leukotriene-e4 and Colitis--Ulcerative

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders collectively referred to as inflammatory bowel diseases (IBD). Cysteinyl leukotrienes are proinflammatory 5-lipoxygenase-derived products that play a major role in the immune and inflammatory response. Consequently, they may be involved in the pathogenesis of IBD. The aim of this study was therefore to evaluate 1) the urinary excretion of leukotriene E(4) (LTE(4)) in IBD patients and healthy volunteers, and 2) the association between LTE(4) production and the activity (relapse/remission) of the disease.. IBD patients and healthy volunteers were prospectively recruited. CD and UC activity was determined on inclusion with the Crohn's Disease Activity Index and Clinical Activity Index, respectively. Urine was collected and the urinary excretion of LTE(4) was measured by liquid chromatography tandem mass spectrometry.. 32 CD patients, 28 UC patients, and 30 controls were enrolled in the study. LTE(4) urinary excretion was significantly increased (P < 0.01) in CD [52.0 pg/mg creatinine (10th-90th percentiles: 26.2-148.0)] and UC [64.1 pg/mg creatinine (10th-90th percentiles: 26.7-178.0)] patients compared to controls [32.3 pg/mg creatinine (10th-90th percentiles: 21.8-58.8)]. LTE(4) levels were higher (P < 0.001) in patients with active disease than in patients in remission, for whom the levels of LTE(4) were similar to the levels of controls.. Cysteinyl leukotriene pathway activation could contribute to the inflammation associated with IBD. The quantification of urinary LTE(4) could be an interesting noninvasive biomarker for the assessment of IBD activity.

Topics: Adult; Biomarkers; Chromatography, Liquid; Colitis, Ulcerative; Crohn Disease; Female; Humans; Inflammatory Bowel Diseases; Leukotriene E4; Male; Middle Aged; Prospective Studies; Recurrence; Tandem Mass Spectrometry

This investigation was performed in order to examine the role of sulfidopeptide-leukotrienes in a chronic inflammatory bowel disease, ulcerative colitis, by use of the recently developed LTD4/LTE4 antagonist, SR 2640 (2-[3-(2-quinolylmethoxy)phenylamino]benzoic acid). Eight ulcerative colitis patients with a mild to moderate disease activity were included in this open and uncontrolled study and SR 2640, 250 mg t.i.d., was administered for 6 weeks. Treatment of the patients with SR 2640 reduced the inhibitory effect of LTD4 on LTB4-directed chemotaxis of neutrophils purified from their blood. This indicates that the dose administered was sufficiently high to obtain systemic LTD4 receptor antagonism. Three of the 8 patients were in clinical remission at the end of the study, and the lack of clinical symptoms persisted for at least 2 months after discontinuing the drug. The condition of 3 patients was unchanged, and that of 2 patients deteriorated after 5 weeks, requiring treatment with sulphasalazine and steroids. SR 2640 was well tolerated by all patients. In a previously published study dealing with 4 weeks sulphasalazine treatment in the same category of patients, remission rates of 5% and 25% were found in the placebo and sulphasalazine groups, respectively, and the remission rate of SR 2640 thus seems to be of the same magnitude as that of sulphasalazine. The serum and faecal concentrations of SR 2640, and its metabolite, the beta-glucuronide, were found to be lower in ulcerative colitis patients as compared to healthy volunteers, and it is therefore possible that altered pharmacokinetics of SR 2640 is present in patients with chronic inflammatory bowel disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Chemotaxis, Leukocyte; Clinical Trials as Topic; Colitis, Ulcerative; Glucuronates; Humans; Leukotriene E4; Neutrophils; Pilot Projects; Quinolines; Remission Induction; SRS-A; Sulfasalazine

Despite the extensive use of sulfasalazine (SAS) and/or 5-aminosalicylic acid (5-ASA) in patients with inflammatory bowel disease and, more recently, rheumatoid arthritis, their mode of action has not been elucidated so far. None of the numerous pharmacological and biochemical effects described, including immunosuppressive, antifolate, and modulatory actions on lymphocyte and leukocyte functions, could be defined unequivocally as mediating their beneficial activity. Recently, interest has focused on actions of SAS and 5-ASA on the various enzymes of the arachidonic acid cascade. Mucosa of patients with inflammatory bowel disease generates excessive amounts of cyclooxygenase products such as prostaglandins (PG) as well as 5-lipoxygenase products such as leukotriene (LT) B4 and sulfidopeptide-LT. Both PG and LT exert proinflammatory actions and are potentially important mediators of mucosal inflammation. SAS and 5-ASA, however, have been found to inhibit PG synthesis under certain experimental conditions only, while increasing PG formation under other conditions. While SAS was found to inhibit colonic LTB4 synthesis, 5-ASA was reported to selectively affect the cyclooxygenase pathway of arachidonate metabolism in this tissue. Our results demonstrate that, like the parent compound, the metabolite 5-ASA in a dose-dependent manner inhibits release of LTB4 and sulfidopeptide-LT from normal human colonic mucosa (IC50 3.5 and 3.7 mmol/liter, respectively). Indomethacin, which has no efficacy in the treatment of patients with inflammatory bowel disease, on the other hand, selectively inhibited PGE2 formation in normal and inflamed colonic mucosa (IC50 1.7 and 1.0 mmol/liter, respectively) without reducing synthesis of LTB4 or sulfidopeptide-LT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aminosalicylic Acids; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Colitis, Ulcerative; Crohn Disease; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Intestinal Mucosa; Leukotriene B4; Leukotriene E4; Mesalamine; Rectum; SRS-A; Sulfasalazine

Release of sulfidopeptide (SP)-leukotrienes (LT) in vitro from normal human colonic mucosa and from mucosal tissue obtained from patients with Crohn's disease (CD) and ulcerative colitis (UC) was investigated. It was found that inflamed mucosal tissue released significantly more SP-LT than normal colonic mucosa both under control conditions and after addition of calcium ionophore A23187. These results indicate the presence of endogenous stimuli as well as an increased responsiveness to an exogenous stimulus of LT formation in the inflamed mucosa. Sulfasalazine (SASP), a drug used in inflammatory bowel diseases, and its active metabolite 5-aminosalicylic acid (5-ASA) were found to inhibit colonic mucosal SP-LT formation, while only 5-ASA inhibited simultaneously synthesis of another arachidonic acid-derived inflammatory mediator, prostaglandin (PG) E2. The results suggest that SP-LT might be important mediators of inflammation in CD and UC.

Topics: Aminosalicylic Acids; Colitis, Ulcerative; Crohn Disease; Humans; Intestinal Mucosa; Kinetics; Leukotriene E4; Mesalamine; Rectum; Reference Values; SRS-A; Sulfasalazine