NSAID-induced Gastric Ulcers Research Articles

Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications

Non-steroidal anti-inflammatory drugs (NSAIDs) are a broad class of non glucocorticoid drugs which are extensively used in anti-inflammatory, analgesic, and antipyretic therapies. However, NSAIDs may cause many side effects, most commonly in gastrointestinal(GI) tract. Cardiovascular system, kidney, liver, central nervous system and hematopoietic system are also involved. NSAID-induced GI side effects not only endanger the patients' health, increase mortality, but also greatly increase the cost of medical care. Therefore, how to reduce GI side effects is of particular concern to clinicians. The Chinese Rheumatism Data Center(CRDC) and Chinese Systemic Lupus Erythematosus Treatment and Research Group(CSTAR) compose a "Recommendation for the prevention and treatment of non-steroidal anti-inflammatory drug-induced gastrointestinal ulcers and its complications" , as following: (1) GI lesions are the most common side effects of NSAIDs. (2) NSAID-induced GI side effects include gastritis, esophagitis, gastric and duodenal ulcers, bleeding, perforation and obstruction. (3) With the application of capsule endoscopy and small intestinal endoscopy, growing attention is being paid to the NASID-induced small intestine mucosa damage, which is mainly erosion and ulcer. (4) Risk factors related to NSAID-induced GI ulcers include: Helicobacter pylori (Hp) infection, age> 65 years, past history of GI ulcers, high doses of NSAIDs, multiple-drug combination therapy, and comorbidities, such as cardiovascular disease and nephropathy.(5) GI and cardiovascular function should be evaluated before using NSAIDs and gastric mucosal protective agents. (6) The risk of GI ulcers and complications caused by selective cyclooxygenase-2 (COX-2) inhibitors is less than that of non-selective COX-2 inhibitors. (7)Hp eradication therapy helps to cure GI ulcers and prevent recurrence when Hp infection is positive in NSAID-induced ulcers. (8) Proton pump inhibitor (PPI) is the first choice for the prevention and treatment of NSAID-induced GI injury. Gastric mucosal protective agents also suggested.(9) H2 receptor antagonist (H2RA) can reduce the risk of NSAID-induced duodenal injury, however, the therapeutic effect of NSAID-induced gastric ulcer remains to be further confirmed. (10) Endoscopic treatment is the first recommendation for NSAID-induced peptic ulcers combined with upper GI bleeding, high-dose PPI effectively prevent rebleeding, reduce the possibility of surgery and mortality rate.

L-Theanine healed NSAID-induced gastric ulcer by modulating pro/antioxidant balance in gastric ulcer margin.

L-Theanine is a unique non-protein-forming amino acid present in tea [Camellia sinensis (L.) O. Kuntze]. In the present work, we evaluated the healing effect of L-theanine on NSAID (indomethacin)-induced gastric ulcer. Histology of the stomach tissues revealed maximum ulceration on the third day after indomethacin administration (18 mg/kg, single dose p.o.) which was accompanied by increased lipid peroxidation; protein carbonylation; Th1 cytokine synthesis, and depletion of thiol, mucin, prostaglandin (PG) E, Th2 cytokine synthesis; and total antioxidant status in mice. L-Theanine healed gastric ulcer at a dose of 10 mg/kg b.w. but aggravated the ulcerated condition at a higher dose of 40 mg/kg b.w. At 10 mg/kg b.w., L-theanine significantly alleviated the adverse oxidative effect of indomethacin through enhanced synthesis of PGE2 by modulation of cyclo-oxygenase-1 and 2 [COX-1 and COX-2] expression, Th1/Th2 cytokine balance, and restoration of cellular antioxidant status at the gastric ulcer margin. The present study revealed for the first time the dose-dependent biphasic effect of a natural neuroprotective agent, L-theanine, on gastric ulcer disease.

Hydroxyproline, a serum biomarker candidate for gastric ulcer in rats: a comparison study of metabolic analysis of gastric ulcer models induced by ethanol, stress, and aspirin.

Gastrointestinal symptoms are a common manifestation of adverse drug effects. Non-steroid anti-inflammatory drugs (NSAIDs) are widely prescribed drugs that induce the serious side effect of gastric mucosal ulceration. Biomarkers for these side effects have not been identified and ulcers are now only detectable by endoscopy. We previously identified five metabolites as biomarker candidates for NSAID-induced gastric ulcer using capillary electrophoresis–mass spectrometry (CE–MS)-based metabolomic analysis of serum and stomach from rats. Here, to clarify mechanism of changes and limitations of indications of biomarker candidates, we performed CE–MS-based metabolomic profiling in stomach and serum from rats with gastric ulcers induced by ethanol, stress, and aspirin. The results suggest that a decrease in hydroxyproline reflects the induction of gastric injury and may be useful in identifying gastric ulcer induced by multiple causes. While extrapolation to humans requires further study, hydroxyproline can be a new serum biomarker of gastric injury regardless of cause.

A Crystal in Ulcer

Purpose: A 61-year-old male presented to the ER complaining of fatigue, dizziness, and BRBPR for two days. Past medical history is significant for GERD, Hep C, GIB secondary to NSAID-induced gastric ulcer, and ESRD s/p two failed renal grafts. Current medications include pantoprazole, sevelamer, kayexalate, senna, and metoprolol. On admission, the patient was found to be hypotensive with a hemoglobin (Hb) of 9 g/dl (baseline 10-11 g/dl). His blood pressure responded appropriately to fluid resuscitation. Subsequent EGD revealed a single non-bleeding gastric ulcer (3 mm) in the pre-pyloric region of the stomach with no stigmata of bleeding. The patient continued to have intermittent episodes of BRBPR, necessitating multiple blood transfusions, and a colonoscopy was done, revealing evidence of colitis and localized ulcerations in the proximal ascending colon and cecum status post biopsies. During the hospitalization, an angiography was also performed, which revealed active bleeding from cecal branches of ileocolic artery status post embolization with cessation of bleeding. Biopsy results from the cecal ulcers on colonoscopy revealed single particle of crystalline material in the background of an ulcer consistent with kayexalate-induced ulcers (Image 1). Many drugs can cause non-specific damage in the large intestine, including solitary hemorrhages, erosions, ulcers, and inflammation. The pathogenesis of the lesions caused by drugs is highly variable, with toxic injury and vascular insufficiency thought to be the most common. Kayexalate-induced intestinal injury reveals rhomboid or triangular basophilic crystals adherent to surface epithelium. Kayexalate is a cation exchange resin which acts in the large intestine by exchanging sodium ions for potassium ions. The mechanism of mucosal damage is not clear, and is reported to be more common in patients with renal failure. It is speculated to be caused by its osmotic action and vasospasm of intestinal vasculature. The patient in this case recovered after discontinuation of kayexalate. This case highlights the importance of medication-induced GI tract injury. Physicians should be aware of colonic ulceration and ischemia in renal failure patients taking kayexalate.Figure: Cecal ulcer biopsy.

The type 2 CCK/gastrin receptor antagonist YF476 acutely prevents NSAID-induced gastric ulceration while increasing iNOS expression

YF476 differs from the proton pump inhibitor (PPI) esomeprazole in mode of action by antagonizing the type 2 receptor of cholecystokinin/gastrin (CCK-2R). YF476 protection against diclofenac-induced gastric ulcers was compared to esomeprazole and correlated with plasma levels of hormones related to gastric pH (gastrin, ghrelin, and somatostatin), gastric gene expression of these hormones, their receptors, and inducible nitric oxide synthase (iNOS). YF476 or esomeprazole pretreatments were followed by diclofenac. Four hours later, gastric tissue was excised and analyzed for ulcer index. An intragastrically implanted Bravo capsule measured pH for 5days during YF476 plus pentagastrin treatment. Changes in gene expression were assayed for gastrin, ghrelin, and somatostatin; their receptors; and iNOS. YF476 acutely (within 4h) protected against diclofenac-induced gastric ulcers equivalent to esomeprazole. Gastric pH recorded during 5days in the presence of pentagastrin was 1.83 (±0.06). YF476 raised pH to 3.67 (±0.09) and plasma ghrelin, gastrin, and somatostatin increased. YF476 increased gene expression of somatostatin receptor and gastrin, while ghrelin receptor decreased; transcripts coding ghrelin, somatostatin, and CCK-2R remained unchanged. In the presence of diclofenac, esomeprazole increased expression of all these transcripts and that of iNOS, while YF476 yielded only decreased CCK-2R and increased iNOS transcripts. YF476 is a potential new preventative treatment for patients at risk of nonsteroidal antiinflammatory drug (NSAID)-induced ulceration. Gastric gene expressions of ghrelin, gastrin, and somatostatin and their receptors differ between esomeprazole and YF476. Despite these differences and different modes of action to raise gastric pH, both drugs acutely increase iNOS, suggesting iNOS expression parallels pH.

Therapeutic effect of paroxetine on stress-induced gastric lesions in mice

Compared to the well-known anti-ulcerogenic properties of tricyclic antidepressants, the impact of selective serotonin reuptake inhibitors (SSRIs) on gastric mucosa is less clear. Human clinical trials have shown that SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) act synergistically and promote stomach ulcer formation and upper gastrointestinal tract bleeding. Acute SSRI treatment confers an additional risk for the formation of NSAID-induced gastric ulcers through increase in gastric acid secretion. Stress, which is often experienced by depressed patients, also deteriorates the gastric environment. Thus the potential for exacerbating stress-induced gastric lesions must be considered before prescribing SSRIs. Therefore, we evaluated the effects of paroxetine by using a water-immersion stress-induced stomach ulcer model of mice, by examining single vs. repeated paroxetine treatments for 8 and 22 days before stress induction. Repeated administration of paroxetine significantly decreased the area of stress-induced stomach lesions. Although stress significantly increased the serum corticosterone concentrations, the levels were not affected by the 8-day paroxetine treatment. We confirmed the anxiolytic and antidepressive effects of 8-day paroxetine treatment at 1 and 5 days after stress induction by using the elevated plus-maze and tail-suspension tests. We concluded that repeated paroxetine treatment significantly attenuates the stress-induced ulcerogenic process in the stomach.

Gastrocolic fistula related to NSAID-induced gastric ulcer

Gastrocolic fistula related to NSAID-induced gastric ulcer

COX2 Hypermethylation in H. pylori-Positive NSAID-Induced Gastric Ulcer Patients

COX2 Hypermethylation in H. pylori-Positive NSAID-Induced Gastric Ulcer Patients

772 Mast Cells are Critical for Prevention of NSAID-Induced Gastric Ulceration

772 Mast Cells are Critical for Prevention of NSAID-Induced Gastric Ulceration

Effects of proton pump inhibitors on healing of gastric ulcerations induced by a continued non steroidal anti-inflammatory drug (NSAID) treatment

Proton pump inhibitors promote ulcer healing in NSAID-treated patients with ongoing NSAID-induced gastric toxicity. However, the underlying mechanisms are unknown. This study examined the molecular pathways contributing to healing actions of esomeprazole (ESO) and lansoprazole (LAN) on NSAID-induced gastric ulcers after a continued NSAID treatment. Ulcers were induced in male rats by daily oral indomethacin (IND, 6 μmol/kg) for 14 days. Animals were then treated with IND (6 μmol/kg), alone or in combination with equivalent acid inhibitory doses of ESO (5 μmol/kg), LAN (15 μmol/kg) or famotidine (FAM, 20 μmol/kg) for 7 days. Stomachs were processed for: 1) histomorphometric analysis of mucosal injury; 2) mucosal levels of prostaglandin E2 (PGE2) and malondialdehyde (MDA); 3) expression of cyclooxygenase-2 (COX-2), VEGF and cleaved caspase-3 (Western blot); 4) expression of Ki-67 (immunohistochemistry). IND for 14 days induced mucosal damage (5.6±0.6%), reduced PGE2 mucosal levels (54.5±21.4 pg/mg) and increased MDA (8.4±1.0 nmol/mg). IND for additional 7 days enhanced further the mucosal damage and MDA, while PGE2 levels remained low. IND enhanced also the expression of COX-2 and caspase-3, reduced VEGF and Ki-67. In the presence of IND, treatment with ESO, LAN or FAM affected differentially most of the tested parameters. In particular: 1) ESO and LAN were more effective than FAM in reducing mucosal damage and MDA levels; 2) ESO and LAN, but not FAM, restored Ki-67 expression; 3) ESO, LAN and FAM partly counteracted IND-induced caspase-3 activation, without affecting the decrease in VEGF expression. The superiority of ESO and LAN over FAM in promoting ulcer healing in the presence of a continued IND treatment is likely to depend on both acid-dependent reduction of pro-apoptotic signalling and acid-independent restoration of repairing pathways.

Attenuation of gastric mucosal inflammation induced by indomethacin through activation of the A2A adenosine receptor in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin induce gastric mucosal lesions in part by the activation of inflammatory cells and the production of proinflammatory cytokines. The activation of adenosine A(2A) receptors inhibits inflammation by increasing cyclic AMP in leukocytes and reducing both the production of various proinflammatory cytokines and neutrophil chemotaxis. The aim of present study was to determine whether administration of an orally active adenosine A(2A) receptor agonist (4-[3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-piperidine-1-carboxylic acid methyl ester; ATL-313) ameliorated indomethacin-induced gastric mucosal lesions in rats. Gastric lesions were produced by oral gavage of indomethacin (30 mg/kg). ATL-313 (1-10 microg/kg) was given orally just before the indomethacin administration. The ulcer index induced by indomethacin was significantly (>50%) reduced by pretreatment with ATL-313 and this effect was blocked completely by the addition of equimolar ZM241385, a selective A(2A) receptor antagonist. The gastric content of myeloperoxidase (MPO) and proinflammatory cytokines was significantly reduced by 10 microg/kg ATL-313, but gastric mucosal prostaglandin 2 (PGE2) was not affected. We conclude that ATL-313 does not inhibit the mucosal damaging effect of indomethacin, but it does block secondary injury due to stomach inflammation. A(2A) agonists may represent a class of new therapeutic drugs for NSAID-induced gastric ulcers.

Helicobacter pylori and NSAID-induced gastric ulcer in a Japanese population

A recent meta-analysis by Huang et al. clarified that Helicobacter pylori infection and nonsteroidal antiinflammatory drugs (NSAIDs) are important factors for peptic ulcer. The results showed that the risk for ulcer in NSAID(+)/H. pylori(+) patients was 61.1 fold higher when compared with NSAID(-)/H. pylori(-) patients. Some gastric ulcers detected in patients on NSAID therapy may actually be caused by H. pylori, but it is difficult to differentiate NSAID-induced gastric ulcer from H. pylori-induced gastric ulcer. Several studies have investigated the effects of H. pylori eradication on ulcer healing. One study reported that H. pylori eradication actually lowered the healing rate of gastric ulcers. Because there have been no studies finding that H. pylori eradication facilitates healing, H. pylori eradication is not recommended for NSAID users. Concerning the efficacy of H. pylori eradication in the prevention of NSAID-induced gastric ulcer, a meta-analysis concluded that among all patients on NSAID therapy, H. pylori eradication lowered the prevalence of ulcer, which was particularly marked in NSAID-naïve patients. When compared with those of proton pump inhibitors (PPIs), the preventative effects of H. pylori eradication were inferior. In Japan, national health insurance does not cover procedures that prevent or lower the risk for NSAID-induced ulcer. When administering NSAID to patients with risk factors, it is desirable to administer antiulcer agents.

Omeprazole promotes gastric epithelial cell migration

Proton pump inhibitors (PPIs) are effective at preventing non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers. They are also superior to histamine H(2)-receptor antagonists and misoprostol in treating NSAID-induced gastric ulcer healing. This study explored whether omeprazole, a PPI, can modulate ulcer healing through epithelial cell proliferation and/or cell migration using a rat normal gastric epithelial cell line (RGM-1). Flow cytometry was used to determine cell proliferation and an artificial wound model was used to measure cell migration. Western blot analysis was performed to evaluate the possible mechanisms of action. Omeprazole treatment (10(-8), 10(-6) and 10(-4)M) for 12 and 24 h did not promote cell proliferation. However, similar doses of the drug (10(-6) and 10(-4)M) incubated for 24-48 h significantly promoted the basal cell migration of gastric epithelial cells. Further, the higher concentration of omeprazole (10(-4)M) reversed the inhibitory action of indometacin (10(-5)) on cell migration. Western blot results showed that omeprazole did not increase cyclooxygenase-2 expression and did not activate signal transduction pathways, including extracellular signal-regulated kinase (ERK1/ERK2), P38 mitogenic-activated protein kinase, and phosphatidyl inositol 3-kinase. The results suggest that omeprazole is beneficial in basal ulcer healing and it reversed the adverse action of indometacin on ulcer repair under acid-independent conditions. These actions are likely to be mediated through the promotion of gastric epithelial cell migration but not cell proliferation.

A Strategy for Development of NSAIDs with Lower Risk for Side Effects

Nonsteroidal antiinflammatory drugs (NSAIDs) are one of the most frequently used classes of medicines worldwide. The major clinical problem encountered with the use of NSAIDs is gastrointestinal complications. In the USA, about 16,500 people per year die as a result of NSAID-associated gastrointestinal complications. COX-2-specific NSAIDs have been developed as safer for the gastrointestinal tract, although the risk of cardiovascular thrombotic disease has recently been noted with the use of COX-2-specific NSAIDs. To find the strategy for the development of gastrointestinally safe NSAIDs other than COX-2-specific NSAIDs, we examined the molecular mechanism for NSAID-induced gastric ulcer formation. We found that NSAIDs induce gastric mucosal cell death in a manner independent of COX inhibition and that this cytotoxic effect is due to their membrane permeabilization activity, which is not required for the antiinflammatory activity of NSAIDs. Furthermore, we showed that in addition to COX inhibition by NSAIDs, direct cytotoxicity of NSAIDs is required for NSAID-induced gastric ulcer formation. These results suggest that NSAIDs that have neither membrane permeabilization activity nor COX-2 specificity would be safe for both the gastrointestinal tract and cardiovascular system and we are now chemically synthesizing such NSAIDs.

Pharmacological compliance and acceptability of lansoprazole orally disintegrating tablets in primary care

ABSTRACTObjective: To evaluate the pharmacological compliance of patients treated with lansoprazole orally disintegrating tablets (LODT) in Primary Care (PC) and their acceptability of this formulation.Research design and methods: A multicenter, observational, cross-sectional study involving 433 PC physicians that included 433 patients aged at least 18 years, either diagnosed with gastroesophageal reflux disease (GERD) or taking LODT to prevent NSAID-induced gastric ulcers. Compliance with LODT treatment was assessed with the Haynes–Sackett self-reported test. Acceptability was based on global patient assessment, rating the drug's organoleptic characteristics and properties recorded with a self-administered 15-item ad hoc questionnaire with 2 and 5-point Likert-type scales.Results: 423 patients (mean age 50.6 years, SD = 13.4) were evaluable for the main endpoint. Of these, 57.16% were men and 53.5% were treated with 30 mg doses of LODT for an average of 37.8 days (SD = 35.5). Compliance was achieved by 92.4% of the patients, mean percentage of compliance was 93.3. Demographical and clinical variables had no effect on compliance. Treatment with LODT was assessed as ‘acceptable’ or ‘highly acceptable’ by 91.7% of the sample. One adverse reaction, not serious, was reported by one patient (0.2%).Conclusions: In this observational study, compliance with lansoprazole orally disintegrating tablets was very high. Patients reported that this formulation improved their compliance. LODT was clearly preferred to previous medication and the drug was well tolerated.

ＮＳＡＩＤｓ胃潰瘍を併発した超高齢者における歯性降下性壊死性縦隔炎の１例

ＮＳＡＩＤｓ胃潰瘍を併発した超高齢者における歯性降下性壊死性縦隔炎の１例

Antiulcer Effect of Mammalian Lignan Precursors from Flaxseed

The antiulcer potential of the crude extract of lignans from flaxseed (Linum usitatissimum. Linn, Linaceae) was evaluated and compared against β -carotene in NSAID-induced gastric ulcers in the Wistar rat model. The isolated stomach tissue was studied for percentage ulcer index and reduced glutathione (GSH) content. The crude extract of lignans exhibited significant protection and better recovery (p < 0.05) against ulcer formation as well as in GSH content maintenance. Further, the antiulcer effect of the crude extract of lignans was comparable with that of standard β -carotene.

Small Bowel Obstruction Produced by a Phytobezoar

A 68-year-old man was admitted to the hospital with a history of daily vomiting and weight loss of 8 kg within 3 weeks. The patient had undergone a selective proximal vagotomy with pyloroplasty for a bleeding duodenal ulcer (1981) and a Billroth I reconstruction with distal gastrectomy for a perforated NSAID-induced gastric ulcer (1999). Laboratory data revealed leukocytosis of 15,400/mm3 (range, 4,200–10,200), with 88% neutrophils (range, 42%–69%) and a modest increase of the C- reactive protein, 7 mg/L (range, <5).

Nonsteroidal anti‐inflammatory drugs induce hypermotilinemia and disturbance of interdigestive migrating contractions in instrumented dogs

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce gastric ulcers due to inhibition of prostaglandin production. Prostaglandins have an influence on physiological gastrointestinal motility, but the relationships between NSAID-induced gastric ulcer, gastrointestinal motility and motilin are unknown. Fifteen dogs were allocated randomly to three groups in which either gelatin, meloxicam or indomethacin was administered. Fecal occult blood and gastrointestinal motility were monitored continuously for 6 days. In addition, analyses of the plasma motilin concentration, gastrointestinal endoscopy and gastric emptying, and detection of motilin cells were performed. Gastrointestinal motility was disturbed in the indomethacin group, presenting as disappearance of interdigestive migrating contractions (IMCs) 3 days before gastric ulcers were detected. Delayed gastric emptying and hypermotilinemia were observed significantly more often in the indomethacin group compared with the other groups. Motilin cell-crypt/villi ratio in the indomethacin group significantly decreased in the duodenum and jejunum, compared with the other groups. No significant changes in any tests were observed in the meloxicam group, when compared with the gelatin group. These findings suggest that the disturbance of IMCs caused by hypermotilinemia, with changes in motilin cell distribution, and delayed gastric emptying induced by indomethacin may contribute to the development of gastric ulcers.

Is Omeprazole or Misoprostol Superior for Improving Indomethacin-Induced Delayed Maturation of Granulation Tissue in Rat Gastric Ulcers?

Background and Aims: Proton pump inhibitors (PPI) and prostaglandin (PG) preparations are believed to both prevent NSAID-induced gastric ulcers and promote the delayed healing of gastric ulcers by NSAIDs, but it remains unclear which of these drugs is superior. The aim of this study was to clarify which achieved better healing of NSAID-induced gastric ulcers, not only with respect to epithelialization but also repair of the submucosal tissues. Methods: We used acetic acid to induce gastric ulcers in rats, and compared the changes between a control group, NSAID group, NSAID + PPI group and NSAID + PG group. After removing the stomach of each animal, an ulcer index was calculated and the collagen content and type III collagen content of granulation tissue were measured. We also studied fibroblast dynamics, including proliferation, collagen synthesis, differentiation into myofibroblasts, and apoptosis. Results: Indomethacin prevented re-epithelialization of the ulcers, interfered with fibroblast function, and also delayed the replacement of type III collagen. Omeprazole promoted epithelialization, but could not fully reverse the influence of indomethacin on granulation tissue maturation. A concomitant dose with misoprostolreversed it completely. Conclusions: From our point of view in this study in the use of experimental ulcers, it was thought that compensation of PG should have priority to gastric acid inhibition in terms of healing of NSAID-induced gastric ulcer.