This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formattedPDF and full text (HTML) ve...
http://www.biomedcentral.com/info/authors/BMC Gastroenterology© 2013 Kuramoto et al.This is an open access article distrib...
Preventive effect of irsogladine or omeprazole onnon-steroidal anti-inflammatory drug-inducedesophagitis, peptic ulcers, a...
Kazuhide Higuchi1**Corresponding authorEmail: higuchi@poh.osaka-med.ac.jp12nd Department of Internal Medicine, Osaka Medic...
Trial registrationThis study was registered in the UMIN Clinical Trials Registry (Registry ID number;UMIN000008114)Keyword...
4) oral use or planned oral use of a drug other than an antiulcer drug, 5) alcohol or chemicaldependency, 6) a history of ...
Figure 1 Examples of typical bleeding (A), mucosal break (B) and reddish lesion (C).Investigators who were to evaluate the...
RandomizationA coordinator performed a simple fixed-allocation randomization by using a block-randomization scheme. Random...
duodenal Lanza scores (Group O, 0.0 ± 0.0 to 0.4 ± 0.8; Group I, 0.0 ± 0.0 to 0.4 ± 0.9; p =0.94) (Table 2).Table 2 The Lo...
after treatment was significantly higher in Group O (1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) thanin Group I (1.0 ± 0.0 to 6....
Previous studies have shown that 55–68% of patients taking NSAIDs and omeprazole havesome mucosal damage in the small inte...
AbbreviationsPPI, Proton pump inhibitor; NSAID(s), Non-steroidal anti-inflammatory drug(s); H. pylori,Helicobacter pyloriC...
5. Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, ArakawaT: Present status and strategy of NSAID...
17. Morita H, Katsuno T, Hoshimoto A, Hatakeyama K, Suzuki Y, Saito Y: Irsogladine, anactivator of gap-junctional intercel...
Figure 1
-1.0-0.50.00.51.01.52.02.53.03.54.0Before treatment After treatment0.10.31.90.5No.oflesions**Irsogladine (n=16)Omeprazole(...
-205.9718.11Before treatment After treatment-100102030405060Irsogladine (n=16)Omeprazole(n=16)Ratio*Figure 3
Figure 4
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Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study

Proton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects.
Published on: Mar 4, 2016
Published in: Health & Medicine      
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Transcripts - Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study

  • 1. This Provisional PDF corresponds to the article as it appeared upon acceptance. Fully formattedPDF and full text (HTML) versions will be made available soon.Preventive effect of irsogladine or omeprazole on non-steroidalanti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinallesions in humans, a prospective randomized controlled studyBMC Gastroenterology 2013, 13:85 doi:10.1186/1471-230X-13-85Takanori Kuramoto (in2091@poh.osaka-med.ac.jp)Eiji Umegaki (in2038@poh.osaka-med.ac.jp)Sadaharu Nouda (sadaharu.nouda.1110@hotmail.co.jp)Ken Narabayashi (naraken2001@hotmail.com)Yuichi Kojima (majiko5580@yahoo.co.jp)Yukiko Yoda (yukiko911@hotmail.co.jp)Kumi Ishida (xe4v7r@bma.biglobe.ne.jp)Ken Kawakami (in2090@poh.osaka-med.ac.jp)Yosuke Abe (y-abe@kg7.so-net.ne.jp)Toshihisa Takeuchi (in2097@poh.osaka-med.ac.jp)Takuya Inoue (ureuretakuwan@yahoo.co.jp)Mitsuyuki Murano (Murano7m@hotmail.com)Satoshi Tokioka (in2073@poh.osaka-med.ac.jp)Kazuhide Higuchi (higuchi@poh.osaka-med.ac.jp)ISSN 1471-230XArticle type Research articleSubmission date 19 November 2012Acceptance date 2 May 2013Publication date 14 May 2013Article URL http://www.biomedcentral.com/1471-230X/13/85Like all articles in BMC journals, this peer-reviewed article can be downloaded, printed anddistributed freely for any purposes (see copyright notice below).Articles in BMC journals are listed in PubMed and archived at PubMed Central.For information about publishing your research in BMC journals or any BioMed Central journal, go toBMC Gastroenterology© 2013 Kuramoto et al.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • 2. http://www.biomedcentral.com/info/authors/BMC Gastroenterology© 2013 Kuramoto et al.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • 3. Preventive effect of irsogladine or omeprazole onnon-steroidal anti-inflammatory drug-inducedesophagitis, peptic ulcers, and small intestinal lesionsin humans, a prospective randomized controlledstudyTakanori Kuramoto1Email: in2091@poh.osaka-med.ac.jpEiji Umegaki1Email: in2038@poh.osaka-med.ac.jpSadaharu Nouda1Email: sadaharu.nouda.1110@hotmail.co.jpKen Narabayashi1Email: naraken2001@hotmail.comYuichi Kojima1Email: majiko5580@yahoo.co.jpYukiko Yoda1Email: yukiko911@hotmail.co.jpKumi Ishida1Email: xe4v7r@bma.biglobe.ne.jpKen Kawakami1Email: in2090@poh.osaka-med.ac.jpYosuke Abe1Email: y-abe@kg7.so-net.ne.jpToshihisa Takeuchi1Email: in2097@poh.osaka-med.ac.jpTakuya Inoue1Email: ureuretakuwan@yahoo.co.jpMitsuyuki Murano1Email: Murano7m@hotmail.comSatoshi Tokioka1Email: in2073@poh.osaka-med.ac.jp
  • 4. Kazuhide Higuchi1**Corresponding authorEmail: higuchi@poh.osaka-med.ac.jp12nd Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka, JapanAbstractBackgroundProton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidalanti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it isunclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, wecompare the efficacy of the gastromucoprotective drug irsogladine with omeprazole inpreventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury inhealthy subjects.MethodsThirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16)receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazolegroup (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy andsmall-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult bloodbefore and after treatment.ResultsThere was no significant difference between Group I and Group O with respect to the changein lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAIDtreatment significantly increased the number of small intestinal mucosal breaks per subject bycapsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in GroupO (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosalbreaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and thebetween-group difference was significant (p = 0.0040). Fecal calprotectin concentration,when the concentration before treatment was defined as 1, was significantly increased both inGroup O (from 1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) and Group I (from 1.0 ± 0.0 to 6.0 ±11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared withthat in Group I (p<0.05). In addition, fecal occult blood levels increased significantly inGroup O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-groupdifference was significant (p = 0.0031).ConclusionIrsogladine protected against NSAID-induced mucosal injuries throughout thegastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole.
  • 5. Trial registrationThis study was registered in the UMIN Clinical Trials Registry (Registry ID number;UMIN000008114)KeywordsSmall-intestinal injury, NSAIDs, Irsogladine, OmeprazoleBackgroundGastroduodenal mucosal lesions are a well-known adverse effect of non-steroidal anti-inflammatory drugs (NSAIDs) [1]. Recently, the serious problem of NSAID-induced small-intestinal damage has become a topic of great interest to gastroenterologists since capsuleendoscopy and balloon enteroscopy have become available for the detection of small-intestinal lesions [2]. Recent studies have shown that 55–68% of patients taking NSAIDshave some mucosal damage in the small intestine [3-5]. Such lesions are of great concern inclinical settings, and methods for their treatment and prevention must be devised as soon aspossible. Proton-pump inhibitors (PPIs) are a standard treatment for the prevention ofNSAID-induced upper gastrointestinal mucosal injuries. However, it is not clear whetherPPIs are effective in the lower digestive tract, where there is no acid. Irsogladine (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine), a drug for the treatment of gastric ulcers that iswidely used in Japan, Korea and China, protects the gastric mucosa by enhancing themucosal integrity of the stomach through the facilitation of gap-junctional intercellularcommunication [6]. Irsogladine also prevents the development of intestinal lesions inducedby indomethacin in rats [7]. Irsogladine can be expected to be effective not only in thestomach but also in other parts of the digestive tract. Previous studies on the prevention ofNSAID-induced digestive tract injuries by various drugs [8-10] have been limited to theupper digestive tract or the small intestine individually, and there have been no studies of theentire digestive tract from the esophagus through the stomach, duodenum, and smallintestine. It would be of great benefit if a single drug could be used to manage NSAID-induced injuries of both the upper and lower digestive tract. In the present study, wecompared the efficacy of irsogladine and omeprazole in preventing NSAIDs-inducedesophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects by usingmultidimensional assessment; that is, esophagastroduodenoscopic evaluation, capsuleendoscopic evaluation, fecal calprotectin concentration and occult fecal blood test.MethodsSubjectsThe study of 32 healthy volunteers was conducted prospectively from April to August 2010at Osaka Medical College Hospital. Subjects eligible for inclusion were healthy adults who 1)were aged between 20 and 79 years of age at the time of obtaining consent, 2) had freelygiven their fully informed consent based on their full understanding, and 3) had taken nomedication during the one-month period before the start of the study. The exclusion criteriawere 1) a history of peptic ulcer or gastrointestinal bleeding, 2) significant hepatic, renal,heart, or respiratory disease, 3) a history of gastrointestinal surgery other than appendectomy,
  • 6. 4) oral use or planned oral use of a drug other than an antiulcer drug, 5) alcohol or chemicaldependency, 6) a history of intestinal obstruction or suspected gastrointestinal obstruction onother tests, 7) a lack of consent to the surgery required if the capsule endoscope was retainedin the body, and 8) a determination by the investigator, at his discretion, that a subject wasineligible for participation in the study for any other reason. All subjects received oral andwritten explanation of the study prior to participation and gave written informed consent. Thestudy was conducted in accordance with the Declaration of Helsinki (1995) after the protocolhad been approved by the Ethics Review Committee of Osaka Medical College.ProtocolThis was a prospective, randomized, study. Every day for two weeks, the irsogladine group(Group I) received diclofenac sodium 75 mg plus irsogladine maleate 4 mg, and theomeprazole group (Group O) received diclofenac sodium 75 mg plus omeprazole 10 mg. Thedose of diclofenac sodium was determined based on the dose approved by the JapaneseMinistry of Health and Welfare and the doses used in other clinical trials [8-10]. Generally,the dosage of a PPI used for the prevention of NSAID-induced gastric ulcers is half thedosage used for the treatment of gastric ulcers in Japan. On this basis, we determined that theappropriate dosage of omeprazole should be 10 mg/day.The subjects were assigned to either Group I or Group O prior to the study. Bowelpreparation, capsule endoscopy with a PillCamTMSB video capsule (Given Imaging,Yoqneam, Israel) and image evaluation were conducted as previously reported [11]. Weconducted a preliminary analysis of the results of these baseline capsule endoscopyexaminations to determine subject eligibility for the remainder of the study. Images wereanalyzed with the software program Rapid Reader 4 (Given Imaging). Lesions wereevaluated according to the Los Angeles classification or the Lanza score [12] byesophagogastroduodenoscopy, and the number of small-intestinal mucosal lesions wasassessed by capsule endoscopy, serum biochemistry, fecal occult blood, and fecal calprotectinbefore and after two weeks of treatment. A diagnosis of Helicobacter pylori (H. pylori)infection was confirmed by a blood antibody test at the beginning of the trial.EsophagogastroduodenoscopyTo standardize the reporting criteria for the endoscopic findings, the two endoscopists (T. K.and E.U.) attended each other’s endoscopic sessions before and regularly during the trial.Capsule endoscopyMucosal breaks in the small intestine were defined as lesions with slough surrounded byerythema, corresponding to the grade 2 category of Goldstein et al. [4]. Typical examples ofthe bleeding, mucosal breaks and reddish lesions found in this study are shown in Figure 1a–c. Reddish lesions, such as reddened folds, denuded areas, and petechiae, were grouped in asingle classification: reddened lesions. Mucosal breaks, reddened lesions and bleeding wereidentified and evaluated by independent blinded reviewers as described below. The numberof mucosal breaks, reddened lesions and sites of bleeding in the small intestine found atbaseline and post-treatment by capsule endoscopy was calculated for each subject andcompared between Groups I and O. The percentage of subjects with at least one mucosalbreak in each treatment group was also calculated.
  • 7. Figure 1 Examples of typical bleeding (A), mucosal break (B) and reddish lesion (C).Investigators who were to evaluate the results of capsule endoscopy of the small intestinewere required to attend a standardized training session on the use of the Given DiagnosticSystem. These two investigators (T.K. and E.U.) independently assessed the capsuleendoscopic images under blinded conditions. Positive findings were classified as eithermucosal bleeding or mucosal injury. If the two observers recorded different findings, theydiscussed the case until they reached agreement.Noninvasive tests of intestinal damageSubjects collected a stool sample for determination of fecal calprotectin as a measure ofintestinal inflammation at baseline and the final visit. Stools were frozen within 12 h ofreceipt and stored at −20 °C for subsequent analysis with an enzyme-linked immunosorbentassay kit (Immundiagnostik, Bensheim, Germany) as previously described [13]. Results areexpressed as micrograms of calprotectin per gram of stool, and a cutoff value of 50 µg/g stoolwas used, as recommended by the manufacturer [14]. The fecal calprotectin value suffers theproblems of variation, so we determined to use the fold increase after treatment when thecalprotectin concentration before treatment was set to 1. Before and after the study, fecaloccult blood was assessed with the tetramethylbenzidine and guaiac tests by using occultfecal blood slide kits from Shionogi Pharma (Osaka, Japan). In both tests, the color intensityof the oxidation product was assigned to one of three categories, +, ± or −, and on this basisdifferences between before and after treatment were denoted “exacerbation”, “invariable” or“improvement”. The hemoglobin and transferrin antibody tests for occult fecal blood wereperformed with an OC-Micro analyzer (Eiken, Tokyo, Japan). Generally, fecal occult blood isinfluenced by the intake of meat, fish, bright red, green or yellow vegetables, and so on.Therefore, we explained to our subjects how these foods affect the results of the occult bloodtests(the tetramethylbenzidine test and the guaiac test), and suggested that they pay attentionto their food intake during the period 4 days prior to the examination date.Sample sizeThe sample size was based on our estimation of the proportion of subjects that would beexpected to exhibit mucosal breaks at post-treatment by capsule endoscopy. We estimatedthat the incidence of mucosal injuries would be approximately 20% in the irsogladine group,on the basis of a preliminary study by Niwa et al. [8] showing that the incidence of NSAID-induced small-intestinal lesions was lower in subjects on daily rebamipide (20%) than insubjects on placebo (80%). In rats, irsogladine suppresses indomethacin-induced small-intestinal lesions as effectively as rebamipide [7]. In addition, we estimated that the incidenceof mucosal injuries would be approximately 70% in the control group, because a recent studyfound small-intestinal lesions in 55–68% of subjects taking NSAIDs [3,4]. Thus, 15 subjectswould need to be recruited to each group (30 subjects in total) for a chi-square test, asignificance level of 5% (two-sided), a power of 80%, and equal allocation. On theassumption that two subjects would not be able to complete the study, a minimum of 32subjects was required.
  • 8. RandomizationA coordinator performed a simple fixed-allocation randomization by using a block-randomization scheme. Random numbers were generated by SAS (SAS Institute, Cary, NC,USA).StatisticsFor continuous or categorical variables, the statistical significance of differences betweengroups was determined with the t test or Wilcoxon rank-sum test, and the statisticalsignificance of differences within a group was determined with the Wilcoxon signed-ranktest. For binary variables, the statistical significance of differences between groups wasdetermined with the chi-square test. All reported p values are two-sided, and values of lessthan 0.05 were considered to indicate statistically significant differences. All statistical valueswere calculated with SAS Ver. 9.2 (SPSS, Chicago, IL, USA), Windows Edition.Results and discussionAnalysis of subjectsThe 32 subjects were randomly assigned to either Group I or Group O and underwentbaseline esophagogastroduodenoscopy and capsule endoscopy. None of the subjects hadsignificant findings in the esophagus through to the small intestine, and all 32 wereconsidered eligible for the study. The characteristics of each group’s subjects, including age,sex, H. pylori infection status, fecal hemoglobin concentration, and the numbers of mucosalbreaks, reddened lesions and sites of bleeding, are shown in Table 1.Table 1 Characteristics of subjects at baseline that underwent full analysisIrsogladinegroupOmeprazolegrouppvalueNo. of subjects 16 16Age (years) (mean ± SD) 25±4 25±4 NSSex (M/F) 10/6 11/5 NSH. pylori infection status (+/−) 1/15 1/15 NSFecal hemoglobin concentration (mg/dL) (mean± SD)14.1 ± 2.0 14.4 ± 1.2 NSNumber of mucosal breaks (mean ± SD) 0.3 ± 0.8 0.1 ± 0.3 NSNumber of reddened lesions (mean ± SD) 0.2 ± 0.4 0.6 ± 0.8 NSNumber of sites of bleeding (mean ± SD) 0.0 ± 0.0 0.1 ± 0.3 NSNS = not significant.EsophagogastroduodenoscopyBy the Los Angeles classification, no esophageal mucosal injuries were observed in eithergroup before or after treatment. In both groups, all 16 subjects were grade O(no mucosalbreaks) both before and after treatment(Table 2). There was no significant difference betweenGroup O (from 0.6 ± 0.9 to 1.5 ± 1.1) and Group I (from 0.5 ± 1.1 to 0.9 ± 1.0) in the gastricLanza score either before or after treatment (p = 0.20). A similar result was obtained for the
  • 9. duodenal Lanza scores (Group O, 0.0 ± 0.0 to 0.4 ± 0.8; Group I, 0.0 ± 0.0 to 0.4 ± 0.9; p =0.94) (Table 2).Table 2 The Los Angeles classification and Lanza scores at baseline and after treatmentBaseline Post-treatment p value1Irsogladine groupLos Angeles classification Grade O (16/16) Grade O (16/16)Lanza scores (stomach) (mean ± SD) 0.5 ± 1.1 0.9 ± 1.0 NSLanza scores (duodenum) (mean ± SD) 0.0 ± 0.0 0.4 ± 0.9 NSOmeprazole group NSLos Angeles classification Grade O (16/16) Grade O (16/16)Lanza scores (stomach) (mean ± SD) 0.6 ± 0.9 1.5 ± 1.1 NSLanza scores (duodenum) (mean ± SD) 0.0 ± 0.0 0.4 ± 0.8 0.00491P-values are baseline versus post-treatment within groups.Capsule endoscopyA significantly higher percentage of subjects in Group O (81.3% (13/16)) had mucosal breaksafter treatment than in Group I (37.5% (6/16); p = 0.012). The increase in the mean numberof small-intestinal mucosal breaks per subject from baseline to study end was significantlygreater in Group O (0.1 ± 0.3 to 1.9 ± 2.0, p = 0.0002) than in Group I (0.3 ± 0.8 to 0.5 ± 0.7;, p = 0.62)( p = 0.0040; Figure 2 and Table 3).; Figure 2 and Table 3). There were nosignificant differences in the numbers of reddened lesions or sites of bleeding per subjectbefore and after treatment (Table 3).Figure 2 Mean mucosal breaks per subject at post-treatment capsule endoscopy (mean± SD).Table 3 Number of small-intestinal lesions per subject by capsule endoscopy at baselineand after treatmentBaseline Post-treatment p value1Irsogladine groupNumber of mucosal breaks (mean ± SD) 0.3 ± 0.8 0.5 ± 0.7 NSNumber of reddened lesions (mean ± SD) 0.2 ± 0.4 0.4 ± 0.6 NSNumber of sites of bleeding (mean ± SD) 0.0 ± 0.0 0.2 ± 0.5 NSOmeprazole groupNumber of mucosal breaks (mean ± SD) 0.1 ± 0.3 1.9 ± 2.0 0.0002Number of reddened lesions (mean ± SD) 0.6 ± 0.8 1.3 ± 1.7 NSNumber of sites of bleeding (mean ± SD) 0.1 ± 0.3 0.3 ± 0.4 NS1P-values are baseline versus post-treatment within groups.Fecal calprotectinThe fecal calprotectin concentration increased after treatment in both groups (Group O: 2400± 4000 to 5000 ± 6700 , Group I: 14000 ± 35000 to 19000 ± 21000). The median baselinefecal calprotectin concentration increased significantly after treatment in both groups.However, when the calprotectin concentration before treatment was set to 1, the fold increase
  • 10. after treatment was significantly higher in Group O (1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) thanin Group I (1.0 ± 0.0 to 6.0 ± 11.1, p = 0.028)( p<0.05, Figure 3).Figure 3 Changes in calprotectin levels after two weeks’ treatment with irsogladine oromeprazole (mean ± SD).Occult blood test of stoolAs assessed by the tetramethylbenzidine test (Figure 4), fecal occult blood was significantlyincreased in Group O after treatment compared with before treatment(p = 0.0018), but therewas no significant change in Group I(p = 1.0), and there was a significant post-treatmentdifference between the groups(p = 0.0031). Similar results were obtained with the guaiac test(Group I, exacerbation 25.0% (4/16), invariable 56.3% (9/16), improvement 18.8% (3/16);Group O, exacerbation 81.3% (13/16), invariable 12.5% (2/16), improvement 6.3% (1/16) (p= 0.0031)). By contrast, the fecal occult blood test results obtained by using an antibody tohuman hemoglobin (Group I, 38.9 ± 13.0 to 35.5 ± 19.5 ng/mL; Group O, 30.8 ± 21.0 to 29.0± 24.0 ng/mL) or transferrin (Group I, 13.1 ± 8.0 to 10.9 ± 7.5 ng/mL; Group O, 2.9 ± 5.4 to3.5 ± 4.7 ng/mL) showed no significant change after treatment compared with beforetreatment in either group.Figure 4 Fecal occult blood after two weeks’ treatment with irsogladine or omeprazolecompared to baseline.TolerabilityNeither irsogladine nor omeprazole produced any side effects.DiscussionOur study demonstrated that short-term administration of irsogladine suppressed NSAID-induced mucosal injuries from the esophagus to the small intestine more effectively thanomeprazole. This is the first trial to include a multidimensional assessment of whether asingle drug can protect against NSAID-induced lesions in the entire digestive tract from theesophagus to the small intestine.In previous investigations of the effectiveness of gastroprotective drugs in the prevention ofsmall-intestinal mucosal injuries induced by NSAIDs in volunteers, evaluation was based oncapsule endoscopic findings only [8-10], so that the full extent of small-intestinal mucosalinjury may not have been appreciated. The use of the biochemical approach (fecal occultblood, calprotectin), in addition to capsule endoscopy, enabled a higher-quality evaluation. Inour study, the irsogladine group showed a significantly smaller increase in the number ofsmall-intestinal mucosal injuries by capsule endoscopy, fecal calprotectin, and fecal occultblood compared with the omeprazole group. Irsogladine was originally developed as a drugfor the treatment of gastric ulcers and so, as might be expected, we found no significantdifferences in the esophagus, stomach and duodenum compared with omeprazole. Previousreports suggest that irsogladine exerts various actions, including inhibiting the reduction ofgastric mucosal blood flow induced by diclofenac [15], the suppression of free-radicalproduction [16] and the facilitation of gap-junctional intercellular communications [6].
  • 11. Previous studies have shown that 55–68% of patients taking NSAIDs and omeprazole havesome mucosal damage in the small intestine [3,4]. In the present study, the development oflesions, including mucosal breaks, was also not inhibited with omeprazole, with lesions foundin 81.3% of subjects in the omeprazole group. In contrast, lesion development wassignificantly inhibited in the irsogladine group. Prior reports suggest that the activation ofgap-junctional intercellular communication by irsogladine leads to a significant decrease inthe paracellular permeability of human intestinal epithelial cell monolayers, partly throughthe up-regulation of claudin-4 [17]. We have found that irsogladine increases mucus secretionand significantly suppresses the decreased mucus response to indomethacin, resulting in thesuppression of bacterial invasion as well as the up-regulation of the expression of induciblenitric oxide synthase [7]. The suppression of small-intestinal injuries by irsogladine may beexplained partly by the maintenance of intestinal permeability and partly by the stimulationof mucus secretion.Although misoprostol lowers gastrointestinal complications caused by NSAIDs in addition topreventing endoscopic gastroduodenal ulcers [9,18], it can cause mild diarrhea at a dose ofonly 600 µg [9]. Therefore, a drug which is safe for use in the prevention of NSAID-inducedenteropathy without any adverse gastrointestinal effects is highly desirable. On irsogladine,not only the present study but also a previous study found no adverse drug reactions such asdiarrhea or abdominal pain [19].PPIs are the standard treatment for the prevention of NSAID-induced upper gastrointestinalmucosal injuries; however, this study has shown that the PPI omeprazole was ineffective inthe lower digestive tract. Furthermore, Wallace JL et al. reported that PPIs exacerbateNSAID-induced small-intestinal mucosal injuries in experimental animals [20]. A strikingeffect of PPIs is a significant reduction in the proportion of Actinobacteria in the jejunum[20], a finding that strongly suggests that the dysbiosis induced by a PPI is a majorcontributing factor to the increased susceptibility to NSAID-induced small-intestinal injuriescaused by enteric microflora.The limitation of this study is that we did not include an NSAID monotherapy group, becauseit would have been ethically unacceptable to administer an NSAID without any prophylacticmedicine for gastric ulcer. Therefore, it is unknown whether omeprazole exacerbated small-intestinal lesions. Also, the usefulness of irsogladine is unclear in patients with a history ofpeptic ulcer or gastrointestinal bleeding when NSAIDs are administered because the studyfocused on healthy subjects with a low risk of digestive-tract injuries. Additionally, the studywas performed in the relatively short period of two weeks, so further study is required tovalidate the long-term usefulness of irsogladine.ConclusionsIn conclusion, in healthy volunteers irsogladine did not show significant differences fromPPIs in the extent of inhibition of lesion development in the esophagus, stomach, andduodenum, but it did significantly inhibit lesion development in the small intestine comparedwith PPIs. Therefore irsogladine may be a useful drug in the situation where patients with alow risk of upper digestive tract injuries are administered NSAIDs, to protect the entiredigestive tract from the esophagus to the small intestine.
  • 12. AbbreviationsPPI, Proton pump inhibitor; NSAID(s), Non-steroidal anti-inflammatory drug(s); H. pylori,Helicobacter pyloriCompeting interestsThe authors have no conflicts of interest to declare.Authors’ contributionsGuarantor of the article: TK. Specific author contributions: Principal investigator, subjectrecruitment, subject evaluation, data collection and manuscript preparation: TK; manuscriptpreparation and statistical analysis: KH: randomization, subject recruitment, subjectevaluation and data collection: TT: subject recruitment, subject evaluation and datacollection: EU, SN, K N, YK, YY, KI, KK, YA, TI, MM and ST. All authors read andapproved the final manuscript.AcknowledgementsAssistance with post-submission English language and technical editing was provided bySheridan Henness, PhD, from inScience Communications, Springer Healthcare.FundingThis research did not receive any specific grant from any fundings agency in the public,commercial, or not-for-profit sector.References1. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI: Gastrointestinal damageassociated with the use of nonsteroidal antiinflammatory drugs. N Engl J Med 1992,327:749–754.2. Kameda N, Higuchi K, Shiba M, Machida H, Okazaki H, Yamagami H, Tanigawa T,Watanabe K, Watanabe T, Tominaga K, Fujiwara Y, Oshitani N, Arakawa T: A prospective,single-blind trial comparing wireless capsule endoscopy and double-balloon enteroscopyin patients with obscure gastrointestinal bleeding. J Gastroenterol 2008, 43:434–440.3. Graham DY, Opekun AR, Willingham FF, Qureshi WA: Visible small-intestinal mucosalinjury in chronic NSAID users. Clin Gastroenterol Hepatol 2005, 3:55–59.4. Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG: Video capsuleendoscopy to prospectively assess small bowel injury with celecoxib, naproxen plusomeprazole, and placebo. Clin Gastroenterol Hepatol 2005, 3:133–141.
  • 13. 5. Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, ArakawaT: Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol2009, 44:879–888.6. Ueda F, Kyoi T, Mimura K, Kimura K, Yamamoto M: Intercellular communication incultured rabbit gastric epithelial cells. Jpn J Pharmacol 1991, 57:321–328.7. Yoda Y, Takeuchi K, Kato S, Amagase K, Umegaki E, Tokioka S, Higuchi K: Search forprophylactic drugs against NSAID-induced small intestinal lesions in rats.Gastroenterology 2008, 134(Suppl 1):A-528.8. Niwa Y, Nakamura M, Ohmiya N, Maeda O, Ando T, Itoh A, Hirooka Y, Goto H:Efficacy of rebamipide for diclofenac-induced small-intestinal mucosal injuries inhealthy subjects: a prospective, randomized, double-blinded, placebo-controlled, cross-over study. J Gastroenterol 2008, 43:270–276.9. Fujimori S, Seo T, Gudis K, Ehara A, Kobayashi T, Mitsui K, Yonezawa M, Tanaka S,Tatsuguchi A, Sakamoto C: Prevention of nonsteroidal anti-inflammatory drug-inducedsmall-intestinal injury by prostaglandin: a pilot randomized controlled trial evaluatedby capsule endoscopy. Gastrointest Endosc 2009, 69:1339–1346.10. Fujimori S, Takahashi Y, Gudis K, Seo T, Ehara A, Kobayashi T, Mitsui K, YonezawaM, Tanaka S, Tatsuguchi A, Sakamoto C: Rebamipide has the potential to reduce theintensity of NSAID-induced small intestinal injury: a double-blind, randomized,controlled trial evaluated by capsule endoscopy. J Gastroenterol 2011, 46:57–64.11. Nouda S, Morita E, Murano M, Imoto A, Kuramoto T, Inoue T, Murano N, Toshina K,Umegaki E, Higuchi K: Usefulness of polyethylene glycol solution withdimethylpolysiloxanes for bowel preparation before capsule endoscopy. J GastroenterolHepatol 2010, 25:70–74.12. Lanza FL, Graham DY, Davis RE, Rack MF: Endoscopic comparison of cimetidineand sucralfate for prevention of naproxen-induced acute gastroduodenal injury. Effectof scoring method. Dig Dis Sci 1990, 35:1494–1499.13. Langhorst J, Elsenbruch S, Mueller T, Rueffer A, Spahn G, Michalsen A, Dobos GJ:Comparison of 4 neutrophil-derived proteins in feces as indicators of disease activity inulcerative colitis. Inflamm Bowel Dis 2005, 11:1085–1091.14. Tøn H, Brandsnes, Dale S, Holtlund J, Skuibina E, Schjønsby H, Johne B: Improvedassay for fecal calprotectin. Clin Chim Acta 2000, 292:41–54.15. Sato M, Manabe N, Hata J, Ishii M, Kamada T, Kusunoki H, Shiotani A, Haruma K:Effect of irsogladine maleate on NSAID-induced reduction of gastric mucosal bloodflow in anesthetized dogs. Digestion 2009, 79:73–78.16. Kyoi T, Noda K, Oka M, Ukai Y: Irsogladine, an anti-ulcer drug, suppressessuperoxide production by inhibiting phosphodiesterase type 4 in human neutrophils.Life Sci 2004, 76:71–83.
  • 14. 17. Morita H, Katsuno T, Hoshimoto A, Hatakeyama K, Suzuki Y, Saito Y: Irsogladine, anactivator of gap-junctional intercellular communication, suppresses paracellularpermeability of human intestinal epithelial cell monolayers through up-regulation ofclaudin-4. Gastroenterology 2006, 130(Suppl 2):241.18. Watanabe T, Sugimori S, Kameda N, Machida H, Okazaki H, Tanigawa T, Watanabe K,Tominaga K, Fujiwara Y, Oshitani N, Higuchi K, Arakawa T: Small bowel injury by low-dose enteric-coated aspirin and treatment with misoprostol: a pilot study. ClinGastroenterol Hepatol 2008, 6:1279–1282.19. Hiraishi H, Haruma K, Miwa H, Goto H: Clinical trial: irsogladine maleate, a mucosalprotective drug, accelerates gastric ulcer healing after treatment for eradication ofHelicobacter pylori infection – the results of a multicentre, double-blind, randomizedclinical trial (IMPACT study). Aliment Pharmacol Ther 2010, 31:824–833.20. Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, Jury J, Bolla M, BercikP, Collins SM, Verdu E, Ongini E: Proton pump inhibitors exacerbate NSAID-inducedsmall intestinal injury by inducing dysbiosis. Gastroenterology 2011, 141:1314–1322.
  • 15. Figure 1
  • 16. -1.0-0.50.00.51.01.52.02.53.03.54.0Before treatment After treatment0.10.31.90.5No.oflesions**Irsogladine (n=16)Omeprazole(n=16)Figure 2
  • 17. -205.9718.11Before treatment After treatment-100102030405060Irsogladine (n=16)Omeprazole(n=16)Ratio*Figure 3
  • 18. Figure 4

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