Gastroduodenal Mucosal Injury Research Articles

Gastroduodenal injury and repair: novel targets for therapeutic intervention.

Although the mucosal barrier serves as a primary interface between the environment and host, little is understood about the repair of acute, superficial lesions or deeper, persistent lesions that if not healed, can be the site of increased permeability to luminal antigens, inflammation and/or neoplasia development. Recent studies have focused on focal adhesion kinase, which regulates controlled matrix adhesion during restitution after superficial injury. Actin polymerization regulates cell migration and the importance of actin-related proteins was also highlighted. Work on SARS-CoV-2 infection lent important new insights on gastroduodenal mucosal injury in patients with Covid-19 infection and work done with organoids and intestine-on-a-chip contributed new understanding about how coronaviruses infect gastrointestinal tissues and its resulting barrier dysfunction. A novel risk stratification paradigm was proposed to assist with decision making about repeat endoscopy for patients with gastric or duodenal ulcers and new therapeutic options were studied for ulcer disease. Lastly, work to support the mechanism of metaplasia development after deep injury and parietal cell loss was provided using novel transgenic mouse models. Recent studies highlight novel molecular targets to promote mucosal healing after injury of the gastroduodenal mucosa.

Effects of melatonin on acetylsalicylic acid induced gastroduodenal and jejunal mucosal injury

We evaluated the effects of melatonin on acetylsalicylic acid (ASA) induced gastroduodenal and jejunal mucosal injury. We used 40 postpubertal rats divided randomly into five groups of eight animals. The control group consisted of untreated animals. The Mel group was injected intraperitoneally (i.p.) with 5 mg/kg melatonin. The ASA group was injected i.p. with 200 mg/kg ASA. The ASA + Mel group was injected i.p. with 5 mg/kg melatonin 45 min after administering 200 mg/kg ASA i.p. The Mel + ASA group was injected i.p. with 5 mg/kg melatonin 45 min before administering 200 mg/kg ASA i.p. We found no statistically significant differences in mean histopathological scores in the ASA + Mel group compared to the ASA group. ASA caused shortened villi and loss of the apical villus in the duodenum. The histopathological score was increased and villus height was decreased in the ASA group compared to untreated controls. Treatment with melatonin attenuated the histological damage. In the ASA group, occasional areas showed erosion of villi in the jejunum; however, differences in mean histopathological score in ASA group compared to the other groups were not statistically significant. Malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) activities were measured in stomach, duodenal and jejunum tissue. We found increased MDA activity in both stomach and duodenal tissues in the ASA group compared to the control group (p < 0.05). We found no statistically significant changes in MDA levels in jejunal tissue in the ASA group compared to the control group. We found no change in SOD activity in either stomach or duodenal tissues in the ASA group compared to the control group. We observed decreased SOD activity in jejunal tissue in the ASA group compared to the control group (p < 0.05). We detected no change in GSH activity in stomach, duodenal or jejunal tissues in the ASA group compared to the control group. The stomach damage was less in melatonin treated groups, but the lesions were not completely eliminated. The jejunum in the ASA group retained a nearly normal appearance. We found that melatonin exhibited some healing effects on ASA induced duodenal mucosal injury.

Gastroprotectants in small animal veterinary practice - a review of the evidence. Part 1: cyto-protective drugs.

Diverse drugs with presumed cytoprotective effect have been used therapeutically in small animal veterinary practice for various gastro-intestinal conditions such as oesophagitis, gastric ulceration, gastritis or chronic gastro-enteropathies. Their efficacy has been doubted in human medicine, raising similar questions in the veterinary field. The aim of this review was to assess the current evidence on the efficacy and safety of these drugs in dogs and cats. Through a systematic review of the literature, we identified 37 articles on the use of misoprostol, sucralfate and other gastroprotectants in dogs and cats. There was evidence to support use of misoprostol in the prevention of aspirin-induced gastroduodenal mucosal injury in dogs, and for use of sucralfate in the prevention of acid-induced oesophagitis in cats. However, the overall quality of evidence supporting the use of these drugs in small animal patients was poor. In contrast, there was evidence of important adverse effects, especially drug interaction and gastro-intestinal signs. We therefore recommend prescribing these drugs with caution until further well-conducted studies reveal a useful gastroprotectant effect.

Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo-controlled, 4-way crossover clinical trial.

BackgroundWhile gastrointestinal (GI) effects of standard ibuprofen and N-acetyl-p-aminophenol (APAP) have been reported, upper GI injury following treatment with fast-dissolving (FD) formulations of these analgesics has not been investigated. We evaluated upper GI effects of over-the-counter doses of 2 FD ibuprofen products and 1 FD-APAP product.MethodsIn a randomized, placebo-controlled, endoscopist-blinded, 4-way crossover study, 28 healthy subjects received FD ibuprofen 2×200 mg liquid capsules 3 times daily (TID), ibuprofen 2×200 mg tablets TID, FD-APAP 2×500 mg tablets 4 times daily (QID), and placebo 2×500 mg tablets QID for 7 days. The primary end point was gastric mucosal damage assessed by endoscopy using the Lanza scale: 0=normal stomach or proximal duodenum, 1=mucosal hemorrhages only, 2=1 or 2 erosions, 3=numerous (3–10) erosions, and 4=large number of erosions (>10) or ulcer. Secondary end points included duodenal mucosal damage (Lanza scale); gastroduodenal mucosal injury, classified as present (gastric and/or duodenal endoscopy score ≥2) or absent (gastric and/or duodenal endoscopy score <2); and number of hemorrhages, erosions, and ulcers counted separately in the stomach and duodenum.ResultsSignificantly greater gastric mucosal injury was observed after treatment with both ibuprofen products vs FD-APAP (p<0.0001 and p=0.0095, respectively). FD-APAP showed no difference from placebo (p=0.4794). The odds of having an incidence of gastroduodenal mucosal injury were over 6 times greater from FD ibuprofen liquid capsule treatment (odds ratio [OR]=6.19, 95% confidence interval [CI]: 1.60, 23.97) and over 3 times greater from ibuprofen tablet treatment (OR=3.19, 95% CI: 0.8, 12.74) vs FD-APAP.ConclusionTreatment with 2 ibuprofen products was associated with significant gastric mucosal injury. Of the 4 treatments studied, FD ibuprofen liquid capsules had the highest risk of incidence of gastroduodenal mucosal injury. Treatment with FD-APAP did not induce any clinically or statistically significant gastroduodenal mucosal injury.

Gastroduodenal Mucosal Injury Profile in Long-Term Low-Dose Aspirin Users and Its Influencing Factors

Background: Low-dose aspirin is the most common drug used for prevention of cardiovascular and cerebrovascular events. Long-term aspirin therapy can induce gastroduodenal mucosal injury, even in a very low dose (10 mg daily). The frequency of gastroduodenal injuries among long-term low-dose aspirin users in Indonesia is currently unknown. The aim of this study is to determine the prevalence of gastroduodenal mucosal injury, endoscopic findings, and influencing factors among long-term low-dose aspirin users in Cipto Mangunkusumo Hospital.Method: This study was a cross-sectional study conducted in Cipto Mangunkusumo Hospital, Jakarta. Subjects were patients aged ≥ 18 years old who had been using low-dose aspirin (75-325 mg) for at least the preceding 28 days. Ninety-five subjects were recruited consecutively in the period of December 2015 – April 2016. History taking, upper endoscopic examination, and histopathology examination for Helicobacter pylori infection were performed in all subjects. Endoscopic findings such as erosions and ulcers were assessed as mucosal injuries. Data were analysed to find prevalence, bivariate analysis (Chi-square test), and multivariate analysis (logistic regression test).Results: Mucosal injury was found in 49 subjects (51.6%; 95% CI: 41.6–61.7%), mucosal erosion in 38 subjects (40%; 95% CI: 30.2–49.9%) and ulcers in 11 subjects (11.6%; 95% CI: 5.2–18.0%). Only 44.9% patients with mucosal injury had dyspepsia symptoms. Double antiplatelet therapy increased the risk of mucosal injury (OR = 3.3; 95% CI: 1.3–8.5). However, proton pump inhibitor (PPI) decreased the risk of mucosal injury (OR = 0,2; 95% CI: 0,04 – 0,60).Conclusion: Gastroduodenal mucosal injury was found in more than half of long-term low-dose aspirin users. Double antiplatelet therapy increased the risk of mucosal injury, while PPI effectively reduced the risk.

Risk Factors for Upper GI Damage in Low-Dose Aspirin Users and the Interaction Between H. pylori Infection and Low-Dose Aspirin Use.

Nowadays, low-dose aspirin is widely administered at low dose as an antithrombotic drug for the prevention of cerebrovascular and cardiovascular diseases. However, aspirin, even at a low dose, can induce varying degrees of gastroduodenal mucosal injury (erosion, ulcer, ulcer bleeding). Hence, co-prescription of proton pump inhibitors with low-dose aspirin is recommended for those at high risk for adverse gastroduodenal events. At present, a history of peptic ulcer, especially that of complicated ulcer, is the most important risk factor for low-dose aspirin-associated gastroduodenal adverse events. Additionally, concomitant use of non-steroidal anti-inflammatory drugs including COX-2 selective inhibitors, anti-platelet agents, anti-coagulants, and oral corticosteroid is recognized to increase the risk for adverse gastroduodenal events in low-dose aspirin users. H. pylori infection could also be associated with the increased risk for adverse gastroduodenal events in low-dose aspirin users, especially in patients with histories of peptic ulcers. Therefore, eradication therapy for such patients can prevent ulcer recurrence. However, the efficacy of eradication therapy on low-dose aspirin-related gastroduodenal lesions in unselected H. pylori-positive lowdose aspirin users without histories of peptic ulcers remains to be clarified.

Investigation of Gastroduodenal Mucosal Injury in Japanese Asymptomatic Antiplatelet Drug Users.

Antiplatelet drugs are widely used for the prevention of cardiovascular disease and cerebral vascular disorders. Although there have been several studies on gastroduodenal mucosal injury with gastrointestinal (GI) symptoms such as GI bleeding, in antiplatelet drug users (including low-dose aspirin (LDA)), there have been few reports on the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users. This study was a cross-sectional study elucidating the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Subjects were 186 asymptomatic Japanese antiplatelet drug users who underwent a regular health checkup. Subjects were divided into those with and without gastroduodenal mucosal injury endoscopically, and the association between gastroduodenal mucosal injury and other data in asymptomatic antiplatelet drug users was investigated.The prevalence of males and drinkers were significantly higher in subjects with gastroduodenal mucosal injury than in those without. In addition, the prevalence of proton pump inhibitor (PPI) users was significantly lower in subjects with gastroduodenal mucosal injury than in subjects without gastroduodenal mucosal injury. Logistic regression analysis showed PPI (odds ratios: 0.116; 95% confidence intervals: 0.021–0.638; P < 0.05) was a significant predictor of a decreased prevalence of gastroduodenal mucosal injury and closed-type (C-type) atrophy (3.172; 1.322–7.609; P < 0.01) was a significant predictor of an increased prevalence of severe gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Gender and lifestyle, such as drinking, may have an impact on risk of gastroduodenal mucosal injury in asymptomatic subjects taking antiplatelet drugs. Although PPI is a significant predictor of a decreased prevalence of gastroduodenal mucosal injury, including in asymptomatic antiplatelet drug users, status of gastric atrophy should also be considered against severe gastroduodenal mucosal injury.

Asetil salisilik asit kullanımına bağlı oluşan ileoçekal valv ülserleri ve deformasyonu sonucunda gelişen çekumda çift lümen görünümü

Günümüzde; non steroidal anti-inflamatuvar ilaçların, özellikle aspirinin kullanımı yaşlanma ve yaşlanmayla ilişkili kardiyovasküler hastalıkların sıklığındaki artışla birlikte giderek artmaktadır. Aspirinin; gastroduodenal mukozal hasar yapıcı etkisi gibi en iyi bilinen yan etkisinin yanında yine aspirin nedeniyle oluşan intestinal hasar da daha sık karşımıza çıkmaktadır. Burada muhtemelen enterik-kaplı asetil salisilik asit kullanımı nedeniyle oluşan rekürran ülserlere bağlı gelişen ileoçekal valv deformasyonlu olguyu sunuyoruz.

Geographic differences in low-dose aspirin-associated gastroduodenal mucosal injury.

Aspirin, even at low doses, has been known to cause upper gastro-intestinal complications, such as gastroduodenal ulcers, despite the definite benefits from its antithrombotic effects. Helicobacter pylori (H. pylori) is major pathogen responsible for gastroduodenal ulcer formation. There have been conflicting results about the potential interaction between these two ulcerogenic factors and the geographic areas involved. In Western countries, the prevalence of gastroduodenal ulcers is consistently higher in H. pylori-positive low-dose aspirin (LDA) users than in H. pylori-negative ones, suggesting that H. pylori infection exacerbates LDA-induced gastroduodenal mucosal injury in these geographic areas. Meanwhile, previous studies from Japan have generally reported a similar prevalence of LDA-induced gastroduodenal mucosal injury regardless of the presence of H. pylori infection, indicating that the infection is not an overall exacerbating factor for drug-induced injury. H. pylori infection could have a synergistic or antagonistic interaction with LDA use in adverse gastroduodenal events depending on gastric acid secretion. It is well-recognized that the net effect of H. pylori infection on gastric acid secretion shows considerable geographic variation at the population level. While gastric acid secretion levels were not decreased and were well-preserved in most patients with H. pylori infection from Western countries, the majority of Japanese patients with H. pylori infection exhibited decreased gastric acid secretion. Such large geographic differences in the net effect of H. pylori infection on gastric acid secretion could be at least partly responsible for the geographically distinct interaction between LDA use and H. pylori infection on adverse gastroduodenal lesions.

Effect of aspirin cessation before endoscopy in Japanese patients with low-dose-aspirin-associated gastroduodenal mucosal injury.

The incidence of upper gastrointestinal injury by low-dose aspirin (LDA) has increased. We aimed to clarify the risk factors and prevention strategies associated with LDA-induced gastroduodenal ulcer in Japanese patients. A retrospective study involving 284 LDA users who underwent oesophagogastroduodenoscopy between January and December 2010 were included. We investigated the patients' clinical characteristics and endoscopic findings. Of 284 patients, 29 (10.2%) had gastro and/or duodenal ulcers. Male gender, peptic ulcer history, abdominal symptoms, half-dose proton pump inhibitors (PPIs), complete-dose PPIs, and nonsteroidal anti-inflammatory drugs were significantly associated with LDA-induced gastro and/or duodenal ulcers: odds ratio (95% confidence interval) 3.62 (1.06-12.27), 6.60 (1.84-23.62), 3.06 (1.12-8.40), 0.16 (0.03-0.94), 0.07 (0.01-0.61), and 9.68 (1.64-57.18), respectively. PPI significantly reduced gastric ulcers and/or duodenal ulcers (p = 0.03). The modified Lanza score for gastric mucosal lesion in the LDA cessation group was significantly lower than in the LDA noncessation group (0.53 vs. 1.02; p = 0.008). Half-dose PPIs as well as complete-dose PPIs were effective for preventing LDA-induced gastric and/or duodenal ulcers. The cessation of LDA before endoscopy may lead to an underestimation of LDA-induced gastric injury.

Risk factor profiles, drug usage, and prevalence of aspirin-associated gastroduodenal injuries among high-risk cardiovascular Japanese patients: the results from the MAGIC study

BackgroundLow-dose aspirin is widely used for the prevention of cardiovascular events. The prevalence of gastroduodenal injuries and the risk factor profile including gastroprotective drug therapy needs to be clarified in Japanese patients taking daily aspirin for cardioprotection.MethodsThis Management of Aspirin-induced Gastro-Intestinal Complications (MAGIC) study was conducted with a prospective nationwide, multicenter, real-world registry of Japanese patients at high-risk of cardiovascular diseases who were taking regular aspirin (75–325 mg) for 1 month or more. All patients underwent endoscopic examination for detection of gastroduodenal ulcer and mucosal erosion. The risk factor profiles including the concurrent drug therapy were compared for those patients with gastroduodenal problems and those without.ResultsGastroduodenal ulcer and erosion were detected in 6.5, and 29.2 % of the 1,454 patients receiving aspirin, respectively. H. pylori infection was associated with an increased risk for ulcer: OR 1.83 (1.18–2.88 p = 0.0082). Risk of erosion was lower with enteric-coated aspirin than with buffered aspirin: odds ratio (OR) 0.47 (0.32–0.70, p = 0.0002). Patients receiving proton pump inhibitors had lower risks for both gastroduodenal ulcer and erosion: OR 0.34 (0.15–0.68, p = 0.0050) and 0.32 (0.22–0.46, p < 0.0001), respectively. However, those receiving histamine 2-receptor antagonists had reduced risks for erosion but not for ulcer: OR 0.49 (0.36–0.68, p < 0.0001).ConclusionGastroduodenal ulcer and erosion are common in Japanese patients taking low dose aspirin for cardioprotection. Proton pump inhibitors reduce the risk of gastroduodenal mucosal injury.Electronic supplementary materialThe online version of this article (doi:10.1007/s00535-013-0839-5) contains supplementary material, which is available to authorized users.

Sa1963 A Randomized, Double-Blind, Placebo-Controlled Study of Rebamipide for Gastric Mucosal Injury in Subjects Taking Low-Dose Aspirin With or Without Clopidogrel

[Introduction] The risk of upper gastrointestinal (GI) mucosal injury in patients receiving low dose aspirin (LDA) therapy is potentiated by the concomitant administration of clopidogrel. Rebamipide may help prevent LDA-induced GI complications. The goal of this study was to investigate whether rebamipide could prevent gastric mucosal injuries induced by LDA with or without clopidogrel in healthy subjects. [Materials and Methods] A randomized, double-blind, placebo-controlled, crossover trial was performed with 32 healthy volunteers who had no previous history of non-steroidal anti-inflammatory drugs/antacid use. Subjects were randomly assigned to a 14-day course of one of the following regimens: group A: LDA (100 mg once-daily) + rebamipide (100 mg tid); group B: LDA and clopidogrel (75 mg once-daily) + rebamipide; group C: LDA + placebo; or group D LDA and clopidogrel + placebo. Subjective symptoms were assessed using the Gastrointestinal Symptom Rating Scale (GSRS), and grade of gastroduodenal mucosal injuries was evaluated by esophagogastroduodenoscopy (EGD) before and after dosing (on day 0 and day 14). The grade of gastric mucosal injury was assessed according to the modified Lanza score (MLS), and patients who were found to have any organic lesions at EGD were excluded from the study. Urea breath test was performed to check for the presence or absence of H. pylori. The study protocol was approved by the Ethics Committee of Hyogo College of Medicine, and written informed consent was obtained from all subjects. [Results] In the placebo groups, the median MLS in group C and D was significantly higher after the regimen (4 and 3, respectively) than before the regimen (1 and 2, respectively). In the rebamipide groups, the median MLS on group A and B was similar or slightly less after dosing (1 and 2, respectively) than before dosing (2 and 2, respectively). There was no statistically significant difference in the median MLS when comparing group A with group B (p=0.373) and when comparing group C with group D (p=0.308). H. pylori infection was found only in four (12.5%) of 32 subjects, which one subject affected in each of the four groups. GSRS score was not significantly different among the four groups. [Conclusions]When comparedwith placebo, rebamipide significantly inhibited upper GI mucosal injury induced by LDA alone or LDA plus clopidogrel in healthy subjects. These data suggest that rebamipide can prevent LDA-induced gastric mucosal damage in low-risk subjects.

Prevalence of gastroduodenal ulcers/erosions in patients taking low-dose aspirin with either 15 mg/day of lansoprazole or 40 mg/day of famotidine: The OITA-GF study 2

BackgroundThe preventive effects of histamine 2 receptor antagonists vs. proton pump inhibitors on low-dose aspirin (LDA)-related gastroduodenal mucosal injury have not been fully investigated. We conducted a cross-sectional study to compare the prevalence of gastroduodenal ulcers or erosions in patients taking LDA with either 40 mg/day of famotidine or 15 mg/day of lansoprazole for at least three months.MethodsOf 84 eligible patients, two taking 40 mg/day of famotidine and four taking 15 mg/day of lansoprazole refused to undergo upper gastrointestinal endoscopy. Ultimately, we performed upper gastrointestinal endoscopy in 78 patients taking either 40 mg/day of famotidine (group F, n = 31) or 15 mg/day of lansoprazole (group L, n = 47). The prevalence of gastroduodenal ulcers or erosions and the magnitude of gastric mucosal injury evaluated using modified Lanza scores were compared between the two groups.ResultsNo patients in either group had gastroduodenal ulcers. Gastroduodenal erosions were more prevalent in group F than in group L (48.4% vs. 17.0%, p = 0.005). The modified Lanza scores (mean ± SD) were significantly higher in group F than in group L (0.9 ± 1.3 vs. 0.3 ± 0.7, p = 0.007). A multivariate logistic regression analysis showed that the use of lansoprazole was negatively associated with gastroduodenal erosions.ConclusionsThis study suggests that 15 mg/day of lansoprazole may be more effective in preventing the development of LDA-related gastroduodenal erosions than 40 mg/day of famotidine. The preventive effects of these two regimens on the development of LDA-related gastroduodenal ulcers require further investigation.

Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges

The injurious effects of NSAIDs on the small intestine were not fully appreciated until the widespread use of capsule endoscopy. It is estimated that over two-thirds of regular NSAID users develop injury in the small intestinal injuries and that these injuries are more common than gastroduodenal mucosal injuries. Recently, chronic low-dose aspirin consumption was found to be associated with injury to the lower gut and to be a significant contributing factor in small bowel ulceration, hemorrhage, and strictures. The ability of aspirin and NSAIDs to inhibit the activities of cyclooxygenase (COX) contributes to the cytotoxicity of these drugs in the gastrointestinal tract. However, many studies found that, in the small intestine, COX-independent mechanisms are the main contributors to NSAID cytotoxicity. Bile and Gram-negative bacteria are important factors in the pathogenesis of NSAID enteropathy. Here, we focus on a promising strategy to prevent NSAID-induced small intestine injury. Selective COX-2 inhibitors, prostaglandin derivatives, mucoprotective drugs, phosphatidylcholine-NSAIDs, and probiotics have potential protective effects on NSAID enteropathy.

Does concomitant use of paracetamol potentiate the gastroduodenal mucosal injury associated with aspirin? A prospective, randomised, pilot study

Paracetamol is commonly prescribed for first-line symptomatic treatment in patients with osteoarthritis and aspirin is often co-administered for cardiovascular prophylaxis. It is not known if an interaction exists between aspirin and paracetamol in regards to gastroduodenal mucosal injury. To investigate whether or not co-administered aspirin with paracetamol results in an increased rate of endoscopic gastroduodenal mucosal injury as compared to either agent alone. In this prospective, double-blind, randomised, three-arm, placebo- and active-controlled, parallel-group pilot study healthy adult subjects (18-75years old) with a normal baseline trans-nasal oesophagogastroduodenoscopy (TN-EGD), received oral paracetamol 4000mg q.d.s. (n=21), aspirin 325mg q.d.s. (n=19) or paracetamol 4000mg q.d.s. and aspirin 325mg q.d.s. (n=20). Upper gastrointestinal mucosal injury was evaluated after 7days of treatment with TN-EGD. The rate of gastric ulcers in subjects receiving paracetamol (0/21, 0%) alone or aspirin (3/19, 16%) or both (2/20, 10%) was not different. There were, however, significantly more subjects with one or more lesions (erosion or ulcer) per subject in the paracetamol and aspirin (16/20, 80%) treated subjects as compared to the aspirin (8/19, 42%, P<0.001) or the paracetamol (3/21, 14%, P<0.01) exposed subjects. The mean number of lesions per subject was also greater (7.9 vs. 0.7, P<0.01) in those treated with aspirin and paracetamol compared to paracetamol alone. Co-administration of paracetamol and aspirin was not associated with a significant difference in endoscopic ulcer rates compared to either drug alone. There was a strong signal for increased endoscopic erosions and ulcers in the combined group compared to either aspirin or paracetamol alone.

Letter: mucosal injury with exposure to low‐dose nonsteroidals

Sirs, We read with interest the article by Hawkey et al., ‘Endoscopic evaluation of the gastro-duodenal tolerance of short-term analgesic treatment with 25 mg diclofenac-K liquid capsules’.1 The study evaluated the incidence of endoscopic gastroduodenal mucosal injury associated with 5 days of exposure to low/over the counter (OTC) doses of nonsteroidal anti-inflammatory drugs (NSAIDs): diclofenac-K liquid or diclofenac-K tablet (each at a total daily dose (TDD) of 75 mg), ASA (TDD of 3 g) or ibuprofen (TDD of 1.2 g). The authors highlight a significant and relatively understudied medical concern; most studies evaluate standard dose NSAIDs for the chronic treatment of inflammatory disorders and focus on endoscopic ulcer rates, tolerability, or bleeding outcomes.2, 3 For short-term low-dose/OTC medications, few studies have looked at such endpoints.4-6 The assumption has been that short courses of low-dose NSAIDs would be both tolerated and have a favourable safety profile. In conducting this study, the authors have attempted to directly compare the relative safety associated with diclofenac-K formulations as compared to comparable doses of ibuprofen or aspirin. The question that arises from this study is how do we accurately evaluate the clinically relevant safety of various medications used at OTC doses for short periods of time? Furthermore, with short exposure and low-dose, do variations in the incidence of erosions actually predict clinical safety? We believe that this may not be the best way to compare safety. Instead, the more clinically relevant endpoints would be to evaluate tolerability and persistence of use in a population who require short-term low-dose therapy. It would also be important to simultaneously measure the therapeutic efficacy for which the safer medication is being tested; as the authors point out, different formulations of medications may impact safety and tolerability differently. We congratulate the authors on highlighting the need to look at the safety of OTC nonsteroidals and look forward to future studies. Declaration of personal interests: Dr Goldstein has served as a speaker, a consultant and/or an advisory board member for Pfizer, Logical Therapeutics, Pozen, AstraZeneca, Takeda, Novartis, Astellas, Proctor and Gamble, and has received research funding from Pfizer, Sucampo, Pozen, Logical Therapeutics and AstraZeneca. Declaration of funding interests: None.

Gastrointestinal defense mechanisms

We have highlighted the recent findings relating to gastroduodenal mucosal defense, including elements that may contribute to the failure of defense systems and factors that enhance mucosal healing, focusing on findings that elucidate new pathophysiological mechanisms. Bicarbonate secretion is mediated by multiple types of prostaglandin E synthases, including membrane-bound prostaglandin E synthase-1. Mucins, growth factors, and trefoil factors are involved in accelerating gastric injury healing through epithelial reconstruction. A combination of NSAIDs and bile induce greater damage on the mucosa than if the two agents were acting alone. Proton pump inhibitors defend the mucosa from injury by promoting cellular restitution as well as inhibiting gastric acid secretion and reactive oxygen species (ROS) damage. Roxatidine, a novel H2 receptor antagonist, acts through a mechanism that involves nitric oxide. Melatonin enhances angiogenesis through the upregulation of plasma levels of gastrin and matrix metalloproteinase expression. The mucosal protective drug polaprezinc exhibits ROS-quenching activities. Lipopolysaccharides induce oxidative stress mediated by p38 mitogen-activated protein kinase (p38 MAPK). Aging weakens gastroduodenal mucosal defense mechanisms. There is a wide array of pathways leading to gastroduodenal mucosal injury in addition to protective defense mechanisms that counteract them to maintain homeostasis. Increased understanding of these systems may help identify novel molecular targets for the prevention and treatment of mucosal injury.

Effects of Zinc‐l‐Carnosine and Vitamin E on Aspirin‐Induced Gastroduodenal Injury in Dogs

Nonsteroidal anti-inflammatory drugs frequently cause gastrointestinal (GI) injury. Zinc-L-carnosine has antioxidant, anti-inflammatory, mucosal protective, and healing properties in rodent models and in some human studies of GI injury. The combination of zinc-L-carnosine and vitamin E attenuates aspirin-induced gastroduodenal mucosal injury. Eighteen healthy random-source Foxhound dogs. In this randomized, double-blinded, placebo-controlled study dogs were treated with placebo (n = 6; 0X group), 30 mg/30 IU (n = 6; 1X group), or 60 mg/60 IU (n = 6; 2X group) zinc-L-carnosine/vitamin E orally every 12 hours for 35 days. Between Day 7 and 35, GI mucosal lesions were induced with aspirin (25 mg/kg p.o. q8h). Mucosal injury lesions (hemorrhage, erosion, and ulcer) were assessed by gastroduodenoscopy on Days 14, 21, and 35 with a 12-point scoring scale. At baseline (Day -1) gastroscopy scores were not significantly different between groups (mean ± SD: 0X, 4.4 ± 0.8; group 1X, 4.4 ± 0.6; group 2X, 4.2 ± 0.3; P= .55). Gastroscopy scores increased significantly in all groups between Day -1 and Days 14, 21, and 35 (P < .0001). On Day 35, gastroscopy scores were 29.2 ± 5.2 (0X), 27.3 ± 3.7 (1X), and 28.6 ± 3.3 (2X). Mean gastroscopy scores were not significantly different among treatment groups on any of the days (P = .61). Administration of the combination of zinc-L-carnosine and vitamin E at 1X or 2X dosing did not attenuate aspirin-induced gastroduodenal mucosal injury.

Prevalence and independent factors for gastroduodenal ulcers/erosions in asymptomatic patients taking low-dose aspirin and gastroprotective agents: the OITA-GF study

Although it is well known that aspirin causes gastroduodenal mucosal injury and that aspirin-induced gastroduodenal mucosal injury is often asymptomatic, the prevalence and independent factors for gastroduodenal mucosal injury have not been clarified in asymptomatic patients taking low-dose aspirin and gastroprotective agents. To clarify the prevalence and independent factors for gastroduodenal ulcers/erosions in asymptomatic patients taking low-dose aspirin and gastroprotective agents. Prospective observational study. We performed endoscopy in 150 asymptomatic patients taking low-dose aspirin and gastroprotective agents for at least 3 months. Gastroduodenal ulcers/erosions were observed in 37.3% [ulcers (4.0%); erosions (34.0%)]. Univariate logistic regression analyses showed that proton-pump inhibitor (PPI) use was negatively associated with gastroduodenal ulcers/erosions [odds ratio (OR) 0.35, 95% confidence interval (95% CI) 0.17-0.75, P=0.007]. A multivariate logistic regression analysis selected PPI use as the only independent factor for gastroduodenal ulcers/erosions (OR 0.35, 95% CI 0.14-0.86, P=0.02). None of the 53 patients with PPI use had any gastroduodenal ulcers, and 11 with standard-dose PPI use tended to have a lower prevalence of gastroduodenal erosions than 42 with low-dose PPI use (0% vs. 28.6%, P=0.052). Gastroduodenal ulcers/erosions were observed in about one-third of asymptomatic patients taking low-dose aspirin and gastroprotective agents, and PPI use was a negative independent factor for gastroduodenal ulcers/erosions in those patients. In addition, standard-dose PPI therapy might be more effective in the prevention of aspirin-induced gastroduodenal mucosal injury than low-dose PPI therapy.

Clinical trial: endoscopic evaluation of naproxen etemesil, a naproxen prodrug, vs. naproxen – a proof‐of‐concept, randomized, double‐blind, active‐comparator study

Nonsteroidal anti-inflammatory drugs are associated with upper gastrointestinal mucosal injury. Naproxen etemesil is a lipophilic, non-acidic, inactive prodrug of naproxen that is hydrolysed to pharmacologically active naproxen once absorbed. We hypothesized that with lesser topical exposure to naproxen from the prodrug, there would be reduced gastroduodenal mucosal injury compared with naproxen. To compare the degree of endoscopic mucosal damage of naproxen etemesil vs. naproxen. This multicentre, randomized, double-blind, double-dummy trial compared oral naproxen etemesil 1200 mg twice daily (n = 61) with naproxen 500 mg twice daily (n = 59) for 7.5 days in 120 healthy subjects (45-70 years; mean 51 years; 58% female) with baseline total modified gastroduodenal Lanza score ≤ 2 (no erosions/ulcers) on endoscopy. The primary endpoint was mean total modified gastroduodenal Lanza score on day 7. A secondary endpoint was incidence of gastric ulcers. The day 7 mean total modified gastroduodenal Lanza score was 2.8 ± 1.7 for naproxen etemesil vs. 3.5 ± 2.0 for naproxen (P = 0.03), and significantly fewer naproxen etemesil-treated subjects (3.3%) developed gastric ulcers compared with naproxen-treated subjects (15.8%) (P = 0.02). In this first proof-of-concept study, naproxen etemesil was associated with significantly lower gastroduodenal mucosal injury compared with naproxen after 7 days of exposure ( NCT00750243).