Efficacy of fexuprazan compared with rebamipide in Korean patients with gastritis: A matching-adjusted indirect comparison.

BACKGROUND: Gastritis is one of the most frequently diagnosed diseases requiring medical treatment in South Korea. Fexuprazan, a novel potassium-competitive acid blocker, has been approved for treating gastritis and erosive esophagitis. Meanwhile, rebamipide is the most commonly used mucoprotective agent for acute and chronic gastritis in real-world settings in South Korea. However, there have been no studies comparing the efficacy of these two drugs yet. AIM: To compare the efficacy of fexuprazan with that of rebamipide for acute and chronic gastritis. METHODS: This was a matching-adjusted indirect comparison. Individual patient data from a phase III study of fexuprazan (10 mg BID) were compared with cumulative data from two matching studies of rebamipide (100 mg TID). Erosion improvement and healing rates were compared between two weeks of fexurapan, two weeks of rebamipide, and four weeks of rebamipide. The two main outcome variables were presented as percentages, and the risk differences (RD) and 95% confidence intervals (CI) were calculated for the relative treatment effects. RESULTS: In the primary analysis, the erosion improvement and healing rates after a two-week treatment with fexuprazan were 64.5% and 53.2%, respectively, while a two-week treatment with rebamipide resulted in erosion improvement and healing rates of 43.6% (RD: 21.0%; 95%CI: 9.6-32.3; P < 0.01) and 35.6% (RD: 17.6%; 95%CI: 6.1-29.2; P = 0.003), respectively. In the additional analysis, the erosion improvement and healing rates for the two-week fexuprazan treatment (64.2% and 51.2%, respectively) were similar to those obtained during a four-week treatment with rebamipide (60.6%; RD: 3.6%; 95%CI: -9.8, 17.0; P = 0.600 and 53.5%; RD: -2.3%; 95%CI: -16.1, 11.5; P = 0.744, respectively). CONCLUSION: The two-week fexuprazan treatment was superior to the two-week rebamipide treatment and similar to the four-week rebamipide treatment for patients with gastritis.

Rebamipide gargle and benzydamine gargle in prevention and management of chemo-radiotherapy and radiotherapy-induced oral mucositis in head and neck cancer patients (randomized clinical trial).

OBJECTIVES: This study aimed to evaluate the preventive and therapeutic effects of rebamipide gargle in comparison with benzydamine in head and neck cancer patients undergoing radiotherapy with or without chemotherapy. MATERIALS AND METHODS: Phase III randomized clinical trial was conducted from January 2021 till August 2022 on one hundred patients with head and neck cancer receiving high doses of radiotherapy. These patients were equally allocated into either rebamipide group or benzydamine group, The measured outcomes were the incidence of oral mucositis ≥ grade1, according to the WHO mucositis scale, in addition to the duration, and the onset of oral mucositis. RESULTS: There was no statistically significant difference between the two groups, regarding the incidence of a severe grade of oral mucositis (WHO grades 3), as well as the onset and duration of oral mucositis. Both gargles succeeded to prevent the development of WHO grade 4 oral mucositis. Side effects reported were mainly burning sensation in benzydamine group and nausea in rebamipide group. CONCLUSION: Rebamipide mouthwash was as beneficial as benzydamine mouthwash in minimizing the incidence of severe oral mucositis induced by treatment of head and neck cancer. However, rebamipide gargle proved to be superior to benzydamine in terms of reduction in the severity of the radiation-induced oral mucositis. TRIAL REGISTRATION: The trial was registered in the protocol Registration and Result system of Clinical Trials (Registration ID: NCT04685395)0.28-12-2020.

Enhancing Corneal Drug Penetration Using Penetratin for Ophthalmic Suspensions.

Eye drops, including solutions and suspensions, are essential dosage forms to treat ophthalmic diseases, with poorly water-soluble drugs typically formulated as ophthalmic suspensions. In addition to low bioavailability, suspensions exhibit limited efficacy, safety, and usability due to the presence of drug particles. Improving bioavailability can reduce the drug concentrations and the risk of problems associated with suspended drug particles. However, practical penetration enhancers capable of improving bioavailability remain elusive. Herein, we focused on penetratin (PNT), a cell-penetrating peptide (CPP) that promotes active cellular transport related to macromolecule uptake, such as micropinocytosis. According to the in vitro corneal uptake study using a reconstructed human corneal epithelial tissue model, LabCyte CORNEA-MODEL24, PNT enhanced the uptake of Fluoresbrite® YG carboxylate polystyrene microspheres without covalent binding. In an ex vivo porcine eye model, the addition of 10 µM PNT to rebamipide ophthalmic suspension markedly improved the corneal uptake of rebamipide; however, the addition of 100 µM PNT was ineffective due to potentially increased particle size by aggregation. This article provides basic information on the application of PNT as a penetration enhancer in ophthalmic suspensions, including the in vitro and ex vivo studies mentioned above, as well as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity assay and storage stability at different pH values.

High-Performance Liquid Chromatography (HPLC) Method Validation for Identifying and Quantifying Rebamipide in Ethosomes.

Introduction The research aimed to develop a robust, high-performance liquid chromatography (HPLC) analytical method for the quantitative assessment of rebamipide encapsulated in ethosomes. Rebamipide, a quinolinone derivative, holds promise as a therapeutic agent for dry eye, but challenges such as low bioavailability and vision clouding post-installation have prompted innovative approaches. Encapsulation in ethosomes, lipid-based nanovesicles, offers a potential solution to enhance ocular bioavailability. Materials and methods The study focused on creating a specific, linear, accurate, precise, and robust HPLC method, addressing entrapment efficiency (%EE), drug content, and drug release of rebamipide in prepared ethosomes. Statistical validation followed International Conference of Harmonization (ICH) specifications. The method's parameters were evaluated within a concentration range of 4-24 µg/ml, with recovery rates indicating accuracy and low % relative standard deviation (RSD) values confirming precision. Limits of detection (LOD) and quantification (LOQ) for rebamipide were determined. Results After preparing the ethosome dosage form by film hydrating method for rebamipide, the rebamipide entrapment efficiency in ethosomes was established at 76% ± 7, while the drug content was found to be 93% ± 6. The drug release process demonstrated zero-order kinetics and five different models of kinetics were applied for a comprehensive analysis. The method exhibited excellent system suitability, specificity, and linearity. Recovery rates for rebamipide ranged from 90% to 100%, and repeatability was confirmed by low %RSD values. The LOD and LOQ for rebamipide were determined to be 1.04 µg/mL and 3.16 µg/mL, respectively. Conclusion The developed HPLC method proved suitable for the quantitative determination of rebamipide in ethosomes, offering rapid and accurate analysis. The results underscore the method's specificity, accuracy, and precision within the specified concentration range. Overall, the validated method contributes to the advancement of ocular drug delivery systems, providing a reliable analytical tool for pharmaceutical research.

Rebamipide Prevents the Hemoglobin Drop Related to Mucosal-Damaging Agents at a Level Comparable to Proton Pump Inhibitors.

Background/Aims: : The effect of proton pump inhibitors (PPIs) on the lower gastrointestinal (GI) tract is uncertain, with potential to worsen damage. This study aimed to find the best method for protecting the entire GI tract from mucosal damage. Methods: : A retrospective cohort study at Samsung Medical Center (2002-2019) included 195,817 patients prescribed GI mucosa-damaging agents. The primary goal was to assess the effectiveness of GI protective agents in preventing significant hemoglobin drops (>2 g/dL), indicating overall GI mucosal damage. Self-controlled case series and landmark analysis were used to address biases in real-world data. Results: : The incidence rate ratios for rebamipide, PPI, and histamine-2 receptor antagonist (H2RA) were 0.34, 0.33, and 0.52, respectively. Rebamipide showed a significantly lower incidence rate than H2RA and was comparable to PPIs. Landmark analysis revealed significant reductions in hemoglobin drop risk with rebamipide and H2RA, but not with PPI. Conclusions: : Rebamipide, like PPIs, was highly effective in preventing blood hemoglobin level decreases, as shown in real-world data. Rebamipide could be a comprehensive strategy for protecting the entire GI tract, especially when considering PPIs' potential side effects on the lower GI tract.

Pharmaceutical analysis for a patient with rebamipide-induced Stevens-Johnson syndrome by clinical pharmacists / 中国药房

OBJECTIVE To provide reference for the diagnosis and treatment of Stevens-Johnson syndrome caused by rebamipide， and to explore the predisposing factors of Stevens-Johnson syndrome. METHODS Clinical pharmacists analyzed the treatment process of a patient with gastrointestinal diseases and evaluated the correlation between the drug used and adverse reactions， in order to determine the suspected allergenic drug causing Stevens-Johnson syndrome. The predisposing factors of patients with Stevens-Johnson syndrome were explored. RESULTS & CONCLUSIONS The suspected allergenic drugs that caused the patient to develop Stevens-Johnson syndrome included Ilaprazole enteric-coated tablets， Rebamipide tablets and Kangfuxin liquid. In summary， the suspect drug was identified as Rebamipide tablets according to the causality evaluation method of the National Center for Adverse Drug Reaction Monitoring， Naranjo’s scoring method and the algorithm of drug causality for epidermal necrolysis scoring criteria. Hypoproteinemia， competitive binding of plasma proteins between drugs， advanced age， bacterial and viral infections were the predisposing factors of Stevens-Johnson syndrome. Therefore， before using rebamipide in clinical practice， it is necessary to inquire about the patient’s allergy history in detail. During the use process， it is necessary to strengthen the patient’s medication monitoring and be alert to the occurrence of serious adverse reactions. If any abnormalities are found， the medication should be stopped immediately and symptomatic treatment should be given as soon as possible to ensure the safety and effectiveness of the patient’s medication.

Effect of rebamipide on the acute gouty arthritis in rats induced by monosodium urate crystals / 北京大学学报(医学版)

OBJECTIVE@#To investigate the role of rebamipide in the treatment of acute gout arthritis rats induced by monosodium urate (MSU) crystal.@*METHODS@#Forty-two male rats were randomly divided into three groups (n=14). Group A was treated with oral rebamipide, group B with oral colchicine, and group C with oral placebo. The rats were monitored for the induction of arthritis with clinical manifestations and pathological changes, and the levels of interleukin (IL)-1β、IL-6、IL-10, and tumor necrosis factor (TNF)-α in serum were measured.@*RESULTS@#In group C, the clinical score and swelling index reached the maximum in 24 h, and then gradually decreased to 72 h. After 24 h of model induced, the clinical scores in group C were significantly higher than those in group A and group B [2 (1-3) vs. 0 (0-1) vs. 1 (0-2), P < 0.01], the swelling indexes in group C were significantly higher than those in group A and group B [0.36 (0.16-0.52) vs. 0.11 (0-0.20) vs. 0.12 (0-0.16), P < 0.01]. Histologically, after 24 h of model induced, there was a large number of neutrophil infiltration in the synovium of group C [scale score: 4 (2-4)], and there was no significant inflammatory cell infiltration in group A [1 (0-2)] and group B [1 (0-2)], the difference was statistically significant (P < 0.001). After 24 h of model induced, the levels of IL-1β, IL-6, IL-10, and TNF-α in serum of group C were significantly higher than those in group A and B [IL-1β: (41.86±5.72) vs. (27.35±7.47) vs. (27.76±5.28) ng/L, IL-6: (1 575.55±167.11) vs. (963.53±90.22) vs. (964.08±99.31) ng/L, IL-10: (37.96±3.76) vs. (21.68±4.83) vs. (16.20±2.49) ng/L, TNF-α: (21.32±1.34) vs. (15.82±2.54) vs. (17.35±7.47) μg/L, P < 0.001].@*CONCLUSION@#Rebamipide has a protective effect on acute gout arthritis rats induced by MUS crystals.

The glycocalyx barrier function in ocular surface and its alteration in dry eye disease / 国际眼科杂志(Guoji Yanke Zazhi)

@#Some studies have shown that the glycocalyx barrier formed by highly glycosylated mucin and galectin-3 in the epithelial cells of the eyeball is important for the maintenance of moisturization and lubrication of the surface of the eye. The decrease in the wettability of the eye surface and the shortening of the tear film breakup time in dry eye patients are closely related to the damage of the glycocalyx barrier. This article outlines the composition of the glycocalyx barrier on ocular surface and its changes in the dry eye patients. It will also introduce a new method for assessing the damage of the glycocalyx barrier in dry eye patients. Finally, two ophthalmological drugs, which target regulating the abnoemality of transmembrane mucins in dry eye disease will be mentioned.

Additive Effects of Rebamipide Plus Proton Pump Inhibitors on the Expression of Tight Junction Proteins in a Rat Model of Gastro-Esophageal Reflux Disease

BACKGROUND/AIMS: The aim of this study was to investigate the effects of rebamipide on tight junction proteins in the esophageal mucosa in a rat model of gastroesophageal reflux disease (GERD). METHODS: GERD was created in rats by tying the proximal stomach. The rats were divided into a control group, a proton pump inhibitor (PPI) group, and a PPI plus rebamipide (PPI+R) group. Pantoprazole (5 mg/kg) was administered intraperitoneally to the PPI and PPI+R groups. An additional dose of rebamipide (100 mg/kg) was administered orally to the PPI+R group. Mucosal erosions, epithelial thickness, and leukocyte infiltration into the esophageal mucosa were measured in isolated esophagi 14 days after the procedure. A Western blot analysis was conducted to measure the expression of claudin-1, -3, and -4. RESULTS: The mean surface area of mucosal erosions, epithelial thickness, and leukocyte infiltration were lower in the PPI group and the PPI+R group than in the control group. Western blot analysis revealed that the expression of claudin-3 and -4 was significantly higher in the PPI+R group than in the control group. CONCLUSIONS: Rebamipide may exert an additive effect in combination with PPI to modify the tight junction proteins of the esophageal mucosa in a rat model of GERD. This treatment might be associated with the relief of GERD symptoms.

The Efficacy of Rebamipide or Ecabet Sodium Supplementation for Helicobacter pylori Eradication Therapy Compared with Quadruple (Concomitant) Regimen / 대한소화기학회지

BACKGROUND/AIMS: Although some previous studies reported that a treatment combined with mucoprotective agent could improve the eradication rate in dual or triple therapy, there are other reports that question the efficacy of combining these drugs in concomitant therapy (CoCTx). The aim of this study was to investigate the effects of rebamipide or ecabet on the Helicobacter pylori (H. pylori) eradication combined with CoCTx. METHODS: We retrospectively reviewed the medical records of 277 patients with proven H. pylori infection. They were assigned to one of 3 regimens for 10 days, twice daily: (a) CoCTx (n=118): lansoprazole 30 mg, amoxicillin 1 g, metronidazole 500 mg, and clarithromycin 500 mg; (b) CoCTx+rebamipide (100 mg) (n=85); (c) CoCTx+ecabet (1 g) (n=74). RESULTS: The baseline characteristics were not significantly different. H. pylori eradication rates were 82.2% (97/118) in CoCTx, 90.6% (77/85) in CoCTx+rebamipide, and 89.2% (66/74) in CoCTx+ecabet (p=0.17), which were statistically insignificant. Overall adverse events were more frequently reported in the CoCTx+rebamipide (50.6%. 43/85) and CoCTx+ecabet (44.6%, 33/74) groups than in the CoCTx (32.2%, 38/118) (p = 0.03) group. Drug compliances were not different between three groups (CoCTx: 95.8%, 113/118; CoCT+rebamipide: 92.9%, 79/85; CoCTx+ecabet 98.6%,73/74) (p=0.209). Multivariate analysis showed that the risk of eradication failure was significantly increased with decreased drug compliance (odds ratio 3.52, 95% confidence interval 1.00–12.32; p=0.05). CONCLUSIONS: Addition of these mucoprotective agent was not superior to CoCTx alone for eradicating H. pylori infection with frequent adverse events. Rather, drug compliance is the most related factor affecting the eradication rate. Our data suggest the importance of drug compliance over the drugs used.

Metabolomics Approach to Explore the Effects of Rebamipide on Inflammatory Arthritis Using Ultra Performance Liquid Chromatography/Quadrupole Time-of-Flight Mass Spectrometry

OBJECTIVE: Rebampide is a gastroprotective agent used to treat gastritis. It possesses anti-inflammatory and anti-arthritis effects, but the mechanisms of these effects are not well understood. The objective of this study was to explore mechanisms underlying the therapeutic effects of rebamipide in inflammatory arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in DBA/1J mice. DBA/1J mice were immunized with chicken type II collagen, then treated intraperitoneally with rebamipide (10 mg/kg or 30 mg/kg) or vehicle (10% carboxymethylcellulose solution) alone. Seven weeks later, plasma samples were collected. Plasma metabolic profiles were analyzed using ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolomics study and metabolite biomarkers were identified through multivariate data analysis. RESULTS: Low dose rebamipide treatment reduced the clinical arthritis score compared with vehicle treatment, whereas high dose rebamipide in CIA aggravated arthritis severity. Based on multivariate analysis, 17 metabolites were identified. The plasma levels of metabolites associated with fatty acids and phospholipid metabolism were significantly lower with rebamipide treatment than with vehicle. The levels of 15-deoxy-Δ¹²,¹⁴ prostaglandin J2 and thromboxane B3 decreased only in high dose-treated groups. Certain peptide molecules, including enterostatin (VPDPR) enterostatin and bradykinin dramatically increased in rebamipide-treated groups at both doses. Additionally, corticosterone increased in the low dose-treated group and decreased in the high dose-treated group. CONCLUSION: Metabolomics analysis revealed the anti-inflammatory effects of rebamipide and suggested the potential of the drug repositioning in metabolism- and lipid-associated diseases.

Rebamipide repairs injury of small intestinal epithelial barrier induced by aspirin in mice / 中国病理生理杂志

AIM:To investigate whether rebamipide repairs the small intestinal epithelial barrier in aspirin-induced small intestinal injury (SII) in mice and its mechanism.METHODS:Small intestinal injury was induced by aspirin (200 mg · kg-1 · d-1 for 5 d) in BALB/c mice.Based on the treatment with aspirin and/or rebamipide (320 mg ·kg-1 · d-1),the mice were divided into 4 groups (n =18 in each group).The living mice in each group (n =6) were sacrificed via cervical dislocation method at day 0,day 5,and day 10.The structure and function of intestinal barrier and the levels of the signaling pathway factors were measured by transmission electron microscopy,immunohistochemistry,qPCR,and Western blot.RESULTS:Tight junctions between intestinal epithelial cells improved significantly after rebamipide treatment.The expression of ZO-1 and occludin in the injured small intestine showed a gradually increasing trend after rebamipide administration (P ＜ 0.05).There was a decreased trend of D-lactate level in rebamipide-treated SII mice (P ＜ 0.05).The expression of cyolooxygenase-2 (COX-2),β-catenin,and c-Myc,and prostaglandin E2 concentration in small intestinal tissues were significantly increased in rebamipide treatment group (P ＜ 0.05).However,down-regulated COX-1 expression in the SII mice was sustained at a low level after rebamipide administration.CONCLUSION:Rebamipide repairs the injury of small intestinal mucosa and improves the structure and function of small intestinal barrier in aspirininduced SII mice by up-regulating the expression of COX-2.

Rebamipide repairs injury of small intestinal epithelial barrier induced by aspirin in mice / 中国病理生理杂志

AIM:To investigate whether rebamipide repairs the small intestinal epithelial barrier in aspirin-induced small intestinal injury (SII) in mice and its mechanism.METHODS:Small intestinal injury was induced by aspirin (200 mg · kg-1 · d-1 for 5 d) in BALB/c mice.Based on the treatment with aspirin and/or rebamipide (320 mg ·kg-1 · d-1),the mice were divided into 4 groups (n =18 in each group).The living mice in each group (n =6) were sacrificed via cervical dislocation method at day 0,day 5,and day 10.The structure and function of intestinal barrier and the levels of the signaling pathway factors were measured by transmission electron microscopy,immunohistochemistry,qPCR,and Western blot.RESULTS:Tight junctions between intestinal epithelial cells improved significantly after rebamipide treatment.The expression of ZO-1 and occludin in the injured small intestine showed a gradually increasing trend after rebamipide administration (P ＜ 0.05).There was a decreased trend of D-lactate level in rebamipide-treated SII mice (P ＜ 0.05).The expression of cyolooxygenase-2 (COX-2),β-catenin,and c-Myc,and prostaglandin E2 concentration in small intestinal tissues were significantly increased in rebamipide treatment group (P ＜ 0.05).However,down-regulated COX-1 expression in the SII mice was sustained at a low level after rebamipide administration.CONCLUSION:Rebamipide repairs the injury of small intestinal mucosa and improves the structure and function of small intestinal barrier in aspirininduced SII mice by up-regulating the expression of COX-2.

Clinical Observation of Rebamipide Triple Therapy in the Treatment of Gastric Ulcer with Bleeding / 中国药房

OBJECTIVE:To observe the efficacy and safety of rebamipide triple therapy in the treatment of gastric ulcer with bleeding. METHODS:130 patients with gastric ulcer with bleeding were randomly divided into control group(65 cases)and obser-vation group(65 cases). Control group received Omeprazole enteric-coated capsule 20 mg,orally,twice a day+Aluminum magne-sium carbonate tablet 500 mg,orally,once a day;observation group was additionally received Rebamipide tablet 0.1 g,orally,3 times a day. They were treated for 12 weeks. Clinical efficacy,remission time of belching,abdominal pain,bloating,hematemesis/hematochezia,clinical symptom score before and after treatment,rebleeding and the incidence of adverse reactions in 2 groups were observed. RESULTS:The total effective rate in observation group was significantly higher than control group,remission time of symptoms and signs were significantly shorter than control group,the incidence of rebleeding was significantly lower than con-trol group,with statistical significances (P0.05). After treatment,the clinical symptom scores in 2 groups were significantly lower than before,and observation group was lower than control group,with statistical significances (P0.05). CONCLUSIONS:Rebamipide triple therapy shows obvious short-term efficacy in the treat-ment of gastric ulcer with bleeding,which can effectively improve patients'gastrointestinal symptoms,reduce rebleeding risk,and does not increase the incidence of adverse reactions.

Effects of Rebamipide on Gastrointestinal Symptoms in Patients with Type 2 Diabetes Mellitus

BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with type 2 diabetes mellitus (T2DM). Rebamipide is an effective gastric cytoprotective agent, but there are few data on its usefulness in T2DM. The aim of this study is to evaluate the improvement of GI symptoms after rebamipide treatment in patients with T2DM. METHODS: Patients with T2DM and atypical GI symptoms were enrolled. They took rebamipide (100 mg thrice daily) for 12 weeks and filled out the diabetes bowel symptom questionnaire (DBSQ) before and after rebamipide treatment. The DBSQ consisted of 10 questions assessing the severity of GI symptoms by a 1 to 6 scoring system. Changes in the DBSQ scores before and after rebamipide treatment were analyzed to evaluate any improvements of GI symptoms. RESULTS: A total of 107 patients were enrolled, and 84 patients completed the study. The mean age was 65.0±7.8, 26 patients were male (24.8%), the mean duration of T2DM was 14.71±9.12 years, and the mean glycosylated hemoglobin level was 6.97%±0.82%. The total DBSQ score was reduced significantly from 24.9±8.0 to 20.4±7.3 before and after rebamipide treatment (P<0.001). The DBSQ scores associated with reflux symptoms, indigestion, nausea or vomiting, abdominal bloating or distension, peptic ulcer, abdominal pain, and constipation were improved after rebamipide treatment (P<0.05). However, there were no significant changes in symptoms associated with irritable bowel syndrome, diarrhea, and anal incontinence. No severe adverse events were reported throughout the study. CONCLUSION: Rebamipide treatment for 12 weeks improved atypical GI symptoms in patients with T2DM.

The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study

BACKGROUND/AIMS: To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. METHODS: A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. RESULTS: The mean decreases in the total symptom score at 4 weeks were estimated to be −18.1±13.8 in the combination therapy group and −15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were −8.4±6.6 in the combination therapy group and −6.8±5.9 in the monotherapy group (p=0.009). CONCLUSIONS: Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.

The Benefits of Combination Therapy with Esomeprazole and Rebamipide in Symptom Improvement in Reflux Esophagitis: An International Multicenter Study

BACKGROUND/AIMS: To investigate the effects of esomeprazole and rebamipide combination therapy on symptomatic improvement in patients with reflux esophagitis. METHODS: A total of 501 patients with reflux esophagitis were randomized into one of the following two treatment regimens: 40 mg esomeprazole plus 300 mg rebamipide daily (combination therapy group) or 40 mg esomeprazole daily (monotherapy group). We used a symptom questionnaire that evaluated heartburn, acid regurgitation, and four upper gastrointestinal symptoms. The primary efficacy end point was the mean decrease in the total symptom score. RESULTS: The mean decreases in the total symptom score at 4 weeks were estimated to be −18.1±13.8 in the combination therapy group and −15.1±11.9 in the monotherapy group (p=0.011). Changes in reflux symptoms from baseline after 4 weeks of treatment were −8.4±6.6 in the combination therapy group and −6.8±5.9 in the monotherapy group (p=0.009). CONCLUSIONS: Over a 4-week treatment course, esomeprazole and rebamipide combination therapy was more effective in decreasing the symptoms of reflux esophagitis than esomeprazole monotherapy.

Protective Effect and Mechanism of Rebamipide on Injury of Human Colon Cancer Cell Line Caco-2 Induced by Aspirin / 胃肠病学

Background:With the development of capsule endoscopy,small intestinal injury induced by non-steroidal anti-inflammatory drugs( NSAIDs)has become an issue of growing concern. Although there are a variety of drugs used for NSAIDs-induced gastric mucosal injury,small intestinal injury caused by NSAIDs is lack of effective prevention and treatment modalities. Aims:To investigate the protective effect and possible mechanism of rebamipide on human colon cancer cell line Caco-2 injury induced by aspirin. Methods:In aspirin group,Caco-2 cells were treated with aspirin 10 mmol/L;in rebamipide group,Caco-2 cells were treated with aspirin and different concentrations of rebamipide(0. 1, 0. 5,1. 0 mmol/L),and a negative control group was established. Cell proliferation inhibition was measured by MTT assay. Cell apoptosis was determined by flow cytometry. Morphological changes of cells were observed under inverted phase contrast microscope. Permeability of cells was assessed by Transwell assay. Expressions of tight junction proteins occludin and zonula occluden-1(ZO-1),as well as mitogen activated protein kinase(MAPK)signaling pathway-associated proteins including extracellular signal-regulated kinase(ERK)1/2,phosphorylated ERK1/2(p-ERK1/2),p38,p-p38,c-Jun N-terminal kinase( JNK),and p-JNK,were determined by Western blotting. Results:Proliferation inhibition rate,apoptosis rate and permeability of Caco-2 cells in rebamipide 0. 1,0. 5,1. 0 mmol/L groups were significantly lower than those in aspirin group in a dose-dependent manner(P<0. 05). Injuries of Caco-2 cells were seen in aspirin group by inverted phase contrast microscope and rebamipide could reduce these injuries. Expressions of occludin,ZO-1 and p-JNK were significantly higher and expressions of p-p38 and p-ERK1/2 were significantly lower in rebamipide 0. 1,0. 5,1. 0 mmol/L groups than those in aspirin group in a dose-dependent manner(P<0. 05). Conclusions:Rebamipide have a protective effect against aspirin-induced Caco-2 cell injury,probably through regulating MAPK signaling pathway( inhibiting p38 and ERK1/2 phosphorylation,stimulating JNK phosphorylation),and subsequently up-regulating the expressions of tight junction proteins and decreasing the permeability of cells.

Preventive Efficacy and Safety of Rebamipide in Nonsteroidal Anti-Inflammatory Drug-Induced Mucosal Toxicity

BACKGROUND/AIMS: 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. METHODS: 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 microg 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. RESULTS: 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). CONCLUSIONS: 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.

Protective effects and its mechanism of rebamipide on aspirin-induced injury in human gastric mucosal epithelium cells / 中华消化杂志

Objective To investigate the protective effects and its mechanism of rebamipide on aspirin-induced injury in human gastric mucosal epithelium cells (GES-1).Methods GES-1 cells monolayer culture model was established in vitro.Then the cells were divided into negative control group,aspirin injured group and combination of rebamipide at different concentration (0.2,0.5,1.0 mrnol/L) and aspirin groups.The cell proliferation,the content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) of each group were detected.The ultrastructural changes of each group were observed by transmission electron microscopy (TEM).The expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) at protein level in the cells of each group were detected by Western blot.Nrf2 interfering suppression test was performed and then the influence of Nrf2 small interfering RNA (siRNA) on the expression of HO-1 protein was observed.One-way analysis of variance was performed for comparison among multi-groups and t-test was used for comparison between the two groups.Results The cell viability of aspirin injured group and combination of rebamipide at different concentration (0.2,0.5,1.0 mmol/L) and aspirin groups were (49.56±3.88)％,(59.34±4.36) ％,(70.79 ± 5.96) ％ and (86.07 ± 5.20) ％,respectively,and the difference was statistically significant (F=30.634,P＜ 0.01).Compared with aspirin injured group,the content of MDA significantly lowered in combination of rebamipide at different concentration (0.2,0.5,1.0 mmol/L) and aspirin groups ((2.26±0.25) nrnol/rng vs (1.85±0.13) nmol/mg vs (1.62±0.11) nmol/mg vs (1.13±0.15) nmol/mg),and the difference was statistically significant (F=23.821,P＜0.05).Compared with aspirin injured group,the activity of SOD significantly increased in combination of rebamipide at 0.5 and 1.0 mmol/L and aspirin groups ((8.49±0.89) U/rng vs (11.50±1.03) U/mg vs (13.74±0.76) U/mg),the difference was statistically significant (F=25.666,P＜0.05).Under TEM,the cell ultrastrucmral was obviously inured in aspirin treated,while rebamipide could relieve the injury.The differences of relative expression quantity of Nrf2 and HO-1 at protein level among combination of rebamipide at 0.2,0.5 and 1.0 mmol/L and aspirin groups and aspirin injured group were statistically significant (0.35±0.04 vs 0.46± 0.05 vs 0.84±0.08 vs 0.15±0.02,0.72±0.09 vs 0.93±0.11 vs 1.29±0.14 vs 0.39±0.07,F=92.550and 38.235,both P＜0.05).After transfected with Nrf2 siRNA,the expression of HO-1 was 0.38±0.04 in aspirin injured group and 0.62±0.08 in combination of rebamipide and aspirin group,which was lower than that before transfection (0.61 ± 0.05,1.33± 0.09),respectively.The differences were statistically significant (t =6.276 and 10.444,both P＜0.05).Conclusion Rebamipide may activate Nrf2/HO-1 pathway and relieve aspiriwinduced oxidative stress in GF1 ceils.