Effects of a reversible beta-tryptase and trypsin inhibitor (RWJ-58643) on nasal allergic responses.
BACKGROUND
beta-Tryptase is a multifunctional mast cell serine protease released during mast cell degranulation and tryptase/trypsin inhibitors are a novel potential therapeutic approach for allergic inflammatory diseases.


OBJECTIVE
This study was performed to assess the effects of RWJ-58643 on nasal symptoms, eosinophil influx, and cytokine and chemokine release following nasal allergen challenge (NAC).


METHODS
Male patients with grass pollen allergic rhinitis (n=16) out of season received single doses of RWJ-58643 (100, 300, 600 microg) or matched placebo given 30 min before NAC in a double-blind, randomized crossover design. A single dose of 200 microg budesonide was studied in an open-label extension phase. NAC was performed with Timothy grass pollen (ALK) via a nasal device, and nasal lavage was performed at times 0 (pre-drug, pre-allergen), 0.5 (30 min post-drug, pre-NAC) 1.5, 2.5, 4.5, 6.5, 8.5, and 24 h after drug administration. Nasal lavage mediators were analysed using a sensitive multiplexed bead immunoassay system.


RESULTS
Low-dose RWJ-58643 (100 microg) and budesonide (200 microg) significantly reduced symptoms, eosinophils and levels of IL-5 following NAC. However, higher doses of RWJ-58643 (300 and 600 microg) caused a late eosinophilia and preceding increases in IL-5 compared with placebo.


CONCLUSIONS
This study suggests that combined beta-tryptase and trypsin inhibition has therapeutic potential in allergic inflammation, however, this property is dose responsive and higher doses are ineffective and may cause eosinophilia.
Erin
E M
EM
Clinical Studies Unit, National Heart and Lung Institute (NHLI), Imperial College, London, UK.
Leaker
B R
BR
Zacharasiewicz
A
A
Higgins
L A
LA
Nicholson
G C
GC
Boyce
M J
MJ
de Boer
P
P
Jones
R C
RC
Durham
S R
SR
Barnes
P J
PJ
Hansel
T T
TT
D000281:Administration, Intranasal; D000328:Adult; D000485:Allergens / Q000276:immunology; D052160:Benzothiazoles; D019819:Budesonide / Q000008:administration & dosage / Q000276:immunology; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000032:analysis; D019742:Chemokines, CC / Q000032:analysis; D002631:Chemotactic Factors, Eosinophil / Q000276:immunology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004804:Eosinophils / Q000276:immunology; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology; D015848:Interleukin-5 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007958:Leukocyte Count; D008297:Male; D008407:Mast Cells / Q000276:immunology; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage / Q000276:immunology*; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology*; D012697:Serine Endopeptidases / Q000276:immunology*; D013844:Thiazoles / Q000008:administration & dosage / Q000276:immunology*; D014361:Trypsin Inhibitors / Q000008:administration & dosage / Q000276:immunology*; D053802:Tryptases; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
C477196:1-acetyl-N-(4-((aminoiminomethyl)amino)-1-(2-benzothiazolylcarbonyl)butyl)-4-hydroxy-2-pyrrolidinecarboxamide; D000485:Allergens; D052160:Benzothiazoles; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D018836:Inflammation Mediators; D015848:Interleukin-5; D016209:Interleukin-8; D011759:Pyrrolidines; D013844:Thiazoles; D014361:Trypsin Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019819:Budesonide; D012697:Serine Endopeptidases; D053802:Tryptases