Protective effect of intra-rectal administration of rebamipide on dextran sulfate sodium-induced rat colitis

BACKGROUND/AIM: Rebamipide, an anti-ulcer drug, has various actions including radical scavenging and mucus-stimulating as well as anti-inflammatory effects, and exhibits both mucosal protective and healing promoting actions in the stomach. In the present study, we examined the effect of rebamipide on an animal model of colitis induced by dextran sulfate sodium (DSS). METHODS: Experimental colitis was induced in rats by daily treatment with 3% DSS in drinking water for 7 days. Rebamipide (3-30 mg/kg), 5-aminosalicylic acid (5-ASA: 150 mg/kg) or metronidazole (10 and 30 mg/kg) was administered intra-rectally once daily for 6 days. The ulceration area, colon length, and mucosal myeloperoxidase (MPO) activity as well as thiobarbituric acid-reactive substance (TBARS) were measured on the 7th day after the onset of DSS treatment. The effects of rebamipide on the secretion of mucus in the colon was also examined. RESULTS: DSS treatment caused severe lesions in the colon, accompanied by an increase in MPO activity and TBARS as well as a decrease in body weight gain and colon length. Repeated administration of rebamipide dose-dependently suppressed the colon lesions and improved the pathological changes induced by DSS treatment. Rebamipide significantly increased the mucus contents in the colon. Both 5-ASA and metronidazole also reduced the severity of DSS-induced lesions. CONCLUSION: These results suggest that intra-rectal administration of rebamipide is effective against DSS-induced colitis. The protective effect of rebamipide may be attributable to both the radical scavenging action and the increase in the production of mucus in the colon, the latter presumably suppressing the process of intestinal bacterial infiltration.     

瑞巴匹特预防葡聚糖硫酸酯钠诱发的小鼠结肠炎疗效观察及作用机制初探

目的近年氧自由基在溃疡性结肠炎(UC)发病过程中作用受到关注,一种新型的黏膜保护剂瑞巴匹特被认为具有清除氧自由基的作用,有望成为治疗溃疡性结肠炎的新药物。本文观察瑞巴匹特灌肠和灌胃治疗葡聚糖硫酸酯钠(DSS)诱发的小鼠结肠炎效果并探讨可能的作用机制。方法 3%DSS予8周龄雄性BALB/c小鼠自由饮用7 d制成小鼠结肠炎模型。予DSS前5 d开始瑞巴匹特(45 mg/kg/d)灌肠或灌胃治疗直到造模结束,处死小鼠取结肠组织,测量小鼠体重、结肠长度,进行大体和病理评分,分光光度法测定髓过氧化物酶、丙二醛含量,免疫组化法测定核因子κB(NFκB)表达水平,RT-PCR法测定过氧化物酶体增殖体激活受体γ(PPARγ)mRNA表达。结果与安慰剂对照组比较,瑞巴匹特灌肠和灌胃治疗组小鼠大体和病理评分显著改善,髓过氧化物酶活性、丙二醛含量、NFκB活性明显降低,PPARγmRNA的表达显著升高。结论瑞巴匹特可有效预防DSS诱发的小鼠结肠炎,其抑制炎症作用至少部分与清除氧自由基,从而维持局部PPARγ表达和抑制NFκB活性有关。     

Protective effect of rebamipide on indomethacin-induced intestinal damage in rats

BACKGROUND AND AIM: We evaluated the effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic acid), a novel anti-ulcer drug, on indomethacin-induced small intestinal lesions in rats. METHODS: The animals were administered indomethacin (10 mg/kg, s.c.), and they were killed 24 h later. Rebamipide (30-300 mg/kg) was administered p.o. twice, 30 min before, and 6 h after indomethacin. RESULTS: Indomethacin caused hemorrhagic lesions in the rat small intestine, accompanied by an increase in enterobacterial translocation, inducible nitric oxide synthase (iNOS) and myeloperoxidase (MPO) activities, as well as thiobarbituric acid (TBA) reactants, and these changes were significantly prevented by the supplementation with 16,16-dimethyl prostaglandin E2 (dmPGE2; 10 microg/kg, i.v.) or the pretreatment of animals with the antibiotic ampicillin. Treatment of the animals with rebamipide dose-dependently prevented the development of intestinal lesions, and this effect was mimicked by i.v. administration of superoxide dismutase (SOD: 3000 U/kg) + catalase (CAT: 5000 U/kg). The protection by rebamipide was accompanied by a significant suppression of the increase in both MPO and iNOS activities, and a complete inhibition of the increase in TBA reactants, while SOD + CAT significantly inhibited the increase of MPO activity and TBA reactants, but not iNOS activity. The bacterial translocation following indomethacin was also significantly decreased by either rebamipide or SOD + CAT. CONCLUSION: These results confirmed the importance of enterobacteria and iNOS/NO in the pathogenesis of indomethacin-induced small intestinal lesions, and suggested that rebamipide prevents the development of these lesions, probably by its radical scavenging action.     

Rebamipide has the potential to reduce the intensity of NSAID-induced small intestinal injury: a double-blind, randomized, controlled trial evaluated by capsule endoscopy

Background

A study reported that rebamipide was effective at reducing short-term nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. The purpose of this study was to re-evaluate the effect of the co-administration of rebamipide on small intestinal injuries induced by short-term NSAID treatment.

Methods

Eighty healthy male volunteers were randomly assigned to two study groups: a control group (N?=?40), which received NSAID (diclofenac sodium, 75?mg/day) and omeprazole (20?mg/day) treatment along with a placebo; and a rebamipide group, which received NSAID, omeprazole and rebamipide (300?mg/day). Small intestinal injuries (mucosal breaks plus denuded areas) were evaluated by capsule endoscopy before and after 14?days of treatment.

Results

A total of 38 control subjects and 34 rebamipide subjects completed the treatment and were evaluated by capsule endoscopy. NSAID therapy increased the mean number of mucosal injuries per subject from a basal level of 0.1?±?0.3 to 16?±?71 and 4.2?±?7.8 in the control and rebamipide groups, respectively, but the difference was not significant. The difference in the percentage of subjects with at least one mucosal injury post-treatment was also not significant (control 63%; rebamipide 47%). Limiting our analysis to subjects with mucosal injuries, rebamipide co-treatment had the tendency to reduce the mean number of mucosal injuries per subject from 25 in the control group to 8.9 in the rebamipide group (multiple comparisons test; p?=?0.088, Mann?CWhitney U test; p?=?0.038).

Conclusions

Rebamipide co-therapy had the potential to reduce the intensity of small intestinal injury induced by 2-week administration of diclofenac.     

Rebamipide alleviates radiation‐induced colitis through improvement of goblet cell differentiation in mice

Background and Aim

Radiation‐induced colitis is a common clinical problem associated with radiotherapy and accidental exposure to ionizing radiation. Goblet cells play a pivotal role in the intestinal barrier against pathogenic bacteria. Rebamipide, an anti‐gastric ulcer drug, has the effects to promote goblet cell proliferation. The aim of this study was to investigate whether radiation‐induced colonic injury could be alleviated by rebamipide.

Methods

This study orally administered rebamipide for 6 days to mice, which were subjected to 13 Gy abdominal irradiation, to evaluate the therapeutic effects of rebamipide against radiation‐induced colitis. To confirm the effects of rebamipide on irradiated colonic epithelial cells, this study used the HT29 cell line.

Results

Rebamipide clearly alleviated the acute radiation‐induced colitis, as reflected by the histopathological data, and significantly increased the number of goblet cells. The drug also inhibited intestinal inflammation and protected from bacterial translocation during acute radiation‐induced colitis. Furthermore, rebamipide significantly increased mucin 2 expression in both the irradiated mouse colon and human colonic epithelial cells. Additionally, rebamipide accelerated not only the recovery of defective tight junctions but also the differentiation of impaired goblet cells in an irradiated colonic epithelium, which indicates that rebamipide has beneficial effects on the colon.

Conclusions

Rebamipide is a therapeutic candidate for radiation‐induced colitis, owing to its ability to inhibit inflammation and protect the colonic epithelial barrier.     

Rebamipide decreases the susceptibility of gastric mucosa to acid-induced injury in rats by inhibiting neutrophil activation

We previously demonstrated that activated neutrophils increased the susceptibility of gastric mucosa to acid-induced injury in rats. As rebamipide, an anti-ulcer agent, inhibits neutrophil activation, we examined whether the rebamipide reduces stress-induced gastric mucosal injury by decreasing susceptibility to acid-induced gastric mucosal injury in rats. Increase in both gastric mucosal permeability and gastric microvascular permeability evaluated by (51)Cr-EDTA clearance and Evans blue leakage, respectively, at 6 hr after Water-Immersion Restraint Stress (WIR) were significantly lower in animals with leukocytopenia than those in controls. Pretreatment with neutrophil elastase (NE) inhibitors, an anti-P-selectin monoclonal antibody (MAb), and rebamipide significantly inhibited these increases at 6 hr after WIR. These treatments also inhibited decrease in gastric mucosal blood flow observed at 6 hr after WIR. Acid-induced exacerbation of gastric mucosal injury in rats at 6 hr after WIR was inhibited by NE inhibitors, anti-P-selectin MAb, and rebamipide. Rebamipide significantly inhibited WIR-induced increase in gastric MPO activity at 8 hr after WIR. Observations in the present study raised a possibility that rebamipide decreases the susceptibility of gastric mucosa to acid-induced injury by inhibiting neutrophil activation.     

Rebamipide Decreases the Susceptibility of Gastric Mucosa to Acid-Induced Injury in Rats by Inhibiting Neutrophil Activation

We previously demonstrated that activated neutrophils increased the susceptibility of gastric mucosa to acid-induced injury in rats. As rebamipide, an anti-ulcer agent, inhibits neutrophil activation, we examined whether the rebamipide reduces stress-induced gastric mucosal injury by decreasing susceptibility to acid-induced gastric mucosal injury in rats. Increase in both gastric mucosal permeability and gastric microvascular permeability evaluated by ⁵¹Cr-EDTA clearance and Evans blue leakage, respectively, at 6 hr after Water-Immersion Restraint Stress (WIR) were significantly lower in animals with leukocytopenia than those in controls. Pretreatment with neutrophil elastase (NE) inhibitors, an anti-P-selectin monoclonal antibody (MAb), and rebamipide significantly inhibited these increases at 6 hr after WIR. These treatments also inhibited decrease in gastric mucosal blood flow observed at 6 hr after WIR. Acid-induced exacerbation of gastric mucosal injury in rats at 6 hr after WIR was inhibited by NE inhibitors, anti-P-selectin MAb, and rebamipide. Rebamipide significantly inhibited WIR-induced increase in gastric MPO activity at 8 hr after WIR. Observations in the present study raised a possibility that rebamipide decreases the susceptibility of gastric mucosa to acid-induced injury by inhibiting neutrophil activation.     

Rebamipide significantly inhibits indomethacin-induced mitochondrial damage, lipid peroxidation, and apoptosis in gastric epithelial RGM-1 cells

Nonsteroidal antiinflammatory drugs (NSAIDs) cause complications such as gastrointestinal injury. NSAIDs were recently reported to cause mitochondrial injury: to dissipate the mitochondrial transmembrane potential (MTP), and to induce mitochondrial permeability transition pore (PTP), which liberates cytochrome c. This enzyme generates reactive oxygen species (ROS) thereby triggers caspase cascade and cellular lipid peroxidation, resulting in cellular apoptosis. However, the mechanism of this NSAID-induced MTP's role in cellular apoptosis remains unknown. Rebamipide, an antiulcer drug, is reported to scavenge ROS and to show the protective effects on indomethacin-induced tissue peroxidations. Since cytochrome c and its generation of ROS are involved in indomethacin-induced cellular apoptosis, rebamipide may attenuate mitochondrial damage. The aim of this study was to elucidate whether indomethacin induces both the MTP decrease and cellular apoptosis, and the effect of rebamipide on these phenomena. We examined the effect of rebamipide on 1) MTP change, 2) lipid peroxidation, 3) apoptosis, and 4) caspase activation using gastric mucosal epithelial cell-line treated with indomethacin. With a specially designed fluorescence analyzing microscope system, MTP change, cellular lipid peroxidation, and cellular apoptosis were investigated with the small star, filled following fluorescent dyes, MitoRed, DPPP, and Hoechst 33,258, respectively. Indomethacin treatment decreased MTP but increased both cellular lipid peroxidation and cellular apoptosis via caspase 3 and 9 activation. Rebamipide clearly inhibited these phenomena {in vitro}. We demonstrated that fluorescent dyes such as MitoRed, DPPP, and Hoechst 33,258 are useful indicators for detecting oxidative cellular injuries in living cells. Rebamipide exerts a protective effect on mitochondrial membrane stability in gastric epithelial cells.     

瑞巴派特治疗慢性非萎缩性胃炎的随机、对照、多中心临床研究

目的 评价瑞巴派特治疗伴糜烂的非萎缩性胃炎的疗效及其对幽门螺杆菌(Hp)相关胃黏膜损伤的保护作用.方法 共选取来自11个中心的452例经内镜确诊的非萎缩性胃炎伴糜烂患者,随机分为瑞巴派特组(300 mg/d)和硫糖铝组(3.0 g/d),疗程8周,其中半数Hp阳性病例在随机化前行Hp根除治疗.观察所有病例治疗前后的症状、内镜评分和病理改变,部分进行胃黏膜中前列腺素PGE2以及氧自由基产物丙二醛(MDA)检测.结果 符合方案集分析(n=415)显示瑞巴派特组的消化不良症状积分在治疗8周后显著下降,且内镜下炎症积分从治疗前的2.65±0.09下降至0.60±0.10(P<0.001),与硫糖铝相比差异有统计学意义(P<0.001),胃黏膜病理与内镜评判的趋势相符.同时,瑞巴派特组的胃黏膜PGE2含量由治疗前的(225.4 ±18.3)pg/g升至(266.7±14.7)pg/g,MDA含量由(325.9±65.6)mmol/g降至(216.5±61.5)mmol/g,与硫糖铝组相比差异有统计学意义(P=0.046).分层分析未发现瑞巴派特的疗效在HP阳性根除组、Hp阳性和Hp阴性组之间差异有统计学意义.结论 瑞巴派特对慢性非萎缩性胃炎的消化不良症状和内镜表现的改善优于硫糖铝,并且其对胃黏膜的保护作用不受Hp感染的影响.     

Augmented increase in tight junction permeability by luminal stimuli in the non-inflamed ileum of Crohn's disease

BACKGROUND: Crohn's disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohn's disease. AIMS: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohn's disease. PATIENTS: Surgical specimens from the distal ileum of patients with Crohn's disease (n=12) were studied, and ileal specimens from colon cancer patients (n=13) served as controls. METHODS: Mucosal permeability to 51Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. RESULTS: Baseline permeability was the same in non-inflamed ileum of Crohn's disease and controls. Sodium caprate induced a rapid increase in paracellular permeability--that is, increased permeation of 51Cr-EDTA and decreased electrical resistance--which was more pronounced in non-inflamed ileum of Crohn's disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohn's disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. CONCLUSIONS: The tight junctions in the non-inflamed distal ileum of Crohn's disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohn's disease.     

Rebamipide Significantly Inhibits Indomethacin-Induced Mitochondrial Damage,Lipid Peroxidation,and Apoptosis in Gastric Epithelial RGM-1 Cells

Nonsteroidal antiinflammatory drugs (NSAIDs) cause complications such as gastrointestinal injury. NSAIDs were recently reported to cause mitochondrial injury: to dissipate the mitochondrial transmembrane potential (MTP), and to induce mitochondrial permeability transition pore (PTP), which liberates cytochrome c. This enzyme generates reactive oxygen species (ROS) thereby triggers caspase cascade and cellular lipid peroxidation, resulting in cellular apoptosis. However, the mechanism of this NSAID-induced MTP's role in cellular apoptosis remains unknown. Rebamipide, an antiulcer drug, is reported to scavenge ROS and to show the protective effects on indomethacin-induced tissue peroxidations. Since cytochrome c and its generation of ROS are involved in indomethacin-induced cellular apoptosis, rebamipide may attenuate mitochondrial damage. The aim of this study was to elucidate whether indomethacin induces both the MTP decrease and cellular apoptosis, and the effect of rebamipide on these phenomena. We examined the effect of rebamipide on 1) MTP change, 2) lipid peroxidation, 3) apoptosis, and 4) caspase activation using gastric mucosal epithelial cell-line treated with indomethacin. With a specially designed fluorescence analyzing microscope system, MTP change, cellular lipid peroxidation, and cellular apoptosis were investigated with the ? following fluorescent dyes, MitoRed, DPPP, and Hoechst 33258, respectively. Indomethacin treatment decreased MTP but increased both cellular lipid peroxidation and cellular apoptosis via caspase 3 and 9 activation. Rebamipide clearly inhibited these phenomena {in vitro}. We demonstrated that fluorescent dyes such as MitoRed, DPPP, and Hoechst 33258 are useful indicators for detecting oxidative cellular injuries in living cells. Rebamipide exerts a protective effect on mitochondrial membrane stability in gastric epithelial cells.     

Effective treatment with oral administration of rebamipide in a mouse model of Sjögren's syndrome

OBJECTIVE: To determine whether oral administration of rebamipide, a mucosal protective agent, is effective in the treatment of Sj?gren's syndrome (SS) in the NFS/sld mouse model of the disease. METHODS: NFS/sld mice were given daily oral doses of rebamipide (0.3 mg/kg of body weight or 3 mg/kg) or vehicle alone starting from the age of 4 weeks to the age of 8 weeks. The volume of saliva and tears was monitored during and after treatment. After the final dose, histologic features of the tissues, TUNEL+ apoptotic duct cells in affected glands, T cell and cytokine function, and levels of immunoglobulin isotypes and serum autoantibodies were examined. RESULTS: The 3-mg/kg dose of rebamipide prevented the development of autoimmune lesions. The average volume of saliva in rebamipide-treated mice was significantly higher than that in control mice. We found decreased TUNEL+ apoptotic duct cells in the salivary and lacrimal glands of rebamipide-treated mice as compared with control mice. Rebamipide treatment suppressed the activation of CD4+ T cells and Th1 cytokines (interleukin-2, interferon-gamma) associated with impaired NF-kappaB activity. Production of serum autoantibodies, IgM, and IgG1 was clearly inhibited. CONCLUSION: Our findings demonstrate the efficacy of oral administration of rebamipide in the treatment of SS. Rebamipide represents a new therapeutic strategy for the treatment of patients with sicca symptoms caused by SS, as well as for patients with other diseases.     

雷贝拉唑对NSAIDs相关小肠损伤大鼠紧密连接蛋白Occludin表达的影响及其机制

目的探讨雷贝拉唑对非甾体类抗炎药(NSAIDs)相关性小肠损伤大鼠紧密连接蛋白Occludin表达的影响及可能的机制。方法将36只SD大鼠随机平均分为阴性对照组、双氯酚酸损伤组和雷贝拉唑处理组。采用双氯酚酸7.5 mg/(kg.d)灌胃,连续4 d,制造大鼠NSAIDs相关性小肠损伤模型;而雷贝拉唑处理组在每次造模前0.5 h予以15 mg/(kg.d)雷贝拉唑灌胃处理,连续4 d。处死大鼠进行大体及病理观察小肠损伤情况,采用免疫组织化学和Western blot方法检测小肠组织中Occludin和磷酸化ERK(p-ERK)蛋白表达水平的变化。结果雷贝拉唑处理组大鼠大体和病理损伤均低于损伤组(P<0.05)。Occludin蛋白在损伤组中表达较对照组明显下降(P<0.05),而在雷贝拉唑处理组中的表达较损伤组上升(P<0.05);与阴性对照组相比,p-ERK蛋白在损伤组中表达上升(P<0.05),在雷贝拉唑处理组中的表达较损伤组下降(P<0.05)。结论雷贝拉唑对大鼠NSAIDs相关性损伤有保护作用,其机制可能是通过MAPK中的ERK途径,增加小肠上皮组织中Occludin蛋白表达,从而增强肠黏膜屏障功能。     

Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries in healthy subjects: a prospective,randomized, double-blinded,placebo-controlled,cross-over study

Background Although obscure gastrointestinal bleeding cannot be detected by colonoscopy or upper endoscopy, wireless video capsule endoscopy (VCE) is capable of imaging it. Few data are available on medical therapy for patients with nonsteroidal anti-inflammatory drug (NSAID)-induced small-intestinal mucosal injuries. The aim of this study was to compare prevention by rebamipide and placebo of NSAID-induced smallintestinal injury in healthy subjects. Methods Ten healthy subjects who provided written informed consent were enrolled. Rebamipide or placebo plus diclofenac was administered with omeprazole for 7 days, and for an additional 7-day period with treatments reversed in the same subjects, with a 4-week washout period between treatments. VCE of the small intestine was performed four times, before and after each of the two study periods. Results The number of subjects with small-intestinal mucosal injuries was higher in the placebo group (8/10) than in the rebamipide group (2/10) (P = 0.023). Two cases of ulcer and one of bleeding were observed in the placebo group, while no ulcer or bleeding was observed in the rebamipide group. Conclusions Rebamipide had significantly higher efficacy than placebo in preventing NSAID-induced small-intestinal mucosal injury.     

Rebamipide, an Antiulcer Drug, Prevents DSS-Induced Colitis Formation in Rats

This study was conducted to investigate the efficacy of rebamipide against experimental colitis induced by dextran sulfate sodium (DSS) in a rat model of inflammatory bowel disease. Experimental colitis was induced in male Wistar rats by oral administration of 3% DSS solution for one week. The rats were provided with standard diet containing 0.105% rebamipide (160 mg/kg/day) for 1 week. In rats treated with rebamipide, clinical (body weight loss, bloody diarrhea, reduced physical activity, severe anemia, shortened colonic length, and perianal injury) and histopathological (pathological lesion score) findings of DSS colitis were significantly less than in rats with DSS colitis not treated with rebamipide. Rebamipide thus inhibited the induction of colitis. Rebamipide significantly reduced concentrations of both interleukin-1 and GRO/CINC-1 (IL-8-like substance) and cell infiltrates in colonic wall, in parallel with decreased activity of myeloperoxidase. It also reduced expression of IL-1 mRNA but did not influence expression of GRO/CINC-1 mRNA. The attenuation of colonic indices of colitis by rebamipide in this rat model suggests that this drug might have beneficial effects in the treatment of human ulcerative colitis. These effects of rebamipide are attributable to its inhibition of inflammatory cytokine-mediated granulocyte (neutrophil) infiltration into the colon.     

Effect of Rebamipide on Quality of Peptic Ulcer Healing in Rat

The aim of this study is to elucidate the effects and the mechanism of rebamipide, omeprazole, and their combination treatment on quality of peptic ulcer healing (QOUH). Peptic ulcer models were induced by acetic acid exposure of the serosa of rat stomach. Forty Sprague-Dawley (SD) rats were divided randomly into four groups of ten rats each. Saline 2 ml/d (group 1), rebamipide 60 mg/kg/d (group 2), omeprazole 10 mg/kg/d (group 3) as well as its combination regimen (group 4) were administrated for 7 days. After sacrifice, size of the ulcer and focal layer structures were measured in vitro by miniature ultrasonic probe, and the mucosal sections were stained with hematoxylin and eosin (HE) for histological examination; the levels of interleukin (IL)-8/prostaglandin E₂ (PGE₂) were evaluated by enzyme-linked immunosorbent assay (ELISA) and malondialdehyde (MDA) level was evaluated by thiobarbituric acid (TBA) method. Macroscopically, compared with the control group, the maximal diameters of the ulcers in the medication groups were significantly reduced (P < 0.05), and the layer echo structures of gastric wall were partially rebuilt. Histologically, ulcer range and inflammatory infiltration were less severe compared with the control group. In addition, mucosal MDA and IL-8 levels were significantly decreased, while PGE₂ level was significantly increased in the medication groups. Between the two monotherapy groups, there was no statistical difference in terms of PGE₂ and MDA levels. However, PGE₂ level was significantly increased, while MDA and IL-8 levels were significantly decreased in the combination group. Rebamipide as well as omeprazole and the combination regimen may improve QOUH through increasing the level of PGE₂, decreasing the levels of IL-8 and MDA in gastric mucosa, and this may potentially result in reduced recurrence of ulcer; moreover, the combination regimen was identified as having more antiulcer effects than monotherapy.     

Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats

The concept that gastroprotection by agents such as mild irritants, antacids, or sucralfate is prostaglandin (PG)-mediated has been challenged recently. These agents do not reproducibly stimulate prostaglandin formation, and indomethacin does not effectively attenuate their protective potency. Rebamipide is a novel antiulcer compound. This study was designed to clarify whether eicosanoids contribute to the gastroprotective activity of the drug. In the rat stomach, rebamipide (100 and 500 mg/kg, intraperitoneally) slightly increased release of PGE₂, 6-keto-PGF₁ thromboxane B₂, and the metabolite 15-keto-13,14-dihydro-PGE₂ from mucosal fragments incubated ex vivo and significantly enhanced secretion of these products into the lumen, resulting in gastric juice eicosanoid levels exceeding those in controls several-fold. Mucosal formation of leukotriene (LT) C₄ was not affected by rebamipide. Rebamipide caused substantial protection against gastric damage produced by ethanol, which was antagonized by pretreatment with indomethacin (0.1–5 mg/kg, subcutaneously). The dose-response relationship of indomethacin for inhibition of prostaglandin formation and rebamipide-induced protection correlated well and 5 mg/kg indomethacin completely prevented the protective effect of rebamipide. The results indicate that: (1) in contrast to most other protective agents, protection by rebamipide involves the endogenous prostaglandin system; (2) the increase in prostaglandin formation results from stimulation of biosynthesis, and not inhibition of degradation; (3) gastroprotection by rebamipide occurs despite increased thromboxane formation and is not associated with reduced generation of LTC₄; and (4) determinations of gastric juice eicosanoids seem to be particularly useful to evaluate effects of agents increasing formation of cyclooxygenase products in the stomach.     

Prevention by Rebamipide of Acute Reflux Esophagitis in Rats

Proinflammatory factors, including neutrophil-derived oxygen free radicals and inflammatory cytokines, have recently been implicated in the pathogenesis of reflux esophagitis. Rebamipide has been widely used as an anti-ulcer agent. The aim of the present study was to assess the protective effect of rebamipide against acute reflux esophagitis in rats. Esophagitis was induced in rats by ligation at the limiting ridge and the lower portion of the duodenum. Vehicle or rebamipide were given as a single dose intraduodenally. Lesion index (LI), thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, mRNA and protein of tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were markedly increased; pretreatment with rebamipide, however, significantly reduced both macroscopic and microscopic injuries and increases in inflammatory mediators. The results of this study indicate that rebamipide protects against the occurrence of esophagitis and has highly promising potential as a new therapeutic agent for reflux esophagitis.     

Prevention by rebamipide of acute reflux esophagitis in rats

Proinflammatory factors, including neutrophil-derived oxygen free radicals and inflammatory cytokines, have recently been implicated in the pathogenesis of reflux esophagitis. Rebamipide has been widely used as an anti-ulcer agent. The aim of the present study was to assess the protective effect of rebamipide against acute reflux esophagitis in rats. Esophagitis was induced in rats by ligation at the limiting ridge and the lower portion of the duodenum. Vehicle or rebamipide were given as a single dose intraduodenally. Lesion index (LI), thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, mRNA and protein of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were markedly increased; pretreatment with rebamipide, however, significantly reduced both macroscopic and microscopic injuries and increases in inflammatory mediators. The results of this study indicate that rebamipide protects against the occurrence of esophagitis and has highly promising potential as a new therapeutic agent for reflux esophagitis.     

Rebamipide Reduces Delay in Gastric Ulcer Healing in Cyclooxygenase-2-Deficient Mice

Rebamipide is an antiulcer drug capable of various actions including the induction of cyclooxygenase-2 (COX-2). In this study, we investigated the effect of rebamipide on gastric ulcer healing in COX-2-deficient mice. Wild-type (N = 34) and COX-2-deficient mice (N = 28) with gastric ulcers were administered 30 mg/kg of rebamipide or the vehicle. Ulcerous tissues were subjected to measurements of ulcer size, immunohistochemical staining of CD31 (an endothelial cell marker), and mRNA levels. COX-2 deficiency delayed ulcer healing and inhibited angiogenesis and bFGF mRNA expression in the granulation tissue. In wild-type mice, rebamipide accelerated ulcer healing and increased COX-2 mRNA expression. In COX-2-deficient mice, rebamipide prevented delayed ulcer healing and reversed the inhibition in angiogenesis and bFGF mRNA expression. The effect of rebamipide on the enhancement of ulcer healing, angiogenesis, and induction of bFGF expression was more prominent in wild-type mice than in COX-2-deficient mice. In conclusion, rebamipide may accelerate gastric ulcer healing through both COX-2-dependent and COX-2-independent mechanisms.