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

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.

• Authors: M T Krishna, A Chauhan, L Little, K Sampson, R Hawksworth, T Mant, R Djukanovic, T Lee, S Holgate
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 107 Issue 6 Pg. 1039-45 (Jun 2001) ISSN: 0091-6749 [Print] United States
• PMID: 11398082 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Allergens
• Dipeptides
• N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide
• Serine Proteinase Inhibitors
• Serine Endopeptidases
• Tryptases

Topics

• Administration, Inhalation
• Adult
• Allergens (immunology)
• Asthma (drug therapy, enzymology, physiopathology)
• Bronchial Hyperreactivity (drug therapy, enzymology, physiopathology)
• Cross-Over Studies
• Dipeptides (administration & dosage, therapeutic use)
• Double-Blind Method
• Female
• Humans
• Male
• Mast Cells (enzymology, immunology)
• Serine Endopeptidases (metabolism)
• Serine Proteinase Inhibitors (administration & dosage, therapeutic use)
• Tryptases