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Background and aim: A 12 month, multicentre, randomised, double blind, placebo controlled, phase 3, dose-response study was carried out. Exisulind inhibits tumour growth by induction of apoptosis. The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas. Patients and methods: A 12 month multicentre randomised double blind placebo controlled phase 3 dose response study was carried out. At baseline colonoscopy, left sided polyps (3-10 mm) were tattooed, measured, and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow up sigmoidoscopy was performed after six months, and removal of any remaining polyps at the 12 month colonoscopy. The primary efficacy variable was change in polyp size from baseline. Results: A total of 281 patients were enrolled and randomised, 155 (55%) fulfilled the criteria for the intention to treat (ITT) analysis and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent the 12 month colonoscopy). The decrease in median polyp size was significantly greater (p = 0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p = 0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400 mg group. Conclusion: Exisulind caused significant regression of sporadic adenomatous polyps but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.

BackgroundA familial defect in intestinal barrier function has been found in Crohn’s disease.AimTo investigate possible genetic and environmental influences on this barrier defect by studying intestinal permeability in both relatives and spouses of patients with Crohn’s disease.SubjectsThe study included 39 patients with Crohn’s disease, 34 healthy first degree relatives, and 22 spouses. Twenty nine healthy volunteers served as controls.MethodsIntestinal permeability was assessed as the lactulose:mannitol ratio in five hour urinary excretion after oral load, both before (baseline) and after ingestion of acetylsalicylic acid. The permeability response represents the difference between the two tests. A ratio above the 95th percentile for controls was classified as abnormal.ResultsBaseline permeability was higher in patients and spouses than in controls. An abnormal baseline permeability was seen in 36% of the patients, 23% of the spouses, 18% of the relatives, and 3% of the controls. After ingestion of acetylsalicylic acid, permeability increased significantly in all groups. Relatives were similar to patients with regard to permeability after exposure to acetylsalicylic acid, whereas spouses were similar to controls. The proportions with an abnormal permeability response to acetylsalicylic acid were 32% in patients, 14% in spouses, 41% in relatives, and 3% in controls.ConclusionThe findings suggest that baseline permeability is determined by environmental factors, whereas permeability provoked by acetylsalicylic acid is a function of the genetically determined state of the mucosal barrier, and support the notion that environmental and hereditary factors interact in the pathogenesis of Crohn’s disease.

Increased activity of phospholipase A2 (PLA2) in the ileal mucosa may contribute to the inflammation in Crohn's disease. The results of this study showed that (a) three months after ileocolonic resection for Crohn's disease the neoterminal ileal mucosa showed endoscopically new inflammation and had higher PLA2 activity than at the time of the operation (n = 8); no such findings were seen in controls (n = 7), (b) histologically normal ileal mucosa (n = 3) contained mRNA for three isoforms of PLA2 (PLA2-I, PLA2-II, and cPLA2), but the amounts of PLA2-II mRNA clearly exceeded the amounts of mRNA for PLA2-I and cPLA2, (c) ileal mucosa from Crohn's patients (n = 2) contained higher values of PLA2-II mRNA than ileal mucosa from two controls, (d) ileal mucosa from Crohn's patients (n = 4) showed increased PLA2-II mRNA three months after ileocolonic resection. In conclusion, these results show that the predominating PLA2 mRNA in the human ileal mucosa is type II PLA2, and the increased synthesis of PLA2-II might be responsible for the increased PLA2 activity found in the ileal mucosa accompanying recurrent ileal inflammation in Crohn's disease.

Phospholipase A2 (EC 3.1.1.4) is a key enzyme in inflammation and is thought to play an important part in inflammatory diseases of the gastrointestinal tract. To investigate the nature and regulation of phospholipase A2 activity in the gastrointestinal mucosa, the distribution of messenger ribonucleic acid (mRNA) for group II phospholipase A2 in various parts of the rat gastrointestinal tract was studied, as well as the influence of endotoxin or dexamethasone, or both, on the group I and II phospholipase A2 mRNA expression and activity in the rat glandular stomach and distal ileum. The results show that (a) group II phospholipase A2 is present along the whole gastrointestinal tract, but in particularly large amounts in the distal ileum, (b) endotoxin increases group II, but not group I, phospholipase A2 mRNA expression in the glandular stomach and distal ileum, and (c) dexamethasone reduces the endotoxin induced increases in group II phospholipase mRNA expression and activity in the gastrointestinal mucosa. These findings suggest that phospholipase A2 of type II is a mediator of endotoxin effects in the gastrointestinal mucosa and that its expression at the mRNA level can be inhibited by corticosteroids.

Background: Crohn9s disease is associated with deranged intestinal permeability in vivo, suggesting dysfunction of tight junctions. The luminal contents are important for development of neoinflammation following resection. Regulation of tight junctions by luminal factors has not previously been studied in Crohn9s disease. Aims: The aim of the study was to investigate the effects of a luminal stimulus, known to affect tight junctions, on the distal ileum in patients with Crohn9s disease. Patients: Surgical specimens from the distal ileum of patients with Crohn9s disease (n=12) were studied, and ileal specimens from colon cancer patients (n=13) served as controls. Methods: Mucosal permeability to 51 Cr-EDTA and electrical resistance were studied in Ussing chambers during luminal exposure to sodium caprate (a constituent of milk fat, affecting tight junctions) or to buffer only. The mechanisms involved were studied by mucosal ATP levels, and by electron and confocal microscopy. Results: Baseline permeability was the same in non-inflamed ileum of Crohn9s disease and controls. Sodium caprate induced a rapid increase in paracellular permeability—that is, increased permeation of 51 Cr-EDTA and decreased electrical resistance—which was more pronounced in non-inflamed ileum of Crohn9s disease, and electron microscopy showed dilatations within the tight junctions. Moreover, sodium caprate induced disassembly of perijunctional filamentous actin was more pronounced in Crohn9s disease mucosa. Mucosal permeability changes were accompanied by mitochondrial swelling and a fall in epithelial ATP content, suggesting uncoupling of oxidative phosphorylation. Conclusions: The tight junctions in the non-inflamed distal ileum of Crohn9s disease were more reactive to luminal stimuli, possibly mediated via disturbed cytoskeletal contractility. This could contribute to the development of mucosal neoinflammation in Crohn9s disease.

Forty two Crohn's disease patients were followed up after ileocolic resection with regard to symptoms and endoscopic appearance of the ileocolic anastomosis. Twenty eight patients resected because of colonic neoplasm served as controls. In all the Crohn's disease patients the ileal resection margin was disease free macroscopically at operation. In addition, intraoperative ileoscopy was performed in 13 and no sign of residual inflammation in the neoterminal ileum was seen. Endoscopy soon after surgery often showed preanastomotic ileal ulceration before symptoms appeared, whereas no anastomotic lesions were observed in the controls. Thus, 22 of 30 Crohn's disease patients examined had ulceration of the anastomotic area after three months, but only 10 had developed symptoms indicating relapse (73 v 33%). Corresponding figures in the 30 patients examined after one year were 93 v 37%, and in 14 patients after three years they were 100 and 86% respectively. The inflammatory lesions in all cases were preanastomotic, in the neoterminal ileum, and showed time related progression from aphthae to larger ulcers and stricture. The study suggests that endoscopically observed inflammatory lesions that appear soon after ileocolic resection for Crohn's disease signify new inflammation and not residual, persistent disease or incomplete anastomotic healing. The data further suggest that despite clinical remission after apparently radical intestinal resection, the bowel is permanently inflamed in Crohn's disease.

The intestinal permeability to low molecular weight polyethyleneglycol (PEG) has been evaluated by means of a simple mathematical model and computer-aided curve-fitting procedures. Macrogolum 400, a mixture of 11 PEGs with molecular weights ranging from 194 to 634 daltons, was taken together with a liquid meal and a six-hour portion of urine collected. The different PEGs were then extracted from the urine, separated from each other by gas-liquid chromatography, and the relative peak area of each individual PEG determined. The distribution of different PEGs in the urine was then compared with the original PEG-distribution in three different ways: (1) by comparing the median values of the molecular weights, (2) by comparing the mean and standard deviation after curve fitting to the normal distribution, and (3) by curve fitting to mathematical filter functions demonstrating molecular exclusion due to size. It thus appeared that molecules were excluded both in the high and in the low molecular weight range, possibly by a combined effect of the intestinal permeability barrier and an escape to other compartments than the urine. However, relatively more of the larger PEGs passed from the intestine to the urine in a patient with Crohn's disease than in an apparently healthy individual.