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

Summary 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.