leukotriene-e4 and Bronchial-Spasm

Topics: Acetophenones; Allergens; Animals; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Dogs; Humans; Leukotriene B4; Leukotriene E4; Sheep; SRS-A; Tetrazoles

Aspirin desensitization has been associated with benefit in management of aspirin-exacerbated respiratory disease (AERD). An intervention that would encourage aspirin desensitization to be performed more frequently has substantial potential for improving outcomes and quality of life in patients with AERD.. We investigated whether omalizumab administration would be associated with attenuation of aspirin-provoked bronchospasm in patients with AERD undergoing aspirin desensitization.. We carried out a randomized, double-blind, placebo-controlled study in which subjects with AERD who fulfilled label criteria for omalizumab received omalizumab or placebo for 16 weeks, and then underwent aspirin desensitization.. Eleven subjects completed aspirin desensitization. Of the 7 who were randomized to omalizumab, 5 had no respiratory reaction during aspirin desensitization. Compared with placebo, omalizumab was associated with a significantly greater likelihood for subjects with AERD to have no respiratory reaction during desensitization (P = .04, Fisher exact test). There was an overall difference in urinary leukotriene E4 (LTE4) levels in subjects who received omalizumab and did not have a respiratory reaction during desensitization compared with subjects randomized to placebo (P = .035, mixed model with interaction). Urinary LTE4 levels were significantly higher with respiratory reaction in placebo subjects compared with levels obtained after the 100-mg dose in AERD subjects who had no respiratory reaction (P < .001, mixed model with interaction).. In atopic AERD subjects, omalizumab administration for 16 weeks was associated with "clinically silent" desensitization. Further studies to investigate the therapeutic utility of omalizumab in patients with AERD who are candidates for aspirin desensitization are warranted based on these findings.. ClinicalTrials.gov Identifier NCT00555971.

Topics: Adult; Anti-Asthmatic Agents; Aspirin; Asthma, Aspirin-Induced; Biomarkers; Bronchial Spasm; Desensitization, Immunologic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Leukotriene E4; Male; Middle Aged; Omalizumab

Urinary leukotriene E4 (LTE4) concentrations have been measured in six asthmatic patients with aspirin sensitivity and in five asthmatic subjects tolerant of aspirin, before and after provocation with aspirin or placebo. Aspirin-sensitive subjects showed an average 21% fall in FEV1 after aspirin challenge whereas control individuals had a 2% fall in FEV1 after ingestion of 100 mg aspirin. The resting urinary LTE4 concentrations in asthmatic subjects sensitive to aspirin were 243 pg/mg creatinine (range 50 to 1,041), and these were on average sixfold greater than those in control asthmatic subjects. Further, there was a mean fourfold increase in urinary LTE4 levels at 3 to 6 h after aspirin, but not placebo, challenge in aspirin-sensitive asthmatic subjects that was not seen in the control asthmatic individuals. Leukotriene release may play a central role in the mechanisms of asthmatic attacks produced by aspirin ingestion.

Topics: Adult; Aspirin; Asthma; Bronchial Provocation Tests; Bronchial Spasm; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Leukotriene E4; Male; Methacholine Chloride; Middle Aged; SRS-A

The bronchoconstrictor activity of an aerosol of leukotriene E4(LTE4) was compared with that of histamine in 5 normal and in 6 asthmatic subjects to define the relative potency of LTE4 between the groups using 3 indices of airway response. The FEV1 and the flow rate measured at 30% of vital capacity from partial and maximal expiratory maneuvers (V30-P and V30-M) were measured. The geometric mean (GSEM) concentration of LTE4 required to reduce the V30-P by 30% was 0.30 (1.46) mM in the normal subjects, and 0.058 (1.63) in the asthmatic subjects; LTE4 was 39-fold more potent than histamine in the former and 14-fold in the latter group. Further, we observed that when normal and asthmatic subjects were compared at a degree of bronchoconstriction resulting in a 30% decrement in the V30-P after inhaling LTE4, there was a greater response in the asthmatic group than in the normal group of the accompanying change in the FEV1. The decrements in the FEV1 were not significantly different between the 2 groups after inhaling histamine. This study demonstrates that LTE4 is a potent bronchoconstrictor agonist in humans and suggests that airway responsiveness to this agonist differs substantially with the index of bronchoconstriction used for assessment of airway response.

Topics: Aerosols; Asthma; Bronchial Spasm; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Histamine; Humans; Leukotriene E4; Male; Maximal Expiratory Flow Rate; Osmolar Concentration; SRS-A; Time Factors; Vital Capacity

The leukotrienes C4, D4, and E4, previously referred to as slow reacting substance of anaphylaxis, elicited long-lasting contractions of bronchi isolated from two birch pollen-sensitive asthmatics. The leukotrienes were 1,000 times more potent on a molar basis than was histamine or prostaglandin F2 alpha. Moreover, allergen released leukotrienes C4, D4, and E4 from the lung tissue of the asthmatics in amounts that appeared to correlate well to the anaphylactic bronchial contraction. Irrespectively of whether the lung was stimulated with specific allergen, the ionophore A23187 or 14C-labeled arachidonic acid, 15-hydroxyicosatetraenoic acid, and other lipoxygenase-derived monohydroxy acids were the major metabolites of arachidonic acid in the lung, and thromboxane A2 and prostaglandin I2 were the predominant cyclooxygenase products identified. However, cyclooxygenase inhibition with indomethacin had no effect on the contraction response to antigen in the bronchi, whereas, in the presence of U-60257, an inhibitor of leukotriene biosynthesis, the allergen neither released leukotrienes from the lung nor caused bronchial contraction. These findings indicate that leukotrienes C4, D4, and E4 are major mediators of allergic bronchoconstriction in man.

Topics: Allergens; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchial Spasm; Histamine; Humans; Leukotriene E4; Lung; SRS-A

Topics: Animals; Arachidonic Acids; Bronchial Spasm; Guinea Pigs; Histamine; In Vitro Techniques; Indomethacin; Leukotriene E4; Lung; Male; Meclofenamic Acid; Muscle, Smooth; Radioimmunoassay; SRS-A; Trachea