Bifidobacterium breve Bif195 ameliorates aspirin-induced gastric mucosal damage: A randomised, double blind, placebo-controlled crossover trial.

BACKGROUND: Gastric and duodenal ulcerations are common during multiple-dosing aspirin treatment, such as for prevention of cardiovascular disease. On capsule endoscopy, oral administration of the bacterial strain Bifidobacterium breve Bif195 (DSM 33360) reduced the risk of aspirin-induced small intestinal damage, without affecting cyclo-oxygenase-2 (COX-2) inhibition. AIM: To evaluate endoscopically the effect of Bif195 on aspirin-induced stomach and duodenal mucosal damage METHODS: Twenty-five healthy volunteers underwent two intervention periods in a randomised, double-blind, placebo-controlled crossover design including four gastroduodenoscopies and 6 weeks washout. Each intervention was a 4-week oral co-treatment of aspirin 300 mg daily and Bif195 (≥1011 colony-forming units daily) or placebo. Primary endpoint was change in Lanza score - ranging from 0 (normal mucosa) to 4 (>10 erosions or ulcer). RESULTS: All 25 participants (56% females); age 27.3 (±4.8) years; BMI 23.2 (±3.4) kg/m2 , completed the trial exhibiting significant increases in Lanza scores during placebo treatment as compared to baseline. Bif195 reduced gastric Lanza score with an odds ratio of 7.2 (95% confidence interval 1.72-30.08, p = 0.009) compared to placebo with no related adverse events. There were no significant changes in Lanza scores in the duodenum. CONCLUSIONS: Bif195 reduces aspirin-induced gastric mucosal damage and may serve as a safe supplement during multiple-dosing aspirin treatment.

Prevention of recurrent idiopathic gastroduodenal ulcer bleeding: a double-blind, randomised trial.

OBJECTIVE: Patients with a history of Helicobacter pylori-negative idiopathic bleeding ulcers have a considerable risk of recurrent ulcer complications. We hypothesised that a proton pump inhibitor (lansoprazole) is superior to a histamine 2 receptor antagonist (famotidine) for the prevention of recurrent ulcer bleeding in such patients. DESIGN: In this industry-independent, double-blind, randomised trial, we recruited patients with a history of idiopathic bleeding ulcers. After ulcer healing, we randomly assigned (1:1) patients to receive oral lansoprazole 30 mg or famotidine 40 mg daily for 24 months. The primary endpoint was recurrent upper GI bleeding within 24 months, analysed in the intention-to-treat population as determined by an independent adjudication committee. RESULTS: Between 2010 and 2018, we enrolled 228 patients (114 patients in each study group). Recurrent upper GI bleeding occurred in one patient receiving lansoprazole (duodenal ulcer) and three receiving famotidine (two gastric ulcers and one duodenal ulcer). The cumulative incidence of recurrent upper GI bleeding in 24 months was 0.88% (95% CI 0.08% to 4.37%) in the lansoprazole arm and 2.63% (95% CI 0.71% to 6.91%) in the famotidine arm (p=0.313; crude HR 0.33, 95% CI 0.03 to 3.16, p=0.336). None of the patients who rebled used aspirin, non-steroidal anti-inflammatory drugs or other antithrombotic drugs. CONCLUSION: This 2-year, double-blind randomised trial showed that among patients with a history of H. pylori-negative idiopathic ulcer bleeding, recurrent bleeding rates were comparable between users of lansoprazole and famotidine, although a small difference in efficacy cannot be excluded. TRIAL REGISTRATION NUMBER: NCT01180179; Results.

[The role and significance of the physical factors in the treatment and prevention of erosive-ulcerative lesions of the stomach and duodenum]. / Rol' i znachenie fizicheskikh faktorov v lechenii i profilaktike érozivno-iazvennykh porazhenii zheludka i dvenadtsatiperstnoi kishki.

This article covers the issues related to the use of the natural and the preformed physical factors for the treatment and prevention of erosive-ulcerative lesions of the gastro-duodenal area. The existing schemes of their therapeutic treatment provide for the influence only on the separate components of the pathological process which does not allow to achieve the proper correction of the local organic and functional disturbances or the associated systemic disorders. In this context, the purpose of the present article is to demonstrate the importance of the inclusion of various physical factors into the therapeutic programs designed for the treatment of the inflammatory and erosive-ulcerative lesions of the upper digestive tract including the stomach and the duodenum. The present review is focused on the modern data available from the current publications in the scientific literature concerning the possibility and the effectiveness of the application of drinking mineral waters, balneotherapy, and pelotherapy in the combination with secondary prophylaxis and a variety of the rehabilitation modalities for the treatment of the patients presenting with the inflammatory and erosive-ulcerative lesions of the upper part of a digestive tube. It is concluded that these measures, taken together, can efficiently eliminate the said pathological conditions and correct the accompanying systemic disorders. The currently available methods of physical therapy can be not only supplementary to the generally accepted therapeutic modalities but also constitute their basis their basis.

Stress ulcer prophylaxis in intensive care unit patients receiving enteral nutrition: a systematic review and meta-analysis.

BACKGROUND: Pharmacologic stress ulcer prophylaxis (SUP) is recommended in critically ill patients with high risk of stress-related gastrointestinal (GI) bleeding. However, as to patients receiving enteral feeding, the preventive effect of SUP is not well-known. Therefore, we performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effect of pharmacologic SUP in enterally fed patients on stress-related GI bleeding and other clinical outcomes. METHODS: We searched PubMed, Embase, and the Cochrane database from inception through 30 Sep 2017. Eligible trials were RCTs comparing pharmacologic SUP to either placebo or no prophylaxis in enterally fed patients in the ICU. Results were expressed as risk ratio (RR) and mean difference (MD) with accompanying 95% confidence interval (CI). Heterogeneity, subgroup analysis, sensitivity analysis and publication bias were explored. RESULTS: Seven studies (n = 889 patients) were included. There was no statistically significant difference in GI bleeding (RR 0.80; 95% CI, 0.49 to 1.31, p = 0.37) between groups. This finding was confirmed by further subgroup analyses and sensitivity analysis. In addition, SUP had no effect on overall mortality (RR 1.21; 95% CI, 0.94 to 1.56, p = 0.14), Clostridium difficile infection (RR 0.89; 95% CI, 0.25 to 3.19, p = 0.86), length of stay in the ICU (MD 0.04 days; 95% CI, -0.79 to 0.87, p = 0.92), duration of mechanical ventilation (MD -0.38 days; 95% CI, -1.48 to 0.72, p = 0.50), but was associated with an increased risk of hospital-acquired pneumonia (RR 1.53; 95% CI, 1.04 to 2.27; p = 0.03). CONCLUSIONS: Our results suggested that in patients receiving enteral feeding, pharmacologic SUP is not beneficial and combined interventions may even increase the risk of nosocomial pneumonia.

Identification of Helicobacter pylori and the evolution of an efficacious childhood vaccine to protect against gastritis and peptic ulcer disease.

Establishment of Helicobacter pylori infection as an etiologic agent of peptic ulcer disease and other gastric pathologies marked a revolution in gastroenterology which spurred an enormous interest in gastric physiology and immunology research. The association was soon also demonstrated in children as well. Application of antimicrobial therapies have proven remarkably efficacious in eradicating H. pylori and curing pediatric patients of duodenal ulcers as well as gastritis, negating a lifetime of ineffective therapy and life-threatening disease. Countries with high H. pylori prevalence and where H. pylori associated gastric cancer remains a primary cause of death due to cancer however would benefit from childhood vaccination. Studies in rodents and humans utilizing oral vaccination with bacterial exotoxin adjuvants demonstrated potential for limiting H. pylori colonization in the stomach. Almost 25 y of vaccine research recently culminated in a phase III clinical trial of over 4,000 children aged 6-15 y old to test an oral vaccine consisting of the H. pylori urease B subunit genetically fused to the E. coli heat labile toxin. Vaccination was demonstrated to have an efficacy of over 70%. Vaccination may now serve as an effective strategy to significantly reduce H. pylori associated disease in children throughout the world.

Aspirin Use in Secondary Cardiovascular Protection and the Development of Aspirin-Associated Erosions and Ulcers.

Aspirin for secondary cardiovascular disease prevention is well established, but treatment discontinuation, often because of gastrointestinal mucosal injury or symptoms, can lead to increased risk for cardiovascular events. Proton pump inhibitor therapy is recommended for aspirin-treated patients at gastrointestinal risk. PA32540 [enteric-coated aspirin (EC-ASA) 325 mg + immediate-release omeprazole 40 mg] was compared with EC-ASA 325 mg alone once daily for 6 months in 2 duplicate, randomized double-blind trials in gastrointestinal-risk patients taking aspirin for ≥3 months for secondary prevention. In this post hoc analysis, we determined the prevalence of endoscopic upper gastrointestinal ulcers at screening and whether baseline endoscopic gastric erosions impacted subsequent ulcer development. At the screening endoscopy, 6% of subjects had upper gastrointestinal ulcers (not eligible for randomization) and 40% had gastric erosions. Conditional logistic regression modeling showed that baseline gastric erosions are significantly associated with endoscopic gastric ulcer development (OR = 2.12, 95% confidence interval, 1.26-3.57). In subjects with baseline gastric erosion, 4.2% of PA32540-treated versus 13.0% of EC-ASA-treated subjects (P = 0.001) subsequently developed endoscopic gastric ulcers. These data suggest that gastric injury predisposes to gastric ulcer development when taking EC-ASA, and exposure to immediate-release omeprazole in the presence of aspirin therapy significantly reduces the likelihood of progressing to gastric ulcers.

Current Topics of Strategy of NSAID-Induced Small Intestinal Lesions.

Small intestinal mucosal injuries have been recently recognized as common complications associated with non-steroidal anti-inflammatory drugs (NSAIDs) because video capsule endoscopy and balloon enteroscopy are now available for the detection of small intestinal lesions. Small intestinal injury occurs not in an acid-dependent mechanism but by various factors such as enteric bacteria, bile acids, prostaglandin (PG) deficiency and topical factors (abnormal intestinal mucosal permeability, mitochondrial dysfunction, reactive oxygen species, endoplasmic reticulum stress and so on), and there is no well-established prophylactic approach. Several experimental and clinical studies found the effectiveness of some of the mucoprotective drugs, PG analogs, but not that of acid suppressants. Considering the effect of proton pump inhibitors (PPIs) for upper gastrointestinal (GI) disease and in the small intestine, the following 2 kinds of strategies against NSAID-induced GI injuries may be recommended. In patients with a high risk of upper GI disease (peptic ulcer etc.), simultaneous administration of a PPI (for upper GI disease) and a mucoprotective drug (for small intestine) is needed to prevent NSAID-induced GI injury. In other cases, an effective mucoprotective drug is enough for the protection of the entire digestive tract, that is, starting from the esophagus to the small intestine. These strategies may fulfill both economical and curative effects.

Gastroprotective efficacy and safety of single-tablet ibuprofen/famotidine vs ibuprofen in older persons.

OBJECTIVES: A combination tablet of ibuprofen 800 mg and famotidine 26.6 mg given three times daily is effective for the treatment of rheumatoid arthritis and osteoarthritis and decreases the risk of developing upper gastrointestinal (GI) ulcers. This analysis evaluated the gastroprotective efficacy and safety of the single-tablet combination of ibuprofen/famotidine compared with ibuprofen alone on the basis of age and the presence of one or more risk factors for development of upper GI ulcer. METHODS: Pooled data from the 24-week, randomized, double-blind, parallel-group REDUCE-1 and REDUCE-2 trials were used. Endoscopies were performed in patients aged 40-80 years. The proportion of patients who developed ≥ 1 upper GI ulcer during treatment with ibuprofen/famotidine versus ibuprofen alone stratified on the basis of age (< 60 or ≥ 60 years) was evaluated. Further, analyses were performed on additional risk factors for ulcer development. RESULTS: Gastroprotective efficacy of the combination was not affected by age. Pooled results demonstrated statistically significantly fewer upper GI (10.0 vs 19.5%, p < 0.0001), gastric (8.9 vs 16.8%, p = 0.0004), and duodenal ulcers (1.1 vs 5.4%, p < 0.0001) in patients < 60 years treated with ibuprofen/famotidine versus ibuprofen alone compared with 12.9 vs 26.6% (p = 0.0002), 11.9 vs 23.4% (p = 0.0011), and 1.0 vs 4.5% (p = 0.0096), respectively, in patients ≥ 60 years. The ibuprofen/famotidine combination provided nearly 51 and 59% reduction in the risk of developing a GI ulcer in patients <60 years and ≥ 60 of age, respectively. Efficacy was maintained in the presence of additional risk factors, as well. CONCLUSIONS: These results indicate that the fixed-combination of ibuprofen/famotidine provides gastroprotection in those of older age, with or without additional risk factors for the development of upper GI ulcers, as compared with ibuprofen alone. US National Institutes of Health registry, http://www.clinicaltrials.gov, NCT00450658 and NCT00450216.

New molecules as drug candidates for the treatment of upper and lower GI tract ulcers.

Ulcers in the stomach, duodenum, ileum/jejunum and colon may look alike grossly and microscopically, but they have very different etiologies and pathogenesis. Unfortunately, there is virtually no etiologic treatment for any of these lesions which are also accompanied by limited or extensive inflammation. This article reviews four groups of new antiulcer drugs discovered and patented in our lab in Boston and Long Beach/Irvine (Table 1). Actually, the first group, pyrazole and its derivatives can be used for prevention, i.e., long lasting protection of gastric mucosa against alcohol- or NSAID-induced erosions. Dopamine seems to be a new etiologic treatment for both upper and lower GI tract ulcers. Angiogenic growth factors like bFGF or PDGF (daily administration as peptides orally or by rectal enemas, or as single or double-dose of gene therapy) accelerated the healing of gastroduodenal ulcers and UC, while VEGF seems to be effective only for upper GI tract ulcers. Last but not least, a novel group of angiogenic steroids which not only stimulate new blood vessel formation and granulation tissue production (essential elements of healing of ulcer types) but may also exert mild or prominent antiinflammatory action and seem to be ideal drugs for the treatment of IBD.

New insight into the mechanisms of gastroduodenal injury induced by nonsteroidal anti-inflammatory drugs: practical implications.

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially acetylsalicylic acid (ASA), are commonly used in the therapy of various diseases. However, the serious side effects of these drugs, such as bleedings, acute lesions, gastric ulcers, and even intestinal perforations, are widely recognized. NSAIDs inhibit cyclooxygenase (COX) activity resulting in the suppression of mucosal generation of gastroprotective prostaglandins (PGs) derived from a constitutive isoform, COX-1, as well as an inducible isoform, COX-2. COX-1-derived PGs are responsible for gastroprotection, while PGs generated via COX-2 activity also play an important role in gastroprotection and ulcer healing. Recently, a new class of NSAIDs has been developed by adding NO moiety to conventional NSAIDs. In contrast to native NSAIDs, their NO-releasing derivatives such as NO-ASA were found to exhibit lower gastric toxicity despite inhibiting both COX-1 and COX-2 activity in the gastric mucosa. Similar limited gastrointestinal toxicity and protective actions were observed with a new class of hydrogen sulfide (H2S)-releasing NSAIDs, such as H2S-releasing naproxen (ATB-346). Dual antiplatelet therapy with ASA and clopidogrel increases the risk of gastrointestinal bleeding in patients with acute coronary syndrome in whom concomitant treatment with a proton-pump inhibitor (PPI) was less effective owing to the interaction of clopidogrel and PPI with the same hepatic cytochrome P-450. In conclusion, new derivatives of NSAIDs releasing vasoactive gaseous mediators NO or H2S are associated with fewer gastrointestinal adverse effects, suggesting that, in the future, they may be used as a safer alternative in everyday clinical practice and antithrombotic therapy.

Role of dietary phospholipids and phytosterols in protection against peptic ulceration as shown by experiments on rats.

Geographically the prevalence of duodenal ulceration is related to the staple foods in the diet in regions of developing countries where the diet is stable. It is higher in regions where the diet is based on milled rice, refined wheat or maize, yams, cassava, sweet potato, or green bananas, and is lower in regions where the staple diet is based on unrefined wheat or maize, soya, certain millets or certain pulses. Experiments on rat gastric and duodenal ulcer models showed that it was the lipid fraction in staple foods from low prevalence areas that was protective against both gastric and duodenal ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs). It also promoted ulcer healing. The lipid from the pulse, Dolichos biflorus, horse gram which was highly protective was used to identify the fractions with protective activity in the lipid. The protective activity lay in the phospholipid, sterol and sterol ester fractions. In the phospholipid fraction phosphatidyl choline (lethicin) and phosphatidyl ethanolamine (cephalin) were predominant. In the sterol fraction the sub-fractions showing protective activity contained ß-sitosterol, stigmasterol, and an unidentified isomer of ß-sitosterol. The evidence from animal models shows that certain dietary phospholipids and phytosterols have a protective action against gastroduodenal ulceration, both singly and in combination. This supports the protective role of staple diets in areas of low duodenal ulcer prevalence and may prove to be of importance in the prevention and treatment of duodenal ulceration and management of recurrent ulcers. A combination of phospholipids and phytosterols could also play an important role in protection against ulceration due to NSAIDs.

Analgesic, antiulcer, antithrombotic drugs and organ damage: a population-based case-control study.

AIM: Oral medication is of paramount importance for pain treatment. Analgesics, antiulcer (AUDs) and antithrombotic drugs (ATDs) are often coprescribed in elderly people. Non-steroidal anti-inflammatory drugs (NSAIDs) require AUDs to lower the risk of peptic ulcer, and potentially interfere with ATDs. The aim of this study was to quantify the prevalence of NSAID use in patients with gastrointestinal, cardiac or kidney damage in the year 2013, compared to the general population. METHODS: We performed a population-based case-control study in the Republic of San Marino to evaluate the Odds-Ratios for upper gastrointestinal damage (gastroduodenal ulcers and/or erosions, GUE), ischemic heart disease (IHD), heart failure (HF), and renal function impairment (assessed using the CKD-EPI formula), in people who had taken AUDs, ATDs, or NSAIDs in the previous 90 days, versus people who had not taken such drugs in the same period of time. RESULTS: We found that AUDs decreased the OR for GUE (OR: 0.762; CI:0.598-0.972), while ATDs and NSAIDs increased the risk (OR: 1.238 and CI: 0.935-1.683; OR:1.203 and CI:0.909-1.592, respectively). NSAIDs seemed to increase the risk of IHD, although this was not statistically significant (OR=1.464; CI=0.592-3.621). AUDs and ATDs significantly increased the risk of renal function impairment (OR=1.369 and CI=1.187-1.579; OR=1.818 and CI=1.578-2.095, respectively), while this effect was not observed for NSAIDs. CONCLUSION: NSAIDs may induce gastrointestinal and cardiovascular damage, not only by themselves, but also when used concomitantly with common medications such as AUDs or ATDs, due to additive and/or synergistic effects. We performed a "pragmatic" analysis of the association of organ damage with use of NSAIDs/AUDs/ATDs, including patient age, treatment duration and dose, to allow for an immediate application of our findings to everyday clinical practice.

Randomised clinical trial: prevention of recurrence of peptic ulcers by rabeprazole in patients taking low-dose aspirin.

BACKGROUND: Few studies have evaluated the effects of rabeprazole on low-dose aspirin (LDA)-induced gastroduodenal injuries. AIM: To conduct a randomised, double-blind, triple-dummy, active-controlled, multicentre trial, named the PLANETARIUM study, to assess the efficacy, dose-response relationship and safety of rabeprazole for peptic ulcer recurrence in Japanese patients on long-term LDA therapy. METHODS: Eligible patients had a history of endoscopically confirmed peptic ulcers and were receiving long-term LDA (81 or 100 mg/day) therapy for cardiovascular or cerebrovascular protection. Subjects were randomly segregated into three groups receiving rabeprazole 10 mg once daily (standard dose in Japan), rabeprazole 5 mg once daily, or teprenone (geranylgeranylacetone; mucosal protective agent commercially available in Japan) 50 mg three times per day as an active control. The primary endpoint was recurrence of peptic ulcers over 24 weeks. RESULTS: Among 472 randomised subjects, 452 subjects (n = 151, 150, 151, respectively) constituted the full analysis set. The cumulative recurrence rates of peptic ulcers over 24 weeks in the 10- and 5-mg rabeprazole groups were 1.4% and 2.8%, respectively, both of which were significantly lower than that in the teprenone group (21.7%). The cumulative occurrence rate of bleeding ulcers over 24 weeks in the teprenone group was 4.6%, while bleeding ulcers were not observed in the 10- or 5-mg rabeprazole groups. Rabeprazole was well tolerated at both doses. CONCLUSION: Rabeprazole prevents the recurrence of peptic ulcers with no evidence of a major dose-response effect in subjects on low-dose aspirin therapy.

[Helicobacter pylori: short overview on selected data from the history and their value for clinical medicine, in particular, surgery - what does the (general/abdominal) surgeon need to know]. / Helicobacter pylori: Kurzabriss zu ausgewählten historischen Etappen des Erkenntnisprozesses und ihre Bedeutung für die klinische Medizin, insbesondere auch die Chirurgie - was der (Allgemein-/Viszeral-)Chirurg wissen sollte.

The discovery of Helicobacter pylori (H. pylori) represents one of the most notable events in the field of experimental and clinical medicine with great impact to daily practice even to surgery. It has led to a paradigm shift in the treatment of peptic ulcer disease. For the time period of almost one century, several scientists had described spiral-shaped bacteria in the stomach of animals and humans. However, it lasted till the early 1980s when Robin Warren and Barry Marshall successfully cultured H. pylori and recognised its causal relationship to chronic gastritis and peptic ulcer disease. Since then, our knowledge about H. pylori and related diseases has been continuously growing. Today, the bacterium is known to be mainly responsible for the development of chronic gastritis, peptic ulcer disease, MALT lymphoma and is considered as the main risk factor for the development of gastric cancer - all this led to a switch in the basic aetiopathogenetic considerations. In particular, eradication of H. pylori helped to i) develop an aetiology-based therapeutic and preventive approach to the diseases listed above according and adapted to findings, stage and manifestation, and ii) define a new role of surgery in the treatment concept. In addition, more and more evidence is being gathered for a possible association between the bacterium and several extragastric diseases.

Risk of upper gastrointestinal ulcers in patients with osteoarthritis receiving single-tablet ibuprofen/famotidine versus ibuprofen alone: pooled efficacy and safety analyses of two randomized, double-blind, comparison trials.

BACKGROUND: Although anti-inflammatory doses of ibuprofen are very effective in treating the signs and symptoms of osteoarthritis (OA), they come with an increased risk for gastrointestinal damage which can limit their use and decrease patient adherence to therapy. OBJECTIVE: Assess the efficacy and safety of an ibuprofen/famotidine fixed-dose tablet for reducing the risk of upper gastrointestinal (UGI) ulcers compared with ibuprofen alone in OA patients. METHODS: Osteoarthritis patients from previously completed randomized, double-blind, comparison registration trials (REDUCE-1 and 2) which included a broad pain patient population, were pooled and analyzed for (1) the risk of endoscopically identified UGI ulcers over 24 weeks and (2) comparative pre-specified treatment emergent adverse events (TEAEs). The primary outcomes were the comparative incidence of UGI, gastric, and duodenal ulcers and TEAEs in (1) the total OA population, (2) those aged ≥ 60 years, and (3) those on low dose aspirin. A total of 776 patients were randomized (safety population), and 713 were evaluable as the study population. RESULTS: Upper gastrointestinal ulcer risk was statistically significantly reduced with the fixed dose tablet compared with ibuprofen alone by 44% in the overall population, 55% in those aged ≥ 60 years and 65% in those on low dose aspirin. Individually, gastric and duodenal ulcers were also significantly reduced in all groups analyzed. Adverse events of special interest were generally similar between the 2 groups, with the exception of dyspepsia. Relative risk reduction for dyspepsia in the overall population was 40% and 55% in those aged ≥ 60 years. Patients not receiving low dose aspirin had a 49% relative risk reduction in dyspepsia. CONCLUSION: The fixed combination of ibuprofen/famotidine significantly reduced the risk for endoscopically documented gastrointestinal ulcers in OA patients and produced clinically meaningful reductions in patient reported dyspepsia compared with the ibuprofen alone.

Deep-sea water containing selenium provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

Deep-sea water (DSW), which is rich in micronutrients and minerals and with antioxidant and anti-inflammatory qualities, may be developed as marine drugs to provide intestinal protection against duodenal ulcers. We determined several characteristics in the modified DSW. We explored duodenal pressure, oxygenation, microvascular blood flow, and changes in pH and oxidative redox potential (ORP) values within the stomach and duodenum in response to tap water (TW, hardness: 2.48 ppm), DSW600 (hardness: 600 ppm), and DSW1200 (hardness: 1200 ppm) in Wistar rats and analyzed oxidative stress and apoptosis gene expressions by cDNA and RNA microarrays in the duodenal epithelium. We compared the effects of drinking DSW, MgCl2, and selenium water on duodenal ulcers using pathologic scoring, immunohistochemical analysis, and Western blotting. Our results showed DSW has a higher pH value, lower ORP value, higher scavenging H2O2 and HOCl activity, higher Mg2+ concentrations, and micronutrients selenium compared with TW samples. Water infusion significantly increased intestinal pressure, O2 levels, and microvascular blood flow in DSW and TW groups. Microarray showed DSW600, DSW1200, selenium water upregulated antioxidant and anti-apoptotic genes and downregulated pro-apoptotic gene expression compared with the TW group. Drinking DSW600, DSW1200, and selenium water but not Mg2+ water significantly enhanced Bcl-2 and thioredoxin reductase 1 expression. Bax/Bcl-2/caspase 3/poly-(ADP-ribose)-polymerase signaling was activated during the pathogenesis of duodenal ulceration. DSW drinking reduced ulcer area as well as apoptotic signaling in acetic acid-induced duodenal ulcers. DSW, which contains selenium, provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

STAT3 and importins are novel mediators of early molecular and cellular responses in experimental duodenal ulceration.

OBJECTIVES: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers. METHODS: We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses. RESULTS: We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and ß in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or ß, and STAT3/DNA binding than wild-type mice in response to cysteamine. CONCLUSIONS: Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.

Low-dose aspirin-associated upper gastric and duodenal ulcers in Japanese patients with no previous history of peptic ulcers.

BACKGROUND: Long-term administration of low-dose aspirin (LDA) is associated with a greater risk of adverse events, including gastroduodenal ulcers. The purpose of this study was to identify the risk factors for and assess the role of medication use in the development of peptic ulcer disease in Japanese patients with no history of peptic ulcers. METHODS: Consecutive outpatients receiving LDA (75 mg/day) who underwent esophagogastroduodenoscopy between January and December 2010 were enrolled. Clinical parameters, peptic ulcer history, concomitant drugs, the presence of Helicobacter pylori infection, reason for endoscopy, and endoscopic findings were analysed. RESULTS: Of 226 total patients, 14 (6.2%) were endoscopically diagnosed with peptic ulcer. Age, sex, current smoking status, current alcohol consumption, endoscopic gastric mucosal atrophy, and abdominal symptoms were not significantly associated with peptic ulcers. Diabetes mellitus was more frequent (42.9% vs. 16.5%; P = 0.024) in patients with peptic ulcers than in those without peptic ulcers. Using multiple logistic regression analysis, co-treatment with anticoagulants or proton pump inhibitors (PPIs) was significantly associated with increased and decreased risk for peptic ulcer, respectively (odds ratio [OR], 5.88; 95% confidence interval [CI], 1.19 - 28.99; P = 0.03 and OR, 0.13; 95% CI, 0.02 - 0.73; P = 0.02, respectively). Co-treatment with additional antiplatelet agents, H2-receptor antagonists, angiotensin II Type 1 receptor blockers, angiotensin-converting enzyme inhibitor, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, or nonsteroidal anti-inflammatory drugs was not associated with peptic ulcer development. CONCLUSION: The use of PPIs reduces the risk of developing gastric or duodenal ulcers in Japanese patients taking LDA without pre-existing gastroduodenal ulcers. However, this risk is significantly increased in both patients ingesting anticoagulants and patients with diabetes. These results may help identify patients who require intensive prophylaxis against aspirin-induced peptic ulcers.

Fixed-dose ibuprofen/famotidine: a review of its use to reduce the risk of gastric and duodenal ulcers in patients requiring NSAID therapy.

A fixed-dose combination of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and the histamine H(2) receptor antagonist famotidine (ibuprofen/famotidine; DUEXIS(®)) is now available for the symptomatic treatment of arthritic symptoms and to reduce the risk of upper gastrointestinal (GI) ulcers in patients who require ibuprofen therapy. The gastroprotective efficacy of oral ibuprofen/famotidine 800/26.6 mg three times daily in patients requiring NSAID therapy for inflammatory conditions and/or pain was evaluated in two 24-week, well-designed trials (REDUCE-1 and -2). According to the post-adjudication analysis of these studies, ibuprofen/famotidine significantly reduced the life table estimated rate of gastric ulcers (primary endpoint of REDUCE-1) but not upper GI ulcers (i.e. gastric or duodenal ulcers) [primary endpoint of REDUCE-2] compared with ibuprofen alone. When life table estimated rates of secondary endpoints were assessed, significantly fewer recipients of the fixed-dose combination than of ibuprofen alone developed upper GI ulcers or duodenal ulcers in REDUCE-1, whereas the between-group difference in gastric ulcers and duodenal ulcers was considered to be nonsignificant in REDUCE-2 because of hierarchical testing. However, in a prespecified pooled analysis of REDUCE-1 and -2, the rate of upper GI ulcers as well as each of the upper GI ulcer components was significantly lower with ibuprofen/famotidine than with ibuprofen. Ibuprofen/famotidine was generally well tolerated, with a tolerability profile consistent with those established for the individual agents.