroidal anti-inflammatory drug

• Animals
• Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Anti-Ulcer Agents/administration & dosage
• Aspirin/administration & dosage
• Aspirin/adverse effects
• Capsule Endoscopy
• Gastrointestinal Hemorrhage/chemically induced
• Gastrointestinal Hemorrhage/drug therapy
• Humans
• Intestinal Diseases/chemically induced
• Intestinal Diseases/drug therapy
• Intestinal Diseases/pathology
• Intestine, Small/drug effects
• Intestine, Small/pathology
• Misoprostol/administration & dosage
• Peptic Ulcer/chemically induced
• Peptic Ulcer/drug therapy
• Peptic Ulcer/pathology

• dual antiplatelet
• peptic ulcer
• prevention

Acid suppressants such as histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are effective in preventing gastrointestinal (GI) bleeding in nonsteroidal anti-inflammatory drugs (NSAIDs) users. Despite widespread acid suppressant use, there remain concerns about several potential risks of long-term use. Therefore, we investigated whether gastroprotective agents (GPAs) other than acid suppression therapy are effective in preventing NSAID-related GI injury. To this end, we studied 9,133 patients with osteoarthritis or rheumatoid arthritis who used NSAIDs for ≥1 month. A decrease of 2 g/dL or more in the hemoglobin level was considered a GI injury indicator. The GPAs included acid suppressants and other mucoprotective agents. Acid suppressants included PPIs and H2RAs. Other mucoprotective agents included misoprostol, rebamipide, and eupatilin. During a median follow-up period of 27 (range, 4.3-51.3) weeks, occult GI bleeding occurred in 1,191 (13%) patients. A comparison of patients who used GPAs concomitantly with that of nonusers in a multivariable analysis revealed the hazard ratios (HRs; 95% confidence intervals [CIs]) for occult GI bleeding were 0.30 (0.20-0.44), 0.35 (0.29-0.43), 0.47 (0.23-0.95), 0.43 (0.35-0.51), and 0.98 (0.86-1.12) for PPIs, H2RAs, misoprostol, rebamipide, and eupatilin, respectively. Compared to PPI co-treatment, H2RA, misoprostol, rebamipide, and eupatilin co-treatments were associated with occult GI bleeding HRs (95% CIs) of 1.19 (0.79-1.79), 1.58 (0.72-3.46), 1.44 (0.96-2.16), and 3.25 (2.21-4.77), respectively. Our findings suggest that mucoprotective agents, such as rebamipide and misoprostol, as well as acid suppressants, are effective in reducing the risk for GI injury in NSAID users.

Stroke patients are at high risk of developing pneumonia, which is major cause of post-stroke mortality. Proton pump inhibitors and H₂ receptor antagonists are anti-ulcer drugs, which may predispose to the development of pneumonia by suppression of the gastric acid with bactericidal activity. Unlike proton pump inhibitors and H₂ receptor antagonists, mucoprotective agents have gastroprotective effects with no or less anti-acid property. We aimed to investigate effects of the acid-suppressive medications (proton pump inhibitors and H₂ receptor antagonists) and mucoprotective agents on risk for post-stroke pneumonia using the National Health Insurance Service-National Sample Cohort in Korea. This retrospective cohort study included 8,319 patients with acute ischemic stroke. Use of proton pump inhibitors, H₂ receptor antagonists, and mucoprotective agents (rebamipide, teprenone, irsogladine, ecabet, polaprezinc, sofalcone, sucralfate, and misoprostol) after stroke were determined based on the prescription records, which were treated as time-dependent variables. Primary outcome was the development of post-stroke pneumonia. During the mean follow-up period of 3.95 years after stroke, 2,035 (24.5%) patients had pneumonia. In the multivariate time-dependent Cox regression analyses (adjusted hazard ratio [95% confidence interval]), there was significantly increased risk for pneumonia with use of proton pump inhibitors (1.56 [1.24–1.96]) and H₂ receptor antagonists (1.40 [1.25–1.58]). In contrast to the proton pump inhibitors and H₂ receptor antagonists, use of mucoprotective agents did not significantly increase the risk for pneumonia (0.89 [0.78–1.01]). In conclusion, the treatment with proton pump inhibitors and H₂ receptor antagonists was associated with increased risk for pneumonia in stroke patients. Clinicians should use caution in prescribing the acid-suppressive medications for the stroke patients at great risk for pneumonia.

• Dyspepsia
• Guideline
• Thailand

• Dyspepsia
• Gastritis
• Meta-analysis
• NSAID gastropathy
• Rebamipide

• Alanine/analogs & derivatives
• Alanine/therapeutic use
• Anti-Ulcer Agents/therapeutic use
• Dyspepsia/drug therapy
• Dyspepsia/etiology
• Humans
• Odds Ratio
• Quinolones/therapeutic use
• Treatment Outcome

• GC002-14HTM University of Malaya Grand Challenge

• NSAID-induced enteropathy
• capsule endoscopy
• non-steroidal anti-inflammatory agents
• obscure gastrointestinal bleeding
• rebleeding

• COX-1/COX-2 inhibition
• NSAID enteropathy
• capsule endoscopy
• diaphragm disease
• pathogenesis
• prophylaxis
• risk factors
• small bowel

• Cytokine
• Injuries of lung and kidney
• Paraquat
• Sucralfate

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Antidotes/therapeutic use
• Cytokines/blood
• Gastric Lavage
• Herbicides/poisoning
• Kidney/drug effects
• Kidney/pathology
• Lung/drug effects
• Lung/pathology
• Male
• Paraquat/poisoning
• Rats
• Rats, Sprague-Dawley
• Sodium Bicarbonate/therapeutic use
• Sucralfate/therapeutic use

• AIMS65
• Upper gastrointestinal bleeding (UGIB)
• elderly patient
• urgent endoscopy

• gastric injury
• indomethacin
• primary cell culture
• rat
• ulcer

Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory, anti-pyretic and analgesic properties and have been widely used in clinical practice; however, they can cause cytotoxicity in the gastrointestinal tract, especially in the intestine. The injurious effects of NSAIDs on the small intestine occur frequently and can lead to severe clinical outcomes. A multifactorial etiology is involved in the pathogenesis of these lesions. Current studies found that, in addition to the suppression of cyclooxygenase activity, several factors including enterobacterial invasion, neutrophil migration, enterohepatic cycling of NSAIDs, bile and mitochondrial injury have been implicated in the pathogenesis of these lesions. This article reviews the mechanisms and therapeutic strategies in NSAIDs induced intestinal injury.

• Non-steroidal anti-inflammatory drugs
• Intestinal injury
• Cyclooxygenase
• Enterobacteria

• Aged
• Alanine/analogs & derivatives
• Alanine/therapeutic use
• Anti-Ulcer Agents/therapeutic use
• Aspirin/adverse effects
• Capsule Endoscopy
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Female
• Humans
• Intestinal Diseases/chemically induced
• Intestinal Diseases/diagnosis
• Intestinal Diseases/drug therapy
• Intestine, Small/drug effects
• Intestine, Small/pathology
• Male
• Quinolones/therapeutic use
• Severity of Illness Index
• Treatment Outcome

• Anti-Inflammatory Agents, Non-Steroidal/administration & dosage
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Aspirin/administration & dosage
• Aspirin/adverse effects
• Capsule Endoscopy
• Drug Administration Schedule
• Gastrointestinal Hemorrhage/chemically induced
• Gastrointestinal Hemorrhage/prevention & control
• Humans
• Intestinal Diseases/chemically induced
• Intestinal Diseases/prevention & control
• Intestine, Small/drug effects
• Platelet Aggregation Inhibitors/administration & dosage
• Platelet Aggregation Inhibitors/adverse effects
• Ulcer/chemically induced
• Ulcer/prevention & control

• GI bleed
• NSAID
• gastrointestinal
• side effects
• ulcer

• Alanine/analogs & derivatives
• Alanine/pharmacology
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Anti-Ulcer Agents/pharmacology
• Humans
• Quinolones/pharmacology

• intestinal flora
• non-steroidal anti-inflammatory drugs
• oxidative stress
• rebamipide
• small intestine

• Administration, Oral
• Aldosterone/blood
• Analysis of Variance
• Animals
• Blood Pressure/drug effects
• Blood Urea Nitrogen
• Celecoxib
• Electrolytes/urine
• Immunoblotting
• Immunohistochemistry
• In Situ Nick-End Labeling
• Kidney Diseases/chemically induced
• Misoprostol/administration & dosage
• Misoprostol/adverse effects
• Potassium/urine
• Pyrazoles/adverse effects
• Rats
• Sodium/urine
• Sulfonamides/adverse effects
• Troponin I/blood

The use of proton pump inhibitors or misoprostol is known to prevent the gastrointestinal complications of nonsteroidal anti-inflammatory drugs (NSAIDs). Rebamipide is known to increase the mucosal generation of prostaglandins and to eliminate free oxygen radicals, thus enhancing the protective function of the gastric mucosa. However, it is unknown whether rebamipide plays a role in preventing NSAID-induced gastropathy. The aim of this study was to determine the effectiveness of rebamipide compared to misoprostol in preventing NSAID-induced gastrointestinal complications in patients requiring continuous NSAID treatment.

We studied 479 patients who required continuous NSAID treatment. The patients were randomly assigned to groups that received 100 mg of rebamipide three times per day or 200 μg of misoprostol three times per day for 12 weeks. The primary endpoint of the analysis was the occurrence rate of gastric ulcers, as determined by endoscopy after 12 weeks of therapy.

Of the 479 patients in the study, 242 received rebamipide, and 237 received misoprostol. Ultimately, 44 patients (18.6%) withdrew from the misoprostol group and 25 patients (10.3%) withdrew from the rebamipide group. There was a significant difference in withdrawal rate between the two groups (p=0.0103). The per protocol analysis set was not valid because of the dropout rate of the misoprostol group; thus, the intention to treat (ITT) analysis set is the main set for the efficacy analysis in this study. After 12 weeks, the occurrence rate of gastric ulcers was similar in the rebamipide and misoprostol groups (20.3% vs 21.9%, p=0.6497) according to ITT analysis. In addition, the therapeutic failure rate was similar in the rebamipide and misoprostol groups (13.6% vs 13.1%, p=0.8580). The total severity score of the gastrointestinal symptoms was significantly lower in the rebamipide group than in the misoprostol group (p=0.0002). The amount of antacid used was significantly lower in the rebamipide group than in the misoprostol group (p=0.0258).

Rebamipide can prevent gastric ulcers when used with NSAIDs and can decrease the gastrointestinal symptoms associated with NSAID administration. When the possibility of poor compliance and the potential adverse effects of misoprostol are considered, rebamipide appears to be a clinically effective and safe alternative.

• Anti-inflammatory agents
• Complications
• Misoprostol
• Rebamipide
• Rheumatic diseases
• non-steroidal

Rebamipide is an amino acid analog of 2 (1H)-quinolinone. It is being introduced and used since 1980 for the treatment of peptic ulcer. Its therapeutic use in recurrent aphthous ulcer was not known. It acts by the decrease in oxygen radicals, increase in blood flow and production of protective prostaglandins in ulcer mucosa, which accelerates the process of healing. In this article, we focus on the pharmacodynamics, pharmacokinetics, side-effects and other therapeutic uses of Rebamipide. It will be a new and effective drug in the dermatologists’ drug armamentarium for the treatment of aphthous ulcers and related diseases.

• Aphthous ulcer
• Behcet's syndrome
• rebamipide

AIM: To prospectively compare the healing rates of endoscopic submucosal dissection (ESD)-induced ulcers treated with either a proton-pump inhibitor (PPI) or rebamipide.

METHODS: 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.

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 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.

CONCLUSION: 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.

• Early gastric cancer
• Rebamipide
• Endoscopic submucosal dissection
• Gastric ulcer
• Proton-pump inhibitor

• Adenocarcinoma/surgery
• Aged
• Alanine/analogs & derivatives
• Alanine/therapeutic use
• Anti-Ulcer Agents/therapeutic use
• Dissection/adverse effects
• Female
• Gastroscopy/adverse effects
• Humans
• Iatrogenic Disease
• Lansoprazole/therapeutic use
• Male
• Middle Aged
• Peptic Ulcer/drug therapy
• Peptic Ulcer/etiology
• Prospective Studies
• Proton Pump Inhibitors/therapeutic use
• Quinolones/therapeutic use
• Stomach Neoplasms/surgery

To investigate the gastroprotective effects of grape seed proanthocyanidin extracts (GSPEs) against nonsteroid anti-inflammatory drug (NSAID)-induced gastric mucosal injury in rats.

Sprague-Dawley rats were randomly allocated to the normal control, indomethacin, low-dose GSPE, high-dose GSPE and misoprostol groups. All groups except the normal control group received pretreatment drugs for 6 consecutive days. On the 5th and 6th day, indomethacin was administered orally to all groups except for normal control group. The microscopic features of injury were analyzed. The levels of gastric mucosal glutathione, gastric mucosal prostaglandin E₂ (PGE₂), and proinflammatory cytokines were investigated.

The total areas of ulceration in the GSPE and misoprostol groups were significantly decreased compared with the indomethacin group (p<0.05). However, a difference in ulcer formation among the drug treatment groups was not observed. Meanwhile, the glutathione levels in the high-dose GSPE group were higher than those of both the indomethacin and misoprostol groups (p<0.05) and were similar to those of the normal control group. Additionally, there was no difference among the groups in the levels of gastric mucosal PGE₂ and proinflammatory cytokines.

High-dose GSPE has a strong protective effect against NSAID-induced gastric mucosal injury, which may be associated with the antioxidant effects of GSPE.

• Antioxidants
• Gastropathy
• Grape seed proanthocyanidins
• Nonsteroid anti-inflammatory drug

• adaptation
• aspirin
• placebo
• rebamipide
• symptoms

AIM: To evaluate the protective properties of novel prostone ClC-2 agonist SPI-8811 in porcine model of gastric acid injury.

METHODS: Porcine gastric mucosa was mounted in Ussing chambers and injured by bathing mucosal tissues in an HCl Ringer’s solution (pH = 1.5) with or without SP1-8811 (1 μmol/L), cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor (inhibitor 172, 10 μmol/L, apical) and ClC-2 inhibitor ZnCl₂, 300 μmol/L, apical), on the apical surface of tissues. Transepithelial resistance and mucosal-to-serosal ³H-mannitol fluxes were measured over a 90-min period. Tissues were analyzed by morph metric techniques, Immunofluorescence and by western blots.

RESULTS: Compared with control tissues, acid exposure decreased transepithelial electrical resistance (TER) and increased ³H-mannitol flux. Pretreatment of gastric mucosa with SPI-8811 was protective against acid-induced decreases in TER (TER, 50 Ω.cm²vs 100 Ω.cm²) and abolished increases in flux (³H-mannitol flux, 0.10 μmol/L.cm²vs 0.04 μmol/L.cm²). Evidence of histological damage in the presence of acid was markedly attenuated by SPI-0811. Immunofluorescence and western analysis for occludin revealed enhanced localization to the region of the tight junction (TJ) after treatment with SPI-8811. Pretreatment with the ClC-2 inhibitor ZnCl₂, but not the selective CFTR inhibitor 172, attenuated SPI-8811-mediated mucosal protection, suggesting a role for ClC-2. Prostone may serve both protective and reparative roles in injured tissues.

CONCLUSION: ClC-2 agonist SPI-8811 stimulated enhancement of mucosal barrier function by protecting TJ protein occludin in porcine gastric mucosa and thus protected the gastric acid injury in porcine stomach.

• Stomach
• Mucosal permeability
• ClC-2 chloride channel
• Tight junction

Gastrointestinal symptoms are a problematic issue for patients who take low-dose aspirin for long time. We conducted a pilot study to investigate the efficacy of combination therapy with proton pump inhibitor and rebamipide. This was a prospective, randomized, double-blind, placebo-controlled cross-over study. All the subjects received aspirin 100 mg and omeprazole 20 mg. The subjects were divided into two groups and received either rebamipide 300 mg or placebo, which was prescribed for 4 weeks. The subjects were instructed to record their gastrointestinal symptom rating scale before the study and 1 and 4 weeks after beginning the protocol. These scores of the groups were compared before and after the treatment to evaluate the severity of their symptoms and the number of symptom items present in each group. For the subjects receiving rebamipide, the total prevalence of lower gastrointestinal symptoms was significantly different from the placebo group (p=0.0093) at week 4. No troublesome symptoms were observed in the rebamipide group. Inconclusion, the administration of rebamipide prevented the occurrence of troublesome symptoms, especially lower gastrointestinal symptoms, in patients taking aspirin and omeprazole. Rebamipide is a candidate drug for combination therapy with proton pump inhibitors to prevent low-dose aspirin-induced gastrointestinal symptoms.

• adaptation
• aspirin
• placebo
• rebamipide
• symptoms

• Animals
• Anti-Inflammatory Agents, Non-Steroidal
• Blotting, Western
• Disease Models, Animal
• Electrophoresis, Gel, Two-Dimensional
• Hemopexin/metabolism
• Ileum/metabolism
• Ileum/pathology
• Immunohistochemistry
• Indomethacin
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Jejunum/metabolism
• Jejunum/pathology
• Male
• Peptic Ulcer/chemically induced
• Peptic Ulcer/metabolism
• Peptic Ulcer/pathology
• Peptide Mapping
• Proteomics/methods
• Rats
• Rats, Wistar
• Severity of Illness Index
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Time Factors
• Up-Regulation

• non-steroidal anti-inflammatory drugs
• rheumatoid arthritis
• osteoarthritis
• gastric or duodenal ulcers
• prevention
• lansoprazole
• active-controlled trial

It is well-known that acetylsalicylic acid induces gastrointestinal complication. Recently, trefoil factor family has been reported as a mucosal protective factor. We focused on trefoil factor family as one of defensive system for gastrointestinal injuries. The aim of this trial was to evaluate trefoil factor family levels in the serum of healthy subjects with low-dose acetylsalicylic acid. Low-dose acetylsalicylic acid with placebo or proton pump inhibitor or rebamipide were administered in 30 healthy subjects. Transnasal endoscopy was performed at 0, 24 h, 3 and 7 day. Changing of trefoil factor family (1,2,3) and numbers of gastric injuries were evaluated. The numbers of gastric injuries were significantly increased in the placebo group at 3 and 7 days. Injuries in the proton pump inhibitor group were not induced, in the rebamipide group were slightly induced. Trefoil factor family level in the placebo group were decreased in 3 and 7 days compared with prior to starting the trial. Trefoil factor family may have an important association with acetylsalicylic acid-induced gastrointestinal damage. Proton pump inhibitor and rebamipide prevented low-dose acetylsalicylic acid-induced gastrointestinal complications compared with the placebo group.

• Low-dose ASA
• proton pump inhibitor
• rebamipide
• transnasal endoscopy
• trefoil factor