Protective effect of H1 and CysLT1 antagonists on allergen induced airway responses in atopic asthma
Davis, Beth E.
Background The mechanism by which allergies trigger asthma occurs through the interaction of antigen, IgE and the FcεR1 receptor on mast cells resulting in the release of mediators that exert their effects on various surrounding tissues causing bronchoconstriction, plasma exudation and mucus hypersecretion. The response is usually maximal within 30 minutes and resolves spontaneously within two hours. At least half of the individuals who exhibit this so called “early response” also manifest a “late response” which is a subsequent episode of bronchoconstriction that is usually maximal around six hours following exposure and involves airway inflammation. Montelukast has proven efficacious in the management of asthma and desloratadine is effective in the treatment of allergic rhinitis and chronic idiopathic urticaria. Since the early response involves the actions of multiple mediators, including histamine and the leukotrienes, the question of whether concurrent mediator blockade would be superior to either agent alone was raised. Additionally, the recent evidence supporting anti-inflammatory activity for these agents suggested potential efficacy against the late airway response. Methods Two double-blind, randomized, placebo-controlled, 4-way crossover allergen inhalation challenge investigations were conducted in twenty (10 per investigation) mild atopic asthmatics. The early response investigation involved the administration of either 5 mg desloratadine, 10 mg montelukast, the combination , or placebo (Vitamin B1) at 26 hours and 2 hours prior to allergen inhalation. The late response investigation involved single dose administration of each agent, alone or in combination, 2 hours prior to allergen inhalation. Measurements of changes in airway responsiveness and inflammation were also conducted. Results The early response was significantly inhibited by montelukast and the combination. Desloratadine did not differ from placebo. The late response was significantly decreased by desloratadine and montelukast and completely blocked with the combination. Desloratadine decreased sputum eosinophils at 7 hours, montelukast at 24 hours, and the combination at both time points. Airway responsiveness to methacholine trended lower with montelukast and the combination. Montelukast was the only treatment to significantly decrease exhaled nitric oxide levels. Conclusion The combination of desloratadine and montelukast provides inhibition that is superior to both monotherapies on the early and the late airway responses to inhaled allergen in people with mild atopic asthma.
DegreeDoctor of Philosophy (Ph.D.)
SupervisorCockcroft, Donald W.
CommitteeRichardson, Steve; Marciniuk, Darcy D.; Gopalakrishnan, Venkat; Yu, Peter; Hickie, Robert