Rebamipide reduces indomethacin-induced gastric injury in mice via down-regulation of ICAM-1 expression

Non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric mucosal injury occurs through subsequent events following free radical production derived from activated neutrophils. In this study, we hypothesized that rebamipide, a novel anti-ulcer agent, exerts a protective effect on NSAID-induced gastric injury through its antioxidant properties. The protective effect of rebamipide in a mouse model of indomethacin-induced gastric injury and mechanisms for this effect were investigated. Pre-treatment with rebamipide significantly inhibited indomethacin-induced gastric mucosal injury in mice. Gastric thiobarbituric acid reactive substances (TBARS) levels and myeloperoxidase (MPO) activity substantially increased 3 hr after indomethacin administration. These increases were significantly inhibited by pre-treatment with rebamipide. Furthermore, rebamipide pre-treatment notably decreased intercellular adhesion molecule-1 (ICAM-1) expression that was up-regulated in gastric tissue treated with indomethacin. Therefore, rebamipide may reduce indomethacin-induced gastric mucosal injuries through its antioxidant effect, which inhibits the neutrophil activation step following up-regulation of ICAM-1 expression on endothelial cells.     

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.     

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.     

Protective effect of Irsogladine on monochloramineinduced gastric mucosallesions in rats:a comparative study with rebamipide

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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.     

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.     

Reactive oxygen species-quenching and anti-apoptotic effect of polaprezinc on indomethacin-induced small intestinal epithelial cell injury

Background

To protect the small intestine from mucosal injury induced by nonsteroidal anti-inflammatory drugs is one of the critical issues in the field of gastroenterology. Polaprezinc (PZ), a gastric muco-protecting agent, has been widely used for the treatment of gastric ulcer and gastritis for its unique effects, such as its strong reactive oxygen species (ROS)-quenching effect. The aim of this study was to clarify the mechanism by which indomethacin-induced small intestinal mucosal injury occurs, by using a rat intestinal epithelial cell line (RIE-1). In addition, the protective role of PZ and the possible mechanism of its effect on indomethacin-induced small intestinal injury were investigated.

Methods

Cell death was evaluated by methyl thiazolyl tetrazolium (MTT) assay and a double-staining method with Hoechst33342 dye and propidium iodide. Indomethacin-induced ROS production was evaluated by detecting the oxidation of a redox-sensitive fluorogenic probe, RedoxSensor, and the oxidation of cysteine residues of proteins (protein S oxidation). The activation of cytochrome c, smac/DIABLO, and caspase-3 was assessed by western blotting. In some experiments, PZ or its components, l-carnosine and zinc, were used.

Results

We found that indomethacin caused apoptosis in RIE-1 cells in a dose- and time-dependent manner. Indomethacin also induced ROS production and an increase in the protein S oxidation of RIE-1. Pretreatment of RIE-1 with PZ or zinc sulfate, but not l-carnosine, significantly reduced the indomethacin-induced apoptosis. PZ prevented ROS production and the increase in protein S-oxidation. PZ inhibited indomethacin-induced cytochrome c and smac/DIABLO release and subsequent caspase-3 activation.

Conclusions

The protective effect of PZ on indomethacin-induced small intestinal injury may be dependent on its ROS-quenching effect.     

Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants.

The effect of rebamipide, a novel antiulcer compound, on Helicobacter pylori activated neutrophil dependent in vitro gastric epithelial cell injury was investigated. Luminol dependent chemiluminescence (ChL), which detects toxic oxidants from neutrophils exhibited a 12-fold increase when the bacterial suspension of H pylori was added to the isolated human neutrophils. This change was significantly attenuated by rebamipide at a concentration less than 1 mM, showing that rebamipide may inhibit oxidant production from H pylori elicited neutrophils. To assess whether rebamipide attenuates gastric mucosal injury, we tested its inhibitory action on H pylori induced gastric mucosal damage associated with neutrophils in vitro. Rabbit gastric mucosal cells were monolayered in culture wells and coincubated with human neutrophils and H pylori, and the cytotoxicity index was then calculated. Cultured gastric cells were significantly damaged when they were incubated with human neutrophils activated by H pylori. This cellular damage was attenuated by rebamipide in a dose-dependent manner. Furthermore, spectrophotometrical measurement showed that rebamipide (1 mM) inhibits urease activity by 21.7%. As monochloramine (an oxidant yielded by reaction of neutrophil derived chlorinated oxidant and ammonia) is proposed as an important toxic molecule in this model, the current findings suggest that the preventive effect of rebamipide on H pylori elicited neutrophil induced gastric mucosal injury may result from its inhibitory actions on the neutrophilic oxidative burst as well as H pylori derived urease activity.     

Effects of Rebamipide, a Novel Anti-Ulcer Agent, on Gastric Mucosal Injury Induced by Platelet-Activating Factor in Rats

We examined the role of gastric mucosal bloodflow, lipid peroxidation, and neutrophil accumulationmediated by platelet-activating factor in the protectiveeffect of rebamipide against gastric mucosal injury in rats. The intravenous injection ofplatelet-activating factor induced hyperemia andhemorrhagic erosions in rat stomachs. Rebamipide did notaffect the decrease in the gastric mucosal blood flow induced by platelet-activating factor. Theincrease in gastric injury score afterplatelet-activating factor injection and the increase inthiobarbituric acid-reactive substances weresignificantly inhibited by the administration of rebamipide. Thegastric injury score was closely correlated with theaccumulation of lipid peroxides. Tissue-associatedmyeloperoxidase activity in the gastric mucosasignificantly increased after platelet activating factorinjection; this increase was not influenced byrebamipide treatment. The protective effect ofrebamipide against the platelet-activitingfactor-induced gastric mucosal injury may be due to direct inhibitionof lipid peroxidation or scavenging of oxygen radicalsthat initiate lipid peroxidation.     

吲哚美辛胃损伤中内皮素、一氧化氮、氧自由基的作用及其与胃动力的关系

目的 :研究吲哚美辛胃损伤中内皮素 (ET)、一氧化氮 (NO)、氧自由基的作用 ,以及胃动力对这种损伤的影响。方法 :雄性DS大鼠随机分 4组 :对照组、吲哚美辛 5mg/kg组、吲哚美辛 2 5mg/kg组、阿托品组 (阿托品 1mg/kg +吲哚美辛 2 5mg/kg)。吲哚美辛灌胃 ,灌胃前 10min阿托品皮下注射。取动脉血测ET、NO、丙二醛 (MDA)、超氧化物歧化酶 (SOD)、谷胱甘肽过氧化物酶 (GSH Px)水平 ,进行胃形态学观察。结果 :5mg/kg吲哚美辛不引起胃粘膜损伤 ,各检测指标与对照组无差异 ;2 5mg/kg吲哚美辛可引起胃粘膜显著出血性损伤 ,损伤指数为 38 5 7± 12 4 7,病理损伤积分为13 36± 3 37;ET 1和MDA水平升高 (P <0 0 1) ,NO、SOD、GSH Px水平降低 (P <0 0 1,P <0 0 1,P <0 0 5 ) ;阿托品组粘膜损伤较轻 ,损伤指数为 8 71± 3 35 ,病理损伤积分为 3 77± 1 0 4,ET 1含量和对照组无差异 ,MDA水平升高 (P <0 0 5 ) ,NO、SOD含量有所下降 (P <0 0 5 ) ,GSH Px含量无变化。结论 :吲哚美辛所致胃粘膜损伤中 ,ET 1和MDA生成增加起损害作用 ,内源性NO、SOD和GSH Px可清除氧自由基 ,有保护作用 ;阿托品对吲哚美辛所致胃粘膜损伤的保护作用 ,提示胃动力增加在吲哚美辛致溃疡中有重要作用。     

Attenuation of indomethacin-induced gastric mucosal injury by prophylactic administration of sake yeast-derived thioredoxin

Background

Indomethacin is one of the group of nonsteroidal anti-inflammatory drugs, which often cause gastric mucosal injury as a side effect. Infiltration and activation of inflammatory cells, production of proinflammatory cytokines and chemokines, generation of reactive oxygen species, and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric injury. We examined whether sake yeast-derived thioredoxin (a small redox-active protein with anti-oxidative activity and various redox-regulating functions) reduced indomethacin-induced gastric injury.

Methods

Gastric injury was produced by the intraperitoneal administration of indomethacin (40?mg/kg body weight) to C57BL/6 mice. Prior to the administration of indomethacin, the mice were offered food pellets containing non-genetically modified sake yeast-derived thioredoxin (thioredoxin 200?μg/g) for 3?days. Histological examinations, assessment of myeloperoxidase activity, and analysis of the gene expressions of proinflammatory cytokines and a chemokine (interleukin [IL]-1β, IL-6, and CXCL1) were statistically evaluated. Indomethacin cytotoxicity was determined by lactate dehydrogenase release from murine gastric epithelial GSM06 cells induced by 24-h treatment with 200 and 400?μM indomethacin after 1-h preincubation with 100?μg/ml sake yeast-derived thioredoxin.

Results

Macroscopic (edema, hemorrhage, and ulcers) and histological (necrosis, submucosal edema, neutrophil infiltration) findings induced by indomethacin were significantly reduced by pretreatment with food pellets containing thioredoxin. Gastric myeloperoxidase activity and the gene expressions of proinflammatory cytokines (IL-1β and IL-6) were also significantly reduced by this pretreatment compared with findings in the mice not pretreated with thioredoxin-containing food pellets. The administration of sake yeast-derived thioredoxin significantly reduced indomethacin-induced cytotoxicity in GSM06 cells.

Conclusions

We conclude that oral administration of sake yeast-derived thioredoxin reduces indomethacin-induced gastric injury. Sake yeast-derived thioredoxin may have therapeutic potential against indomethacin-induced gastric injury.     

Protective effect of melatonin on indomethacin-induced gastric injury in rats

The gastric injury associated with nonsteroidal anti-inflammatory drug (NSAID) therapy has been linked to the detrimental effects of the agents on the processes of prostaglandin synthesis, neutrophil (PMN) activation. and oxygen free radical generation. In the present study, we investigated the in vivo protective effects of melatonin on indomethacin-induced gastric lesions in the rat. Peroxidation of lipids and changes in the activities of related enzymes such as glutathione peroxidase (GSH-px) and myeloperoxidase (MPO), as a marker of PMNs infiltration, were also studied. Intraperitoneal (i.p.) injection of melatonin (0.25. 0.5, 1 mg kg(-1)) 30 min before indomethacin administration prevented gastric injury. The mean ulcer indices significantly (P < 0.05) decreased. Thiobarbituric acid (TBA) reactive substances in the gastric mucosa as an index of peroxidation, was increased after indomethacin administration and this increase was inhibited by melatonin. In addition, pretreatment with melatonin resulted in a significant increase of the enzymatic GSH-px activity up to the control levels; however, inhibition of ulceration by melatonin was not associated with a significant reduction in PMN infiltration. These results suggest that the protection afforded by the pineal hormone against indomethacin-induced gastric injury may be, in addition to other possible mechanisms, to its radical scavenging activity.     

Ketotifen—Old Drug,New Indication:Reduction of Gastric Mucosal Injury

The objective of the present study was to determine the efficacy of ketotifen (Zaditen®), an effective antiasthmatic drug, in preventing indomethacin-induced gastroduodenal mucosal injury in a two-arm prospective, randomized, double-blind, controlled and open study. Thirty healthy volunteers with endoscopic normal-appearing mucosa were randomly treated, double-blindly, for 1 week with either placebo or ketotifen, 2mg twice daily. On day 7 indomethacin, 50 mg three times daily, was added. Two subjects, one from each group, were withdrawn from the study owing to non-compliance. Ten additional subjects received ketotifen, 2 mg twice daily, 24 h before indomethacin administration, in an open manner. A second endoscopy was performed 24 h after indomethacin was initiated. Mucosal damage in the stomach and duodenum (hemorrhages, erosions, ulcers) was scored in accordance with Lanza et al. or counted numerically. Adverse reactions were documented. Ketotifen reduced indomethacin-induced gastric mucosal damage, reducing the mean gastric lesion score from 2.85 ± 0.20 in the placebo-treated group to 1.86 ± 0.36 and in the subjects pretreated with ketotifen for 7 days. Ketotifen protected (lesion score ≤1) 6 of 14 subjects pretreated for 7 days, whereas none of the 14 placebo-treated subjects were protected. Ketotifen had no statistically significant protective effects in the duodenum. In the open study lesion scores of patients pretreated with ketotifen for 24 h were similar to those pretreated for 7 days. Ketotifen is effective in the reduction of indomethacin-induced acute gastric mucosal injury. Further studies are required to verify these data in a more relevant clinical setting.     

Role of prostaglandins and histamine in hyperemic response to superficial and deep gastric mucosal injury and H+ back-diffusion in cats

This study was undertaken to examine the role of prostaglandins and histamine in the hyperemic response to gastric mucosal damage followed by H⁺ back-diffusion. Cat stomachs were exposed to 2 mol/liter NaCl for 10 min followed by luminal perfusion at pH 1. Hypertonic saline caused extensive (microscopic) damage to the surface epithelium, increased gastric mucosal blood flow, and increased release of histamine, PGE₂, and 6-keto PGF_1α (prostacyclin) into portal venous blood. The effect of indomethacin and histamine blockers (H₁+H₂) on the hyperemic response to acid back-diffusion was related to the depth of the mucosal injury and the region of the stomach. In the corpus, indomethacin enhanced mucosal injury. In areas with superficial damage, the hyperemia was inhibited by indomethacin and antihistamines and eliminated by the combination of both. In corpus areas with indomethacin-induced deep lesions, the blood flow was very high, and this hyperemia was partly inhibited by antihistamines. In the antrum the hyperemic response was reduced by antihistamines. Indomethacin increased the release of histamine into the portal venous blood (baseline recordings) and reduced basal gastric mucosal blood flow.     

胃黏膜保护剂及抑酸剂对乙醇性胃黏膜损伤的预防研究

目的探讨胃黏膜保护剂—铝碳酸镁、瑞巴派特、H：受体拮抗剂,单种及联合用药对乙醇所致急性胃黏膜损伤的保护作用。方法将70只大鼠随机分为7组：正常对照组,损伤对照组,铝碳酸镁组,瑞巴派特组,法莫替丁组,铝碳酸镁＋法莫替丁组,瑞巴派特＋法莫替丁组,每组10只。预先给予以上药物,采用白酒诱发大鼠胃黏膜急性损伤的方法造模。比较各组损伤指数（UI）并观察胃黏膜的病理学改变。结果（1）损伤对照组大鼠胃黏膜损伤最严重,UI明显高于其他6组,差异具有统计学意义（P〈0.05）;后5组的UI均低于损伤对照组,但高于正常对照组,差异有统计学意义（P〈0.05）;后5组中,铝碳酸镁组,瑞巴派特组,法莫替丁组UI均高于铝碳酸镁＋法莫替丁联合用药组,瑞巴派特＋法莫替丁联合用药组,组间差异具有统计学意义（P〈0.05）。（2）胃黏膜HE染色镜下观,损伤对照组绝大部分为Ⅲ-Ⅳ级损伤。铝碳酸镁组,瑞巴派特组,法莫替丁组绝大部分为I-Ⅱ级的损伤,与损伤对照组相比有统计学意义（P〈0.05）。联合用药组绝大部分损伤仅为I级,无Ⅲ级以上的损伤,与损伤对照组及单种用药组相比有统计学意义（P〈0.05）。结论铝碳酸镁、瑞巴派特、法莫替丁单种用药均能预防乙醇导致的急性胃黏膜损伤;胃黏膜保护剂与抑酸剂联合用药的预防作用优于单种用药。     

Laparotomy stimulates an endogenous gastric mucosal protective mechanism in the rat. A microcirculatory and morphologic study of ethanol injury

In vivo microscopy in the anesthetized rat unexpectedly revealed that the topical application of 75% ethanol to the gastric mucosa had no effect on the mucosal microcirculation. If, however, the synthesis of endogenous prostaglandin was inhibited by indomethacin, the topical application of 75% ethanol resulted in complete superficial mucosal microcirculatory stasis in the majority of rats. In indomethacin-pretreated rats, Rioprostil, a synthetic prostaglandin E1 analogue, reversed this effect of topical ethanol. The degree of ethanol-induced histologic gastric mucosal damage was inversely correlated with time to complete stasis. Ethanol injury studies under various conditions revealed that laparotomy stimulated a gastric protective mechanism that persisted for between 1 and 2 h and that was blocked by indomethacin. In conclusion, (a) laparotomy stimulates a gastric mucosal protective mechanism that probably is mediated by prostaglandin synthesis, and (b) cessation of mucosal blood flow appears to be an important early step in ethanol-induced gastric mucosal injury, and maintenance of mucosal blood flow by endogenous or exogenous prostaglandin may play a major role in prostaglandin protection.     

Preventive Effects of Rebamipide on NSAID-Induced Gastric Mucosal Injury and Reduction of Gastric Mucosal Blood Flow in Healthy Volunteers

The precise mechanisms of acute damage and the role of gastric mucosal blood flow in gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) remain uncertain. The aim of this study was to evaluate the preventive effect of rebamipide on gastric mucosal injury and reduction of gastric mucosal blood flow (GMBF) after ibuprofen administration. Twenty healthy volunteers were randomized two groups. The rebamipide group took ibuprofen, 1800 mg/day, and rebamipide, 100 mg t.i.d., for 7 days. The placebo group took ibuprofen, 1800 mg/day. The numbers of gastric ulcer subjects were three in the placebo group and zero in the rebamipide group. The mean modified Lanza score after ibuprofen administration was significantly higher in the placebo group than the rebamipide group (2.9±1.7 vs. 1.3±1.0, respectively; P=0.032). The GMBF of the placebo group was significantly decreased at antrum from baseline, from 2.8±0.5 to 2.0±0.5 tissue perfusion units (P=0.005). There was no difference in GMBF change in the rebamipide group. Gastric mucosal injury was correlated with GMBF reduction in antrum (r=−0.677, P=0.001). In conclusion, it is suggested that the decrease in GMBF may have been associated with NSAID-induced gastric mucosal injury, and rebamipide may have prevented NSIAD-induced gastric mucosal injury by maintaining GMBF in healthy subjects.