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


CONCLUSIONS
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.
Krishna
M T
MT
University of Southampton, Southampton General Hospital, Mail Point 810, Tremona Road, Southampton SO16 6YD, UK.
Chauhan
A
A
Little
L
L
Sampson
K
K
Hawksworth
R
R
Mant
T
T
Djukanovic
R
R
Lee
T
T
Holgate
S
S
D000280:Administration, Inhalation; D000328:Adult; D000485:Allergens / Q000276:immunology*; D001249:Asthma / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D018592:Cross-Over Studies; D004151:Dipeptides / Q000008:administration & dosage* / Q000627:therapeutic use; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D053802:Tryptases
D000485:Allergens; D004151:Dipeptides; C094700:N-(1-hydroxy-2-naphthoyl)arginyl-prolinamide; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; D053802:Tryptases