Aim:To investigate the role of Helicobacter pylori, expressing the virulence marker CAGA (cytotoxin associated gene product A) in ulcer complications and its interaction with nonsteroidal anti‐inflammatory drugs (NSAIDs) and other risk factors.Design:Case control study using conditional logistic regression analysis.Setting:University and City Hospitals, Nottingham.Subjects:203 consecutive patients with ulcer bleeding and 203 age‐ and sex‐matched controls.Results:Ulcer bleeding was more likely with positive H. pylori serology (odds ratio = 3.3, 95% CI: 1.7–6.6 for CagA positive, but only OR = 1.6, 95% CI: 0.7–3.7 for CagA negative serology), current smoking (OR 2.2, 95% CI: 1.04–4.7), aspirin ≤ 300 mg daily (OR 7.7, 95% CI: 2.8–20.6), all other nonsteroidal anti‐inflammatory drugs (NSAIDs: OR 10.6, 95% CI: 3.1–35.7 for ≤ 1 defined daily dose lower and OR 22.6, 95% CI: 6.2–82.0 for higher doses) and past ulcer history (OR 5.6, 95% CI: 2.3–14.1). Aspirin ≤ 300 mg daily was used by 25.1% of patients vs. 7.4% of controls. Smoking only enhanced risk in the presence of H. pylori, with a synergistic interaction (interaction odds ratio = 4.9, 2.4–9.9, P=0.002). Conversely, risks with non‐aspirin NSAIDs were reduced in the presence of H. pylori, particularly if CagA‐positive (interaction odds ratio=0.21, 0.05–0.9, P=0.03).Conclusions:CagA positive H. pylori infection is associated with an increased risk of ulcer bleeding. The risk from non‐aspirin NSAIDs is even higher, but is less in H. pylori infected people. Low‐dose aspirin is now commonly associated with ulcer bleeding.

Cyclosporine is a potent suppresser of cell-mediated immunity that is mainly used in organ transplantation to prevent rejection. It is also being used increasingly outside of transplantation and probably is the only new treatment to have made an impact in acute ulcerative colitis (UC) resistant to steroid therapy. We describe a case of Nocardia asteroides lung abscess in a patient treated with cyclosporine for acute steroid resistant UC that was successfully managed with antibiotics and by discontinuing cyclosporine. With increasing use of cyclosporine for acute UC it is to be anticipated that opportunistic infections such as Nocardia will be more frequently encountered in the future.

BACKGROUND:As non-steroidal anti-inflammatory drugs (NSAIDs) become available for over-the-counter use, it is important to define doses that would not cause undue gastroduodenal damage during the short periods for which self-medication with NSAIDs is licensed.AIM:To establish what dose of ketoprofen most closely resembles the maximum dose of ibuprofen (400 mg t.d.s.) licensed for self-medication.METHODS:We studied healthy volunteers in a double-blind double-dummy randomized crossover study. Each subject took, over four separate 10-day dosing periods, ibuprofen 400 mg t.d.s., ketoprofen 12.5 mg t.d.s., ketoprofen 25 mg t.d.s. or ketoprofen 50 mg t.d.s. Mucosal injury was assessed by endoscopy at baseline and on the 3rd and 10th day of each dosing period. Ex vivo gastric mucosal prostaglandin (PG) E2 evoked by vortex mixing was measured by radioimmunoassay. Serum thromboxane was also measured by radioimmunoassay.RESULTS:Ketoprofen 50 mg t.d.s. suppressed prostaglandin synthesis to a significantly greater extent than ibuprofen and caused significantly more gastroduodenal injury. The profile of prostaglandin synthesis and injury on ketoprofen 12.5 mg t.d.s. most closely resembled that of ibuprofen 400 mg t.d.s.CONCLUSIONS:Ketoprofen 12.5 mg t.d.s. is an appropriate dose for self-medication, which is likely to be similar to ibuprofen 400 mg t. d.s. in its effects on the stomach and duodenum.

Introduction:Non-steroidal anti-inflammatory drugs cause gastroduodenal damage by inhibiting prostaglandin (PG)synthesis.An anti-inflammatory turmeric extract, P54, has been developed.The purpose of this study was to compare the acute effects of P54, ibuprofen and aspirin on human gastric mucosa.Methods:20 healthy volunteers(9 female, II male), mean age 28(range 20-45),took aspirin 600mg bd, ibuprofen 400mg Ids or P54 220mg Ids for 5 days on 3 separate occasions in an investigator blind crossover study (\4 day washout between treatments).Subjects were endoscoped before and after each treatment period.The stomach was washed with 50ml water, erosions were counted and 4 antral biopsy specimens taken.Each biopsy specimen was washed and minced prior to stimulation of PGE 2 production by vortex mixing for 3 minutes.Cyclooxygenase(COX)-1 and COX-2 activity were measured as serum thromboxane (TXB 2 ) and lipopolysacharride (LPS) stimulated PGE 2 .Results: Aspirin produced a mean reduction in gastric mucosal PGE 2 levels of 85% compared to baseline (n= 19, 95%CI:77-94, p

Helicobacter pylori is now considered a group I carcinogen to gastric cancer and H. pylori eradication of family members is being recommended

The epithelium of the gastrointestinal tract transports ions and water but excludes luminal microorganisms and toxic molecules. The factors regulating these important functions are not fully understood. Intestinal myofibroblasts lie subjacent to the basement membrane, at the basal surface of epithelial cells. We recently showed that primary cultures of adult human colonic subepithelial myofibroblasts express cyclooxygenase (COX)-1 and COX-2 enzymes and release bioactive transforming growth factor-beta (TGF-beta). In this study we have investigated the role of normal human colonic subepithelial myofibroblasts in the regulation of transepithelial resistance and secretory response in HCA-7 and T84 colonic epithelial cell lines. Cocultures of epithelial cells-myofibroblasts and medium conditioned by myofibroblasts enhanced transepithelial resistance and delayed mannitol flux. A panspecific antibody to TGF-beta (but not piroxicam) antagonized this effect. In HCA-7 cells, myofibroblasts downregulated secretagogue-induced change in short-circuit current, and this effect was reversed by pretreatment of myofibroblasts with piroxicam. In contrast to HCA-7 cells, myofibroblasts upregulated the agonist-induced secretory response in T84 cells. This study shows that intestinal subepithelial myofibroblasts enhance barrier function and modulate electrogenic chloride secretion in epithelial cells. The enhancement of barrier function was mediated by TGF-beta. In contrast, the modulation of agonist-induced change in short-circuit current was mediated by cyclooxygenase products. These findings suggest that colonic myofibroblasts regulate important functions of epithelial cells via distinct secretory products.

Recent advances in inflammatory bowel disease therapeutics have led to improved formulations of existing treatments and new indications for established drugs. Truly novel therapies based on recent understanding of pathogenesis are also being developed. These new treatments and their likely impact on the management of inflammatory bowel disease in the future are discussed.

The effect of chronic exposure to transforming growth factor-alpha (TGF-alpha) on bradykinin-stimulated acute prostanoid production and ion secretion in monolayers of HCA-7 colony 29 colonic epithelial cells has been studied. Monolayers synthesized prostaglandin E-2 (PGE(2)) at a basal rate of 2.10 +/- 0.31 pg.monolayer(-1).min(-1) over 24 h. Bradykinin (10(-8)-10(-5) M) dose dependently increased acute PGE(2) release by three orders of magnitude. This was associated with a rise in cAMP from 1.60 +/- 0.14 to 2.90 +/- 0.1 pmol/monolayer (P < 0.02) and a dose-dependent increase in short-circuit current (SCC). When monolayers were primed by a 24-h exposure to TGF-alpha, basal PGE(2) release rose to 6.31 +/- 0.38 pg.monolayer(-1).min(-1) (TGF-alpha concn 10 ng/ml; P = 0.001). However, the stimulation of acute prostaglandin release,intracellular cAMP, and increased SCC by bradykinin was significantly reduced by preincubation with TGF-alpha. Priming with PGE(2) (10(-8)-10(-6) M) over 24 h mimicked the effect of TGF-alpha on bradykinin-induced changes in cAMP and SCC. These data suggest that enhanced chronic release of prostaglandins in response to stimulation with TGF-alpha may downregulate acute responses to bradykinin. In vivo, TGF-alpha could have an important modulatory function in regulating secretion under inflammatory conditions.

stimulates ulcer healing (e~g., stimulates angiogenesis granulation tissue production, re-epithelization) while amoxicillin and metronidazole do not independently affect ulcer healing.Conclusions: i) The new antiulcer drug egualen exerted anti-Hp effect which was less potent than that of amoxicillin and metronidazole.2) Some of the Hp strains, nevertheless, were sensitive to egualen and resistant to metronidazole. 3) Egualen directly stimulates ulcer healing while the two other drugs do not independently influence ulcer healing.4) Thus, equalen seems to be a promising new antiulcer drug which exerts both anti-Hp activity and direct ulcer healing stimulatory effect.