The sulfidopeptide leukotrienes (LTC4, LTD4, and LTE4), 5-lypoxygenase products of arachidonic acid metabolism, are believed to play a role in the pathogenesis of asthma. The sulfidopeptide leukotrienes constrict human airway smooth muscle, increase secretion of bronchial mucus,2 and increase vascular permeability, resulting in mucosal edema. Because leukotrienes are generated in response to antigen challenges, it has been hypothesized that leukotriene receptor antagonists could modify the airway response to antigen broncho-provocation. One approach to validating this hypothesis is to examine the effects of leukotriene receptor antagonists in subjects with asthma who are challenged in a controlled setting.
ICI 204,219 is a potent, selective, orally active leukotriene antagonist currently undergoing evaluation in clinical trials. Allergen-challenge studies conducted with oral formulations of ICI 204,219 demonstrated inhibition of antigen-induced bronchoconstriction in subjects with asthma. In the present study, we sought to test the antagonism of antigen-induced bronchoconstriction by single 0.2-mg doses of three inhalation formulations of ICI 204,219 in subjects with asthma. In a previous study, two doses (0.1 and 0.2 mg) of an inhalation formulation of ICI 204,219 were equally effective in blocking bronchoconstriction in subjects with asthma. However, the combination of skin testing and screening bronchoprovocation used to demonstrate sensitivity to ragweed did not predict reproducible responsiveness in a standardized inhalation challenge with ragweed, suggesting that reproducible responses from two screening bronchoprovocations with ragweed and one challenge are needed to interpret data from allergen challenges. Therefore, as a means of ensuring the accuracy of the bronchoprovocation test results, we required all subjects participating in the study to have reproducible responses to allergen challenges before undergoing bronchoprovocation. buy allegra
Sixteen subjects with asthma, aged 20 to 43 years, were enrolled in this open-label, three-period, crossover study. Subjects who were selected for the study met the American Thoracic Society criteria for asthma, were nonsmokers, showed no clinical signs or symptoms of airway obstruction, had a forced expiratory volume in 1 s (FEV,) £65 percent of the predicted normal value, and demonstrated a reproducible sensitivity to bronchoprovocation with a standardized allergen (giant ragweed, Hollister-Stier, Spokane, Wash). The FEV, before the second screening challenge had to be within ± 5 percent of the first prediluent FEV, to show comparable baseline airway function. Reproducible sensitivity was defined as a 20 percent decrease in FEV, during both screening challenges at final allergen concentrations within two dilutions (a difference of no more than a factor of four). Subjects were excluded from the study if they had any acute illness or disease, a history of drug or alcohol abuse, an upper or a lower respiratory tract infection, or immunization with live attenuated influenza virus within 6 weeks of the study.