Efficacy of keverprazan for duodenal ulcer: A phase II randomized, double-blind, parallel-controlled trial.

BACKGROUND AND AIM: Considering the limitation of varying acid suppression of proton pump inhibitors, this study was aimed to assess the efficacy, safety, and dose-effect relationship of keverprazan, a novel potassium-competitive acid blocker, in the treatment of duodenal ulcer (DU) compared with lansoprazole. METHODS: A randomized, double-blind, double-dummy, multicenter, low-dose, high-dose, and positive-drug parallel-controlled study was conducted to verify the non-inferiority of keverprazan (20 or 30 mg) to lansoprazole of 30 mg once daily for 4 to 6 weeks and dose-effect relationship of keverprazan in the treatment of patients with active DU confirmed by endoscopy. RESULTS: Of the 180 subjects randomized, including 55 cases in the keverprazan_20 mg group, 61 cases in the keverprazan_30 mg group, and 64 cases in the lansoprazole_30 mg group, 168 subjects (93.33%) completed the study. The proportions of healed DU subjects in the keverprazan_20 mg, keverprazan_30 mg, and lansoprazole_30 mg groups were respectively 87.27%, 90.16%, and 79.69% at week 4 (P = 0.4595) and were respectively 96.36%, 98.36%, and 92.19% at week 6 (P = 0.2577). The incidence of adverse events in the keverprazan_20 mg group was lower than that in the lansoprazole_30 mg (P = 0.0285) and keverprazan_30 mg groups (P = 0.0398). CONCLUSIONS: Keverprazan was effective and non-inferior to lansoprazole in healing DU. Based on the comparable efficacy and safety data, keverprazan of 20 mg once daily is recommended for the follow-up study of acid-related disorders. (Trial registration number: ChiCTR2100043455.).

Vonoprazan non-inferior to lansoprazole in treating duodenal ulcer and eradicating Helicobacter pylori in Asian patients.

BACKGROUND AND AIM: Duodenal ulcers, especially caused by increasingly drug-resistant Helicobacter pylori, are a concern in Asia. We compared oral vonoprazan versus lansoprazole for efficacy (healing duodenal ulcers) and safety in non-Japanese Asian patients. METHODS: In this phase 3, randomized (1:1), double-blind, double-dummy, parallel-group, non-inferiority study (April 5, 2017, to July 19, 2019), patients with ≥ 1 endoscopically confirmed duodenal ulcer, at 52 hospitals (China, South Korea, and Taiwan), received vonoprazan 20 mg once daily (QD) or lansoprazole 30 mg QD for 6 weeks maximum. Patients with H. pylori received bismuth-containing quadruple therapy including vonoprazan 20 mg twice daily (BID) or lansoprazole 30 mg BID, for 2 weeks, followed by vonoprazan or lansoprazole monotherapy QD (4 weeks maximum). Endpoints were endoscopically confirmed duodenal ulcer healing (Week 4/6; primary) and H. pylori eradication (4 weeks post-treatment; secondary); non-inferiority margins were -6% and -10%, using a two-sided 95% confidence interval (CI). RESULTS: Of 533 enrolled patients, one was lost to follow-up and one withdrew (full analysis set: 531 patients [vonoprazan, n = 263; lansoprazole, n = 268]; 85.4% = H. pylori positive). Vonoprazan was non-inferior to lansoprazole for duodenal ulcer healing (96.9% vs 96.5%; difference 0.4% [95% CI -3.00, 3.79]). H. pylori eradication rates were 91.5% (vonoprazan) and 86.8% (lansoprazole; difference 4.7% [95% CI -1.28, 10.69]). Vonoprazan and lansoprazole were well tolerated, with similar safety profiles, no new safety signals; no deaths occurred. CONCLUSIONS: Vonoprazan was well tolerated and non-inferior to lansoprazole for duodenal ulcer healing and achieved H. pylori eradication above the clinically meaningful threshold (90%), in non-Japanese Asian patients.

Drug-induced duodenal perforation in the paediatric patient with thalassemia major, an unreported side effect of iron- chelating agent: A case report.

Duodenal ulcer disease is uncommon in paediatric age group. Its perforation is even rarer. However, it should be kept in mind when examining children with acute abdomen especially if there are signs of shock or possibility of upper gastrointestinal bleed. We report a case of a 6 years old female child, a known case of thalassemia major and taking oral Deferasirox since two years of age. She had atypical presentation as there was no previous history of peptic ulcer disease and she only suffered epigastric pain and vomiting for a week but due to lack of proper diagnosis at a local clinic developed duodenal ulcer perforation, which was ultimately diagnosed at a tertiary care hospital and managed with Graham Patch Closure.

Do glucocorticoids affect the development of ulcers and erosions of the upper gastrointestinal tract in patients taking NSAIDs.

AIM: To assess the frequency of ulceration and erosion in patients with rheumatic diseases (RD) receiving NSAIDs, depending on the concomitant use of GC. MATERIALS AND METHODS: A retrospective comparison was made of the incidence of gastrointestinal lesions detected in patients with RD during endoscopic examination in one medical center for 2007-2016. Three groups were formed: in group 1 patients took only NSAIDs (n=4823, women 80.7%, age 51.1 + 15.4 years), in group 2 patients took NSAIDs and GC (n = 1608, women 89, 8%, age 50.4 + 14.6 years), in group 3 - only patients took GC (n=1135, women 92.7%, age 44.1 + 15.3 years). The detection of multiple erosions (>10, ME) and gastric and / or duodenal ulcers was as-sessed. RESULTS: The frequency of ME and ulcers in patients of groups 1 and 2 did not differ significantly: 10.5% and 8.5%, odds ratio 0.799 (95% confidence interval 0.546-1.169, p=0.072). Risk factors, such as age > 65 years, ulcer history and low-dose aspirin, did not affect this pattern. The incidence of ME and ulcers was significantly lower in Group 3 patients than in Groups 1 and 2: 6.3% (p<0.001, p=0.032). CONCLUSION: The use of GC does not increase the risk of erosion and ulcers of the upper GI tract when taking NSAIDs.

Polysaccharides derived from Ganoderma lucidum fungus mycelia ameliorate indomethacin-induced small intestinal injury via induction of GM-CSF from macrophages.

Non-steroidal anti-inflammatory drugs often cause ulcers in the human small intestine, but few effective agents exist to treat such injury. Ganoderma lucidum Karst, also known as "Reishi" or "Lingzhi", is a mushroom. We previously reported that a water-soluble extract from G. lucidum fungus mycelia (MAK) has anti-inflammatory effects in murine colitis induced by trinitrobenzene sulfonic acid, and induction of granulocyte macrophage colony-stimulating factor (GM-CSF) by MAK may provide anti-inflammatory effects. However, its effects on indomethacin-induced small intestinal injuries are unknown. The present study investigated the preventative effects of MAK via immunological function and the polysaccharides from MAK on indomethacin-induced ileitis in mice. Peritoneal macrophages (PMs) were stimulated in vitro with MAK and adoptively transferred to C57BL/6 mice intraperitoneally, which were then given indomethacin. Intestinal inflammation was evaluated after 24h. We performed in vivo antibody blockade to investigate the preventive role of GM-CSF, which derived from PMs stimulated with MAK. We then used PMs stimulated with MAK pre-treated by pectinase in an adoptive transfer assay to determine the preventive role of polysaccharides. Indomethacin-induced small intestinal injury was inhibited by adoptive transfer of PMs stimulated in vitro with MAK. In this transfer model, pre-treatment with anti-GM-CSF antibody but not with control antibody reversed the improvement of small intestinal inflammation by indomethacin. Pectinase pretreatment impaired the anti-inflammatory effect of MAK. PMs stimulated by MAK appear to contribute to the anti-inflammatory response through GM-CSF in small intestinal injury induced by indomethacin. The polysaccharides may be the components that elicit the anti-inflammatory effect.

[Duodenal ulcers, gastric ulcers and Helicobacter pylori]. / Ulcus duodeni, Ulcus ventriculi und Helicobacter pylori.

The mortality in elderly patients over the age of 80 years with peptic ulcers in the case of complications, such as bleeding and perforation is higher than in the general population. Duodenal ulcers are associated with Helicobacter pylori infections in 90% of cases and in 70% of gastric ulcers. The treatment of elderly patients is often difficult due to multimorbidity and polypharmacy and necessitates a geriatric approach. Ulcers are often caused by medication with nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Despite the fact that progress in therapy has improved the prevalence and prognosis, the treatment of elderly patients with ulcers is complex.

Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the Optimum Patient Care Research Database and the British Thoracic Difficult Asthma Registry.

OBJECTIVE: To determine the prevalence of systemic corticosteroid-induced morbidity in severe asthma. DESIGN: Cross-sectional observational study. SETTING: The primary care Optimum Patient Care Research Database and the British Thoracic Society Difficult Asthma Registry. PARTICIPANTS: Optimum Patient Care Research Database (7195 subjects in three age- and gender-matched groups)-severe asthma (Global Initiative for Asthma (GINA) treatment step 5 with four or more prescriptions/year of oral corticosteroids, n=808), mild/moderate asthma (GINA treatment step 2/3, n=3975) and non-asthma controls (n=2412). 770 subjects with severe asthma from the British Thoracic Society Difficult Asthma Registry (442 receiving daily oral corticosteroids to maintain disease control). MAIN OUTCOME MEASURES: Prevalence rates of morbidities associated with systemic steroid exposure were evaluated and reported separately for each group. RESULTS: 748/808 (93%) subjects with severe asthma had one or more condition linked to systemic corticosteroid exposure (mild/moderate asthma 3109/3975 (78%), non-asthma controls 1548/2412 (64%); p<0.001 for severe asthma versus non-asthma controls). Compared with mild/moderate asthma, morbidity rates for severe asthma were significantly higher for conditions associated with systemic steroid exposure (type II diabetes 10% vs 7%, OR=1.46 (95% CI 1.11 to 1.91), p<0.01; osteoporosis 16% vs 4%, OR=5.23, (95% CI 3.97 to 6.89), p<0.001; dyspeptic disorders (including gastric/duodenal ulceration) 65% vs 34%, OR=3.99, (95% CI 3.37 to 4.72), p<0.001; cataracts 9% vs 5%, OR=1.89, (95% CI 1.39 to 2.56), p<0.001). In the British Thoracic Society Difficult Asthma Registry similar prevalence rates were found, although, additionally, high rates of osteopenia (35%) and obstructive sleep apnoea (11%) were identified. CONCLUSIONS: Oral corticosteroid-related adverse events are common in severe asthma. New treatments which reduce exposure to oral corticosteroids may reduce the prevalence of these conditions and this should be considered in cost-effectiveness analyses of these new treatments.

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.

A refractory duodenal ulcer with a biliary-duodenal fistula following the administration of bevacizumab.

A 65-year-old woman with recurrent breast cancer was repeatedly treated with bevacizumab, an anti-VEGF antibody. In addition, she was also frequently prescribed a nonsteroidal anti-inflammatory drug for abdominal pain. Melena was revealed 2 months after the final treatment with bevacizumab, and an endoscopic study revealed a duodenal ulcer (DU) that was resistant to anti-ulcer therapy. A cholangiography identified a biliary-duodenal fistula with bile juice leaking from the ulcer base. Therefore, a biliary stent was placed into the common bile duct for 3 months until the DU healed. This is the first case of a refractory DU with a biliary-duodenal fistula in a patient treated with bevacizumab.

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.

Effect of Pithecellobium dulce (Roxb.) Benth. fruit extract on cysteamine induced duodenal ulcer in rats.

The edible fruits of Pithecellobium dulce (Roxb.) Benth. are traditionally used for various gastric complications in India. Here, we investigated the antiulcer activity of hydroalcoholic fruit extract of P. dulce (HAEPD) by applying cysteamine induced duodenal ulcer model in rats. Duodenal ulcer was induced in male albino Wistar rats by oral administration of cysteamine @ 420 mg/kg body wt. as a single dose. The rats were pre-administered orally with HAEPD @ 200 mg/kg body wt. for 30 days prior to ulcer induction. Rats pre-administered with ranitidine @ 30 mg/kg body wt. served as reference drug control. Ulcer score, thiobarbituric acid reactive substances (TBARS), glycoproteins, superoxide dismutase, catalase and glutathione peroxidase and reduced glutathione levels were measured in the duodenum. Rats pre-administered with the HAEPD showed significantly reduced ulcer score comparable to that of ranitidine pretreated rats. The co-administration of HAEPD lowered the TBARS level and also restored the levels of glycoproteins, enzymatic and non-enzymatic antioxidants. Histopathological observations confirmed the presence of inflammation, necrosis and hemorrhagic spots in the duodenum of ulcer control rats which were significantly reduced due to HAEPD treatment. No abnormal alterations were observed in normal rats treated with HAEPD at the dosage studied. The results demonstrated antioxidant and cytoprotective nature of P. dulce, and thereby its significant anti ulcer property.

Cingulin is dispensable for epithelial barrier function and tight junction structure, and plays a role in the control of claudin-2 expression and response to duodenal mucosa injury.

Cingulin (CGN) is a 140 kDa protein, which is localized to the cytoplasmic region of vertebrate tight junctions (TJ), and regulates gene expression and RhoA signaling in cultured cells. To investigate the function of CGN at the organism level, we generated CGN knockout (CGN(-/-)) mice by homologous recombination. CGN(-/-) mice are viable and fertile, and are born at the expected mendelian ratios. Immunohistochemistry, immunofluorescence, electron microscopy and permeability assays of epithelial tissues of CGN(-/-) mice show no cingulin labeling at junctions, a normal localization of TJ proteins, and normal TJ structure and barrier function. Microarray analysis of intestinal cells does not show significant changes in gene expression between CGN(-/-) and CGN(+/+) mice, whereas immunoblotting analysis shows a twofold increase in the levels of claudin-2 protein in the duodenum and the kidney of CGN(-/-) mice, compared to CGN(+/+) littermates. Furthermore, CGN(-/-) mice show an exacerbated response to the ulcerogenic action of cysteamine, whereas acute injury of the colon by dextran sodium sulfate elicits undistinguishable responses in CGN(-/-) and CGN(+/+) mice. We conclude that at the organism level cingulin is dispensable for the structure and barrier function of TJ, and is embedded in signaling networks that control the expression of claudin-2, and the mucosal response to acute injury in the duodenum.

Ulcer and bleeding complications and their relationship with dyspeptic symptoms in NSAIDs users: a transversal multicenter study.

OBJECTIVES: To evaluate the prevalence of lesions and digestive complications secondary to the use of non-steroidal anti-inflammatory drugs (NSAIDs), the clinical profile seen for digestive complaints and the relation with the endoscopic findings. METHODS: Prospective, multicentric, open study, evaluating consecutively 1231 patients, divided as follows: group I - NSAID and group II - non-NSAID. All patients answered questionnaire to evaluate the onset, the type of clinical complaint, the use of medication and possible complications associated to digestive bleeding. RESULTS. A total of 1213 patients were evaluated. Among them, 65% were female and 13.1% were smokers; 15.6% mentioned they ingested alcoholic beverages. The main signs and symptoms reported were epigastralgy and pyrosis (67% and 62%, respectively). The upper gastrointestinal (UGI) endoscopy was normal in 3.9% in group I and in 10.7% in group II (p < 0.001). Patient who do not use NSAID will be 2.5 times more likely to have normal UGI endoscopy (p = 0.001). The presence of erosive or ulcer lesions in the stomach and duodenum was more frequent in group I. The incidence of lesions in the stomach when compared to the duodenum is observed (erosions: 49.12% vs. 13.60%, p = 0.001; ulcers: 14.04% vs. 11.84%, p = 0.05). The risk of digestive bleeding is 12 times higher (6.14% vs. 0.51%) in those who used NSAIDs, and the stomach is the site in which bleeding occurs more frequently. Conclusions. The frequency of gastric ulcer, duodenal ulcer and digestive bleeding was higher in patients who used NSAIDs. There was no connection found between endoscopic findings and dyspeptic symptoms.

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.

Luffa echinata: healer plant or potential killer.

Bristly luffa (Luffa echinata), a member of the cucurbitaceae family is an Ayurvedic medicinal plant, which has been used in the traditional system of medicine for variety of symptoms. The active constituents like cucurbitacin, saponin, echinatin, ß-Sitosterol, oleanolic acid and flavonoids have important pathophysiological effects on human body. However, there is no earlier published report of any toxicity on humans. We report a case of a 50-year-old gentleman, who presented with gastrointestinal bleeding, deranged liver function and shock following consumption of dried fruits of Luffa echinata soaked overnight in water. He had antral gastritis and duodenal erosions on upper gastrointestinal endoscopy and was managed conservatively and recovered completely.

Gastrointestinal bleeding after high intake of omega-3 fatty acids, cortisone and antibiotic therapy: a case study.

Omega-3 fatty acids exert a plethora of physiological actions including triglycerides lowering, reduction of inflammatory indices, immunomodulation, anti- thrombotic effects and possibly promotion of exercise performance. Their use is widespread and for commonly ingested doses their side- effects are minimal. We report a case of a 60 y amateur athlete who consumed about 20 g omega-3 fatty acids daily from supplements and natural sources for a year. After the intake of cortisone and antibiotics he presented duodenum ulcer and bleeding although he had no previous history of gastrointestinal problems. Although several animal data support gastro-protective effects of omega-3 fatty acids in the present case they were not able to prevent ulcer generation. The present observation may be explained by (i) the high dose of omega-3 fatty acids and their effect on bleeding, (ii) the fact that cortisone increases their oxidation and may render them proinflammatory, (iii) other antithrombotic microconstituents included in the consumed cod-oil and/or the diet of the subject and (iv) the differences in the coagulation and fibrinolytic systems of well- trained subjects. Further studies are needed to substantiate any possible interaction of cortisone and omega-3 fatty acids in wide ranges of intake.