Effects of a reversible β-tryptase and trypsin inhibitor (RWJ-58643) on nasal allergic responses


Dr Trevor T. Hansel, NHLI Clinical Studies Unit, Royal Brompton Hospital, Fulham Road, London SW3 6HP, UK.
E-mail: t.hansel@imperial.ac.uk


Background β-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.

Objectives 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 μg) or matched placebo given 30 min before NAC in a double-blind, randomized crossover design. A single dose of 200 μg 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 μg) and budesonide (200 μg) significantly reduced symptoms, eosinophils and levels of IL-5 following NAC. However, higher doses of RWJ-58643 (300 and 600 μg) caused a late eosinophilia and preceding increases in IL-5 compared with placebo.

Conclusions This study suggests that combined β-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.