Increased risk of myocardial infarction as first manifestation of ischaemic heart disease and nonselective nonsteroidal anti-inflammatory drugs.

AIMS: Selective cyclooxygenase (COX)-2 inhibitors have recently been implicated as enhancing risk of myocardial infarction (MI). Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are also effective COX-2 inhibitors, so we investigated the hypothesis that they too increase risk of MI. METHODS: We conducted a case-control study with direct structured interview of cases and controls. Cases were all subjects (N = 205) with a first nonfatal MI who had no previously recognized cardiovascular disease. Community controls (N = 258) were randomly selected from the same practice as the index case. Hospital controls (N = 205) were those admitted at the same time as index cases for nonmyocardial conditions not influenced by NSAID use. The effects of aspirin, NSAIDs and previously recognized influences on MI were investigated by unconditional logistic regression analysis. RESULTS: NSAID use was associated with an increase risk of MI with an odds ratio of 1.77 (1.03, 3.03) vs. community controls and 2.61 (1.38, 4.95) vs. hospital controls. These values were 5.00 (1.18, 21.28) and 7.66 (0.87, 67.48), respectively, in aspirin users. Results were similar when naproxen was grouped with aspirin. Odds ratios for smoking and for use of antidiabetic medication were 3.91 (2.52, 6.04) and 3.92 (1.25, 12,33), respectively, vs. community controls. CONCLUSIONS: Like selective COX-2 inhibitors, non-selective NSAIDs [corrected] are associated with an increased risk of MI. The extent to which this reflects interference with aspirin warrants further investigation.

Interactions between Helicobacter pylori and other risk factors for peptic ulcer bleeding.

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 < or = 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 < or = 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 < or = 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.

Nocardia asteroides lung abscess in acute ulcerative colitis treated with cyclosporine.

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.

Dose-dependent effects of ketoprofen on the human gastric mucosa in comparison with ibuprofen.

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.

Human colonic subepithelial myofibroblasts modulate transepithelial resistance and secretory response.

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.

Immunosuppressive therapy for ulcerative colitis: results of a nation-wide survey among consultant physician members of the British Society of Gastroenterology.

BACKGROUND: The role of immunosuppressive therapy in ulcerative colitis remains controversial. There is little information available on how frequently immunosuppressives are used, the circumstances, dose and duration of use and perceived benefit. METHODS: A postal survey was sent to consultant gastroenterologist members of the British Society of Gastroenterology. RESULTS: Questionnaires were returned by 81% of the 496 UK consultants approached. Azathioprine use was frequent, with 93% reporting previous use and 86% use within the past year. Although 95% usually prescribed a < or =2 mg/kg dose, only 39% were prepared to prescribe higher doses. There was marked variation in duration of use, with 46% using azathioprine for <2 years and 17% continuing it for 4 years or longer. Consultants with more experience of azathioprine in ulcerative colitis used it at higher maintenance doses for longer periods, and in patients with less extensive disease. Cyclosporin use was reported by 47% of those caring for ulcerative colitis patients, with 36% having used it at least once in the past year. However, 65% of users estimated that fewer than 50% of patients subsequently avoided colectomy. On stopping cyclosporin only 21% always introduced an alternative immunosuppressive, while 23% never did so. Potentially serious side-effects attributable to azathioprine and cyclosporin were reported by 36% and 45% of users of each drug, respectively. CONCLUSIONS: This survey reveals considerable variation in the amount and pattern of immunosuppressive use in ulcerative colitis, with serious side-effects commonly seen. There is a pressing need for further randomized controlled trials to provide reliable evidence as to how immunosuppressive therapy should be used in ulcerative colitis.

TGF-alpha reduces bradykinin-stimulated ion transport and prostaglandin release in human colonic epithelial cells.

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 E2 (PGE2) 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 PGE2 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 PGE2 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 PGE2 (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.

Novel treatments in inflammatory bowel disease.

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.

Current pharmacotherapy for inflammatory bowel disease.

Ulcerative colitis (UC) and Crohn's disease (CD), collectively termed inflammatory bowel disease (IBD), are chronic spontaneously relapsing enteropathies of unknown aetiology. Pharmacotherapy for IBD has essentially been unchanged for over twenty years, with therapy based around 5-aminosalicylic acid (5-ASA) preparations, corticosteroids, antibiotics and immunosuppression. Much of the controversy surrounding optimal use of these drugs in IBD arises as a consequence of methodological deficiencies in many of the early trials combined with the difficulty in consistent patient selection due to the heterogeneous nature of both UC and CD. More recently, well-designed clinical trials have attempted to provide an 'evidence based' approach to managing IBD which, in time, will allow optimisation of current therapies and accurate evaluation of novel agents. Over the past two decades, improved research methodology has considerably increased our molecular understanding of the aetiopathogenesis of IBD which has ultimately lead to the development of specific mediator directed or 'designer' drug therapy for IBD. This review evaluates the literature on current IBD therapy, summarises the important recent studies which have made an impact on clinical practice, and examines the risks and benefits of the novel agents which are currently under investigation in clinical trials of IBD therapy.

Lack of effectiveness of the platelet-activating factor antagonist SR27417A in patients with active ulcerative colitis: a randomized controlled trial. The Platelet Activating Factor Antagonist Study Group in Ulcerative Colitis.

BACKGROUND & AIMS: Platelet-activating factor (PAF) is increased during relapse of ulcerative colitis. In animal models of experimental colitis, specific inhibition of PAF has reduced inflammation. The aim of this study was to evaluate the efficacy and safety of the PAF antagonist SR27417A in moderately active UC. METHODS: A double-blind multicenter trial was conducted during a 28-day period in hospital outpatients with an exacerbation of ulcerative colitis. Patients were randomized to receive 10 mg/day SR27417A or placebo, and both groups were also given 2.4 g mesalazine. Patient classification at the end of the treatment period was based on sigmoidoscopy and clinical scores. RESULTS: One hundred fifty-one subjects entered the study (75 placebo and 76 SR27417A). The remission rate between placebo- and SR27417A-treated patients at 28 days was not significantly different (29.0% and 35.6% respectively; P = 0.44). Similarly, 49.2% treated with SR27417A had a definite or possible improvement of their symptom score compared with 48.3% of those treated with placebo (P = 0.43). Four subjects in the placebo group and 5 subjects in the SR27417A group discontinued the drug treatment because of adverse events. No significant adverse events were thought to be caused by SR27417A. CONCLUSIONS: Although the specific PAF antagonist SR27417A is safe in humans, there is no evidence of efficacy in the treatment of acute ulcerative colitis.

Short- and long-term outcome of patients treated with cyclosporin for severe acute ulcerative colitis.

BACKGROUND: Recent evidence suggests that the immunosuppressive drug cyclosporin may be of benefit in treating patients with severe colitis who are steroid resistant. Although cyclosporin appears to be effective in reducing colectomy rates in the short term, few data are available on the long-term follow-up of such patients. AIM: To investigate the short- and long-term outcome of patients with severe steroid-resistant ulcerative colitis treated with cyclosporin who were otherwise being considered for colectomy. METHODS: Twenty-two patients with severe steroid-resistant exacerbations of ulcerative colitis who were being considered for colectomy were treated with cyclosporin (4 mg/kg i.v.) daily for 7 days followed by oral treatment (6 mg/kg/day) if colectomy was avoided. RESULTS: Twenty of 22 patients (91%) avoided colectomy during their initial hospital admission. With a mean follow-up period of 39 months (range 31-59), eight of these patients have subsequently relapsed and required colectomy and 12 patients have avoided colectomy (53%). Of the 12 patients avoiding colectomy, seven have successfully been weaned on to azathioprine while five are maintained on an aminosalicylate alone. None of these long-term responders require maintenance corticosteroids. The main side-effects during treatment with cyclosporin were headaches (six patients, 27%), paraesthesia and tremors (four patients, 18%) and hypertension (four patients, 18%). Two patients developed renal impairment on cyclosporin which resolved on lowering the dose. In no case was cyclosporin discontinued because of an adverse reaction. No clinical or laboratory features could be identified that predicted which patients treated with cyclosporin would later require colectomy. CONCLUSION: This study shows that cyclosporin is a viable alternative to emergency colectomy in severe ulcerative colitis in the short term. Although these benefits are not maintained in all patients, more than half were found to avoid colectomy in the longer term.

Safety and efficacy of rabeprazole in combination with four antibiotic regimens for the eradication of Helicobacter pylori in patients with chronic gastritis with or without peptic ulceration.

OBJECTIVES: Rabeprazole is a new fast acting proton pump inhibitor that has recently been proven to be effective in the treatment of peptic ulceration and reflux esophagitis. The aim of this study was to evaluate rabeprazole in combination with antibiotics for the eradication of Helicobacter pylori (H. pylori) in patients with chronic active gastritis with or without peptic ulcer disease. METHODS: Seventy-five H. pylori-infected patients were randomized in a double-blind fashion to receive a 7-day treatment regimen consisting of: RAC, RAM, RCM, or RC (R=rabeprazole 20 mg b.d., A=amoxycillin 1 g b.d., C=clarithromycin 500 mg b.d., M=metronidazole 400 mg b.d.). Randomized patients were H. pylori-positive by gastric biopsy urease test, histology and 13C urea breath test (13C-UBT). H. pylori eradication was assessed by 13C-UBT, 4 and 8 wk after finishing treatment. Endoscopy with histology and culture for antibiotic sensitivity testing was performed pretreatment and if treatment failed. RESULTS: On an intention-to-treat analysis, treatment success was: RCM 100%, RAC 95%, RAM 90%, and RC 63%. The most common side effects were loose stools, headache, and taste disturbance, but there were no serious adverse events related to the study medication. The two patients failing RAM treatment had metronidazole-resistant strains before and after treatment. None of the pretreatment H. pylori isolates from six patients failing RC were clarithromycin resistant, but three of five successfully cultured posttreatment had developed clarithromycin resistance. CONCLUSION: Rabeprazole-based triple therapy with two antibiotics for 1 wk is safe and effective in eradicating H. pylori. Dual therapy with clarithromycin is less successful, and the majority of treatment failures develop clarithromycin resistance.

Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders.

Proton pump inhibitors (PPIs) are drugs which irreversibly inhibit proton pump (H+/K+ ATPase) function and are the most potent gastric acid-suppressing agents in clinical use. There is now a substantial body of evidence showing improved efficacy of PPIs over the histamine H2 receptor antagonists and other drugs in acid-related disorders. Omeprazole 20 mg/day, lansoprazole 30 mg/day, pantoprazole 40 mg/day or rabeprazole 20 mg/day for 2 to 4 weeks are more effective than standard doses of H2-receptor antagonists in healing duodenal and gastric ulcers. Patients with gastric ulcers should receive standard doses of PPIs as for duodenal ulcers but for a longer time period (4 to 8 weeks). There is no conclusive evidence to support the use of a particular PPI over another for either duodenal or gastric ulcer healing. For Helicobacter pylori-positive duodenal ulceration, a combination of a PPI and 2 antibacterials will eradicate H. pylori in over 90% of cases and significantly reduce ulcer recurrence. Patients with H. pylori-positive gastric ulcers should be managed similarly. PPIs also have efficacy advantages over ranitidine and misoprostol and are better tolerated than misoprostol in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs). In endoscopically proven gastro-oesophageal reflux disease, standard daily doses of the PPIs are more effective than H2-receptor antagonists for healing, and patients should receive a 4 to 8 week course of treatment. For severe reflux, with ulceration and/or stricture formation, a higher dose regimen (omeprazole 40 mg, lansoprazole 60 mg, pantoprazole 80 mg or rabeprazole 40 mg daily) appears to yield better healing rates. There is little evidence that PPIs lead to resolution of Barrett's oesophagus or a reduction of subsequent adenocarcinoma development, but PPIs are indicated in healing of any associated ulceration. In Zollinger-Ellison syndrome, PPIs have become the treatment of choice for the management of gastric acid hypersecretion.

Novel approaches to inflammatory bowel disease.

Ulcerative colitis and Crohn's disease, collectively known as inflammatory bowel disease (IBD), are chronic, spontaneously relapsing disorders of unknown cause. These diseases appear to be immunologically mediated and have genetic and environmental influences. Although the cause of these diseases remains obscure, the pathogenesis of chronic intestinal inflammation is becoming clearer, due to improved animal models of enterocolitis and important advances in immunological techniques. Traditional therapy for IBD, although helping to induce and maintain disease remission, does little to alter the underlying fundamental disease process. New IBD therapy has not developed significantly over the past twenty years and includes 5-aminosalicylic acid preparations, corticosteroids and immunomodulatory agents, such as azathioprine, 6-mercaptopurine and methotrexate. There is, therefore, a need for new, specific disease-modifying therapy and the development of such therapy has been hastened by a greater understanding of the pathophysiology of IBD. This review examines the most recent novel therapies for IBD, with specific emphasis on immunomodulatory and novel anti-inflammatory therapies. Recent clinical trials are reviewed, and the potential advances and clinical impact that these novel agents may provide are discussed.

Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease.

BACKGROUND: Tumour necrosis factor-alpha (TNF alpha) is thought to have a central role in the pathogenesis of Crohn's disease. We tested the hypothesis that CDP571, a genetically engineered human antibody to TNF alpha, is effective in modifying disease activity in patients with moderately active Crohn's disease. METHODS: In this double-blind, placebo-controlled study, 31 patients were randomly assigned to CDP571 (n = 21) or placebo (n = 10). The primary endpoint was change in Crohn's disease activity index 2 weeks after a single infusion of CDP571 (5 mg/kg), or human albumin as placebo. One patient who attended no follow-up assessments was excluded from the analyses (CDP571 group). FINDINGS: The median Crohn's disease activity index fell from 263 (IQR 186.5-323.5) at baseline to 167 (137.5-294.0) at 2 weeks in the CDP571-treated patients (p = 0.0003); the change in the placebo group (253 [240-334] to 247 [183-256]) was not significant. In the treated group, there were also significant differences between baseline and 2 weeks in Harvey-Bradshaw score (p = 0.0005), key symptom score (p = 0.049), alpha 1-glycoprotein concentration (p = 0.012), and erythrocyte sedimentation rate (p = 0.01); concentrations of C-reactive protein fell, but not significantly (p = 0.067). Six patients achieved remission (Crohn's disease activity index < or = 150) and three others had activity indices of 156 or lower. There were no significant changes in the placebo group. INTERPRETATION: A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohn's disease at 2 weeks. These data suggest that antibody neutralisation of TNF alpha is a potentially effective strategy in the management of Crohn's disease. The use of CDP571 in Crohn's disease requires further study.

Specific mediator-directed therapy for gastrointestinal diseases.

A number of inflammatory mediators--such as proinflammatory cytokines, lipid derived eicosanoids and reactive oxygen metabolites--are elevated in chronic bowel inflammation. Existing drugs for Crohn's disease and ulcerative colitis, for example aminosalicylates and corticosteroids, work at many sites in the inflammatory cascade to control disease activity. These drugs may be associated with significant side-effects and do not always control the disease. Therefore there is an impetus to develop treatments which are safer and more specific for bowel inflammation. Specific inhibitors of inflammatory mediators have recently become available and some have been shown to be effective in animal models of bowel inflammation. Although far fewer data are currently available on specific mediator-directed therapy of intestinal inflammation in humans, early clinical trials in inflammatory bowel disease have given mixed results. It remains to be determined whether or not this strategy of specific mediator inhibition is an alternative to current therapy for chronic bowel inflammation in humans.

Nitric oxide donating compounds stimulate human colonic ion transport in vitro.

BACKGROUND: Nitric oxide (NO) has been recently implicated as a possible mediator of bowel inflammation and has also been shown to stimulate electrogenic chloride secretion in rat and guinea pig intestine. This study therefore investigated the effect on two NO donors, sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on human colonic ion transport. METHODS: Changes in short circuit current (delta SCC) in response to nitric oxide donating compounds were measured in muscle stripped normal human colon mounted in Ussing chambers. The ion species and intracellular mechanisms responsible for delta SCC evoked by SNP were investigated. RESULTS: Basolateral SNP caused a progressive rise in delta SCC over the range 10(-7) to 10(-4)M (ED50 = 2.5 x 10(-5)M). SNAP 10(-4)M also evoked a qualitatively similar delta SCC compared with SNP 10(-4)M. Basolateral SNP evoked a greater delta SCC than apical and this was significantly attenuated by bumetanide 10(-4)M (52.9 +/- 10.1%) and in chloride free media (68.3 +/- 7.3%). delta SCC response to SNP was not significantly changed by basolateral 4-acetamido-4'-isothio-cyano-2,2'disulphonic acid stillbene (SITS 10(-3)M) an inhibitor of sodium/bicarbonate exchange, or apical amiloride 10(-5)M an inhibitor of sodium absorption. SNP induced delta SCC was also significantly reduced by piroxicam (mean (SEM)) 10(-5)M (57.9 (11.9)%), nordihydroguaretic acid 10(-4)M (48.0 (12.9)%), tetrodotoxin (TTX 10(-6)M, 52.3 (9.1)%), and practically abolished by TTX and piroxicam together (96.8 (3.3)%). CONCLUSION: NO donors stimulate human colonic ion transport in vitro. For SNP, increased delta SCC is at least due in part to chloride secretion, and the response seems to be transduced through enteric nerves and by local prostanoid synthesis. This study provides evidence that NO may be another important mediator of ion transport in human colon.

Regulation of ion transport by histamine in human colon.

Histamine, added to the basolateral side of voltage clamped human colon in vitro, induced a rapid onset, transient inward short circuit current which was concentration dependent over the range 0.01-3 mM. This response was largely due to electrogenic chloride section since it was virtually abolished by bumetanide or by chloride replacement in the bathing solutions. Responses were unaffected by amiloride or acetazolamide. Neither the histamine H2 receptor agonist dimaprit (1 mM) nor the histamine H3 receptor agonist S-(+)-alpha-methyl histamine (1 mM) altered short circuit current. Responses to histamine were significantly reduced by the histamine H1 receptor antagonist mepyramine (1-10 microM) but not altered by the histamine H2 receptor antagonist cimetidine (100 microM) or by the histamine H3 receptor antagonist thioperamide (1 microM). Short circuit current responses to histamine were not altered by tetrodotoxin (1 microM). Piroxicam (10 microM) and nordihydroguaiaretic acid (100 microM) were without effect when used individually but significantly reduced responses to histamine when used simultaneously. These results indicate that histamine stimulates chloride secretion across human colonic epithelium by a mechanism which is mediated exclusively via histamine H1 receptors. This action does not involve intrinsic nerves but appears to be dependent upon eicosanoid synthesis.

Immune regulation of human colonic electrolyte transport in vitro.

The role of lamina propria cells in regulating human colonic ion transport was investigated in vitro. Normal human colonic mucosae were mounted in Ussing chambers, and short circuit current changes (delta SCC) were monitored in response to immune cell activation. Anti-human immunoglobulin E (anti-IgE) and formyl-Methionyl-Leucyl-Phenylalanine (fMLP) were used to stimulate mast cells and phagocytes respectively. Anti-IgE (100 micrograms/ml) and fMLP (100 microM) evoked rapid onset, inward delta SCC (mean (SEM) max delta SCC 19.3 (2.8) and 29.4 (4.7) microA/0.63 cm2 respectively). A pharmacological approach was used to identify the charge carrying ion species and to characterise mediators involved in the SCC response. Responses to each secretagogue were significantly attenuated by bumetanide, indicating that the delta SCC was at least partly due to electrogenic chloride secretion. Piroxicam reduced the delta SCC to mast cell and phagocyte activation by 91.1 (3.4)% and 48.2 (25.2)% respectively, implicating eicosanoids as mediators of the responses. Mepyramine (100 microM) reduced the SCC responses to anti-IgE by 79.6 (12.0)% but did not significantly alter delta SCC responses to fMLP. Desensitisation to repeated anti-IgE or fMLP stimulation, and cross desensitisation between each of the stimuli, were features of immune cell activation. In summary, we have shown that activation of immune cells can stimulate electrogenic chloride secretion. Such events in vivo will result in gradient driven secretory diarrhoea, which may occur as a protective response to enteric-dwelling parasites, or as a feature of local bowel inflammation.