bay-x-7195 and Bronchial-Hyperreactivity

Leukotriene antagonists may inhibit bronchoconstrictive responses to a variety of stimuli.. To evaluate the efficacy and safety of a new CYS LTI antagonist, BAY x 7195, given as a single oral dose of 500 mg, in prevention of allergen-induced asthmatic responses.. This is a randomized, double-blind crossover, placebo-controlled study in mildly asthmatic non-smoking subjects (n = 10), aged 20 to 32 years (mean 24.8). Following an initial baseline allergen challenge, the subjects came back for two other challenges separated by at least a 2-week period, during which placebo or BAY x 7195 was administered two hours before allergen inhalation. Allergen challenges were preceded and followed by a methacholine inhalation test (24 hours before and 30 hours after).. For each subject, the same allergen and doses were used throughout the study. In the randomized (intent-to-treat) population (n = 10), after BAY x 7195, the allergen induced % fall in FEV1 was less than after placebo, with mean between-treatment differences of 31.8 +/- 18.0% during the early asthmatic response, P = .03, and of 54.4 +/- 23.2% during the late asthmatic response (P = .04). The allergen-induced increase in methacholine responsiveness was reduced after BAY x 7195, with a change of -0.45 doubling concentrations of methacholine as compared with -1.77 after placebo; however, the change did not achieve statistical significance, P = .08.. BAY x 7195 shows suppressive effects on allergen-induced responses, suggesting that it may be useful in the treatment of asthma.

Topics: Adult; Allergens; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Forced Expiratory Volume; Humans; Hydroxy Acids; Leukotriene Antagonists; Male

In guinea pigs, a marked increase in airway responsiveness to acetylcholine (Ach) was observed at 2 h after lipopolysaccharide (LPS) inhalation. To examine the mediators responsible for the airway hyperresponsiveness, the changes of peptide-leukotrienes (LTs), tumor necrosis factor (TNF), interleukin-1 (IL-1), histamine and 5-hydroxytryptamine (5-HT) levels in bronchoalveolar lavage fluid (BALF) were measured. Airway responsiveness to Ach reached a peak 2 h after LPS inhalation. The influx of neutrophil into BALF increased gradually and reached a peak 24 h after LPS inhalation. After the inhalation of LPS, LTD4 and TNF contents in BALF increased within the first 2 h after LPS inhalation. However, other mediators were not detected or increased 6 h after LPS inhalation. Aeroinhalation of LTD4 and murine recombinant TNF-alpha caused airway hyperresponsiveness in guinea pigs. In addition, a LTD4 antagonist, BAYx7195, and an inhibitor of TNF, pentoxifylline, inhibited the LPS-induced airway hyperresponsiveness. These results suggest that LTs and/or TNF play an important role in the onset of airway hyperresponsiveness in guinea pigs.

Topics: Acetylcholine; Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Escherichia coli; Guinea Pigs; Histamine; Hydroxy Acids; Interleukin-1; Leukotriene D4; Lipopolysaccharides; Male; Pentoxifylline; Recombinant Proteins; Serotonin; Tumor Necrosis Factor-alpha