leukotriene-e4 and rofecoxib

Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate various forms of urticaria by a nonallergic mechanism involving inhibition of cyclooxygenases.. To assess safety of cyclooxygenase inhibitors in patients with chronic idiopathic urticaria (CIU) and NSAID sensitivity and to evaluate a role of cysteinyl leukotriene metabolism and mast cell activation in sensitivity to NSAIDs in CIU.. Aspirin challenge test followed by randomized, prospective, double-blind, placebo-controlled crossover trial with cyclooxygenase 2 inhibitors.. Tertiary referral center of a university hospital.. Thirty-six patients with CIU.. Aspirin challenge test (up to 500 mg); randomized trial with rofecoxib (up to 37.5 mg) and celecoxib (up to 300 mg) in aspirin-sensitive patients. After completion of the trial, 7 patients received naproxen sodium (500 mg) as a positive control.. Standardized skin examination, skin biopsy with mast cell count, urinary levels of leukotriene E4 (LTE4), and serum levels of mast cell tryptase.. Aspirin induced skin eruption in 18 patients. Rofecoxib or celecoxib did not elicit skin eruption in any of the aspirin-sensitive patients. Patients with CIU had higher urinary excretion of LTE4 than healthy control subjects. Basal urinary levels of LTE4 and serum mast cell tryptase were increased in aspirin-sensitive compared with aspirin-tolerant patients. Severity and duration of aspirin-induced urticaria showed a positive correlation with urinary LTE4 excretion. Naproxen precipitated urticaria in 5 of 7 aspirin-sensitive patients and caused further increase in urinary LTE4.. Cyclooxygenase 2 inhibitors do not induce urticaria in patients with CIU sensitive to NSAIDs. Sensitivity to NSAIDs in CIU is associated with overproduction of cysteinyl leukotrienes and mast cell activation and most likely depends on inhibition of cyclooxygenase 1.

Topics: Adolescent; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biopsy; Celecoxib; Computer Graphics; Cross-Over Studies; Cyclooxygenase Inhibitors; Cysteine; Double-Blind Method; Drug Eruptions; Female; Humans; Lactones; Leukotriene E4; Leukotrienes; Male; Middle Aged; Multivariate Analysis; Naproxen; Prospective Studies; Pyrazoles; Serine Endopeptidases; Skin; Sulfonamides; Sulfones; Treatment Outcome; Tryptases; Urticaria

In a subset of patients with asthma, aspirin and several other non-steroidal anti-inflammatory drugs (NSAID) that inhibit simultaneously cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) precipitate dangerous asthmatic attacks. We tested the hypothesis that in patients with aspirin-induced asthma the attacks are triggered by inhibition of COX-1 and not COX-2. In twelve asthmatic patients (seven men, five women, average age 39 years) oral aspirin challenge precipitated symptoms of bronchial obstruction with fall in FEV1 > 20%, and a rise in urinary leukotriene E4 (LTE4) excretion; also in five patients the stable metabolite of PGD2, 9alpha11betaPGF2, increased in urine. The patients then entered a double-blind, placebo-controlled, cross-over study in which they received either placebo or rofecoxib in increasing doses 1.5-25.0 mg for 5 consecutive days, separated by a 1-week wash-out period. No patient on rofecoxib developed dyspnoea or fall in FEV1 > 20%; mean urinary LTE4 and 9alpha11betaPGF2 urinary levels, measured on each study day for 6 h post-dosing, remained unchanged. Two patients on placebo experienced moderate dyspnoea without alterations in urinary metabolites excretion. At least 2 weeks after completion of the study, all patients received on an open basis 25 mg rofecoxib without any adverse effects. NSAID that inhibit COX-1, but not COX-2, trigger asthmatic attacks in patients with asthma and aspirin intolerance. Rofecoxib can be administered to patients with aspirin-induced asthma.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Asthma; Cross-Over Studies; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Isoenzymes; Lactones; Leukotriene E4; Male; Membrane Proteins; Middle Aged; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Sulfones