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

被引:112
作者
Krishna, MT
Chauhan, A
Little, L
Sampson, K
Hawksworth, R
Mant, T
Djukanovic, R
Lee, T
Holgate, S
机构
[1] Univ Southampton, Southampton Gen Hosp, RCMB Div, Southampton SO16 6YD, Hants, England
[2] Guys Drug Res Unit, London, England
[3] Guys Hosp, GKT Sch Med, Dept Resp Med & Allergy, London, England
关键词
APC; 366; late asthmatic response; tryptase; asthma; mast cell; airway inflammation; bronchial hyperresponsiveness; early asthmatic response;
D O I
10.1067/mai.2001.115631
中图分类号
R392 [医学免疫学];
学科分类号
100102 ;
摘要
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 FEV1 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.
引用
收藏
页码:1039 / 1045
页数:7
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