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Lee JS, Jeon SW, Lee HS, Kwon YH, Nam SY, Bae HI, Seo AN. Rebamipide for the Improvement of Gastric Atrophy and Intestinal Metaplasia: A Prospective, Randomized, Pilot Study. Dig Dis Sci 2022; 67:2395-2402. [PMID: 34052947 DOI: 10.1007/s10620-021-07038-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 05/05/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND The presence of atrophic gastritis (AG) and intestinal metaplasia (IM) is associated with an increased risk of gastric cancer (GC). Thus, the development of new strategies to improve AG/IM is essential for reducing the incidence of GC. AIMS We aimed to evaluate the efficacy of rebamipide for improving AG/IM. METHODS This was a prospective, randomized, pilot study from a single tertiary referral center. Fifty-three (rebamipide, n = 34 vs. placebo, n = 19) patients, who underwent endoscopic resection for gastric dysplasia or early GC, were analyzed. We obtained tissue samples from the antrum and corpus of the stomach, at the time of screening and 1-year later. The histologic grading of inflammation was performed by histopathologists RESULTS: The AG grade in the antrum improved significantly after rebamipide treatment (pre-administration, 1.870 ± 0.932 vs. post-administration, 1.430 ± 0.986; P = 0.013). Additionally, the severity of IM in the antrum was significantly improved (pre-administration, 1.750 ± 0.963 vs. post-administration, 1.370 ± 1.032; P = 0.038). The rebamipide subgroup analysis revealed that patients with no Helicobacter pylori (HP) infection showed significant improvements in AG in the antrum (pre-administration, 1.880 ± 1.040 vs. post-administration, 1.250 ± 0.894; P = 0.028) and IM in antrum (pre-administration, 1.840 ± 1.012 vs. post-administration, 1.180 ± 0.912; P = 0.020). CONCLUSIONS This study demonstrated that the administration of rebamipide improves AG and IM in the antrum, especially in patients with HP non-infection (KCT0001915).
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Affiliation(s)
- Joon Seop Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 807 Hokuk-ro, Buk-gu, Daegu, 41404, South Korea
| | - Seong Woo Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 807 Hokuk-ro, Buk-gu, Daegu, 41404, South Korea.
| | - Hyun Seok Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 807 Hokuk-ro, Buk-gu, Daegu, 41404, South Korea
| | - Yong Hwan Kwon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 807 Hokuk-ro, Buk-gu, Daegu, 41404, South Korea
| | - Su Youn Nam
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 807 Hokuk-ro, Buk-gu, Daegu, 41404, South Korea
| | - Han Ik Bae
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, South Korea
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Rebamipide attenuates alcohol-induced gastric epithelial cell injury by inhibiting endoplasmic reticulum stress and activating autophagy-related proteins. Eur J Pharmacol 2022; 922:174891. [PMID: 35288192 DOI: 10.1016/j.ejphar.2022.174891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 11/22/2022]
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Hydrogel Formulations Incorporating Drug Nanocrystals Enhance the Therapeutic Effect of Rebamipide in a Hamster Model for Oral Mucositis. Pharmaceutics 2020; 12:pharmaceutics12060532. [PMID: 32527029 PMCID: PMC7356607 DOI: 10.3390/pharmaceutics12060532] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/07/2020] [Accepted: 06/08/2020] [Indexed: 12/20/2022] Open
Abstract
A mouthwash formulation of rebamipide (REB) is commonly used to treat oral mucositis; however, this formulation does not provide sufficient treatment or prevention in cases of serious oral mucositis. To improve treatment, we attempted to design a hydrogel incorporating REB nanocrystals (R-NPs gel). The R-NPs gel was prepared by a bead mill method using carbopol hydrogel, methylcellulose and 2-hydroxypropyl-β-cyclodextrin, and another hydrogel incorporating REB microcrystals (R-MPs gel) was prepared following the same protocol but without the bead mill treatment. The REB particle size in the R-MPs gel was 0.15–25 μm, and while the REB particle size was 50–180 nm in the R-NPs gel. Next, we investigated the therapeutic effect of REB nanocrystals on oral mucositis using a hamster model. Almost all of the REB was released as drug nanocrystals from the R-NPs gel, and the REB content in the cheek pouch of hamsters treated with R-NPs gel was significantly higher than that of hamsters treated with R-MPs gel. Further, treatment with REB hydrogels enhanced the healing of oral wounds in the hamsters. REB accumulation in the cheek pouch of hamsters treated with the R-NPs gel was prevented by an inhibitor of clathrin-dependent endocytosis (CME) (40 μM dynasore). In conclusion, we designed an R-NPs gel and found that REB nanocrystals are taken up by tissues through CME, where they provide a persistent effect resulting in an enhancement of oral wound healing.
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The Effect of Rebamipide Ophthalmic Solution on Cytokine and Mucin Secretion in Culture of Conjunctival Epithelial Cells From the Cu, Zn-Superoxide Dismutase-1 (SOD-1) Knock-Down Mouse. Eye Contact Lens 2019; 45:93-98. [PMID: 30365413 DOI: 10.1097/icl.0000000000000558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To evaluate the in vitro effects of 1-mM rebamipide ophthalmic solution on the expression of inflammatory cytokines and MUC5AC in Cu, Zn-superoxide dismutase-1 (SOD-1) knock-down conjunctival epithelium. METHODS Conjunctival epithelium from C57BL/6 wild-type mice was cultured and treated with rebamipide ophthalmic solution. Using cytometric bead array, we examined the levels of interleukin-(IL)-6, IL-10, IL-17, monocyte chemoattractant protein-1, interferon-γ (INF-γ), tumor necrosis factor, and IL-12p70 in the culture supernatants. The culture supernatants were obtained from the culture medium of nontreated or SOD-1 knock-down conjunctival epithelium using small interfering RNA (siRNA). In addition, ELISA was performed to ascertain the MUC5AC concentration in the culture medium. RESULTS After rebamipide ophthalmic solution was applied, IL-6 concentration in the supernatants of conjunctival epithelial cells treated with and without siRNA showed a significant timewise decrease from 0 to 24 hr (963±42 to 0.07±0.05 pg/mL and 932±168 to 2.2±0.05 pg/mL, respectively) (P<0.001). Compared with baseline values, MUC5AC concentrations significantly increased 24 hr after rebamipide application to the conjunctival cultures-both with and without SOD-1 siRNA treatment (P<0.05 in both cases). CONCLUSIONS Rebamipide seems to increase MUC5AC levels and suppress inflammation by decreasing IL-6 levels in mouse conjunctival epithelial cell cultures. SOD-1 siRNA-treated mouse conjunctival epithelial cell culture is a practical method for investigating changes in mucosa-associated mucins and proinflammatory cytokines in response to therapeutic interventions.
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Babu PK, Bodireddy MR, Puttaraju RC, Vagare D, Nimmakayala R, Surineni N, Gajula MR, Kumar P. Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation. Org Process Res Dev 2018. [DOI: 10.1021/acs.oprd.7b00382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Prashanth Kumar Babu
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Mohan Reddy Bodireddy
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Reshma Choudlu Puttaraju
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Dnyaneshwar Vagare
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Raghu Nimmakayala
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Naresh Surineni
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Madhusudana Rao Gajula
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
| | - Pramod Kumar
- Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India
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Takeuchi I, Kamiki Y, Makino K. Therapeutic efficacy of rebamipide-loaded PLGA nanoparticles coated with chitosan in a mouse model for oral mucositis induced by cancer chemotherapy. Colloids Surf B Biointerfaces 2018; 167:468-473. [PMID: 29723818 DOI: 10.1016/j.colsurfb.2018.04.047] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 04/23/2018] [Accepted: 04/24/2018] [Indexed: 12/31/2022]
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Tsubaki M, Takeda T, Asano RT, Matsuda T, Fujimoto SI, Itoh T, Imano M, Satou T, Nishida S. Rebamipide suppresses 5-fluorouracil-induced cell death via the activation of Akt/mTOR pathway and regulates the expression of Bcl-2 family proteins. Toxicol In Vitro 2018; 46:284-293. [PMID: 29054700 DOI: 10.1016/j.tiv.2017.10.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Revised: 09/12/2017] [Accepted: 10/16/2017] [Indexed: 02/08/2023]
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Tachibana T, Ogino M, Makino R, Khan MSI, Cline MA. Lipopolysaccharide reduces food passage rate from the crop by a prostaglandin-independent mechanism in chickens. Br Poult Sci 2016; 58:100-106. [PMID: 27871194 PMCID: PMC5359745 DOI: 10.1080/00071668.2016.1237768] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
1. We examined the effect of lipopolysaccharide (LPS), a component of Gram-negative bacteria, on food passage in the digestive tract of chickens (Gallus gallus) in order to clarify whether bacterial infection affects food passage in birds. 2. Food passage in the crop was significantly reduced by intraperitoneal (IP) injection of LPS while it did not affect the number of defecations, suggesting that LPS may affect food passage only in the upper digestive tract. 3. Similar to LPS, prostaglandin E2 (PGE2), one of the mediators of LPS, also reduced crop-emptying rate in chickens while it had no effect on the number of defecations. 4. Pretreatment with indomethacin, which is an inhibitor of cyclooxygenase (COX), a prostaglandin synthase, had no effect on LPS-induced inhibition of crop emptying. 5. IP injection of LPS did not affect the mRNA expression of COX2 in the upper digestive tract of chickens. 6. It is therefore likely that LPS and PGE2 reduced food passage rate in the crop by a prostaglandin-independent pathway in chickens.
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Affiliation(s)
- T Tachibana
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - M Ogino
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - R Makino
- a Department of Agrobiological Science, Faculty of Agriculture , Ehime University , Matsuyama , Japan
| | - M S I Khan
- b Department of Anatomy and Embryology , Ehime University Graduate School of Medicine , Toon , Japan
| | - M A Cline
- c Department of Animal and Poultry Sciences , Virginia Polytechnic Institute and State University , Blacksburg , VA , USA
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Effect of Rebamipide on the Premalignant Progression of Chronic Gastritis: A Randomized Controlled Study. Clin Drug Investig 2015; 35:665-73. [PMID: 26369655 DOI: 10.1007/s40261-015-0329-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Rebamipide does not interfere with the antitumor effect of radiotherapy or chemotherapy in human oral tumor-bearing nude mice. J Pharmacol Sci 2015; 129:18-25. [PMID: 26320673 DOI: 10.1016/j.jphs.2015.07.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 07/15/2015] [Accepted: 07/23/2015] [Indexed: 12/18/2022] Open
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Urocortin 2 blocks the suppression of gastric antral contractions induced by lipopolysaccharide in freely moving conscious rats. ACTA ACUST UNITED AC 2014; 190-191:12-7. [PMID: 24793550 DOI: 10.1016/j.regpep.2014.04.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2013] [Revised: 04/02/2014] [Accepted: 04/22/2014] [Indexed: 12/15/2022]
Abstract
Lipopolysaccharide (LPS) inhibits gastric antral contractions in conscious rats. Since LPS regulates corticotropin-releasing factor type 2 receptor (CRF2) expression in the rat stomach, and activation of peripheral CRF2 alters gastric motility, we tried to determine the role of peripheral CRF2 in the LPS-induced suppression of gastric antral contractions. Intraluminal gastric pressure waves were measured in freely moving conscious non-fasted rats using the perfused manometric method. We assessed the area under the manometric trace as the motor index (MI), and compared this result with those obtained 1h before and after intraperitoneal injection of drugs. LPS (0.2 mg/kg) significantly decreased MI. Indomethacin (10 mg/kg) itself did not alter MI but blocked this inhibitory action by LPS. Astressin 2-B (200 μg/kg), a selective CRF2 antagonist, modified neither the basal MI nor the action by LPS. Meanwhile, urocortin 2 (30 μg/kg), a selective CRF2 agonist, reversed the suppression by LPS without affecting the basal MI. This action by urocortin 2 was blocked by pretreatment with astressin 2-B. In conclusion, LPS inhibited gastric antral contractions possibly through a prostaglandin-dependent pathway. Peripheral CRF2 stimulation reversed this response by LPS.
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Wang J, Guo X, Ye C, Yu S, Zhang J, Song J, Cao Z, Wang J, Liu M, Dong W. Efficacy and safety of proton pump inhibitors (PPIs) plus rebamipide for endoscopic submucosal dissection-induced ulcers: a meta-analysis. Intern Med 2014; 53:1243-8. [PMID: 24930641 DOI: 10.2169/internalmedicine.53.2160] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE To compare the efficacy of proton pump inhibitors (PPIs) with rebamipide versus PPIs alone for the treatment of ulcers after endoscopic submucosal dissection (ESD). METHODS PubMed, Web of Science, Medline, Embase, the Cochrane Central Register of Controlled Trials and China Naitonal Knowledge Infrastructure were searched up to the end of October 2013 in order to identify all randomized controlled trials reporting the effects of PPIs plus rebamipide on healing ulcers after ESD. The outcome measurement was complete ulcer healing. RESULTS A total of six studies involving 724 patients were included. The pooled data suggested a significantly higher rate of ulcer healing after endoscopic therapy among patients treated with PPIs plus rebamipide than among those treated with PPIs alone [odds ratio (OR)=2.40, 95% confidence interval (CI): 1.68-3.44]. The subgroup analysis showed PPI plus rebamipide therapy to be more effective in healing ESD-induced ulcers than treatment with PPIs alone after both four (OR=2.22, 95%CI: 1.53-3.24) and eight weeks of treatment (OR=3.19, 95%CI: 1.22-8.31). In addition, the combination therapy was found to be significantly more effective than the use of PPIs alone for all ESD ulcers greater than 20 mm in size (OR=4.77, 95%CI: 2.22-10.26). There were no significant differences between the treatment groups with regard to ulcer location (low, middle or upper stomach) or the presence of absence of H. pylori infection. No serious adverse events were observed in either group. CONCLUSION The results of this meta-analysis suggest that treatment with PPIs plus rebamipide is superior to PPI monotherapy for healing ESD-induced ulcers over four weeks, particularly large ulcers. However, more well-designed trials are needed to confirm these findings.
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Affiliation(s)
- Jun Wang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, China
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Abstract
PURPOSE Membrane-associated mucins (MAMs) play important roles in barrier function and tear stability, and their expression on the ocular surface is altered in dry eye disease. Rebamipide is a mucin secretagogue that promotes the production of mucin-like glycoproteins in human corneal epithelial (HCE) cells. However, the expression of MAMs on the corneal epithelia (MUC1, MUC4, MUC16), which is induced by rebamipide, is poorly understood. In this study, we investigated the effect of rebamipide on the regulation of MAM expression in HCE cells. MATERIALS AND METHODS MUC16, Ki67 and PCNA expression levels in HCE cells isolated at confluence and at 24 hours after confluence were examined by Western blotting to assess cell proliferation. HCE cells isolated at 24 hours after confluence were cultured in medium supplemented with 1-10 µM rebamipide or 0.3-30 nM of epidermal growth factor (EGF). Real-time PCR (RT-PCR) and Western blot analysis of MAMs were performed to evaluate the effect of rebamipide. Western blot analysis of cells treated with an EGF receptor inhibitor (AG1478) or MEK1/2 inhibitor (U0126) was performed to reveal the relationship between EGF receptor activation and rebamipide-induced MAM expression. RESULTS HCE cells isolated at 24 hours after confluence had lower cell proliferation activity and increased MUC16 expression compared with cells isolated at confluence. RT-PCR and Western blot analysis revealed that rebamipide increased MAM gene expression for 2 hours and protein expression for 24 hours in HCE cells. EGF inhibitor treatment led to reduced levels of all three MAMs that are normally induced by rebamipide, whereas EGF induced the expression of all three MAMs. CONCLUSIONS We suggested that rebamipide increased MUC1, MUC4 and MUC16 expression levels through signals involved in EGF receptor activation in the human corneal epithelia. These data suggest that rebamipide may improve subjective symptoms of dry eye disease by upregulating MAM expression.
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Affiliation(s)
- Shinsaku Itoh
- Ako Research Institute, Otsuka Pharmaceutical Co, Ltd. , Hyogo , Japan
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Tsuchiya Y, Nozu T, Kumei S, Ohhira M, Okumura T. IL-1 receptor antagonist blocks the lipopolysaccharide-induced inhibition of gastric motility in freely moving conscious rats. Dig Dis Sci 2012; 57:2555-61. [PMID: 22610882 PMCID: PMC3458191 DOI: 10.1007/s10620-012-2210-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Accepted: 04/25/2012] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Endotoxin/lipopolysaccharide (LPS) alters gastrointestinal functions. However, little is known as to whether LPS could change gastric antral contractility in freely moving conscious animals. We tried to clarify this problem and the associated mechanisms. METHODS In this study, we recorded intraluminal gastric pressure waves in freely moving conscious rats by manometric catheter located in the antrum. Area under the manometric trace was evaluated as motor index (MI). RESULTS Intraperitoneal injection of LPS at doses of 0.2 mg/kg or more significantly inhibited MI. The inhibition started immediately after the administration of LPS and lasted over 1 h. Intraperitoneal injection of IL-1β potently decreased MI while neither IL-6 nor TNF-α inhibited gastric motility, suggesting IL-1β specifically reduced gastric motility. Next, we examined the hypothesis that endogenous IL-1 mediates the LPS-induced inhibition of gastric motility. To address the speculation, an IL-1 receptor antagonist (IL-1Ra) was used to block IL-1 signaling. Pretreatment with IL-1Ra at a dose of 20 mg/kg significantly blocked the inhibition of gastric contractility by LPS at a dose of 0.2 mg/kg. CONCLUSIONS These results suggest for the first time that LPS or IL-1β is capable of inhibiting gastric motility in conscious rats and that endogenously released IL-1 may mediate the LPS-evoked inhibition of gastric antral motility. This evidence also led us to speculate that IL-1Ra may be a therapeutic tool for patients with disturbed gastrointestinal functions under septic conditions.
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Affiliation(s)
- Yoshihiro Tsuchiya
- Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510 Japan
| | - Tsukasa Nozu
- Department of Regional Medicine and Education, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510 Japan
| | - Shima Kumei
- Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510 Japan
| | - Masumi Ohhira
- Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510 Japan
| | - Toshikatsu Okumura
- Department of General Medicine, Asahikawa Medical University, Midorigaoka Higashi 2-1-1, Asahikawa, 078-8510 Japan
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Park SH, Cho CS, Lee OY, Jun JB, Lin SR, Zhou LY, Yuan YZ, Li ZS, Hou XH, Zhao HC, Kachintorn U, Kositchaiwat C, Lertkupinit C. Comparison of Prevention of NSAID-Induced Gastrointestinal Complications by Rebamipide and Misoprostol: A Randomized, Multicenter, Controlled Trial-STORM STUDY. J Clin Biochem Nutr 2011; 40:148-55. [PMID: 18188417 PMCID: PMC2127224 DOI: 10.3164/jcbn.40.148] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2006] [Accepted: 11/07/2006] [Indexed: 12/13/2022] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects such as dyspepsia, peptic ulcer, hemorrhage, and perforation. Misoprostol and PPIs have been used to prevent NSAID-induced gastroduodenal injury. Rebamipide increases gastric mucus and stimulates the production of endogenous prostaglandins. The prophylactic effect of rebamipide on NSAID-induced gastrointestinal complications is unknown. The aim of this study was to compare NSAID-induced gastrointestinal complications in rebamipide- and misoprostol-treated groups. Patients were randomized to two groups and took a conventional NSAID plus rebamipide or misoprostol for 12 weeks. Gastric mucosal damage was evaluated by endoscopy at screening and the end of the study. The prevalences of active gastric ulcer were 7/176 (3.9%) in the rebamipide group and 3/156 (1.9%) in the misoprostol group. The prevalences of peptic ulcer were 8/176 (4.5%) in the rebamipide group and 7/156 (4.4%) in the misoprostol group. The cumulative incidences of peptic ulcer in the high-risk subgroup were 6/151 (4.0%) for rebamipide and 6/154 (3.9%) for misoprostol. In conclusion, rebamipide prevented NSAID-induced peptic ulcer as effectively as misoprostol in patients on long-term NSAID therapy. Rebamipide may be a useful therapeutic option for the prevention of NSAID-induced gastrointestinal ulcer because of its therapeutic effect and safety.
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Affiliation(s)
- Soo-Heon Park
- St. Mary’s Hospital, The Catholic University of Korea, Seoul 150-713, Korea
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Fujiwara S, Morita Y, Toyonaga T, Kawakami F, Itoh T, Yoshida M, Kutsumi H, Azuma T. A randomized controlled trial of rebamipide plus rabeprazole for the healing of artificial ulcers after endoscopic submucosal dissection. J Gastroenterol 2011; 46:595-602. [PMID: 21359522 DOI: 10.1007/s00535-011-0372-3] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2010] [Accepted: 01/10/2011] [Indexed: 02/06/2023]
Abstract
BACKGROUND Endoscopic submucosal dissection (ESD) is an increasingly common technique for the resection of early gastric cancers. Although 8 weeks of treatment with a proton pump inhibitor (PPI) reportedly heals most patients with ESD-derived artificial ulcers, it does not heal those with severe atrophic gastritis, for whom there is little data. This study examined whether healing rates of the latter especially were improved by the addition of the non-PPI mucosal healing agent rebamipide after ESD. METHODS Patients were randomly assigned to two treatment groups for 8 weeks following ESD: patients in the PPI group received daily rabeprazole alone (20 mg), whereas those in the combination group received daily rabeprazole (20 mg) and rebamipide (300 mg). At the primary endpoint (56 days after ESD) we determined the proportion of patients in whom ulcers had healed to scar-stage (S-stage, complete healing). A pre-specified subgroup analysis examined ulcer healing in patients with severe atrophic gastritis. RESULTS Overall, progression to S-stage occurred in 54.8% in the PPI group, and 86.7% in the combination group (odds ratio 5.3, 95% confidence interval 1.50-19.02, p = 0.006). Among those patients with severe atrophic gastritis, healing to S-stage occurred in 30.0% in the PPI group, and in 92.9% in the combination group (odds ratio 30.3, 95% confidence interval 2.63-348.91, p = 0.0023). CONCLUSION Treatment with a PPI plus rebamipide improved healing rates at 8 weeks for patients with ESD-derived artificial ulcer, and appeared to be particularly effective for patients with severe atrophic gastritis.
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Affiliation(s)
- Shoko Fujiwara
- Department of Gastroenterology, Kobe University, School of Medicine, Kobe, Japan
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Tanigawa T, Watanabe T, Ohkawa F, Nadatani Y, Otani K, Machida H, Okazaki H, Yamagami H, Watanabe K, Tominaga K, Fujiwara Y, Takeuchi K, Arakawa T. Rebamipide, a mucoprotective drug, inhibits NSAIDs-induced gastric mucosal injury: possible involvement of the downregulation of 15-hydroxyprostaglandin dehydrogenase. J Clin Biochem Nutr 2011; 48:149-53. [PMID: 21373268 PMCID: PMC3045688 DOI: 10.3164/jcbn.10-75] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Accepted: 07/26/2010] [Indexed: 01/12/2023] Open
Abstract
Prostaglandin E2 plays an important role in the maintenance of gastric mucosal integrity. The level of biologically active prostaglandin E2 in the tissue is regulated by the balanced expression of its synthetic enzymes, such as cyclooxygenase, and its catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase. We examined the effect of rebamipide, a mucoprotective drug, on prostaglandin E2 production and metabolism in the gastric tissue and its effect on indomethacin-induced gastric mucosal injury in mice. Rebamipide suppressed indomethacin-induced gastric mucosal injury. Suppressive effect of rebamipide on indomethacin-induced gastric mucosal injury was also observed in cyclooxygenase-2-knockout mice. The mice that were treated with rebamipide showed a 2-fold increase in cyclooxygenase-2 mRNA expression in the gastric tissue, whereas 15-hydroxyprostaglandin dehydrogenase mRNA expression markedly decreased as compared to vehicle-treated control mice. Rebamipide did not affect the expression of cyclooxygenase-1 in the gastric tissue. Rebamipide did not increase prostaglandin E2 production in the gastric tissue; however, it induced a 1.4-fold increase in the concentration of prostaglandin E2 in the gastric tissue as compared to vehicle-treated control mice. These results suggest that the suppressive effect of rebamipide on non-steroidal anti-inflammatory drugs-induced gastric mucosal injury can be attributed to reduced 15-hydroxyprostaglandin dehydrogenase expression, which increases the prostaglandin E2 concentration in the gastric tissue.
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Affiliation(s)
- Tetsuya Tanigawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka City, Osaka 545-8585, Japan
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18
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Management of recurrence of symptoms of gastroesophageal reflux disease: synergistic effect of rebamipide with 15 mg lansoprazole. Dig Dis Sci 2010; 55:3393-8. [PMID: 20198424 DOI: 10.1007/s10620-010-1166-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2009] [Accepted: 02/11/2010] [Indexed: 12/19/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are effective in healing reflux esophagitis and relieving the symptoms of gastroesophageal reflux disease (GERD). Prevention of recurrence of symptoms has become a therapeutic aim in patients with these conditions. AIMS We investigated the effects of rebamipide, a mucosal protective anti-ulcer agent, on recurrence of reflux symptoms during PPI maintenance therapy. METHODS Patients with esophagitis of Los Angeles classification A or B were treated with PPIs for 8 weeks. Patients with relief of symptoms were enrolled for further study. Forty-one patients were randomized to maintenance therapy with 15 mg of lansoprazole daily or 15 mg of lansoprazole and 300 mg rebamipide daily, and recurrence of symptoms was monitored over 12 months. In some patients, concentration of rebamipide and interleukin(IL)-8 expression in the esophageal mucosa were estimated. RESULTS During the 12-month period, 11/20 patients (52.4%) taking lansoprazole 15 mg daily suffered recurrence of symptoms, compared to 4/20 patients (20%) treated with lansoprazole 15 mg and rebamipide 300 mg daily (P < 0.05). Rebamipide was detected in the esophageal mucosa 90-180 min after oral administration. IL-8 mRNA expression in the esophageal mucosa of patients with rebamipide was significantly decreased compared with that of patients without rebamipide. CONCLUSIONS Combination therapy with rebamipide and lansoprazole appears to be highly effective in preventing recurrence of symptoms during long-term maintenance treatment for GERD.
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19
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Kato T, Araki H, Onogi F, Ibuka T, Sugiyama A, Tomita E, Nagaki M, Moriwaki H. Clinical trial: rebamipide promotes gastric ulcer healing by proton pump inhibitor after endoscopic submucosal dissection--a randomized controlled study. J Gastroenterol 2010; 45:285-90. [PMID: 19957195 DOI: 10.1007/s00535-009-0157-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2009] [Accepted: 10/22/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND Endoscopic submucosal dissection (ESD) is useful for treating gastric tumors. Several trials have shown the efficacy of 4 or 8 weeks of proton pump inhibitor (PPI) administration for post-ESD ulcers. However, if the size of the post-ESD ulcer is larger than predicted, PPI administration alone might not be sufficient for the ulcer to heal within 4 weeks. We examined the efficacy of a combination therapy of PPI and rebamipide, a mucosal-protective antiulcer drug, on the acceleration of post-ESD ulcer healing. METHODS Patients were randomly assigned to either the PPI and rebamipide therapy or the PPI alone. Sixty-two consecutive patients with gastric tumors gave informed consent for enrolling in the study. In all cases, the estimated size of the post-ESD ulcer was larger than 20 mm. Oral administration of the drug was started on the 2nd day post-ESD and continued to the 28th day. RESULTS All patients received the assigned pharmaceuticals and adhered well to the treatment regimen for 28 days. The endpoint ulcers reached S1 (scar stage) in 11/31 (36%) patients in the PPI-only group and in 21/31 (68%) in the combination group (P = 0.010). CONCLUSIONS The combination of PPI plus rebamipide was more effective than the PPI alone for treating ulcers larger than 20 mm within 4 weeks after ESD.
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Affiliation(s)
- Tomohiro Kato
- Department of Gastroenterology, Gifu University Hospital, Gifu, Japan.
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20
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Rodríguez JA, Theoduloz C, Sánchez M, Yáñez T, Razmilic I, Schmeda-Hirschmann G. Gastroprotective activity of a new semi-synthetic solidagenone derivative in mice. J Pharm Pharmacol 2010; 57:265-71. [PMID: 15720793 DOI: 10.1211/0022357055461] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Abstract
The gastroprotective activity of the new semi-synthetic solidagenone derivative 15,16-epoxy-8(9),13(16),14-labdatrien-7β-methoxy-6β-ol (ELMO) has been assessed on the model of HCl/EtOH-induced gastric lesions in mice. Human gastric epithelial cells (AGS) and fibroblasts (MRC-5) were used to determine its mode of action. The effect of ELMO on the prostaglandin E2 content, cellular reduced glutathione (GSH) and protection against damage induced by sodium taurocholate was assessed against AGS cells. The effect of ELMO on the growth of AGS and fibroblast cultures was evaluated. The superoxide anion scavenging capacity of the compound was studied also. The cytotoxicity of ELMO, expressed as cell viability, was assessed using two independent endpoints: neutral red uptake (NRU) and the reduction of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) for MRC-5 fibroblasts and NRU for AGS cells. A single oral dose of ELMO (10 and 20 mg kg−1) inhibited the appearance of gastric lesions in mice displaying similar values to lansoprazole at 20 mg kg−1. At 40 μm ELMO increased the prostaglandin E2 content but not GSH in AGS cells. The compound showed no effect on sodium taurocholate-induced damage and was devoid of superoxide anion scavenging activity. Concentrations of 0.5, 1, 2 and 4 μm stimulated fibroblast but not AGS cell proliferation. The compound showed weak cytotoxicity with values (IC50) of 411 (NRU) and 418 μm (MTT) for fibroblasts and 261 μm (NRU) for AGS cells. The results support further pharmacological study of this compound as a potential new anti-ulcerogenic drug.
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Affiliation(s)
- Jaime A Rodríguez
- Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Casilla 747, Talca, Chile.
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21
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Ogasawara N, Sasaki M, Hijikata Y, Masui R, Tanida S, Kanematsu T, Kamiya T, Kataoka H, Joh T, Kasugai K. Successful treatment for pouchitis with rebamipide refractory to a combination of metronidazole (MNZ) and ciprofloxacin (CFX). Clin J Gastroenterol 2009; 2:404-407. [PMID: 26192795 DOI: 10.1007/s12328-009-0115-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2009] [Accepted: 09/11/2009] [Indexed: 11/29/2022]
Abstract
A 35-year-old male who had undergone proctocolectomy and ileo-anal pouch surgery (IPAA) because of ulcerative colitis presented with worsening diarrhea and hematochezia. Pouchitis was diagnosed, and he was prescribed with metronidazole (MNZ) and a betamethasone enema. However, his condition did not remarkably improve despite these strategies. Endoscopy revealed ulceration and inflammation in the ileal pouch together with contact bleeding and mucous discharge. He underwent granulocytapheresis (G-CAP) and was prescribed anal 5-aminosalicylic acid (5-ASA) and oral prednisolone. Oral azathioprine (AZA) and a combination of MNZ and ciprofloxacin (CFX) did not result in any improvement. He was then treated with rebamipide enemas twice daily for 8 weeks without additional drug therapy. Two weeks thereafter, stool frequency started to decrease, fecal hemoglobin became negative, and his symptoms gradually improved. Endoscopic findings after the rebamipide therapy showed that the ulcers in the ileal pouch had mostly healed without obvious inflammation and bleeding. Rebamipide was thus maintained throughout the therapeutic period and for 13 months of follow-up. Rebamipide effectively treated severe pouchitis that was refractory to intensive conventional medication including antibiotics and corticosteroids.
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Affiliation(s)
- Naotaka Ogasawara
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi, 480-1195, Japan
| | - Makoto Sasaki
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi, 480-1195, Japan.
| | - Yasutaka Hijikata
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi, 480-1195, Japan
| | - Ryuta Masui
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi, 480-1195, Japan
| | - Satoshi Tanida
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takayoshi Kanematsu
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takeshi Kamiya
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Hiromi Kataoka
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Takashi Joh
- Departments of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Science, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Kunio Kasugai
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi, 480-1195, Japan
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22
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Suzuki T, Yoshida N, Nakabe N, Isozaki Y, Kajikawa H, Takagi T, Handa O, Kokura S, Ichikawa H, Naito Y, Matsui H, Yoshikawa T. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci 2008; 106:469-77. [PMID: 18360096 DOI: 10.1254/jphs.fp0071422] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and anti-inflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects.
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Affiliation(s)
- Takahiro Suzuki
- Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan
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23
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Symonds EL, Tran CD, Butler RN, Omari TI. Gastric emptying is altered with the presence of gastritis. Dig Dis Sci 2008; 53:636-41. [PMID: 17763957 DOI: 10.1007/s10620-007-9928-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Accepted: 07/09/2007] [Indexed: 12/09/2022]
Abstract
Helicobacter pylori infection and gastritis can cause symptoms suggestive of altered gastrointestinal function; however, it is unclear if H. pylori influences gastric motility. This study assessed gastric emptying rates in mouse models of gastritis. Gastritis was induced in C57BL/6 mice via ethanol treatment or via challenge with H. pylori or H. felis. Gastric emptying rates of nutrient and non-nutrient liquids were assessed with the non-invasive (13)C-breath test, and the results were compared to healthy mice. Gastric emptying of the non-nutrient liquid was unaltered with the presence of gastritis; however, gastric emptying of the nutrient liquid was accelerated after a 4-week infection with H. pylori. H. felis infection and ethanol treatment caused a more severe gastritis and disruptions to the normal gastric emptying. Changes to gastric emptying in mouse models of gastritis are associated with the presence of nutrients. Altered gastric emptying may contribute to symptoms commonly reported in humans with gastritis.
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Affiliation(s)
- Erin L Symonds
- Gastroenterology Unit, Children, Youth and Women's Health Service, North Adelaide 5006, South Australia.
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24
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Ríos JD, Shatos M, Urashima H, Tran H, Dartt DA. OPC-12759 increases proliferation of cultured rat conjunctival goblet cells. Cornea 2006; 25:573-81. [PMID: 16783146 DOI: 10.1097/01.ico.0000208819.24990.0d] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE To determine if the gastroprotective drug OPC-12759 increased proliferation of rat conjunctival goblet cells in culture. METHODS Cultured goblet cells were incubated with 10(-12) to 10(-8) M OPC-12759 for 1 to 7 days. Fetal bovine serum (FBS) was used as a positive control. Cell proliferation was determined by a MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] colorimetric assay and by immunohistochemical staining with anti-Ki-67, a marker of cell division. Goblet cells were identified by double-labeling with anti-Ki-67, a marker of cell division, and Ulex europaeus agglutinin I lectin, anti-MUC5AC and anticytokeratin 7. Stratified squamous cells were identified by using Griffonia (Bandeiraea) simplicifolia lectin and anticytokeratin 4 antibody. RESULTS As determined by MTT conversion to formazan, OPC-12579 at 10(-11) M induced an almost 2-fold increase in goblet cell proliferation on Days 1 and 3 of incubation but not on Days 5 and 7. The FBS at 10% increased cell proliferation by 2- to 3-fold at each time point. Daily replenishment of OPC-12579 for 3 consecutive days induced cell proliferation at all concentrations. Proliferation as determined by the number of Ki-67 positive cells increased by 4- and 3-fold at Days 1 and 3, respectively with addition of 10(-11) M OPC-12579. The FBS at 10% induced a 10-fold increase in goblet cell proliferation on Days 1, 3, and 5. Colocalization of Ulex europaeus agglutinin I, MUC5AC and anticytokeratin 7 with Ki-67 indicated that proliferating cells were goblet cells. Proliferating cells were negative for the nongoblet cell markers Bandeiraea lectin and anticytokeratin 4. CONCLUSIONS The OPC-12759 stimulates proliferation of conjunctival goblet cells in primary culture.
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Affiliation(s)
- José D Ríos
- Schepens Eye Research Institute, Harvard Medical School, Boston, MA 02114-2500, USA.
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25
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Martinez V, Wang L, Taché Y. Peripheral adrenomedullin inhibits gastric emptying through CGRP8-37 -sensitive receptors and prostaglandins pathways in rats. Peptides 2006; 27:1376-82. [PMID: 16337713 DOI: 10.1016/j.peptides.2005.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2005] [Revised: 11/04/2005] [Accepted: 11/04/2005] [Indexed: 11/24/2022]
Abstract
The effects of intravenous (iv) adrenomedullin (AM) on gastric emptying were investigated in conscious rats. AM induced a maximal 50% inhibition of gastric emptying at a dose of 1.2 nmol/kg. AM was about two-fold less potent than alpha-calcitonin gene-related peptide (alpha-CGRP), which induced a similar 50% maximal inhibition of gastric emptying at 0.6 nmol/kg. Delayed gastric emptying induced by i.v. AM and alpha-CGRP was prevented by peripheral injection of the selective CGRP1 antagonist, CGRP8-37, and by pretreatment with indomethacin, while not altered by blockade of the sympathetic nervous system with propranolol. These data indicate that peripheral AM inhibits gastric emptying through the interaction with CGRP8-37 -sensitive receptors, likely CGRP1 receptors, and the recruitment of prostaglandin-dependent mechanisms.
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Affiliation(s)
- V Martinez
- CURE: Digestive Diseases Research Center, Department of Medicine, David Geffen School of Medicine at UCLA, University of California Los Angeles and VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
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26
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Miyata M, Konagaya T, Kakumu S, Mori T. Successful treatment of severe pouchitis with rebamipide refractory to antibiotics and corticosteroids: A case report. World J Gastroenterol 2006; 12:656-8. [PMID: 16489687 PMCID: PMC4066106 DOI: 10.3748/wjg.v12.i4.656] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The antibiotics, metronidazole and ciprofloxacin, are the first-line treatment for pouchitis. Patients who do not respond to antibiotics or conventional medications represent a major challenge to therapy. In this report, we have described a successful treatment of severe refractory pouchitis with a novel agent, rebamipide, known to promote epithelial cell regeneration and angiogenesis. A 27-year-old male with ileo-anal pouch surgery presented with worsening anal pain, diarrhea, and abdominal pain. The patient was diagnosed to have pouchitis and was given metronidazole together with betamethasone enema (3.95 mg/dose). However, despite this intensive therapy, the patient did not improve. On endoscopy, ulceration and inflammation were seen in the ileal pouch together with contact bleeding and mucous discharge. The patient was treated with rebamipide enema (150 mg/dose) twice a day for 8 wk without additional drug therapy. Two weeks after the rebamipide therapy, stool frequency started to decrease and fecal hemoglobin became negative at the 4th wk. At the end of the therapy, endoscopy revealed that ulcers in the ileal pouch had healed with no obvious inflammation. The effect of rebamipide enema was dramatic and was maintained throughout the 11-mo follow-up. The patient continued to be in remission. No adverse effects were observed during the treatment or the follow-up period. The sustained response seen in this case with severe and refractory pouchitis indicates that agents, which promote epithelial cell growth, angiogenesis and mucosal tissue regeneration, are potential therapeutic agents for the treatment of refractory colorectal lesions.
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Affiliation(s)
- Mitsuki Miyata
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagokute-cho, Aichi 480-1195, Japan.
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27
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Makiyama K, Takeshima F, Hamamoto T. Efficacy of rebamipide enemas in active distal ulcerative colitis and proctitis: a prospective study report. Dig Dis Sci 2005; 50:2323-9. [PMID: 16416182 DOI: 10.1007/s10620-005-3055-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Accepted: 03/22/2005] [Indexed: 02/06/2023]
Abstract
Rebamipide has a broad spectrum of pharmacological actions that include suppression of neutrophil functions and stimulation of mucosal epithelial cell regeneration by increasing the expression of epithelial growth factor (EGF) and the EGF receptor. Sixteen patients with active ulcerative colitis (UC; mild in 1 patient, moderate in 11, and severe in 4) were recruited. Enemas containing 150 mg rebamipide per dosing were administered during the daytime after passage of stool, twice a day for 4 weeks. UC disease activity index (UC-DAI), endoscopic activity index (EAI), and Floren's grading (FG) of mucosal biopsy specimens were measured at entry and at 4 weeks. Five of 16 patients did not complete the study, and therefore, final efficacy assessment was done on 11 patients who completed the 4 weeks of treatment. Improvements were observed in UC-DAI (P = 0.0049), EAI (P = 0.0043), and FG (P = 0.0084). There was no serious rebamipide-related side effect in any of the 16 patients. In conclusion, rebamipide topical therapy appears to be effective for the treatment of mildly to moderately active distal UC. Further controlled studies are warranted for this promising drug.
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Affiliation(s)
- K Makiyama
- Department of Endoscopy, Nagasaki University Hospital of Medicine and Dentistry, Sakamoto, Nagasaki, Japan.
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28
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Miyata M, Kasugai K, Ishikawa T, Kakumu S, Onishi M, Mori T. Rebamipide enemas-new effective treatment for patients with corticosteroid dependent or resistant ulcerative colitis. Dig Dis Sci 2005; 50 Suppl 1:S119-23. [PMID: 16184413 DOI: 10.1007/s10620-005-2816-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Accepted: 06/06/2005] [Indexed: 12/11/2022]
Abstract
In this study we investigated the effect of rebamipide enema in patients with steroid-resistant and/or dependent ulcerative colitis. Rebamipide enemas were administered twice daily for a 12-week period; this treatment was further continued longer in patients who requested this. Disease activity index as reflecting the clinical condition and endoscopic index with histological grading were determined before and after the treatment period. Nine of 11 (81.8%) patients on 12-week treatment with rebamipide approved and were classified as colitis in remission. Moreover, seven of 11 patients requested long-term medication, the longest medication term being 80 weeks. These results medicated that rebamipide enemas may be effective in patients with steroid-resistant and/or dependent ulcerative colitis.
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Affiliation(s)
- Mitsuki Miyata
- Department of Gastroenterology, Aichi Medical University School of Medicine, Aichi-Gun, Aichi 480-1195, Japan. mmiyata@ aichi-med-u.ac.jp
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29
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Nakashima T, Maeda T, Nagamoto H, Kumakura T, Takai M, Mori T. Rebamipide enema is effective for treatment of experimental dextran sulfate sodium induced colitis in rats. Dig Dis Sci 2005; 50 Suppl 1:S124-31. [PMID: 16184415 DOI: 10.1007/s10620-005-2817-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2005] [Accepted: 06/06/2005] [Indexed: 12/13/2022]
Abstract
We investigated therapeutic efficacy of rebamipide using dextran sulfate sodium (DSS) induced colitis model in rats. Three percent DSS solution was given to rats for 9 days. After that, we evaluated the drug efficacy on colitis sustained with continuous drinking of 1% DSS. Twice-daily treatment with 0.3% or 1% rebamipide for 14 days significantly ameliorated the stool abnormality in the colitis model, preferentially suppressed hematochezia. The colonic mucosal lesion, determined by Alcian blue staining on day 24, was significantly reduced by rebamipide enema in a dose-dependent manner. Either rebamipide or 5-aminosalycilic acid (5-ASA) enema treated once daily significantly ameliorated colitis. The minimum effective dose of rebamipide was 0.3% in once-daily treatment, and that of 5-ASA was 10%. In a mechanistic study, the epithelial cell sheet formation of the T84 colon cancer cell was measured as an increase in generation of trans-epithelial electrical resistance in vitro. Rebamipide accelerated the increase, while 5-ASA conversely suppressed it. These results suggest that rebamipide enema is effective for treatment of experimental ulcerative colitis (UC).
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Affiliation(s)
- Takako Nakashima
- Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Co. Ltd., Tokushima 771-0192, Japan
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30
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Sakurai K, Osaka T, Yamasaki K. Rebamipide reduces recurrence of experimental gastric ulcers: role of free radicals and neutrophils. Dig Dis Sci 2005; 50 Suppl 1:S90-6. [PMID: 16184427 DOI: 10.1007/s10620-005-2812-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2005] [Accepted: 06/06/2005] [Indexed: 12/09/2022]
Abstract
Mucosal inflammation is a crucial factor for the recurrence of peptic ulcer. In this study, we examined the effect of rebamipide on neutrophils infiltration, lipid peroxidation, and antioxidative enzyme activities in the recurrence of experimental gastric ulcer. Ulcer recurrence was examined at 60, 100, and 140 days after production of acetic acid-induced gastric ulcers in rats. Gastric neutrophil infiltration, lipid peroxidation, and antioxidative enzyme activities were determined by analyses of myeloperoxidase (MPO) activity, thiobarbituric acid reactive substance (TBARS) levels, and glutathione peroxidase (GSHpx) and superoxide dismutase (SOD) activities in the ulcer region, respectively. The effect of rebamipide, an antigastric-ulcer agent, on ulcer recurrence was assessed following oral administration at 60 mg/kg/day from day 20. In the control and rebamipide groups, gastric ulcer indices were reduced on day 100 compared with day 60; however, increases were observed on day 140, indicating ulcer recurrence. In the rebamipide group, the ulcer index was smaller than in the control group at each time point and the effect was significant on day 140. Although marked elevation of MPO activities was observed in the control group during the experiment, no significant elevations were seen in the rebamipide group on days 100 and 140. TBARS levels were significantly elevated in the control group on day 140, but not in the rebamipide group. Rebamipide suppressed the decrease in GSHpx activity on day 60. These results suggest that lipid peroxidation of gastric tissue mediated by free radicals from neutrophils is responsible for the recurrence of acetic acid-induced gastric ulcers in rats, and that the elimination of free radicals by rebamipide may contribute to the reduction of severity in ulcer recurrence.
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Affiliation(s)
- Kazushi Sakurai
- Free Radical Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima 771-0192, Japan.
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Hiratsuka K, Logan SM, Conlan JW, Chandan V, Aubry A, Smirnova N, Ulrichsen H, Chan KHN, Griffith DW, Harrison BA, Li J, Altman E. Identification of a D-glycero-D-manno-heptosyltransferase gene from Helicobacter pylori. J Bacteriol 2005; 187:5156-65. [PMID: 16030209 PMCID: PMC1196013 DOI: 10.1128/jb.187.15.5156-5165.2005] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
We have identified a Helicobacter pylori d-glycero-d-manno-heptosyltransferase gene, HP0479, which is involved in the biosynthesis of the outer core region of H. pylori lipopolysaccharide (LPS). Insertional inactivation of HP0479 resulted in formation of a truncated LPS molecule lacking an alpha-1,6-glucan-, dd-heptose-containing outer core region and O-chain polysaccharide. Detailed structural analysis of purified LPS from HP0479 mutants of strains SS1, 26695, O:3, and PJ1 by a combination of chemical and mass spectrometric methods showed that HP0479 likely encodes alpha-1,2-d-glycero-d-manno-heptosyltransferase, which adds a d-glycero-d-manno-heptose residue (DDHepII) to a distal dd-heptose of the core oligosaccharide backbone of H. pylori LPS. When the wild-type HP0479 gene was reintegrated into the chromosome of strain 26695 by using an "antibiotic cassette swapping" method, the complete LPS structure was restored. Introduction of the HP0479 mutation into the H. pylori mouse-colonizing Sydney (SS1) strain and the clinical isolate PJ1, which expresses dd-heptoglycan, resulted in the loss of colonization in a mouse model. This indicates that H. pylori expressing a deeply truncated LPS is unable to successfully colonize the murine stomach and provides evidence for a critical role of the outer core region of H. pylori LPS in colonization.
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Affiliation(s)
- Koji Hiratsuka
- Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada
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Quintana E, Hernández C, Moran AP, Esplugues JV, Barrachina MD. Transcriptional up-regulation of nNOS in the dorsal vagal complex during low endotoxemia. Life Sci 2005; 77:1044-54. [PMID: 15935400 DOI: 10.1016/j.lfs.2005.03.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2004] [Accepted: 03/07/2005] [Indexed: 11/17/2022]
Abstract
The present study analyses the expression and distribution of neuronal nitric oxide synthase (nNOS) in the brainstem of animals pre-treated with Escherichia coli or Helicobacter pylori LPS, at doses that modulate gastric motor function. Systemic administration of H. pylori LPS prevented in a dose-dependent manner (5, 40 and 100 microg kg(-1), i.v.) the increase in intragastric pressure induced by 2-deoxy-D-glucose (200 mg kg(-1), i.v.) in urethane-anaesthetized rats. Quantitative analysis showed a significant increase in the amount of nNOS mRNA induced by E. coli or H. pylori LPS (2 h later), in a segment of the brainstem containing the dorsal vagal complex (DVC). Immunohistochemical studies showed nNOS presence in the DVC of vehicle-treated rats. Both E. coli (40 microg kg(-1), i.p.) and H. pylori LPS (100 microg kg(-1), i.p.) significantly increased (2 h later) the number of nNOS immunoreactive cells in this area, mainly at the most rostral level. The present study shows that systemic administration of E. coli or H. pylori LPS induces a transcriptional up-regulation of the nNOS in the DVC of the brainstem and suggests a role for NO synthesis in this area in the control of gastric motor function under endotoxemia.
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Affiliation(s)
- Elsa Quintana
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
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Chang FY, Lu CL, Chen CY, Luo JC, Jium KL, Lee SD. Effect of Helicobacter pylori eradicated therapy on water gastric emptying in patients with active duodenal ulcer. J Gastroenterol Hepatol 2003; 18:1250-6. [PMID: 14535981 DOI: 10.1046/j.1440-1746.2003.03168.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIMS It remains debatable if duodenal ulcer (DU) or Helicobacter pylori infection has a definite impact on human gastric emptying (GE). We explored the nature of water GE in active DU patients before and after ulcer healing and the influence of H. pylori eradication on GE. METHODS A home made applied potential tomography (APT) was used to measure liquid GE. Twelve electrodes were placed in a circular array around the upper abdomen of studied subjects. After drinking 500 mL of ion-free water, paired electrodes injected electrical current and the remaining 10 electrodes recorded signals, one-by-one in a rotating order. Based on tomographical calculation, the serial changes of averaged signals from altered resistivities were constructed to display GE. Initially, 64 H. pylori infected active DU patients were enrolled. After APT measurement, one-week triple therapy (omeprazole, amoxicillin and clarithromycin) was dispensed. Patients were asked back to determine ulcer/H. pylori status and GE on a scheduled date 3 months later. Finally, 58 patients finished the trial with valid and readable GE data obtained. RESULTS The ulcer healing and H. pylori eradicated rates were 91.4% and 82.8%, respectively. In general, liquid GE was prolonged in all DU patients at follow up. Of 48 eradicated patients, 35.4% manifested either enhanced or delayed GE before treatment, whereas only five (10.4%) had abnormal GE after treatment (P < 0.0001). In contrast, this characteristically normalized GE was not found in non-eradicated patients. CONCLUSIONS Water GE of active DU patients ranges from enhanced to delayed, while an effective H. pylori triple therapy is useful not only for healing ulcers, but also for restoring abnormal GE.
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Affiliation(s)
- Full-Young Chang
- Division of Gastroenterology, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan
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Genta RM. Review article: the role of rebamipide in the management of inflammatory disease of the gastrointestinal tract. Aliment Pharmacol Ther 2003; 18 Suppl 1:8-13. [PMID: 12925136 DOI: 10.1046/j.1365-2036.18.s1.5.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
Rebamipide stimulates the generation of endogenous prostaglandins in the gastric mucosa and is reported to accelerate ulcer healing. This review discusses whether rebamipide can prevent Helicobacter pylori infection, reduce inflammation, accelerate healing after eradication, promote ulcer healing, and prevent progression of preneoplastic lesions. Furthermore, we evaluate its usefulness in other inflammatory conditions of the gastrointestinal tract. We conclude that rebamipide is an important candidate for long-term suppression of gastro-intestinal inflammation, particularly if reducing the complications of H. pylori infection without eradicating the organism becomes accepted. If its ability to accelerate mucosal normalization is confirmed, rebamipide could be added to eradication regimens. Little information exists on whether such therapy could help limit the development of pre-neoplastic lesions. In light of the dearth of effective drugs to control inflammation in idiopathic inflammatory bowel disease, the potential of any promising new and safe compound deserves to be fully explored. The next step is to devise a targeted plan of translational research, so that results from the bench may be used to design rigorously controlled international clinical trials.
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Affiliation(s)
- R M Genta
- Department of Pathology, University of Geneva, Switzerland.
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Okabe S, Amagase K. [An overview of acetic acid ulcer models and their utility for drug screening]. Nihon Yakurigaku Zasshi 2003; 122:73-92. [PMID: 12843575 DOI: 10.1254/fpj.122.73] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Since Takagi et al. reported an experimental chronic gastric ulcer model [acetic acid ulcers induced by submucosal injection of acetic acid (Type 1)], we further modified the methodology and subsequently devised three more models. The second model involves inducing ulcers by serosal application of an acetic acid solution (Type 2) and the third model achieves ulcer induction by intragastric application of an acetic acid solution (Type 3). The forth model was modification of the third model by giving the acetic acid solution and the same volume of air to make one ulcer in the stomach (Type 4). In general, animals accepted the procedures without problems and no undesirable effects were noticed. More importantly, this experimental animal model allows production of ulcers that highly resemble human ulcers in terms of both pathology and healing. Indeed, relapse is even endoscopically observed for 360 days after ulceration. The ulcers produced not only respond well to various anti-ulcer medications, such as antisecretory and mucosal protective drugs and growth factors, but also demonstrate appropriate responses to ulcerogenic agents such as NSAIDs. In addition, we have recently demonstrated that H. pylori infection resulted in delayed ulcer healing and recurrence of healed acetic acid ulcers induced in Mongolian gerbils. The present article gives a brief summary of the ulcer history before establishment of acetic acid ulcers and characteristic features of acetic acid ulcer, including both their merits and shortcomings.
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Affiliation(s)
- Susumu Okabe
- Department of Applied Pharmacology, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan.
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Hasegawa S, Sekino H, Matsuoka O, Saito K, Sekino H, Morikawa A, Uchida K, Koike M, Azuma J. Bioequivalence of Rebamipide Granules and Tablets in Healthy Adult Male Volunteers. Clin Drug Investig 2003; 23:771-9. [PMID: 17536891 DOI: 10.2165/00044011-200323120-00002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
OBJECTIVE Rebamipide tablets, which are used in the treatment of patients with gastric ulcers or gastritis, can be difficult to administer in subjects with reduced swallowing ability or impaired swallowing. The granule formulation may be more easily administered in these patients. The bioequivalence between rebamipide granules (20%/0.5g) and tablets (100mg) was determined in healthy male adult volunteers, in accordance with the Partially Revised Guidelines for Bioequivalence Studies of Generic Products. STUDY DESIGN In a randomised, nonblind, crossover design, 28 individuals were allocated into two groups of 14 to receive either rebamipide granules or rebamipide tablets. Each individual, under fasting conditions, was administered a single oral dose of rebamipide 100mg followed by a 7-day washout period. Individuals then received a single oral dose of the other rebamipide formulation. Blood samples were collected at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours. Plasma rebamipide concentrations were measured by validated high-performance liquid chromatography with tandem mass spectrometry. RESULTS The plasma concentration-time profiles and pharmacokinetic parameters of rebamipide after administration of the granule formulation were similar to those of the tablet in 27 healthy male volunteers. Following administration of the granule formulation, the area under the plasma concentration-time curve from time 0-24 hours (AUC(24h)) was 912.82 mug/L . h, the maximum plasma concentration (C(max)) was 241.82 mug/L, time to maximum plasma concentration (t(max)) was 2.5 hours, and plasma elimination half-life (t((1/2))) was 1.97 hours. Corresponding values for the tablet formulation were 873.55 microg/L . h, 216.19 mug/L, 2.4 hours, and 1.94 hours. The difference in mean log values was 1.01 for AUC(24h) and 1.09 for C(max) after granule and tablet administration. The 90% confidence interval of this difference in mean log value was 0.93-1.10 for AUC(24h), and 0.97-1.21 for C(max). This satisfies the criteria for bioequivalence in the guidelines [within log (0.8) to log (1.25)]. CONCLUSIONS Rebamipide granules (20%/0.5g) and tablet (100mg) were bioequivalent. Rebamipide granules may therefore be a more practical treatment option in patients with gastric ulcers or gastritis who have difficulty swallowing tablets.
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Ishiyama H, Kawai K, Azuma A, Nagano C. Therapeutic effect of rebamipide in a modified acetic acid-induced buccal mucosal ulcer model. Inflammopharmacology 2002. [DOI: 10.1163/156856002321544864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Hiruma-Lima CA, Gracioso JS, Bighetti EJB, Grassi-Kassisse DM, Nunes DS, Brito ARMS. Effect of essential oil obtained from Croton cajucara Benth. on gastric ulcer healing and protective factors of the gastric mucosa. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2002; 9:523-529. [PMID: 12403161 DOI: 10.1078/09447110260573155] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
The bark of Croton cajucara Benth. (Euphorbiaceae) is used widely in Amazonian folk medicine for the treatment of a wide range of gastrointestinal symptoms. Infusions of C. cajucara bark contain dehydrocrotonin (DHC), the furan diterpene, and an essential oil, a rich mixture of sesquiterpenes. Although the antiulcerogenic activity of the essential oil has been studied in different gastric ulcer models in mice and rats, its mechanism remains unclear. In this work, we examined the ability of this essential oil to increase PGE2 release from mucus cells, as well as its effects on the amount of gastric mucus and on the healing of acetic acid-induced gastric ulcers. The essential oil (100 mg/kg body wt., p.o), significantly increased PGE2 production by glandular cells (by 102% as compared to control) and the amount of Alcian blue binding to the gastric mucus. In chronic gastric ulcers, a single daily oral dose of essential oil (100 mg/kg body wt.) for 14 consecutive days accelerated ulcer healing to an extent similar to that seen with an equal dose of cimetidine. Thus, the protective and healing actions of the essential oil from C. cajucara bark on gastric lesions resulted mainly from an increase in PGE2 release and gastric mucus formation which would protect the gastric mucosa.
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Affiliation(s)
- C A Hiruma-Lima
- Departamento de Fisiologia, Instituto de Biociências, Universidade Estadual Paulista, Botucatu, SP, Brazil.
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Torres J, Pérez-Pérez G, Goodman KJ, Atherton JC, Gold BD, Harris PR, la Garza AM, Guarner J, Muñoz O. A comprehensive review of the natural history of Helicobacter pylori infection in children. Arch Med Res 2000; 31:431-69. [PMID: 11179581 DOI: 10.1016/s0188-4409(00)00099-0] [Citation(s) in RCA: 165] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Across populations of children, Helicobacter pylori prevalence ranges from under 10% to over 80%. Low prevalence occurs in the U.S., Canada, and northern and western Europe; high prevalence occurs in India, Africa, Latin America, and eastern Europe. Risk factors include socioeconomic status, household crowding, ethnicity, migration from high prevalence regions, and infection status of family members. H. pylori infection is not associated with specific symptoms in children; however, it is consistently associated with antral gastritis, although its clinical significance is unclear. Duodenal ulcers associated with H. pylori are seldom seen in children under 10 years of age. H. pylori-infected children demonstrate a chronic, macrophagic, and monocytic inflammatory cell infiltrate and a lack of neutrophils, as compared with the response observed in adults. The effect of H. pylori infection on acid secretion in children remains poorly defined. The events that occur during H. pylori colonization in children should be studied more thoroughly and should include urease activity, motility, chemotaxis, adherence, and downregulation of the host response. The importance of virulence determinants described as relevant for disease during H. pylori infection has not been extensively studied in children. Highly sensitive and specific methods for the detection of H. pylori in children are needed, especially in younger pediatric populations in which colonization is in its early phases. Criteria for the use of eradication treatment in H. pylori-infected children need to be established. Multicenter pediatric studies should focus on the identification of risk factors, which can be used as prognostic indicators for the development of gastroduodenal disease later in life.
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Affiliation(s)
- J Torres
- Unidad de Investigación Médica en Enfermedades Infecciosas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
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Tarnawski AS, Tomikawa M, Ohta M, Sarfeh IJ. Antacid talcid activates in gastric mucosa genes encoding for EGF and its receptor. The molecular basis for its ulcer healing action. JOURNAL OF PHYSIOLOGY, PARIS 2000; 94:93-8. [PMID: 10791688 DOI: 10.1016/s0928-4257(00)00149-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In previous studies [Gut 35 (1994) 896-904], we demonstrated that antacid talcid (TAL) accelerates gastric ulcer healing and provides better quality of mucosal restoration within the scar than the omeprazole (OME). However, the mechanisms of TAL-induced ulcer healing are not clear. Since growth factors promote cell proliferation, re-epithelization, angiogenesis and ulcer healing, we studied whether TAL and/or OME affect expression of epidermal growth factor (EGF) and its receptors (EGF-R) in both normal and ulcerated gastric mucosae. Rats with or without acetic acid-induced gastric ulcers (n = 64) received i.g. twice daily 1 mL of either: A) placebo (PLA); B) TAL 100 mg; or C) OME 50 mg x kg(-1) for 14 d. Studies of gastric specimens: 1) ulcer size; 2) quantitative histology; 3) expression of EGF mRNAs was determined by RT/PCR; 4) gastric sections were immunostained with antibodies against EGF and its receptors. In non-ulcerated gastric mucosa of placebo or omeprazole treated group, EGF expression was minimal, while EGF-R was localized to few cells in the mucosal proliferative zone. Gastric ulceration triggered overexpression of EGF and its receptor in epithelial cells of the ulcer margin and scar. In ulcerated gastric mucosa TAL treatment significantly enhanced (versus PLA and omeprazole) expression of EGF and EGF-R. OME treatment reduced expression of EGF in ulcerated mucosa by 55 +/- 2% (P < 0.01). It is concluded that: 1) treatment with TAL activates genes for EGF and its receptor in normal and ulcerated gastric mucosae; 2) since EGF promotes growth of epithelial cells and their proliferation and migration, the above actions of TAL provide the mechanism for its ulcer healing action and improved (versus OME) quality of mucosal restoration.
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Affiliation(s)
- A S Tarnawski
- Gastroenterology Section, VA Medical Center, Long Beach, CA 90822, USA
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