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Nearly all peptic ulcers are caused either by Helicobacter pylori infection or by use of non-steroidal anti-inflammatory drugs (NSAIDs), which include aspirin. As H. pylori infection is becoming less prevalent in developed countries, NSAIDs are an increasingly important cause of ulceration, including ulcers complicated by bleeding. Only about 15% of H. pylori-infected people develop an ulcer in their lifetime; virulence of the H. pylori strain, host genetics and environment (particularly smoking) determine the risk. NSAID ulcers are largely the result of suppression of gastro-protective cyclo-oxygenase 1 (COX-1). The presence and type of ulcers cannot be predicted accurately from symptoms and the differential diagnosis is wide. Older dyspeptic patients and those with ‘alarm’ symptoms or signs require endoscopy to exclude upper gastrointestinal cancer and make a diagnosis; younger patients with simple dyspepsia are treated empirically with a course of proton pump inhibitors (PPIs) or an H. pylori ‘test and treat’ strategy. For H. pylori-associated ulcers, H. pylori treatment induces healing and prevents relapse. NSAID ulcers are treated by NSAID withdrawal and a PPI course; NSAID naive users requiring ongoing treatment who are positive for H. pylori will need eradication, whereas others should be prescribed concomitant PPI or a selective COX-2 inhibitor. Treatment of functional dyspepsia is difficult and requires a multi-factorial approach.

Background: The cadherin–catenin complex is the key component of the adherens junction in epithelial cells, and changes in this complex are implicated in gastric adenocarcinoma. Germline mutations in E-cadherin have been described in diffuse-type gastric adenocarcinoma. Helicobacter pylori infection is the first stage in gastric carcinogenesis. Aims: To determine whether H pylori was associated with changes in the complex, and whether this was affected by virulence of the strain. Methods: Epithelial cell lines were cultured with H pylori using the wild-type pathogenic and non-pathogenic strains and CagE null and VacA null isogenic mutants. Gastric biopsy specimens at endoscopy were obtained from patients with (n = 17) and without (n = 15) H pylori infection, and E-cadherin and β–catenin expression was assessed by immunohistochemistry. H pylori was typed by polymerase chain reaction from these patients for CagE and VacA . Results: In vitro studies showed that coculture with a pathogenic strain of H pylori led to disruption of epithelial junctional β-catenin expression, but without evidence of nuclear translocation or signalling. This effect was independent of a functional Cag pathogenicity island and vacuolating activity, but dependent on live bacteria. No marked differences in β-catenin or E-cadherin expression were seen in gastric biopsy specimens in patients with and without H pylori infection. Conclusion: Acute H pylori infection disrupts junctional β-catenin in vitro, but chronic infection by H pylori has no effect on E-cadherin and β-catenin expression, as seen in gastric biopsy specimens at the initial gastritis stage of the proposed Correa pathway of gastric carcinogenesis. A later effect at the later stages of atrophy or intestinal metaplasia cannot be ruled out.

Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract.Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay.Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was reduced by 69% by naproxen (P0.001 vs. placebo) and 29% by lumiracoxib (P0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib.Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.

Cyclooxygenase inhibiting nitric oxide donators (CINODs) are a new class of anti-inflammatory and analgesic drugs that may minimise gastrointestinal toxicity compared with standard non-steroidal anti-inflammatory drugs (NSAIDs) by virtue of nitric oxide donation.A proof of concept study of the gastrointestinal safety of AZD3582, the first CINOD available for human testing, was conducted. Thirty one subjects were randomised to receive placebo, naproxen 500 mg twice daily, or its nitroxybutyl derivative AZD3582 in an equimolar dose (750 mg twice daily) for 12 days in a double blind three period crossover volunteer study. At the start and end of each dosing period, gastroduodenal injury was assessed by endoscopy and small bowel permeability by differential urinary excretion of lactulose and L-rhamnose. Pharmacokinetic profiles were assessed at steady state.On naproxen, the mean total number of gastroduodenal erosions was 11.5 (and one subject developed an acute ulcer) versus 4.1 on AZD3582 (p0.0001). More than half of the subjects had no erosions on AZD3582. Differences were seen for both the stomach and duodenum. Naproxen increased intestinal permeability (lactulose:L-rhamnose ratio 0.030 before v 0.040 after treatment) whereas AZD3582 (0.029 before, 0.029 after; p=0.006 v naproxen) and placebo (0.030 before, 0.028 after; p0.001 v naproxen) did not. The steady state bioavailability of naproxen metabolised from AZD3582 was 95% (95% confidence interval 87-101%) of that after naproxen administration.This human study supports animal data showing reduced gastrointestinal toxicity with the CINOD AZD3582. The potential combination of effective pain relief and gastrointestinal protection offered by AZD3582 warrants further evaluation in human clinical studies.

Background and aims: Matrix metalloproteinase-7 (MMP-7) is important in normal and pathological remodelling of epithelial-matrix interactions, and is upregulated in gastric cancer. Helicobacter pylori infection is the first stage in gastric carcinogenesis, and therefore our aim was to determine if H pylori upregulated gastric MMP-7 expression and if this was affected by strain virulence. Methods: We took gastric biopsy specimens at endoscopy from H pylori infected (n = 17) and uninfected (n = 18) patients and assessed MMP-7 expression by ELISA, real time polymerase chain reaction (PCR), and immunohistochemistry (concentrating on epithelial cells in the proliferative zone). We PCR typed H pylori for cagE and vacA. We performed H pylori/cell line coculture studies with wild-type pathogenic and non-pathogenic H pylori strains and with CagE− and VacA− isogenic mutants. Results: Gastric biopsy specimens from H pylori+ patients expressed higher levels of MMP-7 at the protein and mRNA levels in the antrum and corpus (for example, by ELISA: H pylori+ 0.182 OD units vH pylori− 0.059; p = 0.009 antrum). Epithelial cells from H pylori+ patients stained more intensely for MMP-7 than those from uninfected patients, including in the proliferative zone containing pluripotent cells (p

Objective: To determine whether mastic gum suppresses or eradicates Helicobacter pylori infection in humans. Patients and methods: Nine patients with H. pylori infection, and without gastroduodenal ulceration, were recruited from day-case endoscopy lists and treated with mastic 1 g four times daily for 14 days. ( 13 C)Urea breath tests (UBTs) were carried out immediately before, on day 15 and 5 weeks after treatment with mastic. Results: Mastic had no effect on H. pylori status in any of the eight completed patients; all remained H. pylori positive by UBT with no change in δ scores (pre-treatment mean ± S.E.M. 19.1 ± 3.7‰, day 15 (post-treatment) 18.7 ± 3.8‰, P = 0.8, paired t-test). Conclusion: Despite reported anti-H. pylori action in vitro, this preliminary study shows that mastic has no effect on H. pylori in humans.

We show here that Helicobacter pylori broth culture supernatants disrupt the actin cytoskeleton of epithelial cell lines, leading to cell rounding and apoptosis through anoikis. We demonstrate that there are marked quantitative differences between strains and that there are different cell line sensitivities. By constructing VacA null isogenic mutants, we show that the effect is not due to the vacuolating cytotoxin.

Background: H.py/oriis implicated in the pathogenesis of gastric cancer. The cadberin-cotenin complex (of which ,8-catenin is a key signalling component) promotes stable adhesion of epithelial monolayers and is altered in several epithelial cancers, including gastric cancer+ Furthermore, germline mutations in the E-cadhenn gene have been described in familial gastric cancer. Aims: To assess the effect of H.pylori on cadberin-catenin expression in epithelial cell lines. Methods: Immunoblofting for a,/],~-catenin and E-cadherin was performed on lysed cell extracts of HeLa, AGS, RK13 and HT29 cells. H.pylonstrains 60190 (vac,4 slim1, caoA+) and Tx30a (vacA s2/m2, cagA-) were co-cultured with HT29 cells for 24 hours at 37C. Cells were also incubated with VacA (purified from 60190 by broth culture, precipitation, anion exchange and gel filtration chromatography). Using monoclonal antibodies and confocal microscopy, the distribution of E-cadherin and/3-eatanin was studied in two consecutive optical slices, taken 5/~m apart. Intensity of staining was graded as strong/weak/absent in 200 cell-cell junctions (systematic randomised selection) from treated and control cells. Experiments were performed on at least three occasions. Western blots were performed on cell extracts of HT29 cells for ~,/3,-/-catenin and E-cadberin comparing untreated cells with treated cells (60198,Tx30a co-culture and purified 60190 VacA). Results: Of the cell lines studied, only HT29 cells possessed the entire cadherin-catenin complex; and these molecules were Iocalised to junctional membrane domains. Co-culture of HT29 cells with H.pyloristr~n 60190 lead to a consistent decrease in junctional expression o f / ~ e n i n (mean of four experiments: strong staining in 84% of cell-cell junctions in untreated cells vs. 54% in H.pyloriexposed cells, p =0.05, paired t test). No redistribution of/Y-catsnin to nuclear regions was noted. Intensity and Iocalisation of E-cadberin remained unchanged. No gross changes ware seen with co-culture with strain Tx30a and with addition of purified VacA. Western blotting of untreated and treated HT29 cells revealed no maior alterations in levels of cadberin-catenin expression, Conclusion: Co-culture of a toxioenic caoA+ strain of H.pylori (but not a nontoxigenic cagAstrain)with epithelial cells leads to perturbation of/],.cetenin but has no effect on E-cadherin. We speculate that modification of junctional/]-eatanin may be important in the pathogenicity of H.py/ofi.