Yukiko Yoda

Present status and strategy of NSAIDs-induced small bowel injury

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. The prevalence of NSAIDs-induced small intestinal injury is higher than had been expected. Recent studies show that more than 50% of patients taking NSAIDs have some mucosal damage in the small intestine. The gross appearance of NSAID-induced enteropathy varies, appearing variously as diaphragm-like strictures, ulcers, erosions, and mucosal redness. To investigate NSAID-induced enteropathy, and to rule out other specific enteropathies, other useful methods (in addition to capsule endoscopy and balloon enteroscopy) include such modalities as radiological examination of the small intestine, the permeability test, scintigraphy or the fecal excretion test using 111Indium-labeled white blood cells, and measurement of the fecal calprotectin concentration. Diaphragm-like strictures and bleeding from mucosal breaks may be treatable with interventional enteroscopy. Misoprostol, metronidazole, and sulfasalazine are frequently used to treat NSAID-induced enteropathy, but have undesirable effects in some cases. In the experimental model, we confirmed that several existing drugs for gastroduodenal ulcers prevented indomethacin-induced small intestinal injury. Such drugs may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine. We hope to examine these drugs in future clinical studies.

Prevention of NSAID-Induced Small Intestinal Mucosal Injury: Prophylactic Potential of Lansoprazole

Non-steroidal anti-inflammatory drugs (NSAIDs), which are used for the treatment of several inflammatory disorders including rheumatoid arthritis, are well known to cause gastroduodenal mucosal lesions as an adverse effect. Recently, the serious problem of NSAID-induced small intestinal damage has become a topic of great interest to gastroenterologists, since capsule endoscopy and double-balloon enteroscopy are available for the detection of small intestinal lesions. Such lesions have been of great concern in clinical settings, and their treatment and prevention must be devised as soon as possible. Proton pump inhibitors (PPI), such as lansoprazole and omeprazole, show a potent anti-secretory effect. PPIs also have a gastroprotective effect, independent of their anti-secretory actions, which is probably mediated by inhibition of neutrophil functions as well as antioxidant actions. Administration of lansoprazole reduced the severity of the intestinal lesions in a dose-dependent manner, but omeprazole had no effect. The amount of heme oxygenase-1 (HO-1) protein in the intestinal mucosa was significantly increased by lansoprazole, but not by omeprazole. These results suggest that lansoprazole, but not omeprazole, ameliorates indomethacin-induced small intestinal ulceration through upregulation of HO-1/carbon monoxide. Therefore, lansoprazole may be useful for preventing the adverse effects of NSAIDs not only in the stomach but also in the small intestine.

Utility and problems of endoscopic submucosal dissection for early gastric cancer in elderly patients.

Background and Aim:  Endoscopic submucosal dissection (ESD) is reported to be a safe and reliable procedure for the elderly, but these reports could have already had a bias at the time ESD was performed. However, the reports have not clearly stated the criteria of indications. In the present study, we retrospectively elucidated the usefulness and problems of ESD for early gastric cancer in elderly patients (≥ 65 years) in comparison with non‐elderly patients.

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

BackgroundProton-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.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 omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment.ResultsThere was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group 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 with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031).ConclusionIrsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole.Trial registrationThis study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114)

Significance of chymase-dependent matrix metalloproteinase-9 activation on indomethacin-induced small intestinal damages in rats.

The side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) include gastrointestinal damage not only in the stomach but also in the small intestine. Chymase converts promatrix metalloproteinase-9 to matrix metalloproteinase (MMP)-9, which plays an important role in NSAID-induced gastric damage, but it has been unclear whether chymase-dependent MMP-9 activation is involved in the NSAID-induced small intestinal damage. To clarify the involvement of chymase-dependent MMP-9 activation on NSAID-induced small intestinal damage, the effect of a chymase inhibitor, 2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl] thiazole-4-carboxylic acid (TY-51469), on indomethacin-induced small intestinal damage in rats was evaluated. Until 6 h after oral administration of indomethacin in rats, intestinal MMP-9 activity was unchanged compared with normal rats, but significant increases in MMP-9 activity were observed 12 and 24 h after indomethacin administration. Significant increases in the small intestinal damage score were also observed 12 and 24 h after indomethacin administration. In the extract from the small intestine 24 h after indomethacin administration, the MMP-9 activation was significantly attenuated by TY-51469. Intraperitoneal injection of TY-51469 (10 mg/kg) 3 h before indomethacin administration significantly attenuated the MMP-9 activity in the small intestine compared with placebo treatment. Myeloperoxidase activity, which indicates accumulation of neutrophils, was significantly increased in the small intestine in the placebo-treated rats, but its activity was significantly attenuated by TY-51469 treatment. The area of small intestinal damage was also significantly ameliorated by TY-51469 treatment. These findings suggest that chymase-dependent MMP-9 activation has a significant role in indomethacin-induced small intestinal damage in rats.

Risk Management for Gastrointestinal Endoscopy in Elderly Patients: Questionnaire for Patients Undergoing Gastrointestinal Endoscopy

More elderly patients now undergo gastrointestinal endoscopy following recent advances in endoscopic techniques. In this study, we conducted a high-risk survey of endoscopies in Japan, using a questionnaire administered prior to upper gastrointestinal tract endoscopy (UGITE), and identified anticholinergic agents and glucagon preparations as high-risk premedication. We also evaluated the cardiovascular effects of anticholinergic agents and glucagon through measurements of plasma levels of human atrial natriuretic peptide (hANP) and human brain natriuretic peptide (hBNP). The subjects were 1480 patients who underwent UGITE. Nurses administered a pre-endoscopy questionnaire, questioning subjects regarding heart disease, hypertension, glaucoma, and urinary difficulties as risk factors for anticholinergic agents, and Diabetes mellitus as a risk factor for glucagon preparations. Evaluation of subjects divided into under 65 and over 65 age groups revealed that in subjects aged 65 and over, risk factors for anticholinergic agents were significantly more high than those for glucagon. Analysis of the cardiovascular effects of anticholinergic agents and glucagon, in the elderly patients showed that hANP levels were significantly higher following administration of anticholinergic agents, but the change was not significant for glucagon premedication. Taking a detailed history before UGITE with the aid of a questionnaire at the same time as informed consent is obtained, is extremely useful in terms of risk management and selection of the appropriate premedication.

Protective effect of roxatidine against indomethacin‐induced small intestinal mucosal injury in rats

Background and Aims:  Non‐steroidal anti‐inflammatory drugs (NSAIDs) are among the most significant causative factors of gastroduodenal ulcers. Recent reports have demonstrated that NSAIDs can also frequently induce ulceration and erosions of the small intestine. The aim of this study was to examine whether or not roxatidine (an H2 receptor antagonist), which is known to increase gastric mucus in addition to inhibiting gastric acid, might suppress indomethacin‐induced small intestinal mucosal injury, through an increase in mucus in rats.

Gastric ulcer healing after treatment of endoscopic submucosal dissection in Japanese: comparison of H2 receptor antagonist and proton pump inhibitor administration

Endoscopic submucosal dissection has made it possible to resect large lesions during a single operation. The present study was undertaken to compare the time taken for recovery from artificial ulcers after endoscopic submucosal dissection between an H2 Receptor Antagonist treatment group and a Proton Pump Inhibitor treatment group, focusing on analysis of the time course of reduction rate in ulcer area. The powerful acid suppression by Proton Pump Inhibitor may not be needed to treat Japanese post-endoscopic submucosal dissection ulcer which usually develops after early gastric carcinoma in the mucosa of low acid secretory capacity. The study involved 60 patients with 69 artificial ulcers following endoscopic submucosal dissection for the treatment of tumors remaining in the gastric mucosa. Of all lesions, 36 were allocated to the H2 Receptor Antagonist group and 33 to the Proton Pump Inhibitor group. Patients in both groups underwent endoscopy at 4 and 8 weeks after the start of administration. There were no significant differences between two groups and ulcer healing rates were similar in the two groups. The efficacy of H2 Receptor Antagonists in curing this type of ulcer can thus be expected to be comparable to that of Proton Pump Inhibitors.

Strategies for peptic ulcer healing after 1 week proton pump inhibitor-based triple Helicobacter pylori eradication therapy in Japanese patients: differences of gastric ulcers and duodenal ulcers.

Helicobacter pylori (H. pylori) eradication therapy alone is insufficient to ensure healing of large ulcers with H. pylori-positive gastric ulcer (GU). The question of what is the optimum antiulcer treatment following H. pylori eradication therapy has not been fully elucidated. Furthermore, the ulcer healing effects of eradication therapy itself with H. pylori-positive duodenal ulcer (DU) have not been investigated. In GU study, the eradication therapy + proton pump inhibitor (PPI) group (group A) were administered eradication therapy followed by 7 weeks of a PPI, and the eradication therapy + gastroprotective drug (GP) group (group B) eradication therapy followed by 7 weeks of a GP. In DU study, the eradication therapy + PPI group (group C) were administered eradication therapy followed by 5 weeks of a PPI, and the eradication therapy only group (group D) was eradication therapy alone. In GU study, healing rates for ulcer of ≥15 mm in diameter were significant greater in the group A. In DU study, high healing rates were seen both the group C and D. In conclusion, a PPI could significantly heal GU than a GP after eradication therapy in GU. Meanwhile, the eradication alone is sufficient for DU.

Tu1657 Evaluation of Additive Effects of Narrow Band Imaging (NBI) Magnification in Borderline Gastric Cancer Diagnosis: Randomized Comparative Study of Conventional/Dye Endoscopy With and Without NBI-Magnification

Evaluation of Additive Effects of Narrow Band Imaging (NBI) Magnification in Borderline Gastric Cancer Diagnosis: Randomized Comparative Study of Conventional/Dye Endoscopy With and Without NBI-Magnification Toshihisa Takeuchi*, Eiji Umegaki, Yuichi Kojima, Ken Narabayashi, Yukiko Yoda, Akira Imoto, Sadaharu Nouda, Kumi Ishida, Yosuke Abe, Daisuke Masuda, Takuya Inoue, Satoshi Tokioka, Kazuhide Higuchi 2nd Dep of Internal Medicine, Osaka Medical Collage, Takatsuki, Japan Introduction: Endoscopic submucosal dissection (ESD) is used globally for early gastric cancer, and accurate borderline lesion diagnosis is important. Current qualitative gastric cancer diagnosis involves magnification NBI. Distinguishing benign and malignant tumors by surface microstructural and capillary patterns, and diagnosing excavated gastric cancer histotypes, are reported to be possible, but there is no firm position on NBI-magnification borderline gastric cancer diagnosis. Objectives: To investigate additive effects of NBI-magnification for borderline diagnosis of ESD-target gastric cancer, and pathological characteristics of lesions not diagnosable even with NBI-magnification. Subjects and Methods: ESD-target gastric cancer cases were randomly allocated, 250 lesions each, to borderline diagnosis by conventional/dye endoscopy, with and without NBImagnification. The former used maximum magnification, structural reinforcement B8, and an Evis Lucera magnifying endoscope with a slit-tip transparent hood. Cancer and other tissues were distinguished by Yao’s VS classification system, and lesion border demarcation lines were determined. With each group, three endoscopists performed or attended pre-ESD borderline lesion diagnosis, marking approx. 5 mm outside lesions, and ESD. Preoperative borderline diagnosis and ESD specimens were compared pathologically, and the rate of failing borderline diagnosis (lateral margin positivity), and causative factors, were evaluated. Results: There were no significant inter-group differences in lesion size, shape, or position, or ESD duration. Conventional/dye endoscopy borderline diagnosis failure rate was significantly lower with than without NBImagnification, at 1.6% (4/250) and 5.6% (14/250; p 0.05). Lesions failing borderline diagnosis are (a) well-differentiated adenoma with mucosal surface layer replacement-type growth; (b) moderately differentiated adenoma dominated by mucosal middle layer invasion, with little surface layer atypia; or (c) undifferentiated cancer with mucosal middle layer invasion. Conclusions: In borderline gastric cancer diagnosis in ESD-target patients, addition of NBImagnification to conventional/dye endoscopy significantly increased diagnostic accuracy, showing the method’s additive effects. However, in histological evaluation of lesions (well-differentiated adenoma with little mucosal surface layer atypia, low-atypia cancer with mucosal middle layer invasion, etc) failing borderline diagnoses even with NBI-magnification, identification of the demarcation line was considered to be difficult.