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International audience; PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13–16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2–0.9) to 0.5 (95% CI, 0.3–1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8–1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

SUMMARY To test the hypothesis that administration of a non-steroidal anti-inflammatory drug formulated as a pro-drug, inactive as a cyclooxygenase inhibitor until after absorption, might cause less intestinal damage than conventional non-steroidal anti-inflammatory drugs, intestinal permeation to 51Cr-EDTA and mannitol was assessed in healthy volunteers before and after oral treatment for 1 week with either the pro-drug sulindac or the conventional non-steroidal anti-inflammatory drug indomethacin. Indomethacin, but not sulindac, significantly increased intestinal permeation to 51Cr-EDTA and reduced haemoglobin and haematocrit; neither affected mannitol permeation.

The pathophysiology of inflammatory bowel disease (IBD) is gradually being unravelled and new therapies are being developed to target the disturbed biological processes. This article outlines the clinical features of IBD, its current therapy and pathogenesis. The difficulties for clinical pharmacologists and gastroenterologists associated with designing, executing and interpreting clinical trials in IBD are then discussed. The final section reviews methods that can used to demonstrate the pharmacological actions of new treatments in patients with IBD. It is emphasized that proof of the therapeutic efficacy of a novel agent with a specific mechanism of action yields not only clinical benefit to patients with IBD, but also indicates the importance of the targeted biochemical pathway in the pathogenesis of the disease.

Background: Thromboxanes are produced in excess and platelets are activated in active Crohn’s disease. Preliminary reports have suggested that ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist, may have therapeutic benefit in patients with inflammatory bowel disease. Aims: To investigate the efficacy of ridogrel in patients with active Crohn’s disease. Patients and methods: This was an international, multicentre, randomized, double-blind, placebo-controlled trial of 5 mg/day oral ridogrel for 12 weeks in 85 patients with moderately active Crohn’s disease. Sixty patients were randomized to receive ridogrel, and 25 to placebo. The Crohn’s disease activity index (CDAI) was used to assess disease activity: remission was defined as a CDAI

Herbal medicines are now used by up to 50% of the Western population, in a substantial minority of instances for the treatment or prevention of digestive disorders. Although most indications for the use of such remedies are anecdotally or traditionally derived, controlled trials suggest some benefits for ginger in nausea and vomiting, liquorice extracts in peptic ulceration, Chinese herbal medicine in irritable bowel syndrome, opium derivatives in diarrhoea and senna, ispaghula and sterculia in constipation. Herbal preparations contain many bioactive compounds with potentially deleterious as well as beneficial effects. There is clearly a need for greater education of patients and doctors about herbal therapy, for legislation to control the quality of herbal preparations, and in particular for further randomized controlled trials to establish the value and safety of such preparations in digestive and other disorders.

The introduction of novel anti-tumor necrosis factor (TNF) agents has not only led to impressive new therapeutic opportunities but also resulted in uncertainty regarding their optimal use and possible side effects. Guidelines are presented here for the use of anti-TNF agents in gastrointestinal disorders. Experts were chosen from different European countries by an algorithm to avoid bias. An expert consensus on guidelines was established using a two-stage procedure of systematic Medline and abstract search for evidence and a qualifying meeting to derive recommendations. Detailed guidelines were developed for the use and the future clinical development of anti-TNF agents in inflammatory bowel disease. Grading of available evidence and grading of recommendations were performed according to AHCPR guidelines. At present infliximab is the only registered agent for Crohn's disease. Infliximab should be always used at a dose of 5 mg/kg. The guidelines define the indications both in refractory and in fistulating disease for the readministration and before surgery. Guidelines for safety and for concomitant treatments are given. Prospects, potential clinical use, and future directions for the clinical development of other anti-TNF agents are detailed. Clinical use of anti-TNF agents will be influenced by a large number of clinical trials being concluded in 2001 and 2002. It is likely that anti-TNF therapies will become an important long-term therapy for a proportion of patients with Crohn's disease. Biological agents will be followed by smaller and more stable, orally available compounds. These guidelines will be succeeded by a formal public consensus in 2002/2003.

Background: Reactive oxygen species may be pathogenic in ulcerative colitis. Oral iron supplements anecdotally exacerbate inflammatory bowel disease and iron levels are elevated in the inflamed mucosa. Mucosal iron may enhance hydroxyl ion production via Fenton chemistry. Conversely, the iron chelator, desferrioxamine, is reportedly beneficial in Crohn’s disease. Aims: To assess the in vitro effects of exogenous iron and of iron chelators on the production of reactive oxygen species by colonic biopsies from normal control subjects and patients with ulcerative colitis. Methods: Luminol-amplified chemiluminescence was used to measure mucosal reactive oxygen species production both before and after addition in vitro of ferric citrate (100 μM), desferrioxamine (1 m M) and 1,10-phenanthroline (1 m M). Results: Ferric citrate had no effect on the chemiluminescence produced by human colonic mucosa. However, desferrioxamine and phenanthroline reduced chemiluminescence by 47% (n=7, P=0.018) and by 26% (n=10, P=0.005), respectively, in inactive ulcerative colitis, and by 44% (n=9, P=0.008) and 42% (n=11, P=0.006) in active disease. Conclusion: The lack of effect of ferric citrate suggests that sufficient free iron is already present in inflamed biopsies to drive the Fenton reaction maximally. The effects of desferrioxamine and 1,10-phenanthroline on the chemiluminescence of biopsies from patients with ulcerative colitis suggest that a clinical trial of topical iron chelation in active disease is indicated.

Background : The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties. Aim : To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil). Methods : Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence. Results : 5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 m M) and balsalazide (20 m M) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 m M). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 m M) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 m M), and both oxidized and reduced glutathione (10 m M), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies. Conclusions : The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy.

Aims Previous uncontrolled reports have suggested that appendiceal inflammation may occur as a discontinuous lesion in ulcerative colitis. This study aims semiquantitatively to compare the prevalence and histological features of appendiceal inflammation in patients with ulcerative colitis and Crohn's disease, using colonic carcinoma and acute appendicitis specimens as controls. Methods and results Surgical pathology records and original histological slides for the period 1980–1994 were examined. The prevalence of appendiceal inflammation in ulcerative colitis (24/50, 48%), was higher than in colonic carcinoma (5/65, 8%, P

SUMMARY Whilst the mechanism by which Helicobacter pylori causes different gastroduodenal diseases is uncertain, strains producing the cytotoxin-associated protein (CagA) have greater pathogenicity. Hsps are immunogenic molecules induced by inflammatory mediators. The aim of this study was to assess pathogenicity of hsp antibodies in H. pylori-infected patients. ELISA techniques were used to assay sera of H. pylori-positive patients with gastritis, gastric atrophy, duodenal or gastric ulcer, and H. pylori-negative controls, for antibodies to CagA and to human, mycobacterial, and in 20 sera, H. pylori (hspB) 60-kD hsp. IgA antibodies to mycobacterial hsp60 in atrophy patients were elevated compared with patients with gastritis (P

Background : Inflammatory bowel disease is associated with increased mucosal release of eicosanoids. Among these, thromboxane A 2 has been proposed as a possible inflammatory mediator ; its suppression may be a useful therapeutic option. Methods : Using a tissue incubation technique, we compared release of immunoreactive thromboxane B 2 by colonic biopsies from patients with ulcerative colitis, Crohn's disease and controls, and assessed the inhibitory effect of picotamide, a thromboxane synthesis inhibitor-receptor antagonist, which has been widely used in Italy for management of ischaemic heart and cerebrovascular disease. Results : Increased amounts of thromboxane B 2 were released from biopsies from patients with active ulcerative colitis (median 238 pg/20 min/mg wet weight (interquartile range 147-325), n = 12) and active Crohn's disease (252 (174-450), 6) compared with those from patients with quiescent ulcerative colitis (95 (61-140), 12) or Crohn's disease (105 (57-201), 13), or controls (136 (64-206), 8). Incubation with picotamide at concentrations between 100 μM and 1 mM reduced thromboxane B 2 release (IC 50 890 μM). Conclusion : Since increased thromboxane A 2 production may have pathogenetic importance, thromboxane synthesis inhibitor-receptor antagonists such as picotamide merit therapeutic trial in the management of inflammatory bowel disease.

We present a review of epidemiological studies of inflammatory bowel disease and abdominal tuberculosis in various migrant communities in the United Kingdom. The differences between various South Asian groups such as Gujaratis, Bangladeshis and Punjabis are discussed in the context of age standardisation of incidence data and various dietary and social activities.

The technetium hexamethylpropyleneamineoxime labelled white cell scan (WCS) is not widely used as a screening test for Crohn's disease primarily because, though sensitive, it is perceived as being insufficiently specific. A series of 42 patients screened for Crohn's disease by this method was analysed retrospectively. The sensitivity was 100% and specificity 91%. This performance was maintained in a subgroup of these patients with very low prevalence of disease. If appropriate criteria for interpretation are used the WCS is a specific as well as a sensitive screening test for Crohn's disease.

There is increasing concern about the apparently rising incidence and worsening outcome of Clostridium difficile infection (CDI) associated with inflammatory bowel disease (IBD). We have systematically reviewed the literature to evaluate the incidence, risk factors, endoscopic features, treatment and outcome of CDI complicating IBD.To systematically review: clostridium difficileinflammatory bowel disease.Structured searches of Pubmed up to September 2010 for original, cross-sectional, cohort and case-controlled studies were undertaken.Of 407 studies, 42 met the inclusion criteria: their heterogeneity precluded formal meta-analysis. CDI is commoner in active IBD, particularly ulcerative colitis, than in controls. Certainty about a temporal trend to its increasing incidence in IBD is compromised by possible detection bias and miscoding. Risk factors include immunosuppressants and antibiotics, the latter less commonly than in controls. Endoscopy rarely shows pseudomembranes and is unhelpful for diagnosing CDI in IBD. There are no controlled therapeutic trials of CDI in IBD. In large studies, outcome of CDI in hospitalised IBD patients appears worse than in controls.The complication of IBD by Clostridium difficile infection has received increasing attention in the past decade, but whether its incidence is really increasing or its outcome worsening remains unproven. Therapeutic trials of Clostridium difficile infection in IBD are lacking and are needed urgently.

Although patients with inflammatory bowel disease (IBD) are at increased risk of osteoporosis, low bone mineral density (BMD) alone confers only a modest increase in risk of fracture. The FRAX score, developed by the WHO, is a free web-based clinical scale assessing the 10-year fracture risk and need for lifestyle advice/reassurance, dual X-ray absorptiometry (DEXA) scanning or preventive treatment.To assess the accuracy of pre-BMD FRAX scores in identifying at risk IBD patients needing BMD measurement (intermediate risk) and/or therapy (high risk).We calculated FRAX scores retrospectively in 116 consecutive IBD out-patients (81 Crohn's disease, 35 ulcerative colitis), who were having DEXA scans in 2005-2009 because they were considered at risk of osteoporosis.On DEXA scans, 47% (38/81) and 12% (10/81) patients with Crohn's disease were osteopaenic and osteoporotic, respectively; equivalent figures for patients with UC were 34% (12/35) and 14% (5/35). The clinical FRAX score alone, when compared with the FRAX score including the BMD result, had a sensitivity of 100% (95% CI: 70-100%), specificity of 40% (95% CI: 31-50%), positive predictive value of 16% (95% CI: 9-27%) and negative predictive value of 100% (95% CI: 90-100%) in identifying those patients needing BMD measurement (intermediate risk) or preventive therapy (high risk).In patients with IBD perceived to be at risk of osteoporosis and/or osteopaenia, the clinical FRAX score alone can predict accurately the risk of osteoporotic fracture, and thereby reduce the need for DEXA scans and unnecessary anti-osteoporosis treatment.

Antibodies to endothelial cells may be involved in the pathogenesis of vasculitic disorders. In view of recent evidence implicating intestinal vascular injury in the pathogenesis of inflammatory bowel disease, we have sought anti-endothelial cell antibodies in affected patients, examined their relationship to vascular injury, and tested their ability to mediate endothelial cell cytotoxicity in vitro. Anti-endothelial cell antibody levels were elevated in ulcerative colitis (P < 0.0001) and Crohn's disease (P < 0.05) compared with healthy controls. In ulcerative colitis, anti-endothelial cell antibody levels were related to disease activity and correlated with circulating levels of von Willebrand factor (r = 0.58, P < 0.01), a marker of vascular injury. Anti-endothelial cell antibodies, however, were not directly cytotoxic to endothelial cells in vitro. These data indicate, for the first time, an association between anti-endothelial cell antibody levels and vascular injury in vivo and suggest that they may be important in the pathogenesis of inflammatory bowel disease, particularly ulcerative colitis.

A retrospective epidemiological study of abdominal tuberculosis in a defined population in the London Borough of Tower Hamlets was conducted between January 1985 and 31 December 1989. The total population of 163,900 included a mean of 20,732 Bangladeshis. Of the 13 cases diagnosed 8 were Bangladeshi, with equal involvement of the peritoneum and intestine. The crude incidence in the Bangladeshi community was 7.7 cases/10(5)/year, which was significantly higher than that in Europeans (0.3 cases/10(5)/year, chi 2 with Yate's correction = 14.0 P < 0.001). The highest age-specific incidence was amongst those aged 16-20 years and 41-45 years. Most patients had a laparotomy or peritoneal biopsy to confirm the diagnosis. The response to therapy was good. Only 62% of cases were notified. This study confirms the importance of tuberculosis in the differential diagnosis of abdominal symptoms in Bangladeshi patients.

Raised circulating von Willebrand factor is a recognised marker of vascular injury. To evaluate the role of vascular injury in the pathogenesis of inflammatory bowel disease, serum von Willebrand factor in Crohn's disease, ulcerative colitis, confirmed bacterial diarrhoea, and healthy subjects was measured. von Willebrand factor values were raised in 9/14 patients (p = 0.007) with active Crohn's disease, 15/28 (p = 0.0004) with inactive Crohn's disease, 16/23 (p = 0.0003) with active ulcerative colitis, 9/27 (p = 0.04) with inactive ulcerative colitis, and 15/17 (p = 0.0001) patients with bacterial diarrhoea. Serum von Willebrand factor was unrelated to disease activity in Crohn's disease but was significantly raised in active (p = 0.02) compared with inactive ulcerative colitis. In contrast to controls, the detection of von Willebrand factor from inflammatory bowel disease sera and that from fractured endothelial cells was significantly inhibited by the reducing agent, dithiothreitol, suggesting the presence of an additional dithiothreitol sensitive form of the molecule derived from injured endothelial cells in inflammatory bowel disease. That serum von Willebrand factor is raised in quiescent as well as active Crohn's disease is compatible with the proposal that vascular injury is a fundamental abnormality in this disorder. The raised von Willebrand factor values in active inflammatory bowel disease and bacterial diarrhoea could be caused by either vascular injury, occurring secondary to bowel inflammation, or to an acute phase response resulting from endothelial cell stimulation by mediators released during the inflammatory process. Raised circulating von Willebrand factor could contribute to the increased risk of thrombosis associated with active inflammatory bowel disease.

To assess the incidence of ulcerative colitis and proctitis in a defined migrant population, a retrospective, epidemiological community study was performed in the London Borough of Tower Hamlets from 1972 to 1989. The population of 164,000 includes 28,000 Bangladeshis. Potential cases were identified from hospital departments of pathology and medical records. There were 107 cases of ulcerative colitis in Europeans and 5 in Bangladeshis. There were 74 and 2 cases of proctitis in these communities, respectively. The mean standardised incidence of ulcerative colitis in Bangladeshis (1.8 cases/10(5)/year) was marginally lower than in Europeans (6.2 cases/10(5)/year, Z = 0.7, n.s.). The mean standardised incidence of proctitis in Bangladeshis was 0.6 cases/10(5)/year and in Europeans 3.2 cases/10(5)/year (Z = 0.6 n.s.). Anatomical extent of colitis was similar in all ethnic communities, although complications were less likely in minority groups. These findings suggest that the incidence of ulcerative colitis and proctitis in Bangladeshis, in Britain, is amongst the lowest in the world.

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) in which there is recurrent inflammation of the mucous membranes of the colon. Inflammation is accompanied by the production of reactive oxygen species (ROS) including, amongst others, hydrogen peroxide. Selenium in the form of the selenoprotein glutathione peroxidase (GSH-Px) acts as a catalyst in the reaction which reduces hydrogen peroxide to water. It may therefore beneficial to supplement the diets of patients who suffer from UC with selenium. In this preliminary study nine patients suffering from moderate UC were supplemented with selenium-β tablets (300 μg Se per tablet) twice daily. Blood samples were taken at the start of the trial and at 1, 2 and 4 week intervals. Freeze-dried serum samples were analysed for their selenium content using the technique of instrumental neutron activation analysis (INAA). Samples were also analysed by particle induced X-ray emission (PIXE) to monitor other trace elements levels. Selenium concentrations were found to increase during supplementation and iron concentrations to decrease. Stool frequency was also found to improve suggesting that ROS may be important in the pathogenesis of UC.

Ulcerative colitis (UC) affects women of all ages, with a peak incidence in the third and fourth decades, at the prime of their reproductive years [Baiocco PJ, Korelitz BI (1984) The influence of inflammatory bowel disease and its treatment on pregnancy and fetal outcome. J Clin Gastroenterol 6(3):211–216]. We describe a case of fulminating UC at 28 weeks' gestation treated by combined emergency subtotal colectomy and caesarean section with excellent foetal and maternal outcome. A treatment algorithm is suggested, and the literature surrounding inflammatory bowel disease in pregnancy is reviewed.

The herbal preparation, aloe vera, has been claimed to have anti-inflammatory effects and, despite a lack of evidence of its therapeutic efficacy, is widely used by patients with inflammatory bowel disease.To perform a double-blind, randomized, placebo-controlled trial of the efficacy and safety of aloe vera gel for the treatment of mildly to moderately active ulcerative colitis.Forty-four evaluable hospital out-patients were randomly given oral aloe vera gel or placebo, 100 mL twice daily for 4 weeks, in a 2 : 1 ratio. The primary outcome measures were clinical remission (Simple Clinical Colitis Activity Index/= 2), sigmoidoscopic remission (Baron score/= 1) and histological remission (Saverymuttu score/= 1). Secondary outcome measures included changes in the Simple Clinical Colitis Activity Index (improvement was defined as a decrease of/= 3 points; response was defined as remission or improvement), Baron score, histology score, haemoglobin, platelet count, erythrocyte sedimentation rate, C-reactive protein and albumin.Clinical remission, improvement and response occurred in nine (30%), 11 (37%) and 14 (47%), respectively, of 30 patients given aloe vera, compared with one (7%) [P = 0.09; odds ratio, 5.6 (0.6-49)], one (7%) [P = 0.06; odds ratio, 7.5 (0.9-66)] and two (14%) [P0.05; odds ratio, 5.3 (1.0-27)], respectively, of 14 patients taking placebo. The Simple Clinical Colitis Activity Index and histological scores decreased significantly during treatment with aloe vera (P = 0.01 and P = 0.03, respectively), but not with placebo. Sigmoidoscopic scores and laboratory variables showed no significant differences between aloe vera and placebo. Adverse events were minor and similar in both groups of patients.Oral aloe vera taken for 4 weeks produced a clinical response more often than placebo; it also reduced the histological disease activity and appeared to be safe. Further evaluation of the therapeutic potential of aloe vera gel in inflammatory bowel disease is needed.

Oral aloe vera gel is widely used by patients with inflammatory bowel disease and is under therapeutic evaluation for this condition.To assess the effects of aloe vera in vitro on the production of reactive oxygen metabolites, eicosanoids and interleukin-8, all of which may be pathogenic in inflammatory bowel disease.The anti-oxidant activity of aloe vera was assessed in two cell-free, radical-generating systems and by the chemiluminescence of incubated colorectal mucosal biopsies. Eicosanoid production by biopsies and interleukin-8 release by CaCo2 epithelial cells in the presence of aloe vera were measured by enzyme-linked immunosorbent assay.Aloe vera gel had a dose-dependent inhibitory effect on reactive oxygen metabolite production; 50% inhibition occurred at 1 in 1000 dilution in the phycoerythrin assay and at 1 in 10-50 dilution with biopsies. Aloe vera inhibited the production of prostaglandin E2 by 30% at 1 in 50 dilution (P = 0.03), but had no effect on thromboxane B2 production. The release of interleukin-8 by CaCo2 cells fell by 20% (P0.05) with aloe vera diluted at 1 in 100, but not at 1 in 10 or 1 in 1000 dilutions.The anti-inflammatory actions of aloe vera gel in vitro provide support for the proposal that it may have a therapeutic effect in inflammatory bowel disease.

The pathophysiology of inflammatory bowel disease (IBD) is gradually being unravelled and new therapies are being developed to target the disturbed biological processes. This article outlines the clinical features of IBD, its current therapy and pathogenesis. The difficulties for clinical pharmacologists and gastroenterologists associated with designing, executing and interpreting clinical trials in IBD are then discussed. The final section reviews methods that can used to demonstrate the pharmacological actions of new treatments in patients with IBD. It is emphasized that proof of the therapeutic efficacy of a novel agent with a specific mechanism of action yields not only clinical benefit to patients with IBD, but also indicates the importance of the targeted biochemical pathway in the pathogenesis of the disease.

Diverticular colitis is a recently recognized nosological entity in which a chronic focal mucosal sigmoid colitis occurs in association with diverticulosis. It usually presents with rectal bleeding and may be difficult to distinguish clinically, endoscopically and pathologically from other segmental colitides including ulcerative, Crohn's, ischaemic, infective and NSAID-induced colitis as well as diverticulitis. Uncontrolled data suggests that most patients respond satisfactorily to treatment with a high fibre diet, antibiotics and/or aminosalicylates, but a minority with persistent or recurrent symptoms require sigmoid resection. This paper reviews the literature on diverticular colitis and concludes with an algorithm suggesting the optimal management of patients who present with rectal bleeding in association with segmental sigmoid colitis and diverticulosis.

Herbal remedies used by patients for treatment of inflammatory bowel disease include slippery elm, fenugreek, devil's claw, Mexican yam, tormentil and wei tong ning, a traditional Chinese medicine. Reactive oxygen metabolites produced by inflamed colonic mucosa may be pathogenic. Aminosalicylates (5-ASA) are antioxidant and other such agents could be therapeutic.To assess the antioxidant effects of herbal remedies in cell-free oxidant-generating systems and inflamed human colorectal biopsies.Luminol-enhanced chemiluminescence in a xanthine/xanthine oxidase cell-free system was used to detect superoxide scavenging by herbs and 5-ASA, and fluorimetry to define peroxyl radical scavenging using a phycoerythrin degradation assay. Chemiluminescence was used to detect herbal effects on generation of oxygen radicals by mucosal biopsies from patients with active ulcerative colitis.Like 5-ASA, all herbs, except fenugreek, scavenged superoxide dose-dependently. All materials tested scavenged peroxyl dose-dependently. Oxygen radical release from biopsies was reduced after incubation in all herbs except Mexican yam, and by 5-ASA.All six herbal remedies have antioxidant effects. Fenugreek is not a superoxide scavenger, while Mexican yam did not inhibit radical generation by inflamed biopsies. Slippery elm, fenugreek, devil's claw, tormentil and wei tong ning merit formal evaluation as novel therapies in inflammatory bowel disease.

Medical care of patients with inflammatory bowel disease (IBD) comprises general measures and specific pharmacological, nutritional, endoscopic and surgical therapies (Table ​(Table11)[1-3]. In this paper, current management options for patients with two commonly difficult presentations of IBD, acute severe ulcerative colitis (UC) and steroid-refractory or dependent ileocaecal Crohn's disease (CD), are discussed. Practical considerations and newer developments are emphasized. Table 1 Principles of management of acute severe ulcerative colitis MANAGEMENT OF ACUTE SEVERE ULCERATIVE COLITIS These patients should be admitted immediately to a gastroenterology ward for close joint medical, surgical and nursing care. The nutrition team and a stoma therapist in patients likely to need surgery should be involved promptly. Patients undergoing an acute attack of UC need to be made aware from the outset that they have a one in four chance of failing to respond to the primary treatment (intravenous steroids), and thus need either cyclosporin or colectomy during their admission (Table ​(Table11). Establishing the diagnosis, extent and severity of disease A carefully targeted history and appropriate investigations can help establish the diagnosis (Table ​(Table2)2) in patients presenting for the first time and, in those with established UC, to exclude infection and to assess disease extent (if not already known) and severity. Table 2 Management of active ileocaecal Crohn's disease. General measures, monitoring progress and supportive treatment are essentially as for ulcerative colitis Blood and stool tests Stool should be sent to look for pathogens, and serology checked for amoebiasis, strongyloidiasis and schistosomiasis. Blood tests are better for establishing the activity of UC than making the diagnosis or identifying its extent. However, a raised platelet count is more common in UC than in infective colitis. The best measures of disease activity are haemoglobin, platelet count, ESR, C-reactive protein[4] and serum albumin. Sigmoidoscopy and rectal biopsy Cautious rigid or flexible sigmoidoscopy in the unprepared patient, and without excessive air insufflation, provides immediate confirmation of active colitis. Sigmoidoscopy also allows biopsy for histology: to minimise the risks of bleeding and perforation a small superficial biopsy should be taken from the posterior rectal wall less than 10 cm from the anal margin using small-cupped forceps. Anecdotally, colonoscopy may cause colonic perforation and dilatation in acute severe UC, and although some authorities have reported that it is both safe and useful for decision-making[5], most patients can be managed satisfactorily without it. In patients with established UC, rectal biopsy is not routinely necessary. However, in those presenting for the first time, infective colitis may be suggested by an acute, focal and superficial inflammatory infiltrate with minimal goblet cell depletion and preservation of crypt architecture[6]. Although colitis due to Clostridium difficile, cytomegalovirus, amoebiasis and Crohn's disease often has characteristic macroscopic appearances, histology may confirm these diagnoses. Plain abdominal X-ray A plain film at presentation can be used to assess disease extent, since faecal residual visible on X-ray usually indicates sites of uninflamed colonic mucosa. Plain abdominal X-ray is also used to assess disease severity and in particular to exclude colonic dilatation (diameter > 5.5 cm) in sick patients, however, the gas pattern on a plain film may be misleading if there has been excessive air insufflation during a sigmo idoscopy or colonoscopy done shortly beforehand. In patients with suspected colonic perforation, the diagnosis can be confirmed by erect chest X-ray or a later al decubitus abdominal film. Radiolabelled leucocyte scans The intensity and extent of colonic uptake one hour after injection of autologous 99Tc-HMPAO or 111Indium-labelled leukocytes provides information about disease activity and particularly extent, respectively, where doubt exists in patients with UC. Colonic uptake of leucocytes is not of course specific for UC and positive results are obtained in other inflammatory colonic diseases.

Introduction It is not uncommon for patients to require both immunosuppression and anticoagulation and for warfarin and thiopurines to be prescribed concurrently. There is limited evidence that thiopurines can inhibit the actions of warfarin. This potential interaction needs to be addressed when monitoring patients established on warfarin as they commence thiopurines or change dose. IBD patients are increasingly changed to combination low dose thiopurine and allopurinol for high methylmercaptopurine: thioguanine nucleotide (MeMP:TGN) ratio to optimise thiopurine efficacy. However, allopurinol also may potentiate warfarin and this could further exacerbate the effect of Azathioprine/mercaptopurine dose lowering on warfarin activity. Aim To raise awareness of risk of harm from a clinically important interaction between thiopurines and warfarin +/- allopurinol. Methods We studied 8 patients, identified from our anticoagulation database, who had been previously established on warfarin, and then commenced azathioprine or mercaptopurine for inflammatory bowel disease (2), systemic lupus erythematosus (1), nephritic syndrome (1), Wegener’s granulomatosis (1), polyarteritis nodosa (1), dermatomyositis (1) and renal transplant (1). The effect of thiopurine on international normalised ratio (INR), and warfarin dose prior to and following commencement of thiopurine was recorded. Results In 6/8 patients, following introduction of azathioprine or mercaptopurine, the warfarin dose had to be significantly increased (100% [18–500], Median [range]) in order to maintain a therapeutic INR. Any subsequent reductions in thiopurine dose were mirrored by a rise in INR and lower requirement for warfarin. In 2 IBD patients, each with a high warfarin requirement, thiopurine metabolites were measured. In both patients MeMP:TGN ratio was >11. Thiopurine dose was reduced to 25% and allopurinol 100 mg added. INR was carefully monitored. In both cases INR increased within a week (to 6.9 and 11.2) and warfarin doses were subsequently reduced by ½ and 2/3 respectively to regain therapeutic INR. Conclusion It is important for clinicians to be aware of the potential inhibitory action of thiopurines on warfarin’s anticoagulant effect. Close INR monitoring is essential when initiating thiopurines and especially when reducing their dose and/or adding allopurinol. Failure to recognise the latter could result in bleeding due to over-anticoagulation. The high MeMP:TGN ratio in 2 of our patients also raises the possibility that thiopurine metabolites may play a role in the interaction between thiopurines and warfarin. Disclosure of Interest None Declared.

Thromboxanes are produced in excess and platelets are activated in active Crohn's disease. Preliminary reports have suggested that ridogrel, a dual thromboxane synthase inhibitor and receptor antagonist, may have therapeutic benefit in patients with inflammatory bowel disease.To investigate the efficacy of ridogrel in patients with active Crohn's disease.This was an international, multicentre, randomized, double-blind, placebo-controlled trial of 5 mg/day oral ridogrel for 12 weeks in 85 patients with moderately active Crohn's disease. Sixty patients were randomized to receive ridogrel, and 25 to placebo. The Crohn's disease activity index (CDAI) was used to assess disease activity: remission was defined as a CDAI150. Changes in clinical condition, as assessed by the Harvey-Bradshaw index, global evaluation by the investigator and the patient, and blood measures of inflammation, were used as secondary outcomes.The patients' mean (s.d.) CDAI at recruitment was 277 (68) in the ridogrel treated group and 265 (70) in the placebo group. At their final assessment, 20 out of 60 (35%) patients who had been given ridogrel in an intention-to-treat analysis and seven out of 25 (28%) patients given placebo were in remission (no significant difference). No significant differences in Harvey- Bradshaw index or global evaluation were noted between patients given ridogrel and those given placebo. Adverse events were similar in both groups.A 5-mg dose of oral ridogrel was not more effective than placebo in inducing remission in patients with moderately active Crohn's disease. If thromboxane synthesis and platelet function are to be targeted for the treatment of Crohn's disease, more potent agents require development and assessment.

Herbal medicines are now used by up to 50% of the Western population, in a substantial minority of instances for the treatment or prevention of digestive disorders. Although most indications for the use of such remedies are anecdotally or traditionally derived, controlled trials suggest some benefits for ginger in nausea and vomiting, liquorice extracts in peptic ulceration, Chinese herbal medicine in irritable bowel syndrome, opium derivatives in diarrhoea and senna, ispaghula and sterculia in constipation. Herbal preparations contain many bioactive compounds with potentially deleterious as well as beneficial effects. There is clearly a need for greater education of patients and doctors about herbal therapy, for legislation to control the quality of herbal preparations, and in particular for further randomized controlled trials to establish the value and safety of such preparations in digestive and other disorders.

A minority of patients with Crohn's have disease refractory to or dependent on corticosteroids who are inappropriate for surgery; most will also have failed to respond to aminosalicylates, antibiotics, and/or a liquid formula diet. Firstline immunomodulatory therapy, given to initiate and maintain remission and allow tapering of steroid therapy, is usually azathioprine or 6-mercaptopurine. Unfortunately, approximately 20% of patients are resistant to or intolerant of thiopurines, and their management provides a difficult therapeutic challenge. The possible benefits of mycophenolate mofetil are unconfirmed, while infliximab is expensive and unproved in its long term efficacy and safety.#### Key points Methotrexate is of proven value in psoriasis and rheumatoid arthritis.1 2 Since its effects in Crohn's disease were first reported …

Reactive oxygen species may be pathogenic in ulcerative colitis. Oral iron supplements anecdotally exacerbate inflammatory bowel disease and iron levels are elevated in the inflamed mucosa. Mucosal iron may enhance hydroxyl ion production via Fenton chemistry. Conversely, the iron chelator, desferrioxamine, is reportedly beneficial in Crohn's disease.To assess the in vitro effects of exogenous iron and of iron chelators on the production of reactive oxygen species by colonic biopsies from normal control subjects and patients with ulcerative colitis.Luminol-amplified chemiluminescence was used to measure mucosal reactive oxygen species production both before and after addition in vitro of ferric citrate (100 microM), desferrioxamine (1 mM) and 1,10-phenanthroline (1 mM).Ferric citrate had no effect on the chemiluminescence produced by human colonic mucosa. However, desferrioxamine and phenanthroline reduced chemiluminescence by 47% (n=7, P=0.018) and by 26% (n=10, P=0.005), respectively, in inactive ulcerative colitis, and by 44% (n=9, P=0. 008) and 42% (n=11, P=0.006) in active disease.The lack of effect of ferric citrate suggests that sufficient free iron is already present in inflamed biopsies to drive the Fenton reaction maximally. The effects of desferrioxamine and 1,10-phenanthroline on the chemiluminescence of biopsies from patients with ulcerative colitis suggest that a clinical trial of topical iron chelation in active disease is indicated.

Platelets play an important role in inflammation and are activated in inflammatory bowel disease. Micro-vascular thrombosis in the gut wall leading to intestinal micro-infarction may be a pathogenic feature of Crohn's disease. 5-Aminosalicylic acid is an effective treatment for patients with inflammatory bowel disease.To assess the effects of 5-aminosalicylic acid on platelet activation, when taken orally and in vitro by patients with inflammatory bowel disease.Spontaneous and thrombin-induced platelet activation were studied using fluorescent antibodies to the activated platelet surface glycoprotein P-selectin and flow cytometry.Baseline platelet activation in inflammatory bowel disease was significantly greater than that in controls (P=0.0003). Independent of diagnosis or disease activity, spontaneous ex-vivo platelet activation was 50% lower in patients with inflammatory bowel disease taking 5-aminosalicylic acid orally than in those not on such treatment (P0.05). In vitro, 5-aminosalicylic acid significantly reduced both spontaneous (P0. 03 for/=1 microM 5-aminosalicylic acid) and thrombin-induced platelet activation (P0.02 for/= 1 microM 5-aminosalicylic acid).5-Aminosalicylic acid given either orally or in vitro inhibits platelet activation. If this effect reflects an in vivo action in the gut, it could contribute to the beneficial actions of 5-aminosalicylic acid in inflammatory bowel disease.

Thromboxanes, prostaglandins, reactive oxygen metabolites and pro-inflammatory cytokines are produced in excess in inflammatory bowel disease. Preliminary reports suggest that ridogrel, a thromboxane synthesis inhibitor and receptor blocker, may have therapeutic benefits in ulcerative colitis.To investigate the anti-inflammatory profile of ridogrel.The effects of ridogrel on the production of eicosanoids, reactive oxygen metabolites and cytokines by cultured inflamed colorectal mucosal biopsies were made using ELISA and chemiluminescence, reactive oxygen metabolite generation in a cell-free system, and platelet activation using flow cytometry. The effects of oral ridogrel on mucosal release of eicosanoids in two patients with active ulcerative colitis were assessed using rectal dialysis.Ridogrel significantly reduced the release of thromboxane B2, but not prostaglandin E2 or tumour necrosis factor-alpha, from biopsies (P0.01 for 10 microM ridogrel). Ridogrel showed no direct antioxidant activity but significantly reduced reactive oxygen metabolite production from cultured biopsies (P0.01 for 10 microM ridogrel). Platelet activation in vitro was inhibited by ridogrel (P/= 0.05 for/= 10 microM ridogrel). Mean rectal mucosal thromboxane B2 release was reduced to 86% of pre-treatment levels in two patients treated with oral ridogrel.Its inhibition of mucosal production of thromboxane B2, reactive oxygen metabolites, and of platelet activation, suggests that ridogrel could have a therapeutic role in inflammatory bowel disease.

The aetiology of ulcerative colitis is unknown. Two patients without pre-existing inflammatory bowel disease in whom end colostomy for faecal incontinence was complicated by diversion colitis in the defunctioned rectosigmoid colon, are described. In both instances, colitis with the clinical, colonoscopic, and microscopic features of ulcerative colitis developed about a year later in the previously normal in-stream colon proximal to the colostomy. These cases suggest that diversion colitis may be a risk factor for ulcerative colitis in predisposed individuals and that ulcerative colitis can be triggered by anatomically discontinuous inflammation elsewhere in the large intestine.

Platelet activation results in changes in a number of cell surface molecules including an increase in P-Selectin (CD62P) that may be rapidly and conveniently measured by immunofluorescent flow cytometry. The ADVIA 120 (Bayer) is a new system that facilitates more accurate measurement of platelet volume and in addition provides an approximate measure of the mean refractive index (RI) of the platelets reported as mean platelet component (MPC) concentration. We were interested to determine whether changes in MPC might reflect changes in platelet activation status. To investigate this, the platelet CD62P expression, determined by flow cytometry, and change in MPC, measured on the ADVIA 120 system, was first examined in vitro after stimulation of EDTA anticoagulated whole blood with submaximal concentrations of bovine thrombin in the presence or absence of the thromboxane synthase inhibitor, Ridogrel. Thrombin produced a dose-dependent increase in platelet CD62P expression and a decrease in MPC that could be inhibited by Ridogrel at physiological concentrations. In the second set of experiments, blood from 20 normal controls was collected into both EDTA and sodium citrate (SC) anticoagulants. Within 30 min of venesection and again at 3 h post-venesection after storage at room temperature, the platelet MPC and CD62P expression were determined. Platelets in all samples with both anticoagulants showed very low levels of CD62P expression when first analysed. At 3 h there was a small increase in CD62P expression on platelets in whole blood anticoagulated with SC, but a significant (P0.001) increase was observed on platelets anti-coagulated with EDTA. A negative correlation was found between the change in MPC of the platelets and the increase in the mean fluorescence intensity (MFI) (r = -0.69, P0.001, n = 20) and the percentage (r = -0.72, P0.001, n = 20) of CD62P positive platelets at 3 h in blood anticoagulated with EDTA. We conclude that a reduction in MPC as measured by the ADVIA 120 may be used to detect anticoagulant induced, as well as thrombin stimulated, in vitro platelet activation in blood anticoagulated with EDTA. Further, we conclude that platelet activation is negligible for up to 3 h in sodium citrate anticoagulated whole blood.

The therapeutic efficacy of 5-aminosalicylic acid in inflammatory bowel disease may be related to its antioxidant properties.To compare in vitro the antioxidant effects of conventional drugs (5-aminosalicylic acid, corticosteroids, metronidazole), with new aminosalicylates (4-aminosalicylic acid, balsalazide) and other potential therapies (ascorbate, N-acetylcysteine, glutathione, verapamil).Compounds were assessed for efficacy in reducing the in vitro production of reactive oxygen species by cell-free systems (using xanthine/xanthine oxidase, with or without myeloperoxidase) and by colorectal biopsies from patients with ulcerative colitis using luminol-amplified chemiluminescence.5-aminosalicylic acid and balsalazide were more potent antioxidants than 4-aminosalicylic acid or N-acetyl-5-aminosalicylic acid in cell-free systems. 5-aminosalicylic acid (20 mM) and balsalazide (20 mM) inhibited rectal biopsy chemiluminescence by 93% and 100%, respectively, compared with only 59% inhibition by 4-aminosalicylic acid (20 mM). Hydrocortisone, metronidazole and verapamil had no significant effect on chemiluminescence in any system. Ascorbate (20 mM) inhibited chemiluminescence by 100% in cell-free systems and by 60% in rectal biopsies. N-acetyl cysteine (10 mM), and both oxidized and reduced glutathione (10 mM), completely inhibited chemiluminescence in cell-free systems, but not with rectal biopsies.The antioxidant effects of compounds varies between cell-free systems and inflamed colorectal biopsies. The effect of drugs on the chemiluminescence produced by these two assay systems is useful for screening potentially new antioxidant treatments for inflammatory bowel disease. Ascorbate seems worth further study as a novel therapy.

In the vast majority of cases, Clostridium difficile-associated diarrhoea and pseudomembranous colitis develop following the use of antibiotics. We report a case in which C. difficile-associated diarrhoea was diagnosed in the absence of previously reported predisposing factors. It transpired that the patient had a colonic carcinoma. We suggest that a diagnosis of C. difficile-associated diarrhoea in the absence of a history of antibiotics or other established causes should prompt a colonoscopy to search for alternative explanations for the alteration in bowel flora which such an infection indicates.

Mesenteric microvascular thrombosis may be an early pathogenic event in Crohn's disease (CD), and intravascular platelet aggregates have been identified in mucosal biopsies in ulcerative colitis (UC). Activated platelets are involved in thrombogenesis and exhibit inflammatory properties. In active inflammatory bowel disease (IBD) increased numbers of platelet aggregates are detectable in the peripheral circulation. The aim of this study was to test the hypothesis that in IBD, platelet aggregation is triggered in the mesenteric vasculature.Platelet numbers, platelet aggregate ratios and differential leucocyte counts were compared in mesenteric arterial and venous blood obtained from paired vessels at the time of intestinal resection from 13 patients with inflammatory bowel disease and, as controls, 6 patients with colonic carcinoma or diverticular disease.In UC and CD, but not in controls, fewer neutrophils were found in blood draining the intestine compared with that supplying it (arteriovenous gradient median 1.0 x 10(9)/l (interquartile range 0.2-1.3) for UC, P0.05; 0.8 (0.2-1.5) for CD, P0.02; 0.4 (-0.3-1.1) for controls, P = NS). In CD, increased numbers of circulating platelet aggregates were identified in venous samples (platelet aggregate ratio 0.83 (0.71-0.93)) than in paired arterial samples (0.99 (0.95-1.01), P0.02) and control venous samples (0.99 (0.93-0.97), P0.05). The mesenteric arteriovenous gradient for neutrophils in IBD reflects their migration into the extravascular tissue and lumen of the inflamed intestine. Increased circulating platelet aggregates in the mesenteric venous circulation support the hypothesis that platelet activity is stimulated in the mesenteric microcirculation in CD.

An elevated platelet count is well recognized as a marker of inflammatory bowel disease activity. There is an increased incidence of systemic thromboembolism in this disease. Recent work indicates that platelets exhibit several proinflammatory properties including release of inflammatory mediators, and recruitment, chemotaxis and modulation of the activity of other inflammatory cells. Furthermore there is evidence that microvascular thrombosis and a procoagulant state may play a role in the pathogenesis of inflammatory bowel disease. These observations prompted recent studies of platelet activity in inflammatory bowel disease, which indicate enhanced platelet aggregation in vivo and in vitro, and increased platelet activation as measured by increased release of intracellular proteins into plasma and expression of platelet surface markers, including P-selectin and GP53. These abnormalities could contribute to the pathogenesis of inflammatory bowel disease by enhancing inflammation and promoting microinfarction. Aminosalicylates reduce platelet activity although they also have many other additional properties to explain their efficacy in inflammatory bowel disease. There are however several specific antiplatelet drugs now available which may provide new therapeutic possibilities in the management of this disease.

BACKGROUND: Reactive oxygen species may mediate tissue injury in inflammatory bowel disease. Aminosalicylates have antioxidant activity and the antioxidants, superoxide dismutase and allopurinol, are of reported benefit in inflammatory bowel disease. AIM: To develop a convenient technique for testing the antioxidant potential of standard and novel therapeutic agents for use in inflammatory bowel disease. METHODS: Amplified chemiluminescence was used to measure reactive oxygen species production by colonic biopsy specimens from rats with acetic acid induced colitis and to assess the in vitro effect of conventional antioxidants, standard therapies and proposed novel therapies for inflammatory bowel disease. RESULTS: The model was validated by demonstrating that the profile of effects on chemiluminescence of acetic acid induced colitis biopsy specimens given by conventional antioxidants (sodium azide, catalase, copper-zinc superoxide dismutase, dimethyl sulphoxide, N-acetylcysteine and ascorbate) and standard therapies (5-aminosalicylate and hydrocortisone) resembled that previously reported using biopsy specimens from ulcerative colitis. Human recombinant manganese superoxide dismutase did not alter chemiluminescence. Two novel compounds, LY231617 (10 mM) and amflutizole (20 mM), reduced chemiluminescence by 98% (n = 5, p = 0.009) and 88% (n = 5, p = 0.03), respectively. CONCLUSIONS: The similarity of the chemiluminescence responses of colonic biopsy specimens from acetic acid induced colitis and ulcerative colitis to a range of conventional antioxidants and standard treatments suggests that this model is a useful method for testing the antioxidant potential of new therapies for inflammatory bowel disease. The antioxidant actions of dimethyl sulphoxide, ascorbate, and the novel compounds, amflutizole and LY231617 in this model suggest that these agents merit further assessment in the treatment of inflammatory bowel disease.

A high prevalence of metronidazole resistance in Helicobacter pylori is reported in developing countries. This study examined whether migrants referred for diagnostic gastroscopy at a United Kingdom centre (n = 54), had a higher prevalence of metronidazole resistance than subjects born in the United Kingdom attending endoscopy (n = 46). Records of nitroimidazole treatment prescribed in the United Kingdom was obtained in 83 patients to find out if there was an association between H pylori metronidazole resistance and previous ingestion of either metronidazole or tinidazole. The prevalence of metronidazole resistant isolates varied according to country of birth: Bangladesh (90%, 27 of 30), other countries (67%, 16 of 24), and United Kingdom (37%, 17 of 46) (p < 0.001). Among those born in the United Kingdom, women were more likely to harbour resistant H pylori than men (54% v 18% respectively, p = 0.01) and more likely to have a history of previous nitroimidazole ingestion (41% v 11% respectively, p = 0.02). Patients previously exposed to either metronidazole or tinidazole were more likely to harbour resistant strains (84% (27 of 32) v 41% (21 or 51), p < 0.0001). The distribution of gastroduodenal disease, assessed endoscopically, was not affected by metronidazole resistance status.

Pouchitis may complicate the construction of an ileal pouch after colectomy for ulcerative colitis (UC) but not familial adenomatous polyposis (FAP). To examine whether differences in eicosanoid metabolism might explain why pouchitis is largely confined to UC patients, this study compared arachidonic acid stimulated release of immunoreactive leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) from macroscopically uninflamed pouch mucosal biopsy specimens incubated in vitro from patients with UC and FAP. The study also compared eicosanoid release from inflamed and uninflamed pouches in patients with UC. In uninflamed pouches, median LTB4 release was nearly twice as high in UC as in FAP (p = 0.001), but there was no significant difference in PGE2 production. In UC, stimulated eicosanoid release from uninflamed functioning pouch mucosa was not significantly different from that from either ileostomy or defunctioned pouch mucosa. LTB4 and PGE2 release were significantly greater from inflamed than uninflamed pouch mucosa in UC (p = 0.001 and 0.01, respectively). Leukotriene synthesis inhibition or receptor antagonism, or both merit therapeutic evaluation in pouchitis. Increased release of LTB4 from endoscopically normal pouch mucosa suggests increased 5-lipoxygenase activity in patients with UC and could contribute to their predisposition to pouchitis.

Helicobacter pylori infection has been associated with stimulation of gastric mucosal reactive oxygen metabolite production. To provide further evidence of a causal relationship we looked for a dose-response relationship. We studied antral biopsy material from 110 patients. Quantitative H. pylori assessments were made using histologic and microbiologic methods. Reactive oxygen metabolite production was measured by luminol-dependent chemiluminescence. The usefulness of timed urease test colour changes as a guide to infective load was assessed. There was a positive association between mucosal reactive oxygen metabolite production and histologic (p = 0.002, n = 69) and microbiologic (Spearman's R = +0.6, p = 0.05, n = 18) quantitative H. pylori assessments. H. pylori infective load varied markedly over small areas (coefficient of repeatability of paired cultures (in colony-forming units/mg) = 1.9 x 10(6). Urease test timing correlated with histologic (p = 0.01) and microbiologic (p = 0.03) H. pylori quantitation. Histologically assessed mucosal damage was related to quantitative H. pylori assessment and to mucosal reactive oxygen metabolite production (p = 0.0001). These results support the hypothesis that H. pylori stimulates gastric mucosal reactive oxygen metabolite production and that this phenomenon is of pathogenic importance.

To determine if reactive oxygen metabolites have a pathogenic role in Helicobacter pylori (H pylori) related gastroduodenal disease, this study measured their production in antral mucosal biopsy specimens. Two related chemiluminescence techniques were used comparing H pylori positive (n = 105) and negative patients (n = 64) with a similar spectrum of macroscopic disease. After chemiluminescence assays, biopsy specimens were graded histologically. Increased luminol dependent chemiluminescence (detecting reactive oxygen metabolites through peroxidase catalysed reactions) was found in H pylori positive patients (median photon emission = 6.4 x 10(3)/min/mg wet weight (95% confidence intervals 3.6 to 9.9)) but not H pylori negative cases (-0.9 (-1.3 to -0.6)) (p = 0.0001). Similar results were found using lucigenin (which reacts directly with oxygen metabolites, particularly superoxide): (H pylori positive 0.9 (0.1 to 3.2); H pylori negative -1.2 (-3.4 to -0.6)) (p = 0.0003). Chemiluminescence was greater in H pylori positive compared with negative tissue when samples were grouped by equivalent macroscopic or microscopic damage. This difference was in part accounted for by a greater neutrophil infiltration in the H pylori positive mucosa, but when biopsy specimens with equivalent neutrophil infiltration could be compared directly, positive specimens gave greater chemiluminescence than negative. Smoking, drugs, and alcohol consumption had no independent effect. It is concluded that excess mucosal reactive oxygen metabolite production is associated with H pylori gastric antral infection and may be an important pathogenic mechanism. There is no evidence for reactive oxygen metabolite participation in the pathogenesis of gastric mucosal injury in cases unrelated to H pylori infection.