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Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma

2001; Elsevier BV; Volume: 107; Issue: 6 Linguagem: Inglês

10.1067/mai.2001.115631

1097-6825

Mamidipudi Thirumala Krishna, Anoop Chauhan, Louise Little, K Sampson, Richard J. Hawksworth, Tim Mant, Ratko Djukanović, TH Lee, Stephen T. Holgate,

Allergic Rhinitis and Sensitization

Abstract Background: APC 366, a selective inhibitor of mast cell tryptase, has been shown to inhibit antigen-induced early asthmatic response (EAR), late asthmatic response (LAR), and bronchial hyperresponsiveness (BHR) in a sheep model of allergic asthma. Objective: The purpose of this study was to investigate the effects of APC 366 on antigen-induced EAR, LAR, and BHR in mild atopic asthmatics not on any anti-inflammatory therapy. Methods: Sixteen mild atopic asthmatics, each with a demonstrable antigen-induced EAR, LAR, and BHR to histamine, were recruited into this randomized, double-blinded, crossover study. APC 366 (5 mg)/placebo was administered by aerosol inhalation 3 times per day on treatment days 1 through 4. Allergen challenge was carried out on day 4. Histamine challenge was performed the following morning, 1 hour after final dosing. Results: Subjects were shown to have a significantly smaller overall mean area under the curve for the LAR ( P = .012) and mean maximum fall in FEV 1 for the LAR ( P = .007) after pretreatment with APC 366 in comparison with placebo. No significant effects on BHR were demonstrable. Although the EAR was reduced by 18% after treatment with APC 366 in comparison with placebo, this was not statistically significant. Conclusion: Short-term repeated administration of APC 366 significantly reduced the magnitude of antigen-induced LAR in atopic asthmatics, which supports the role of mast cell tryptase in the pathophysiology of the LAR. (J Allergy Clin Immunol 2001;107:1039-45.)