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

Krishna, Mamidipudi Thirumala, Chauhan, Anoop, Little, Louise, Sampson, Karen, Hawksworth, Richard, Mant, Tim, Djukanovic, Ratko, Lee, Tak and Holgate, Stephen (2001) Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma. Journal of Allergy and Clinical Immunology, 107 (6), 1039-1045. (doi:10.1067/mai.2001.115631).

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? 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.

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Contributors

Author: Ratko Djukanovic

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