Original Articles: Mechanisms Of Allergy
Inhibition of mast cell tryptase by inhaled APC 366 attenuates allergen-induced late-phase airway obstruction in asthma,☆☆

https://doi.org/10.1067/mai.2001.115631Get rights and content

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 FEV1 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.)

Section snippets

Study design

In this randomized, double-blinded, placebo-controlled, 2-period crossover study, subjects were randomized to receive either APC 366 followed by placebo or vice versa. During each of the 2 treatment periods, every subject received the treatment 3 times per day at intervals of 6 hours for 4 consecutive days and 1 time on the fifth day. On day 4, after the 10th dose of medication, every subject underwent allergen challenge followed by repeated spirometry to document an EAR and an LAR. On day 5,

Results

Allergen provocation caused both early- and late-phase falls in FEV1 after both active and placebo treatments (Fig 1).

. Effect of APC 366 and placebo on allergen-induced dual asthmatic responses. Significant differences (P = .012) were seen for AUC (for LAR) between APC 366 and placebo. In addition, comparison of mean percentage change in FEV1 from baseline during LAR at respective time points between the 2 study days showed significant differences at 6, 7, and 9 hours, as shown by asterisk (P <

Discussion

This study has highlighted the contribution of mast cell tryptase to late-phase allergic responses in asthmatics after challenge with inhaled allergen. Short-term administration (by inhalation) of APC 366, a selective tryptase inhibitor, significantly attenuated the LAR by 33% and had a significant effect on the mean maximum fall in FEV1 during the LAR. However, no significant effects were demonstrable on the allergen-induced EAR and BHR. These findings suggest that mast cell tryptase, through

Acknowledgements

We express our thanks to all Clinical Research Fellows in Southampton who provided night medical cover during the study; to the research nurses for their help with patient care, drug administration, and challenges at both centers; to F. Anderson and Dr Dik Ng for help with administration; and to all of the patients without whose participation this study would not have been possible.

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    This study was sponsored by Axys Pharmaceutical Corporation, San Francisco, Calif.

    ☆☆

    Reprint requests: Dr M. T. Krishna, Medical Specialties (RCMB Division), Mail Point 810, Level D, Centre Block, Southampton General Hospital, Tremona Road, Southampton S016 6YD, United Kingdom.

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