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Background: Proton-pump inhibitors (PPIs) prevent aspirin-associated gastric and duodenal mucosal damage. However, long-term use of PPIs can lead to various adverse reactions, such as gastric polyps and enterochromaffin-like cell hyperplasia. Current research indicates that the abovementioned adverse reactions are mainly related to hypergastrinemia. We investigated whether low-frequency administration of omeprazole could effectively repair aspirin-induced mucosal damage and reduce the increase in gastrin levels associated with long-term use of PPIs., Methods: Sprague‒Dawley rats were divided into four treatment groups: daily aspirin, daily aspirin and omeprazole once every day (qd), daily aspirin and omeprazole once every other day (qod), and daily aspirin and omeprazole once every three days (1/d3). After 15 days of feeding, blood samples were collected, and the stomachs of sacrificed rats were subjected to macroscopic, histological, and immunohistochemical studies. Moreover, in clinical practice, patients with peptic ulcers caused by aspirin took a standard dose of omeprazole (20 mg) every other day. Two months later, gastroscopy was performed to examine the healing of the ulcers., Results: Both the omeprazole qd and omeprazole qod administrations effectively prevented aspirin-induced gastric peptic ulcers, with no significant difference between the two groups in the inhibition of parietal cell secretion of gastric acid and cell apoptosis. However, omeprazole 1/d3 failed to completely prevent aspirin-induced gastric mucosal injury. Notably, the gastrin levels, cell proliferation ability and cholecystokinin B receptor expression of the omeprazole qd group were significantly higher than those of the omeprazole qod group. In clinical work, patients with peptic ulcers caused by aspirin were given a standard dose of omeprazole every other day, and their ulcers healed after 2 months, as observed by gastroscopy., Conclusions: Omeprazole administration once every other day can effectively prevent aspirin-induced peptic ulcers and reduce hypergastrinemia, which may reduce the long-term adverse effects of PPI treatment., (© 2024. The Author(s).)

A comprehensive overview of the associations between air pollution and the risk of gastrointestinal (GI) diseases has been lacking. We aimed to examine the relationships of long-term exposure to ambient particulate matter (PM) with aerodynamic diameter ≤2.5 μm (PM 2.5 ), 2.5-10 μm (PM c oarse ), ≤10 μm (PM 10 ), nitrogen dioxide (NO 2 ), and nitrogen oxides (NO x ), with the risk of incident GI diseases, and to explore the interplay between air pollution and genetic susceptibility. A total of 465,703 participants free of GI diseases in the UK Biobank were included at baseline. Land use regression models were employed to calculate the residential air pollutants concentrations. Cox proportional hazard models were used to evaluate the associations of air pollutants with the risk of GI diseases. The dose-response relationships of air pollutants with the risk of GI diseases were evaluated by restricted cubic spline curves. We found that long-term exposure to ambient air pollutants was positively associated with the risk of peptic ulcer (PM 2.5 : Q4 vs. Q1: hazard ratio (HR) 1.272, 95% confidence interval (CI) 1.179-1.372, NO 2 : 1.220, 1.131-1.316, and NO x : 1.277, 1.184-1.376) and chronic gastritis (PM 2.5 : 1.454, 1.309-1.616, PM 10 : 1.232, 1.112-1.366, NO 2 : 1.456, 1.311-1.617, and NO x : 1.419, 1.280-1.574) after Bonferroni correction. Participants with high genetic risk and high air pollution exposure had the highest risk of peptic ulcer, compared to those with low genetic risk and low air pollution exposure (PM 2.5 : HR 1.558, 95%CI 1.384-1.754, NO 2 : 1.762, 1.395-2.227, and NO x : 1.575, 1.403-1.769). However, no significant additive or multiplicative interaction between air pollution and genetic risk was found. In conclusion, long-term exposure to ambient air pollutants was associated with increased risk of peptic ulcer and chronic gastritis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Low-dose aspirin (LDA) administration is associated with an elevated risk of recurring peptic ulcer (PU) and gastrointestinal (GI) hemorrhage., Aims: This systematic review and Bayesian network meta-analysis aimed to comprehensively assess the effectiveness of diverse medications in preventing the recurrence of PU and GI hemorrhage in patients with a history of PU receiving long-term LDA therapy., Methods: This systematic review and network meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and was registered on PROSPERO (CRD42023406550). We searched relevant studies in main databases from inception to March 2023. All statistical analyses were performed using R (version 4.1.3), with the "Gemtc" (version 1.0-1) package. The pooled risk ratio (RR), corresponding 95% credible interval (95% CrI), and the surface under the cumulative ranking curve (SUCRA) were calculated., Results: 11 Randomized clinical trials (RCTs) were included. The analysis underscored pantoprazole was the most efficacious for reducing the risk of PU recurrence (RR [95% CrI] = 0.02 [0, 0.28]; SUCRA: 90.76%), followed by vonoprazan (RR [95% CrI] = 0.03 [0, 0.19]; SUCRA: 86.47%), comparing with the placebo group. Pantoprazole also performed well in preventing GI hemorrhage (RR [95% CrI] = 0.01[0, 0.42]; SUCRA: 87.12%) compared with Teprenone., Conclusions: For patients with a history of PU receiving LDA, pantoprazole and vonoprazan might be the optimal choices to prevent PU recurrence and GI hemorrhage., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with caution in adults aged 65 years and older. Their gastrointestinal adverse event risk might be further reinforced when using concomitant cholinesterase inhibitors (ChEIs). We aimed to investigate the association between NSAIDs and ChEI use and the risk of peptic ulcers in adults aged 65 years and older., Methods: Register-based self-controlled case series study including adults ≥65 years with a new prescription of ChEIs and NSAIDs, diagnosed with incident peptic ulcer in Sweden, 2007-2020. We identified persons from the Total Population Register individually linked to several nationwide registers. We estimated the incidence rate ratio (IRR) of peptic ulcer with a conditional Poisson regression model for four mutually exclusive risk periods: use of ChEIs, NSAIDs, and the combination of ChEIs and NSAIDs, compared with the non-treatment in the same individual. Risk periods were identified based on the prescribed daily dose, extracted via a text-parsing algorithm, and a 30-day grace period., Results: Of 70,060 individuals initiating both ChEIs and NSAIDs, we identified 1500 persons with peptic ulcer (median age at peptic ulcer 80 years), of whom 58% were females. Compared with the non-treatment periods, the risk of peptic ulcer substantially increased for the combination of ChEIs and NSAIDs (IRR: 9.0, [6.8-11.8]), more than for NSAIDs alone (5.2, [4.4-6.0]). No increased risks were found for the use of ChEIs alone (1.0, [0.9-1.2])., Discussion: We found that the risk of peptic ulcer associated with the concomitant use of NSAIDs and ChEIs was over and beyond the risk associated with NSAIDs alone. Our results underscore the importance of carefully considering the risk of peptic ulcers when co-prescribing NSAIDs and ChEIs to adults aged 65 years and older., (© 2023 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: To investigate the risk factors for gastrointestinal bleeding in patients with cerebral infarction after dual antiplatelet therapy., Methods: Cerebral infarction patients who received dual antiplatelet therapy during January 2019 and December 2021 in Nanchang University Affiliated Ganzhou Hospital were included. Patients were divided into a bleeding group and a nonbleeding group. Propensity score matching was used to match the data between the two groups. The risk factors for cerebral infarction with gastrointestinal bleeding after receiving dual antiplatelet therapy were analyzed by conditional logistic regression., Results: There were 2370 cerebral infarction patients who received dual antiplatelet therapy included in the study. There were significant differences between the bleeding group and the nonbleeding group in terms of sex, age, smoking, drinking, hypertension, coronary heart disease, diabetes and peptic ulcer before matching. After matching, 85 patients were included in the bleeding group and nonbleeding group, and there was no significant difference between the two groups in terms of sex, age, smoking, drinking, previous cerebral infarction, hypertension, coronary heart disease, diabetes, gout or peptic ulcer. Conditional logistic regression analysis showed that long-term use of aspirin and severity of cerebral infarction were risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy, whereas the use of PPI was a protective factor against gastrointestinal bleeding., Conclusions: Long-term use of aspirin and severity of cerebral infarction are risk factors for gastrointestinal bleeding in cerebral infarction patients receiving dual antiplatelet therapy. The use of PPIs could reduce the risk of gastrointestinal bleeding., Competing Interests: Declaration of Competing interest Authors declare no Conflict of Interests for this article., (Copyright © 2023. Published by Elsevier B.V.)

Goals: The aim was to systematically evaluate risks and benefits of proton pump inhibitor (PPI) use for stress ulcer prophylaxis in the critically ill patient., Background: Whether PPIs increase mortality in the critically ill patient remains controversial., Study: Systematic review and meta-analysis of randomized controlled trials (RCTs) and cohort studies with trial sequential analysis, Bayesian sensitivity analysis, and fragility index analysis., Results: A total of 31 studies in 78,009 critically ill adults receiving PPIs versus any comparator were included. PPI use was associated with an increased mortality risk in all studies [19.6% PPI vs. 17.5% comparator; RR: 1.10; 95% confidence interval (CI): 1.02-1.20; P =0.01], in the subgroup of RCTs (19.4% vs. 18.7%; RR: 1.05; 95% CI: 1.0-1.09, P =0.04), but not cohort studies (19.9% vs. 16.7%; RR: 1.12; 95% CI: 0.98-1.28, P =0.09). Results were maintained with a Bayesian sensitivity analysis (RR: 1.13; 95% credible interval: 1.035-1.227) and a fragility index analysis, but not sequential analysis ( P =0.16). RCTs with a higher baseline severity of illness revealed the greatest mortality risk with PPI use (32.1% PPI vs. 29.4% comparator; RR: 1.09; 95% CI: 1.04-1.14; P <0.001). PPI use reduced clinically important bleeding in RCTs (1.4% PPI vs. 2.1% comparator; RR: 0.67; 95% CI: 0.5-0.9; P =0.009) but increased bleeding in cohort studies (2.7% PPI vs. 1.2% comparator; RR: 2.05; 95% CI: 1.2-3.52; P =0.009). PPI use was not associated with a lower incidence of clinically important bleeding when compared with histamine-2 receptor antagonists (1.3% vs. 1.9%; RR: 0.59; 95% CI: 0.28-1.25, P =0.09)., Conclusions: This meta-analysis demonstrated an association between PPI use and an increased risk of mortality., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Proton pump inhibitors (PPIs) are effective in reducing marginal ulcers after pancreatoduodenectomy. However, their impact on perioperative complications has not been defined., Methods: We retrospectively analyzed the effect of postoperative PPIs on 90-day perioperative outcomes in all patients who underwent pancreatoduodenectomy at our institution from April 2017 to December 2020., Results: 284 patients were included; 206 (72.5%) received perioperative PPIs, 78 (27.5%) did not. The two cohorts were similar in demographics and operative variables. Postoperatively, the PPI cohort had significantly higher rates of overall complications (74.3% vs. 53.8%) and delayed gastric emptying (28.6% vs. 11.5%), p < 0.05. However, no differences in infectious complications, postoperative pancreatic fistula, or anastomotic leaks were seen. On multivariate analysis, PPI was independently associated with a higher risk of overall complications (OR 2.46, CI 1.33-4.54) and delayed gastric emptying (OR 2.73, CI 1.26-5.91), p = 0.011. Four patients developed marginal ulcers within 90-days postoperatively; all were in the group who received PPIs., Conclusion: Postoperative proton pump inhibitor use was associated with a significantly higher rate of overall complications and delayed gastric emptying after pancreatoduodenectomy., Competing Interests: Conflict of interest None to declare., (Copyright © 2023 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Background and Objective: Pancreatic cancer (PC) is the seventh leading cause of death among cancers mortality. Pancreatic carcinogenesis remains poorly understood. There is still an urge to allocate other related risk factors that may help in better recognition of this pathogenesis. There is increasing evidence suggested that peptic ulcer disease (PUD), and its treatment might affect the development of PC however, studies findings reported conflicting results. Our meta-analysis aimed to study the association between PUD and its treatments (proton pump inhibitors [PPIs] and histamine-2 receptor antagonists [H2RAs]) and risk of PC., Methods: We searched PubMed/MEDLINE, Embase, and Cochrane library databases from inception through January 2022. We included case-control studies, cohort, and randomized control trials which reported the association between PUD, PPIs, and H2RAs and the risk of PC. Odds ratio (OR) were used to calculate pooled estimates for PC risk. The association were evaluated using random-effects models, in two sided statistical tests., Results: A total of 22 publications were retained for the meta-analysis. PUD was associated with a significant increase in PC risk (OR 1.26, 95% CI= 1.01-1.57, P= 0.038, I2= 92%). The risk of developing PC were significant in patients receiving PPIs (OR 1.76, 95% CI= 1.26-2.46, P=0.001, I2= 98%) and H2RAs (OR 1.25, 95% CI = 1.042- 1.49, P= 0.016, I2= 80%)., Conclusions: There is a 1.26-fold increase risk of PC in patients with PUD. The elevated PC is also attributable to 1.76-fold greater risk in PPIs group compared to 1.25-fold in H2RAs group.

Background: Overuse of stress ulcer prophylaxis is prevalent globally despite guidelines leading to the added cost, especially the intravenous proton pump inhibitor (IVPPI). This study aims to analyze the prevalence of such overuse and be aware of rational use which may help develop local guidelines., Methods: This study analyzed the prospectively collected data on IVPPI use in adult patients in general wards of medicine and surgery at Patan Hospital, Patan Academy of Health Sciences, Nepal, from April-Jun 2022. Ethical approval was obtained. Variables analyzed were the patient's age, gender, history of peptic ulcer disease, risk for stress ulcer and gastrointestinal bleeding, the status of nil per os (NPO ≥12 hours), appropriate use of IVPPI, and cost., Results: Prevalence of IVPPI use was 36.24% (274/756 admissions), surgery 39.45(189/479), medicine ward 30.68% (85/277). The mean age was 43.1 ±18.6 years, males 113(41.2%), surgery 189 (69%). Inappropriate overuse in 253(92.3%, significantly more in surgery-182 than medicine-7, p=0.001. Appropriate use was in 21 (7.7%, i.e., NPO-15, NPO + gastrointestinal bleed, and NPO + non steroid anti-inflammatory drugs each 3)., Conclusions: Prevalence of IVPPI use was 36.24%. Inappropriate overuse of IVPPI was high (92.2%, 253/274), more in surgery. The nil per os status was the main reason for appropriate use of IVPPI.

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion, used as first-line agents in treating peptic ulcers. However, we have previously reported that PPIs may diminish the therapeutic effect of anti-vascular endothelial growth factor (VEGF) drugs in patients with cancer. In this study, we explored the effects of vonoprazan, a novel gastric acid secretion inhibitor used for the treatment of peptic ulcers, on the secretion of VEGF in cancer cells and attempted to propose it as an alternative PPI for cancer chemotherapy. The effects of PPI and vonoprazan on VEGF expression in cancer cells were compared by real-time reverse transcription-polymerase chain reaction and ELISA. The interaction of vonoprazan and PPIs with transcriptional regulators by docking simulation analysis. In various cancer cell lines, including the human colorectal cancer cell line (LS174T), PPI increased VEGF messenger RNA expression and VEGF protein secretion, while this effect was not observed with vonoprazan. Molecular docking simulation analysis showed that vonoprazan had a lower binding affinity for estrogen receptor alpha (ER-α), one of the transcriptional regulators of VEGF, compared to PPI. Although the PPI-induced increase in VEGF expression was counteracted by pharmacological ER-α inhibition, the effect of vonoprazan on VEGF expression was unchanged. Vonoprazan does not affect VEGF expression in cancer cells, which suggests that vonoprazan might be an alternative to PPIs, with no interference with the therapeutic effects of anti-VEGF cancer chemotherapy., (© 2022 Wiley Periodicals LLC.)

Introduction: The proportion of gastroduodenal ulcers caused by drugs is increasing. However, the risk of gastroduodenal ulcer from drugs other than nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin is unclear. An association between immunosuppressive drugs and gastroduodenal ulcers has been suggested. We aimed to identify the immunosuppressive drugs and clinical characteristics associated with gastroduodenal ulcers in post-liver transplant patients., Methods: The study investigated 119 patients who underwent esophagogastroduodenoscopy after liver transplantation, and 2 patients were excluded. Clinical characteristics, medications, and endoscopic images were retrospectively reviewed., Results: Among 117 post-living donor liver transplant recipients, gastroduodenal ulcers were found in 10 (9.2%) patients. The ulcer group had endoscopic gastritis more frequently (40%) compared with the non-ulcer group (10%). Logistic regression analysis revealed gastritis, NSAID use, and mycophenolate mofetil were risk factors in the post-liver transplant patients. Among 103 patients not on NSAIDs, 8 (7.8%) had peptic ulcer. The most common ulcer site and ulcer shape were the gastric antrum and a circular shape, respectively. All patients in the ulcer group were taking mycophenolate mofetil, which was the only immunosuppressive drug that showed a significant difference between the two groups. Five out of 8 ulcer patients (63%) were taking gastric acid suppressants, and gastroduodenal ulcers in post-liver transplant recipients were suggested to be refractory., Conclusion: Patients treated with immunosuppressive drugs after liver transplantation can develop gastroduodenal ulcers, even with gastric acid suppressant medication. Mycophenolate mofetil may increase the risk of gastroduodenal ulcers compared with other immunosuppressive drugs., (© 2023 S. Karger AG, Basel.)

Background: To investigate the effect of Anwei Qingyou formula on the clinical treatment of patients with peptic ulcer (PU) and its effect on the levels of epidermal growth factor (EGF) and prostaglandin E2 (PGE2)., Methodology: Medical records of 83 patients with PU, treated in our hospital from January 2020 to January 2021, were retrospectively analyzed. Among them, 40 patients received conventional triple therapy (scheme I), that is, oral omeprazole, clarithromycin and amoxicillin, twice a day, and 43 patients received conventional triple therapy + Anwei Qingyou formula, taken orally twice a day (scheme II). The improvement of clinical symptoms, the quality of ulcer healing, clinical effectiveness and recurrence rate were analyzed after 4 weeks of treatment. Patients were followed up for six months., Results: After treatment with corresponding regimen, the total clinical effective rate of scheme II was 97.57% (42/43), which was significantly higher than 82.50% (33/40) of scheme I. Six-month follow-up results showed that the recurrence rate in scheme II patients was 4.65% (2/43), which was significantly lower than 20.00% (8/40) in the scheme I group (χ 2 = 5.479, 4.607, all P < .05). After one course of treatment, the levels of serum EGF and PGE2 in scheme II group were higher than those in scheme I group (P < .05)., Conclusion: In combination with the conventional western medicine treatment, Anwei Qingyou formula administration in PU patients effectively improves the overall control of the disease and therapeutic effectiveness., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Histamine-2-receptor antagonists (H 2 RAs) have been largely replaced by proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) despite the inconclusive evidence concerning comparative effectiveness., Objective: To compare the effectiveness of PPIs and H 2 RAs on SUP in real-world setting., Methods: PubMed, Embase, and the Cochrane Library were searched from inception to September 19, 2021. We included cohort studies comparing PPIs with H 2 RAs in critically ill adult patients and explicitly reporting the outcome of gastrointestinal (GI) bleeding or mortality. Newcastle-Ottawa Scale was used to assess potential risk of bias. We conducted a random-effects meta-analysis and only the studies with adjusted effect estimates were pooled. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of the evidence., Results: Thirteen cohort studies (N = 145 149) were eligible and 11 of them available for full texts were of low to moderate risk of bias. Meta-analysis of adjusted effect estimates indicated that PPIs were associated with a significantly higher risk of GI bleeding, compared with H 2 RAs (8 studies, odds ratio [OR] = 1.98, 95% confidence interval [CI] = 1.30-3.01, low certainty). Post hoc pooling analysis also suggested that PPIs were associated with a slightly higher risk of mortality in comparison with H 2 RAs (7 studies, OR = 1.27, 95% CI = 1.13-1.42, low certainty)., Conclusion and Relevance: The systematic review of cohort studies showed that PPIs were associated with higher risks of GI bleeding and mortality, although the certainty of evidence was low. Overall, we suggest not excluding H 2 RAs for SUP, while further studies are essential for elucidating the risk stratification, optimal regimen, and specific duration.

Aims: Previous studies reported proton pump inhibitor (PPI) use may increase the risk of fracture; however, the findings may be susceptible to indication bias because peptic ulcer disease (PUD), 1 major indication for PPIs, may affect skeletal health. Determining whether PUD would increase hip fracture risk may help identify high-risk populations and explore risk factors., Methods: We conducted a cohort study using data from The Health Improvement Network (THIN) in the United Kingdom. THIN contains patient information such as disease diagnosis and medicine prescriptions. Up to 5 non-PUD individuals (n = 138 265) were matched to each case of incident PUD (n = 27 653) by age, sex, and body mass index. We examined the association between PUD and hip fracture by a multivariable Cox proportional hazard model. We repeated the same analysis among individuals with incident PUD and gastroesophageal reflux disease (GERD) (n = 27 160), another disease with similar indication for PPIs, as a positive control exposure., Results: Over a mean of 5.6 years of follow-up, hip fracture occurred in 589 individuals with PUD and 2015 individuals without PUD (3.8 vs 2.6/1000 person-years), with a multivariable-adjusted hazard ratio (HR) being 1.44 (95% confidence interval [CI], 1.31-1.58). The association persisted among subgroups stratified by sex and age. In positive control exposure analysis, the hip fracture risk was also higher in PUD than GERD (3.8 vs 2.4/1000 person-years; multivariable-adjusted HR = 1.65; 95% CI, 1.45-1.7)., Conclusions: This general population-based cohort study suggests, after controlling for acid-lowering medication and other potential risk factors, PUD is independently associated with an increased risk of hip fracture., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Peptic ulcer disease is a frequent clinical problem with potentially serious complications such as bleeding or perforation. A decisive factor in the pathogenesis of peptic ulcers is gastric acid, the secretion of which is controlled by the hormone gastrin released from gastric G cells. However, the molecular mechanisms regulating gastrin plasma concentrations are poorly understood. Here, we identified a semaphorin-plexin signaling pathway that operates in gastric G cells to inhibit gastrin expression on a transcriptional level, thereby limiting food-stimulated gastrin release and gastric acid secretion. Using a systematic siRNA screening approach combined with biochemical, cell biology, and in vivo mouse experiments, we found that the RasGAP protein Rasal1 is a central mediator of plexin signal transduction, which suppresses gastrin expression through inactivation of the small GTPase R-Ras. Moreover, we show that Rasal1 is pathophysiologically relevant for the pathogenesis of peptic ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs), a main risk factor of peptic ulcers in humans. Last, we show that application of recombinant semaphorin 4D alleviates peptic ulcer disease in mice in vivo, demonstrating that this signaling pathway can be harnessed pharmacologically. This study unravels a mode of G cell regulation that is functionally important in gastric homeostasis and disease.

Objective: Management of erosive oesophagitis (EE) remains suboptimal, with many patients experiencing incomplete healing, ongoing symptoms, and relapse despite proton pump inhibitor (PPI) treatment. The Study of Acid-Related Disorders investigated patient burden of individuals with EE in a real-world setting., Design: US gastroenterologists (GIs) or family physicians (FPs)/general practitioners (GPs) treating patients with EE completed a physician survey and enrolled up to four patients with EE for a patient survey, with prespecified data extracted from medical records., Results: 102 GIs and 149 FPs/GPs completed the survey; data were available for 73 patients (mean age at diagnosis, 45.4 years). Omeprazole was healthcare professional (HCP)-preferred first-line treatment (60.8% GIs; 56.4% FPs/GPs), and pantoprazole preferred second line (29.4% and 32.9%, respectively). Price and insurance coverage (both 55.5% HCPs) and familiarity (47.9%) key drivers for omeprazole; insurance coverage (52.0%), price (50.0%), familiarity (48.0%), initial symptom relief (46.0%), and safety (44.0%) key drivers for pantoprazole. Only 49.3% patients took medication as instructed all the time; 56.8% independently increased medication frequency some of the time. Despite treatment, 57.5% patients experienced heartburn and 30.1% regurgitation; heartburn was the most bothersome symptom. 58.9% patients believed that their symptoms could be better controlled; only 28.3% HCPs were very satisfied with current treatment options. 83.6% patients wanted long-lasting treatment options. Fast symptom relief for patients was a top priority for 66.1% HCPs, while 56.6% would welcome alternatives to PPIs., Conclusion: This real-world multicentre study highlights the need for new, rapidly acting treatments in EE that reduce symptom burden, offer durable healing and provide symptom control., Competing Interests: Competing interests: CP and RJ are employees of Phathom Pharmaceuticals. All other authors are consultants to Phathom Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: The purpose of this meta-analysis was to evaluate the efficacy and safety of proton pump inhibitors (PPIs) plus antithrombotic strategy in patients with coronary artery diseases compared with antithrombotic strategy alone. We searched PubMed, EMBASE, Cochrane Library, and Chinese Biomedical Medical Literature databases to retrieve randomized controlled trials investigating PPIs combined with antithrombotic strategy in coronary artery diseases. The primary efficacy outcome was major adverse cardiovascular and cerebrovascular events (MACCE). The primary safety outcome was gastrointestinal events. Secondary outcomes included all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, significant bleeding from gastroduodenal lesions, and gastroduodenal ulcer. Overall, 43,943 patients were enrolled from 19 trials. The incidence of MACCE [relative risk (RR) 1.05; 95% confidence interval (CI) 0.96-1.15], all-cause death (RR 0.84; 95% CI 0.69-1.01), cardiovascular death (RR 0.88; 95% CI 0.69-1.12), myocardial infarction (RR 0.98; 95% CI 0.88-1.09), stent thrombosis (RR 1.01; 95% CI 0.76-1.34), and gastroduodenal ulcer (RR 0.40; 95% CI 0.13-1.29) did not increase significantly in patients receiving PPIs compared with patients without those. There were significant differences in the risk of gastrointestinal events (RR 0.34; 95% CI 0.21-0.54) and significant bleeding from gastroduodenal lesions (RR 0.09; 95% CI 0.03-0.28) between the 2 groups. In patients with coronary artery diseases, PPIs plus antithrombotic strategy could reduce the risk of gastrointestinal events and significant bleeding from gastroduodenal lesions but may not affect the incidence of MACCE, all-cause death, cardiovascular death, myocardial infarction, stent thrombosis, and gastroduodenal ulcer (PROSPERO: CRD42021277899, date of registration October 10, 2021)., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: The aim of this study was to evaluate the safety and effectiveness of Hemospray (Cook Medical, Winston-Salem, NC, USA), a hemostatic powder, as monotherapy for active peptic ulcer bleeding., Methods: In this prospective, multicenter, single-arm study, patients with Forrest Ia or Ib peptic ulcers underwent endoscopic application of Hemospray as treatment of first intent. Effectiveness endpoints were successful hemostasis at the end of the index endoscopy, recurrent bleeding within 72 hours and from 72 hours to 30 days, adverse events requiring reintervention or resulting in morbidity or mortality, and 30-day mortality., Results: Hemospray was successfully administered in 98.5% of patients (66/67). Hemostasis was achieved at the index endoscopy in 90.9% of patients (60/66) with Hemospray alone and in an additional 4 patients treated with additional modalities, yielding an overall hemostasis rate of 97.0% (64/66). Rebleeding occurred in 13.3% of patients (8/60), 5 within 72 hours and 3 between 72 hours and 30 days. Two cases of perforation and 2 patient deaths occurred during the study, but none of these cases or any other adverse events were attributed to the use of Hemospray. The rate of early rebleeding was significantly higher in patients with Forrest Ia ulcers compared with patients with Forrest Ib ulcers. Higher rates of early bleeding in patients with Forrest Ia ulcers is consistent with results from studies where Hemospray was used as rescue after failure of conventional methods., Conclusions: Hemospray is an effective initial treatment for patients with active peptic ulcer bleeding, but care should be taken to monitor for recurrent bleeding. (Clinical trial registration number: NCT01306864.)., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Oral bisphosphonates and direct oral anticoagulants are related to upper gastrointestinal ulcers. The present study investigated whether concomitant use of these drugs increase the risk of upper gastrointestinal ulcers and report no increased risk of upper gastrointestinal ulcers compared to the use of either drug alone, when individuals with previous upper gastrointestinal ulcers are excluded., Introduction: This study examines whether concomitant use of oral bisphosphonates (oBP) and direct oral anticoagulants (DOAC) increases the risk of peptic ulcers more than any drug alone., Methods: A population-based cohort study was performed. We sampled a cohort of oBP and DOAC users from a sample of 2,622,742 individuals, consisting of diabetes patients and age- and gender-matched controls, obtained from the Danish National Patient Register. The exposures were concomitant use of oBP and DOAC and single use of DOAC and single use of oBP. The primary endpoint was the first incident peptic ulcer. Information on exposure and outcome were collected from national registries. The period of observation was from 01.01.2008 until 31.12.2018. Unadjusted and adjusted Cox regressions were performed., Results: 8077 individuals received concomitant treatment with DOAC and oBP; 96,451 individuals used DOAC and no oBP; and 118,675 used oBP and no DOAC. The mean duration of follow-up was 1.9 years for concomitant users, 2.5 years for DOAC users, and 4.5 years for oBP users. A total of 4742 individuals with incident peptic ulcers were collected. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to single DOAC treatment in the adjusted analysis (HR = 1.23, 95% CI: 1.03; 1.48). However, the effects were abolished when excluding individuals with a previous ulcer. We observed an increased risk of incident ulcer in users of DOAC and oBP compared to users of oBP in the adjusted model (HR = 1.34, 95% CI: 1.11; 1.63)., Conclusion: Based on our results, concomitant use of oBP and DOAC is associated with a slight increase in the risk of peptic ulcers compared to either drug alone. The prescribing physician should weigh the slight increased risk of ulcer in concomitant users of oBP and DOAC with beneficial reductions in stroke and fractures., (© 2022. International Osteoporosis Foundation and National Osteoporosis Foundation.)

This study aimed to detect safety signals of rebamipide and search for adverse events (AEs) of rebamipide that are more common than those of other drugs for peptic ulcer disease (PUD) and gastroesophageal reflux disease (GERD) in the elderly population. A total of 101,735 AE reports for drugs used to treat PUD and GERD between 2009 and 2018 from the KIDS-KAERS database (KIDS-KD) were used. Disproportionality analysis was performed to calculate the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). Drug labels in Korea, Japan, and China were reviewed to identify signals that have been listed. AEs frequently reported in the elderly population were also analyzed. Seriousness and median time to AEs were evaluated for statistically significant AEs. A total of 14 signals were detected, and 4 signals (dry mouth, dermatitis, purpura/petechia, and fluid overload) were not listed on drug labels; however, they may be included as part of other listed AEs. In the elderly population, 11 AEs such as dyspepsia/indigestion/gastrointestinal distress, somnolence, dry mouth, and edema were common. These AEs were not serious and occurred within 2-9 days. This study identified possible AEs of rebamipide, a relatively safe drug., (© 2022. The Author(s).)

Trigonella foenum graecum (Fenugreek) is used in traditional phytomedicine for its anti-inflammatory, antiseptic, antidiabetic, and several other therapeutic virtues. The current study was intended to investigate the protecting effects of fenugreek seeds' aqueous extract (FSAE) using experimentally ethanol (EtOH)-induced gastric peptic ulcer in rats, as immense alcohol consumption can lead to gastric ulcer. Sixty adult male Wistar rats were divided into 6 groups of 10 each: control, EtOH (4 g/kg body weight [b.w.]), EtOH + several doses of FSAE (50, 100, and 200 mg/kg b.w.), and EtOH + Omeprazole (OM, 20 mg/kg orally [ p.o. ]). Animals were p.o. pretreated with FSAE for 21 days and exposed to a single oral administration of EtOH (4 g/kg b.w.) for 2 h. Gastric ulcer in rats was induced with a single dose of EtOH. Ulcer index, malondialdehyde (MDA), hydrogen peroxide (H 2 O 2 ), and thiol groups (-SH) content in stomach, and antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were measured. Our recorded results showed that EtOH induced gastric damage, evidenced by the level of oxidative stress markers such as MDA and H 2 O 2 in rats exposed to EtOH. However, significant increases in the activities of antioxidant enzymes were recorded, such as SOD, CAT, and GPx, and a decrease in nonenzymatic antioxidants, such as (-SH). Moreover, histopathological examinations showed the presence of lesions associated with severe tissue damage in the untreated rats. Interestingly, FSAE meaningfully protects against all gastric damages caused by EtOH. We propose that FSAE exhibits protective effects in EtOH-induced peptic ulcer in rats. This protection might be related to its antioxidant and anti-inflammatory properties as well as its opposite effects on some studied intracellular mediators.

Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy). NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation., (Copyright © 2021 Elsevier España, S.L.U. All rights reserved.)

Background: Low-dose aspirin can cause gastric and duodenal ulceration, hereafter called peptic ulcer disease (PUD). Predisposition is thought to be related to clinical and genetic factors; our aim was to identify genetic risk factors associated with aspirin-induced PUD., Methods: Patients (n=1478) were recruited from 15 UK hospitals. Cases (n=505) were defined as patients with endoscopically confirmed PUD within 2 weeks of using aspirin and non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). They were compared to two control groups: patients with endoscopically confirmed PUD without any history of NSAID use within 3 months of diagnosis (n=495), and patients with no PUD on endoscopy (n=478). A genome-wide association study (GWAS) of aspirin-induced cases (n=247) was compared to 476 controls. The results were validated by replication in another 84 cases and 162 controls., Findings: The GWAS identified one variant, rs12678747 (p=1·65×10 -7 ) located in the last intron of EYA1 on chromosome 8. The association was replicated in another sample of 84 PUD patients receiving aspirin (p=0·002). Meta-analysis of discovery and replication cohort data for rs12678747, yielded a genome-wide significant association (p=3·12×10 -11 ; OR=2·03; 95% CI 1·65-2·50). Expression of EYA1 was lower at the gastric ulcer edge when compared with the antrum., Interpretation: Genetic variation in an intron of the EYA1 gene increases the risk of endoscopically confirmed aspirin-induced PUD. Reduced EYA1 expression in the upper gastrointestinal epithelium may modulate risk, but the functional basis of this association will need mechanistic evaluation., Funding: Department of Health Chair in Pharmacogenetics, MRC Centre for Drug Safety Science and the Barts Cardiovascular NIHR Biomedical Research Centre, British Heart Foundation (BHF)., Competing Interests: Declaration of Competing Interest MP has received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UK Pharmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb UCB. He has developed a HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. None of these funding sources were used for this study. DMP reports consultancy work from Ipsen pharmaceuticals, Advanced Accelerator Applications, and Mayoly Spindler laboratories, grants from Trio Medicines Ltd, outside the submitted work. All other authors have nothing to declare., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Hemostatic powder (HP) in gastrointestinal bleeding (GIB) is mainly used as rescue therapy after failure of conventional hemostatic procedures (CHP)., Aim: To define the best field of application and the efficacy of HP as first choice monotherapy or rescue therapy., Methods: We compared the efficacy of HP monotherapy, HP rescue therapy, and CHP in the management of active GIB due to neoplastic and non-neoplastic lesions., Results: A total of 108 patients, 43 treated with HP as either first choice or rescue therapy and 65 with CHP, were included in the study. The most frequent sources of bleeding were peptic ulcer and malignancy. Immediate hemostasis rates were: HP monotherapy = 100% in peptic ulcer and 100% in malignancy; HP rescue therapy = 93.2% in peptic ulcer and 85.7% in malignancy; CHP = 77.9% in peptic ulcer and 41.7 in malignancy. Definitive hemostasis rates were: HP monotherapy = 50% in peptic ulcer and 45.5% in malignancy; HP rescue therapy = 73.3% in peptic ulcer and 85.7% in malignancy; CHP = 69.1% in peptic ulcer and 33.3% in malignancy. No difference was found in terms of additional intervention between the three groups., Conclusions: HP is highly effective as monotherapy and rescue therapy in GIB. GIB related to malignancy may be the best field of application of HP, but confirmatory studies are necessary.

Background and Objectives : Drug-induced esophageal ulcer is caused by focal drug stimulation. It may occur in adults and children. Limited research is available in pediatric patients with drug-induced esophageal ulcer; therefore, we designed this study to determine the characteristics of this disease in this population. Materials and Methods : Thirty-two pediatric patients diagnosed with drug-induced esophageal ulcers from a hospital database of upper gastrointestinal tract endoscopies were included. After treatment, patients were followed for 2 months after upper gastrointestinal endoscopy. Results : Female patients were predominant (56.2%/43.8%). The mean age of patients was 15.6 years (median, 16 years; interquartile range, 2 years). Doxycycline was administered in most cases (56.3%); other drugs were dicloxacillin, amoxicillin, clindamycin, L-arginine, and nonsteroidal anti-inflammatory drugs. Doxycycline was associated with kissing ulcers. Esophageal ulcers induced by nonsteroidal anti-inflammatory drugs were more often associated with gastric or duodenal ulcers. The most common location was the middle-third of the esophagus (78.1%). Patients were treated with proton pump inhibitors, sucralfate, or H2-blockers. The mean duration for which symptoms lasted was 9.2 days. No esophageal stricture was found in 24 patients who were followed for 2 months after upper gastrointestinal endoscopy. Conclusions : The authors suggest informing patients to take medicine with enough water (approximately 100 mL) and enough time (15-30 min) before recumbency, especially high-risk drugs, such as doxycycline or nonsteroidal anti-inflammatory drugs.

Background/aims: The incidence of peptic ulcer disease has decreased in past decades; however, the trends in peptic ulcer bleeding (PUB) are inconsistent among regions. This study aimed to investigate the trends in PUB incidence and the effect of risk factors on PUB in Korea., Methods: The records of patients hospitalized with PUB from 2006 to 2015 were retrieved from the Korean National Health Insurance Service Database. Standardized incidences of PUB were calculated, and the clinical characteristics such as age, sex, Helicobacter pylori infection, drug exposure, comorbidities, and mortality were obtained., Results: In total, 151,507 hospitalizations with PUB were identified. The overall annual hospitalization rate was 34.98 per 100,000 person-years. The incidence of PUB showed no significant change from 2006 to 2008 and decreased from 2008 to 2015, with an annual change of -2.7% (p<0.05); however, this change was only significant in men. The incidence of PUB was higher in men than in women between 40 and 70 years old and higher in women than in men older than 80 years. From 2006 to 2015, the H. pylori infection rate increased significantly in patients with PUB; however, there was no significant change in exposure to nonsteroidal anti-inflammatory drugs or other drugs that increase the risk of PUB., Conclusions: Over the past decade, the incidence of PUB has decreased in a sex-specific manner. There has been a decreasing trend in the H. pylori infection rate and no change in exposure to drugs that increase the risk of PUB in Korea.

Over-the-counter analgesic medications are widely used amongst American adults and are also available in powder forms. Their adverse effects have been well documented in literature. Gastrocolic fistulas as a complication of peptic ulcer disease from analgesic powder usage have been previously unreported. Here, we report a patient with upper gastrointestinal bleeding and acute anaemia secondary to peptic ulcer complicated by gastrocolic fistula in a patient using analgesic powder., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

PPIs (Proton-pump inhibitors) offers the best treatment for acid related diseases. The predominant indications for PPI prescription are: GERD eradication of H. pylori-infection in combination with antibiotics H. pylori-negative peptic ulcer  healing of and prophylaxis against NSAID/COXIB--induced gastroduodenal lesions  acid hypersecretory states such as Zollinger-Ellisons syndrome. The market for PPIs continues to expand in most countries. A significant over- and misuse of PPIs prevails in hospital care as well as in general practice. The predominant reasons for and mechanisms behind the over- and misuse of PPIs are well recognised. The most important consequences of this overprescription of PPIs are increasing medical costs and risk for long-term adverse side effects. Continued education and dedicated information are key factors to guide physicians, medical personnel and patients to adopt to generally accepted principles for and balanced use of PPIs.

Background: Peptic ulcer disease (PUD) continued to be a source of significant morbidity and mortality worldwide. Recently, it has been reported that exposure to air pollution is a potential risk factor for PUD, but evidence on the association still remains inconsistent., Methods: We performed an ecological study to examine the association between short-term exposure to air pollution and daily hospital visits for PUD in Yinzhou, China from January 1st, 2017 to December 31st, 2019. Distributed lag nonlinear models were used to estimate the nonlinear and lag-response effects of air pollutants. Subgroup analyses stratified by sex, age and season were conducted to examine the effect modifications., Results: Overall, we found that short-term exposure to air pollution including SO 2 , NO 2 , CO, O 3 and PM 2.5 was significantly associated with hospital visits for PUD among all subjects. The lag-response effects of SO 2 , NO 2 and O 3 varied at different concentrations and lag days. The cumulative risk ratios of CO and PM 2.5 showed nearly linear adverse effects and increased to maxima of 2.68 (95% CI: 1.49-4.78) and 2.40 (95% CI: 1.36-4.24) with their ranges from the references to the maximum concentrations, respectively. Moreover, the cumulative risks of particulate matters on hospital visits for PUD increased significantly in cold seasons, but not in warm seasons., Conclusions: Our findings could provide growing evidence regarding the adverse health effects of air pollution on PUD, thereby strengthening the hypothesis that air pollutants have harmful impacts on digestive system., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Proton pump inhibitors (PPIs) with a high therapeutic index have strong evidence to support their efficacy in the management of common gastrointestinal (GI) conditions such as gastroesophageal reflux (GERD), peptic ulcer diseases, H. pyloriinfection etc. Despite this, the list of adverse effects being cited across literature with chronic use of these drugs is on an upward trend. Studies and published literature have associated PPI use with risk of bone fractures, various micronutrient deficiencies, gastro-intestinal infection, pneumonia, cardiac complications, dementia, kidney disease, intestinal bacterial overgrowth and drug interactions. It is however of clinical interest to note that in most of the studies published, the risk association reported with PPIs is weak. Unfortunately, widespread media publicity around these studies has prompted discontinuation of the drug in patients in whom it is indicated and created generalized anxiety among its users 20 years later since their introduction. The primary objective is to review the literature for an unbiased translation of the knowledge to appropriately guide decision in clinical practice., (© Journal of the Association of Physicians of India 2011.)

Introduction: currently, the non-steroid anti-inflammatory drugs constitute a veritable object of auto medication throughout the world. The goal of this study was to evaluate the endoscopic and clinical aspects of gastro-duodenal ulcer secondary to taking of non-steroid anti-inflammatory of various sources., Methods: this was a cross-sectional study which was conducted between July 2016 and December 2017. All adult patients admitted to hospital for clinical symptoms suggestive of gastroduodenal involvement after taking anti-inflammatory drugs and having undergone upper digestive endoscopy were included in this study. Data analysis was done with Epi-info version 7 Software., Results: a total of 114 patients were included, the mean age was 47.18±26 years with a male predominance (64.9%). Among the patients, only 1.75% had taken a non-steroid anti-inflammatory (NSAIDs) from pharmacy. The NSAIDs used were of different types: diclofenac, aceclofenac, aspirin and non-selective NSAIDs. For each drug used, more than half were derived from the streets. Clinically we noted: the dyspepsia (38.58%), hemorrhages (11.40%), the ulcerous syndrome (77.19%), haematemesis (19.29%), haematemesis associated with melena (37.71%), and the rectorrhagia in 6.14 of cases. The specific endoscopic lesions were bulbar ulcer (45.61%), gastric ulcers (20.17%), antral ulcerations (5.26%) and acute gastritis (9.64%), esophagitis (7.89%), esophageal varices (6.14%), and uncomplicated hiatal hernia in 7.01% of cases., Conclusion: the serious gastroduodenal lesions observed in this study and due to use of NSAIDs are mainly attributable to unauthorized molecules due to safety concerns. It would be necessary to conduct sensitization days at the community level and in each health facility., Competing Interests: The authors declare no competing interests., (Copyright: Oumar Traoré et al.)

Advanced age, history of peptic ulcer disease, Helicobacter pylori, coadministration of nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, anticoagulation, and antiplatelets are risk factors for gastrointestinal bleeding in the elderly. Awareness of these risks and appropriate use of NSAIDs, particularly in those needing antiplatelet or anticoagulant therapy, is critical to optimal management. Careful selection of elderly patients requiring antiplatelet, anticoagulation, or chronic NSAID therapy for cotherapy with proton pump inhibitors can significantly reduce morbidity and mortality from gastrointestinal bleeding., Competing Interests: Disclosure Dr Katz is a Consultant for Phathom Pharma., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Non-steroidal anti-inflammatory drugs (NSAIDs) are agents that are used for various properties such as analgesic activity, anti-inflammatory activity, antipyretic activity, etc. But this class of drugs is associated with different side effects such as dyspepsia, gastroduodenal ulcers, gastrointestinal (GI) bleeding and perforation. The prodrug approach is quite beneficial to curb these side effects. Prodrugs are the inactive compounds that, on metabolism get converted into an active metabolite exhibiting desired activities. Commonly used approaches for synthesizing prodrugs are amide, esters, and mutual prodrugs by suppressing the free carboxylic groups responsible for these side effects. In this review, different schemes reported for the synthesis of NSAIDs that are devoid of undesired side effects such as irritation to gastric mucosa, gastrotoxicity, and ulcerogenicity have been compiled. Docking studies and the structure-activity relationship of some compounds are also discussed. The paper shall help the researchers to understand the methods to expedite the synthesis by carrying out substitutions of various groups of the parent compound and establish the mechanism of action of these derivatives of masking the unwanted side effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Proton pump inhibitors reduce the risk of peptic ulcer bleeding in patients at risk. The knowledge about the extent of gastroprotection in patients at increased risk and factors associated with prophylactic treatment is limited., Aims: (1) to analyze the extent of gastroprotective undertreatment in patients using aspirin/non-steroidal anti-inflammatory drugs and (2) to analyze which patient characteristics are associated with proton pump inhibitor prophylaxis among those at increased ulcer bleeding risk., Methods: A Danish nationwide register-based study. Based on a risk stratification model we identified citizens at increased ulcer bleeding risk and analyzed the proportion concomitantly treated with proton pump inhibitors. Further, we analyzed associations between use of ulcer prophylaxis and comorbidity and socioeconomic characteristics., Results: Some 44.4% of the high-risk patients were concomitantly treated with proton pump inhibitors. In the crude analyses cohabiting, having a high educational level and a high income were significantly associated with lower odds of being treated with proton pump inhibitors. When adjusting for medication use, age, sex and comorbidity the associations were insignificant., Conclusions: There is room for improvement in the extent of ulcer prophylaxis but no clear social gradient in under prescribing of gastroprotection. With the substantial risk-reducing possibility concomitant proton pump inhibitor use could save numerous patients from ulcer bleeding each year. Our study calls for increased awareness of peptic ulcer bleeding risk and dissemination of knowledge to clinicians about risk factors for gastrointestinal hemorrhage and the risk reducing potential of co-prescribing proton pump inhibitors to patients at risk.

Nonsteroidal anti-inflammatory drugs (NSAID) are some of the most commonly prescribed medications in clinical practice. The long-term use of NSAIDs is one of the main causes of peptic ulcers and the increased risk of upper gastrointestinal tract complications, such as perforation and bleeding. Thus, the prevention of NSAID-induced peptic ulcers is an important clinical issue. Previous studies have evaluated various strategies for preventing ulcers in patients requiring prolonged NSAID use. The Korean clinical practice guidelines have been published recently based on the evidence of the currently available data. This review describes the strategies for the prevention of peptic ulcers due to NSAID. An assessment of the risk factors for peptic ulcers from NSAID is recommended to identify patients who should be considered for primary prophylaxis. The risk of NSAID-induced peptic ulcers can be reduced by the concomitant use of proton pump inhibitors (PPI), misoprostol, and histamine-2 receptor antagonists. Selective cyclooxygenase-2 inhibitors can be used with caution due to concerns regarding cardiovascular toxicity. Attempts should be made to use the lowest dose and shortest duration of the NSAID.

Non-steroidal anti-inflammatory drugs (NSAIDs) and aspirin are the most frequently prescribed drugs worldwide, and their long-term use often leads to peptic ulcers (PUs) along with serious complications, such as bleeding and perforation. Helicobacter pylori ( H. pylori ) infection is a significant risk factor for developing NSAID-related PU and ulcer bleeding during long-term aspirin use. In a revised version of the Clinical Guidelines for Drug-induced Peptic Ulcer, two statements regarding H. pylori eradication are recommended. 1) Patients scheduled for long-term NSAID therapy should be tested and treated for H. pylori infection to prevent PU and its complications. 2) Patients with a history of PU receiving long-term low-dose aspirin (LDA) therapy should undergo treatment for H. pylori infection to prevent PU and its complications. On the other hand, unlike NSAID-naïve patients, the preventive effects of H. pylori eradication in chronic NSAID users are unclear. In addition, anti-ulcer drugs, such as proton pump inhibitors, may be necessary for maintenance therapy after H. pylori eradication in a subset of long-term LDA users, particularly if the patients are taking concomitant antiplatelet agents or anticoagulants.

Korean guidelines for nonsteroidal anti-inflammatory drug (NSAID)-induced peptic ulcer were previously developed in 2009 with the collaboration of the Korean College of Helicobacter and Upper Gastrointestinal Research and Korean Society of Gastroenterology. However, the previous guidelines were based mainly upon a review of the relevant literature and expert opinion. Therefore, the guidelines need to be revised. We organized a guideline Development Committee for drug-related peptic ulcer under the auspices of the Korean College of Helicobacter and Upper Gastrointestinal Research in 2017 and developed nine statements, including four for NSAIDs, three for aspirin and other antiplatelet agents, and two for anticoagulants through a de novo process founded on evidence-based medicine that included a literature search and a meta-analysis, A consensus was reached through the application of the modified Delphi method. The primary target of these guidelines is adult patients undergoing long-term treatment with NSAIDs, aspirin or other antiplatelet agents and anticoagulants. The revised guidelines reflect the expert consensus and is intended to assist clinicians in the management and prevention of druginduced peptic ulcer and associated conditions.

Objective: To determine the frequency of clinically important bleeding (CIB) among children hospitalized for status asthmaticus with and without exposure to stress ulcer prophylaxis (SUP). Methods: We performed a single-center, retrospective cohort in 217 children admitted for asthma exacerbation aged 5-18 years from May 2015 to May 2017. We assessed cohorts with and without exposure to SUP to determine if differences in frequency of CIB exist. Study outcomes included frequency of CIB, gastrointestinal complications (occult bleeding, macroscopic bleeding, gastric perforation, and acquired gastritis), and SUP-related adverse events (ventilator associated pneumonia, C. difficile colitis, necrotizing enterocolitis, and acute thrombocytopenia). Results: Ninety-two (42%) children received SUP of which 82 were admitted to the pediatric intensive care unit (PICU). There were no differences in asthma severity or known risk factors for CIB in children with and without SUP in the PICU subcohort. We observed no CIB or SUP-related adverse events. Two subjects acquired gastritis in the no-SUP cohort and one additional subject experienced occult gastrointestinal bleeding with spontaneous symptom resolution. Conclusion : Children admitted for status asthmaticus with and without SUP had no observed incidence of CIB. In this specific population, we propose a prerequisite assessment for the presence of known stress ulcer related gastrointestinal bleeding risk factors prior to the blanket administration of SUP.

Recent advances in small-bowel endoscopy such as capsule endoscopy have shown that non-steroidal anti-inflammatory drugs (NSAIDs) frequently damage the small intestine, with the prevalence rate of mucosal breaks of around 50% in chronic users. A significant proportion of patients with NSAIDs-induced enteropathy are asymptomatic, but some patients develop symptomatic or complicated ulcers that need therapeutic intervention. Both inhibition of prostaglandins due to the inhibition of cyclooxygenases and mitochondrial dysfunction secondary to the topical effect of NSAIDs play a crucial role in the early process of injury. As a result, the intestinal barrier function is impaired, which allows enterobacteria to invade the mucosa. Gram-negative bacteria and endogenous molecules coordinate to trigger inflammatory cascades via Toll-like receptor 4 to induce excessive expression of cytokines such as tumor necrosis factor-α and to activate NLRP3 inflammasome, a multiprotein complex that processes pro-interleukin-1β into its mature form. Finally, neutrophils accumulate in the mucosa, resulting in intestinal ulceration. Currently, misoprostol is the only drug that has a proven beneficial effect on bleeding small intestinal ulcers induced by NSAIDs or low-dose aspirin, but its protection is insufficient. Therefore, the efficacy of the combination of misoprostol with other drugs, especially those targeting the innate immune system, should be assessed in the next step.

Curry leaves (Murraya koenigii) are a leafy spice used in Indian cookery for its fragrant aroma. Many bioactive functional compounds have been identified, and among them carbazole alkaloids have attracted wide attention due to their multi-dimensional medicinal value. Even though it has been established that the carbazole alkaloid is responsible for the anti-ulcer effect showed by this culinary herb, there is no further evidence to say which phytochemical is responsible for this. In the present study, we investigated the gastro-protective effects and mechanism of girinimbine, a major carbazole alkaloid present in curry leaves. Rats were administered with ethanol to produce gastric ulcers, and the prophylactic effect of girinimbine was evaluated. A macroscopic and histological examination was carried out to examine the lesions. Furthermore, the mucus production, NO production, PGE2 synthesis, mucosal nonprotein sulphydryls, glutathione (GSH) level, lipid peroxidation (MDA) level and COX inhibition were assessed. In addition, in particular, TNF-α and IL-6, two important cytokines, were evaluated. Immunohistochemical and gene expression studies were conducted to determine the HSP70 and iNOS biomarkers. Our results indicated that girinimbine significantly reduced the ulcer index and totally safeguarded the mucosa from lesions. The protective effect of girinimbine was complemented through the restoration of the reduced GSH and NP-SH level. This was associated with a reduction of MDA, which was elevated by the administration of ethanol. Pre-treatment of the ethanol induced ulcer with girinimbine reduced the NO concentration in the plasma and elevated PGE2 together with a decreased level of TNF-α and IL-6. Girinimbine had shown suppressing effects on COX-2 enzymes, but not on COX-1. In addition, significantly upregulated HSP70 and downregulated iNOS were observed in girinimbine treated rat tissue at both the transcriptional and translational level. Our results clearly indicated that girinimbine displayed a significant gastro-protection effect, via the capacity to inhibit inflammatory responses and antioxidant potential.

Background: To compare the efficacy and safety of combination of curcuminoid complex and diclofenac vs diclofenac alone in the treatment of knee osteoarthritis (OA)., Methods: In this randomized trial, 140 patients of knee OA received either curcuminoid complex 500 mg (BCM-95) with diclofenac 50 mg 2 times daily or diclofenac 50 mg alone 2 times daily for 28 days. Patients were assessed at baseline, day 14 and day 28. Primary efficacy measures were Knee injury and OA outcome score (KOOS) subscale at day 14 and day 28. Anti-ulcer effect and patient-physician's global assessment of therapy at day 28 were included as secondary endpoints. Safety after treatment was evaluated by recording adverse events and laboratory investigations., Results: Both treatment groups showed improvement in primary endpoints at each evaluation visit. Patients receiving curcuminoid complex plus diclofenac showed significantly superior improvement in KOOS subscales, viz. pain and quality of life at each study visit (P < .001) when compared to diclofenac. Less number of patients required rescue analgesics in curcuminoid complex plus diclofenac group (3%) compared to diclofenac group (17%). The number of patients who required histamine 2 (H2) blockers was significantly less in curcuminoid complex plus diclofenac group compared to diclofenac group (6% vs 28%, respectively; P < .001). Adverse effects were significantly less in curcuminoid complex plus diclofenac group (13% vs 38% in diclofenac group; P < .001). Patient's and physician's global assessment of therapy favored curcuminoid complex plus diclofenac than diclofenac., Conclusion: Combination of curcuminoid complex and diclofenac showed a greater improvement in pain and functional capacity with better tolerability and could be a better alternative treatment option in symptomatic management of knee OA., Trial Registration: ISRCTN, ISRCTN10074826.

Peptic ulcer induced upper gastrointestinal hemorrhage is a frequent digestive emergency and is one of the most common cause of hospitalization. There are several intrinsic risk factors for peptic ulcer bleed such as advanced age, previous gastro-intestinal hemorrhage, male sex and the presence of Helicobacter pylori. In high risk patients for peptic ulcer disease, gastric protection measures should be considered, most often by treatment with proton pump inhibitors. The eradication of Helicobacter pylori should also be discussed for long-term treatments., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Background: Gastrointestinal symptoms are common in patients with Wilson disease (WD) and may be related to the disease itself or to adverse drug reactions (ADRs). Aim: To investigate gastroscopy findings in patients with WD and to analyze the risk of gastropathy in the context of different manifestations and treatments of WD as well as Helicobacter pylori infection status. Methods: This cross-sectional study included patients diagnosed or monitored for WD between 2007 and 2017. All enrolled patients were examined with gastroscopy and checked for infection with a urease test. Based on predominant manifestations, WD was classified as pre-symptomatic, hepatic (only liver symptoms) or neurological. Patients were divided into three treatment groups: untreated, treated with d-penicillamine (DPA) or zinc sulfate therapy. Results: Of 115 patients, 58 were male and the median age was 30 years. Gastropathy was observed in 65.2% of all patients. Factors that increased the risk of gastropathy were zinc sulfate (odds ratio [OR] = 3.01; 95% confidence interval [CI]: 1.12-8.09, p  = .03), H. pylori infection (OR = 2.96; 95%CI: 1.34-6.56, p  = .01) and neurological manifestations (OR = 2.55; 95%CI: 1.16-5.60, p  = .02). In total, 9.6% of patients had gastric or duodenal ulcers and 29.6% had esophageal varices but no difference was seen by treatment status. In multivariate analysis, zinc sulfate remained associated with higher risk of gastropathy compared with no treatment (OR = 4.57; 95%CI: 1.21-17.19; p  = .03) and DPA (OR = 6.28; 95%CI: 1.43-27.56; p  = .01). Conclusions: Our results show that gastropathy in WD may be influenced by the treatment used.KeypointsIn a retrospective study of 115 patients with Wilson's disease, gastric injury was frequent.Patients receiving zinc sulfate had increased gastropathy risk compared with those receiving no treatment or d-penicillamine.

Background: Although the effectiveness and safety of prasugrel for the prevention of cardiovascular events in patients with ischemic heart disease (IHD) undergoing percutaneous coronary intervention (PCI) have been demonstrated, long-term real-world data of Japanese unique doses are insufficient. Therefore, we report the results of an analysis of 1-year follow-up data from a postmarketing observational study (PRASFIT-Practice II).Methods and Results:The safety and effectiveness analysis sets included 4,155 IHD patients receiving prasugrel (loading dose/maintenance dose, 20/3.75 mg) as dual antiplatelet therapy (DAPT) with aspirin. At 360 days (after treatment start), 62.2% continued DAPT. Cumulative incidences of major adverse cardiovascular events and stent thrombosis were 1.6% and 0.2%, respectively. Cumulative incidences of Thrombolysis In Myocardial Infarction (TIMI) major bleeding and TIMI major or minor bleeding were 1.0% and 2.0%, respectively. Risk factors for TIMI major or minor bleeding in the first 30 days of treatment were age ≥80 years, anemia, female sex, and liver disease, and from day 31 to the end of month 12, hypertension and peptic ulcer., Conclusions: The 1-year follow-up results showed long-term effectiveness and safety of prasugrel at dosages approved in Japan for the treatment of IHD patients undergoing PCI.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal-regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Objectives: Low-dose aspirin is the standard treatment for the prevention of cardiovascular events in at-risk patients. We performed a randomized, placebo-controlled study to determine the efficacy of teprenone for primary prevention of gastrointestinal injury in patients taking LDA for vascular protection. Methods: Patients were eligible for enrollment if they required aspirin 100 mg/day. Aspirin- naïve patients without gastroduodenal ulcer and Helicobacter pylori infection were randomized to receive teprenone 150 mg/day or placebo for 12 weeks. Primary outcome was assessed by the incidence rate of gastroduodenal ulcer. Secondary outcomes were assessed by the incidence rate of gastric mucosal injury, the improvement in modified Lanza score (MLS), gastrointestinal symptom rating scale (GSRS) and the change of gastric immunohistochemical expression for COX-1. Results: Total of 130 patients were randomized, 64 in teprenone group and 66 in placebo group. There was no incidence of ulcer after 12 weeks in both groups. Incidence of gastric mucosal injury was higher in placebo group than in teprenone group (40.0 vs. 13.38%, p  = .039). Mean change of MLS was higher in placebo group than in teprenone group (0.767 ± 0.467 vs. 0.271 ± 0.158, p  = .003). Scores of mucosal edema, hyperemia and hemorrhage and the change of GSRS were not different between the two groups. Change of COX-1 immunoreactive score was higher in placebo group than in teprenone group (2.433 ± 1.476 vs. 1.233 ± 0.955, p  = .001). There were no treatment-related adverse events. Conclusions: Teprenone is effective in preventing gastric mucosal injury in patients taking LDA. Preventive effects of teprenone on LDA-related gastroduodenal ulcers require further investigation.

Background and Aim: Long-term use of dual antiplatelets is increasing, and most patients need primary peptic ulcer prophylaxis. The long-term use of proton pump inhibitors (PPIs) is associated with adverse events. We evaluated the efficacy of rebamipide for peptic ulcer prevention., Methods: This randomized controlled trial was conducted between July 2014 and November 2017. Patients receiving dual antiplatelets for ≥ 1 year with no history of peptic ulcer bleeding or perforation were recruited and randomly assigned to the rebamipide (300 mg/day) group or the placebo group. Patients who used proton pump inhibitors were excluded. The primary endpoint was a new mucosal break on esophagogastroduodenoscopy at 3 or 12 months after treatment initiation. The secondary endpoints were hematocrit changes from the baseline, gastrointestinal bleeding, and chest pain. Antiplatelet function was assessed., Results: In total, 95 eligible patients were identified; 12 were excluded, and 83 patients were randomized, with 66 (79.5%) and 59 (71.1%) patients eligible at the 3- and 12-month follow ups, respectively. The baseline characteristics were equivalent between the groups. During the 12 months of follow up, 13 patients (43.3%) taking rebamipide and 19 (65.5%) taking the placebo experienced mucosal injury (P = 0.07). Two patients (6.7%) taking rebamipide and eight (27.6%) taking the placebo had peptic ulcers ≥ 5 mm or < 5 mm with pigmented spots (P = 0.03). The changes in hematocrit were not different between the two groups. Neither bleeding ulcers nor chest pain was observed., Conclusion: Rebamipide is safe and may prevent peptic ulcers ≥ 5 mm in diameter or those with pigmented spots in patients receiving dual antiplatelets for 1 year (NCT02166008)., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background & Aims: Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk., Methods: We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation., Results: There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528)., Conclusions: In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Trachyspermum ammi (L.) Sprague is used for treating gastrointestinal disorders. Several studies indicated gastric antiulcer activity of T. ammi extract, yet the effect of its essential oil has not been studied on., Objectives: The present study evaluates chemical composition of T. ammi essential oil and anti-peptic ulcer effect of the essential oil as well as its three major components in ethanol induced-gastric ulcers in rats., Methods: Primarily chemical composition of the essential oil was analyzed by gas chromatography-mass spectrometry (GC/MS). Rats received the essential oil (500, 250, 125, 62.5, 31.25 mg/kg), thymol (30, 100 mg/kg), para-cymene (100, 150 mg/kg) and gamma-terpinene (100, 150 mg/kg) using gavage tube along with ethanol 80%. Finally, dissected stomachs were assessed both macroscopically and microscopically to evaluate anti-ulcerative effect of the essential oil and the pure compounds. Moreover, molecular docking was utilized to explore the interactive behavior of the main components with active site residues of H + /K + ATPase., Results: Analysis of the essential oil indicated that para-cymene (37.18%), gamma-terpinene (35.36%) and thymol (20.51%) are the main components. Administration of different doses of the essential oil noticeably diminished the number of peptic ulcers in a dose-dependent manner. Among the main components, thymol was more potent than para-cymene and gamma-terpinene. Administration of the essential oil (500 mg/kg) and thymol (100 mg/kg) observed maximum inhibition percentage (98.58% and 79.37%, respectively). Molecular docking study provides the evidence of thymol ability to inhibit H + /K + ATPase., Conclusions: The findings revealed that T. ammi essential oil can be applied to treat gastric ulcer as a natural agent. Graphical abstract.

Rationale When patients are using carbasalate calcium or acetylsalicylic acid (ASA), it is recommended to prescribe a proton pump inhibitor (PPI) in order to prevent gastrointestinal (GI) bleeding. Should this recommendation also be followed for patients who are using clopidogrel in monotherapy, which is increasingly the case in practice? Method In a systematic literature review of the occurrence of GI bleeding when using clopidogrel versus ASA, we included 9 studies that compared the risk of GI bleeding when using ASA with clopidogrel monotherapy. Results These 9 studies on clopidogrel and ASA show that the risk of GI bleeding is also elevated when using clopidogrel monotherapy and that it is comparable with the risk of GI bleeding when using ASA. Conclusion Based on the current literature, we recommend prescribing pantoprazole to patients who are using clopidogrel monotherapy and have additional risk factors for GI bleeding, in accordance with the procedure for low-dose ASA. The risk of GI bleeding must be weighed against the disadvantages of using PPIs.