Matrix Metalloproteinase Secretion by Gastric Epithelial Cells Is Regulated by E Prostaglandins and MAPKs

Because matrix metalloproteinases (MMPs) play roles in inflammatory tissue injury, we asked whether MMP secretion by gastric epithelial cells may contribute to gastric injury in response to signals involved in Helicobacter pylori-induced inflammation and/or cyclooxygenase inhibition. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and epidermal growth factor (EGF) stimulated gastric cell MMP-1 secretion, indicating that MMP-1 secretion occurs in inflammatory as well as non-inflammatory situations. MMP-1 secretion required activation of the MAPK Erk and subsequent protein synthesis but was down-regulated by the alternate MAPK, p38. In contrast, secretion of MMP-13 was stimulated by TNF-alpha/IL-1beta but not EGF and was Erk-independent and mediated by p38. MMP-13 secretion was more rapid (peak, 6 h) than MMP-1 (peak > or =30 h) and only partly depended on protein synthesis, suggesting initial release of a pre-existing MMP-13 pool. Therefore, MMP-1 and MMP-13 secretion are differentially regulated by MAPKs. MMP-1 secretion was regulated by E prostaglandins (PGEs) in an Erk-dependent manner. PGEs enhanced Erk activation and MMP-1 secretion in response to EGF but inhibited Erk and MMP-1 when TNF-alpha and IL-1beta were the stimuli, indicating that the effects of PGEs on gastric cell responses are context-dependent. These data show that secretion of MMPs is differentially regulated by MAPKs and suggest mechanisms through which H. pylori infection and/or cyclooxygenase inhibition may induce epithelial cell signaling to contribute to gastric ulcerogenesis.ope

Helicobacter pylori-induced Apoptosis in Gastric Cancer Cell Lines

Background/Aims: Helicobacter pylori (H. pylori) is associated with active gastritis and peptic ulcer disease. Mechanism for H. pylori-induced gastric epithelial damage is still incompletely understood. However, the increase of apoptotic cells in H. pylori-infected mucosa suggested that apoptosis could be a major mechanism for cellular damage. As an effort to clarify the mechanism, we investigated whether H. pylori directly induce apoptosis in gastric cancer cells in vitro. Methods: Cultured H. pylori (ATCC 43504) were suspended as 109/mL. IL (interleukin)-8 was measured by enzyme linked immunosorbent assay. Cell survival was assessed by MTT [3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Apoptosis was detected and confirmed by demonstration of DNA fragmentation and morphologic changes. Results: H. pylori induced IL-8 production as well as decrease of cell survival in gastric cancer cell lines in a time- and concentration-dependen way. Addition of H. pylori to gastric cancer cells induced apoptosis. Such induction was not organ specific. Heat or formalin treatment of H. pylori almost completely inhibited IL-8 production but only partially blocked apoptosis. H. pylori- induced apoptosis was potentiated by interferon-γ pretreatment in HT-29 but not in AGS and KATO III. Conclusions: These results suggest that H. pylori affects on gastric epithelial cell growth by direct induction of apoptosis.ope

A Case with Gastric Anisakiasis Presented with a Submucosal Tumor

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Randomised clinical trial: comparison of tegoprazan and placebo in non-erosive reflux disease

Background: Tegoprazan is a novel, fast- and long-acting potassium-competitive acid blocker that suppresses gastric acid secretion, which could benefit patients with non-erosive reflux disease (NERD), a type of gastroesophageal reflux disease. Aim: To evaluate the efficacy and safety profiles of tegoprazan compared with those of a placebo in Korean patients with NERD. Methods: In this phase 3, double-blind, placebo-controlled, multicentre study, 324 Korean patients with NERD were randomised into three treatment groups: tegoprazan 50 mg, tegoprazan 100 mg and placebo. These drugs were provided once daily for 4 weeks. The primary endpoint was the proportion of patients with complete resolution of major symptoms (both heartburn and regurgitation) for the last 7 days of the 4-week treatment period. Other outcomes related to efficacy, safety and tolerability were also evaluated. Results: Among all, 42.5% (45/106), 48.5% (48/99) and 24.2% (24/99) of patients showed complete resolution of major symptoms at week 4 after receiving tegoprazan 50 mg, tegoprazan 100 mg, and placebo, respectively. Both doses of tegoprazan showed superior efficacy than the placebo (P = 0.0058 and P = 0.0004, respectively). The complete resolution rates of heartburn and proportions of heartburn-free days (as other efficacy outcomes) were significantly higher in both tegoprazan groups than in the placebo group (P < 0.05 for all). No significant difference in the incidence of treatment-emergent adverse events were noted. Conclusions: Tegoprazan 50 and 100 mg showed superior therapeutic efficacy compared with the placebo, as well as a favourable safety profile in patients with NERD. Registration number: ClinicalTrials.gov identifier NCT02556021.ope

Phase 4 Study in Patients From Asia With Gastroesophageal Reflux Disease Treated With Dexlansoprazole

Background/aims: Since the use of dexlansoprazole in Asian subjects with gastroesophageal reflux disease (GERD) has not been adequately characterized, this study was conducted to evaluate the efficacy and safety of dexlansoprazole modified-release in Asian subjects with non-erosive reflux disease (NERD) and erosive esophagitis (EE). Methods: In this phase 4, open-label, non-randomized, uncontrolled, multicenter, multi-country study sponsored by Takeda, subjects aged ≥ 20 years with persistent typical GERD symptoms for at least 6 months underwent endoscopy. Based on endoscopic findings, they were assigned to either dexlansoprazole modified-release 30 mg once-daily for 4 weeks (NERD group) or dexlansoprazole modified-release 60 mg once-daily for 8 weeks (EE group). The primary endpoint was the percentage of days that subjects did not experience any 24hour heartburn or acid regurgitation. Results: Of the 445 subjects screened from Hong Kong, South Korea, and Taiwan, 208 were enrolled in the NERD group (mean age: 53.6 years, male: 34.6%) and 88 in the EE group (mean age: 51.7 years, male: 55.7%). Over the treatment period, the median percentage of days that subjects did not experience any 24-hour heartburn or acid regurgitation was 26.9% and 65.5% in the NERD and EE groups, respectively; for nighttime heartburn or acid regurgitation the proportions were 59.3% and 83.3%, respectively. The treatment was well tolerated with low incidence of treatment-related adverse events in NERD and EE groups (6.7% and 5.7%, respectively). Conclusions: In Asian patients with GERD, treatment with dexlansoprazole modified-release indicates a favorable efficacy and safety profile in relieving heartburn and acid regurgitation symptoms.ope

Concomitant, sequential, and 7-day triple therapy in first-line treatment of Helicobacter pylori infection in Korea: study protocol for a randomized controlled trial

Background: Most international guidelines recommend triple-therapy regimens consisting of a proton pump inhibitor, clarithromycin, and amoxicillin/metronidazole for at least 7 days for the eradication of Helicobacter pylori. However, the efficacy of 7-day clarithromycin-based standard triple therapy for H. pylori infection is currently unacceptable in Korea. In this study, we will compare the efficacy and safety of 7-day standard triple therapy, 10-day sequential therapy, and 10-day concomitant therapy for the first-line treatment of H. pylori infection in Korea. Methods/design: In this multicenter, investigator-blinded, randomized trial we are recruiting adult patients with H. pylori infection from 15 hospitals in Korea to determine whether sequential or concomitant treatment is superior to standard triple therapy. Patients are randomly assigned to receive either standard triple therapy (lansoprazole, amoxicillin, and clarithromycin) for 7 days, or sequential treatment (lansoprazole and amoxicillin for the first 5 days, followed by lansoprazole, clarithromycin, and metronidazole for another 5 days) for 10 days, or concomitant therapy (lansoprazole, amoxicillin, clarithromycin, and metronidazole) for 10 days. The primary outcome is the rate of H. pylori eradication in the intention-to-treat population. Discussion: The results of this study will be crucial for determining the optimal regimen for the primary treatment of H. pylori infection in Korea. This study will produce vital evidence that will lead to revisions to guidelines concerning first-line treatment regimens for H. pylori infection. Trial registration: Clinical Research Information Service (CRIS), Republic of Korea, KCT0001980 . Registered on 25 July 2016.ope

Efficacy of S-pantoprazole 10 mg in the Symptom Control of Non-erosive Reflux Disease: A Phase III Placebo-controlled Trial

Background/aims: S-isomer (S) pantoprazole is more bioavailable and less dependent on cytochrome 2C19 than is racemic pantoprazole. We aim to evaluate the efficacy and safety of 10 mg S-pantoprazole for treatment of non-erosive reflux disease (NERD). Methods: In this phase 3, double-blind, randomized placebo controlled, multicenter study, 174 NERD patients were randomized to one of both treatment groups: 10 mg S-pantoprazole, or placebo once daily for 4 weeks. Symptoms and safety were assessed. The efficacy endpoints were complete relief of symptoms, > 50% improvement of all reflux symptoms and recurrence. Results: Eighty-eight patients were assigned to the S-pantoprazole group (25 males, mean 43.7 years old) and 86 to the placebo group (32 males, mean 43.0 years old), and 163 patients were subjected to full Analysis Set. A higher proportion of patients in the S-pantoprazole group had complete symptom relief (42.0 % [34/81] vs 17.1% [14/82], P 50% symptom responses (66.0% vs 50.0%, P = 0.010 for heartburn; 64.2% vs 28.0%, P = 0.010 for acid regurgitation; and 51.9% vs 30.5%, P = 0.03 for epigastric discomfort) compared to the placebo group. The factors associated with poor responsiveness to PPI were older age, female, greater body mass index, and severe baseline symptoms. Conclusions: Low dose of S-pantoprazole (10 mg) for 4 weeks was more efficacious than placebo in providing reflux symptom relief in patients with NERD, especially acid regurgitation. More doses or longer periods of treatment with S-pantoprazole would be needed to completely eliminate symptoms.ope

A case of gastric and colonic fistulas with pancreatic and peripancreatic abscess after acute necrotizing pancreatitis

According to several reports, the incidence of pancreatic and peripancreatic abscess after acute pancreatitits is quoted at about 5 percentage and this rare complication may cause fistulas with multiple intra- abdominal organs. Mortality rates are nearly 100 per cent, mostly due to sepsis and hemorrhage in the abscence of surgical intervention and even with surgical drainage and celiotomy, death rate of 30 to 50 percentage are noted due to recurrence. The pathogenesisi of these fistulas may be multifactorial ; activated pancreatic enzyme and the products of secondary infection penetrating visceral wall directly, and vascular thrombosis and shock causing ischemic necrosis of the gastrointestinal wall. The gastrointestinal fistulas after acute necrotizing pancreatitis have been reported rarely in Korea. The authors experienced a sixty three year old male patient case of gastric and colonic fistulas in communication with retroperitoneal pancreatic abscess after acute pancreatitis. The patient received broad- spectrum antibiotics and percutaneous catheter drainage without surgical intervention. After treatment, he recovered well complete. Conservative care with drainage procedure may be a suitable alternative for managing the gastrointestinal fistulas with the pancreatic and peripancreatic abscess after acute nectrotizing pancreatitis .(Korean J Med 58:675- 680, 2000)ope

Phase III Clinical Trial of Revaprazan (Revanex？) for Gastritis

Background/Aims: We performed a randomized, double-blind, phase III, multicenter trial to assess the comparative efficacy and safety of revaprazan, which is a novel acid pump antagonist in comparison with ranitidine for treating patients suffering with acute gastritis and acute aggravation of chronic gastritis. Methods: Five hundred and twelve subjects were randomized to 2 weeks of treatment with either revaprazan 200 mg q.d. or ranitidine 150 mg b.i.d. The primary efficacy parameter was the estimated improvement rate according to endoscopy, and the secondary efficacy parameter was the improvement rate for the subjects' symptoms. Results: The estimated improvement rates at 2 weeks (intention-to-treat analysis) were 79.9% with revaprazan and 60.5% with ranitidine; a significant difference was found between the two groups (p＜0.0001). On the per-protocol analysis, the estimated improvement rates for revaprazan and ranitidine were 79.4% and 60.2%, respectively. There was a significant difference in the estimated improvement rates between the two groups (p＜0.0001). On both analyses, there were no significant differences between the two groups for the improvement rates of the subjects' symptoms. Both drugs were well tolerated. Conclusions: The efficacy of revaprazan was higher than that of ranitidine for the estimated improvement rate according to endoscopy and also for the symptomatological improvement rate, and revaprazan was well tolerated by the subjects suffering with gastritis.ope

Clinical Guidelines for Drug-induced Peptic Ulcer, 2020 Revised Edition

The Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcers were previously developed under co-work with the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology at 2009. On the other hand, the previous guidelines were based mainly on a literature review and expert opinions. Therefore, the guidelines need to be revised. In this study, a guideline development committee for drug-induced peptic ulcers was organized under the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017. Nine statements were developed, including four for NSAID, three for aspirin and other antiplatelet agents, and two for anticoagulants through de novo processes based on evidence-based medicine, such as a literature search, meta-analysis, and the consensus was established using the modified Delphi method. The primary target of this guideline was adult patients taking long-term NSAIDs, aspirin, or other antiplatelet agent and anticoagulants. The revised guidelines reflect the consensus of expert opinions and are intended to assist relevant clinicians in the management and prevention of drug-induced peptic ulcers and associated conditions.ope