Joos G F, Van Schoor J, Kips J C, Pauwels R A
Department of Respiratory Diseases, University Hospital, Ghent, Belgium.
Am J Respir Crit Care Med. 1996 Jun;153(6 Pt 1):1781-4. doi: 10.1164/ajrccm.153.6.8665034.
The tachykinins substance P and neurokinin A (NKA) are present in sensory airway nerves and have been implicated in the pathogenesis of asthma. FK224 is a cyclopeptide tachykinin antagonist previously shown to inhibit both tachykinin NK-1 and NK-2 receptor mediated airway responses in guinea pigs. Inhaled FK224 protected against bradykinin-induced bronchoconstriction and cough in asthmatics. In this study we examined the reproducibility of the NKA challenge and the effect of inhaled FK224 on NKA-induced bronchoconstriction in 10 patients with stable asthma. On Day 1 baseline lung function and PC20 methacholine were determined. On Days 2 and 3 increasing doubling concentrations of NKA (3.3 x 10(-9) to 1.0 x 10(-6) mol/ml) were administered via inhalation, with intervals of 10 min. On both days NKA caused a concentration-dependent decrease in specific airways conductance (sGaw) and FEV1. Mean +/- SEM, log PC35, sGaw NKA (mol/ml) was -6.61 +/- 0.10 on Day 2 and -6.57 +/- 0.14 on Day 3 (not significant [NS]). On Days 4 and 5 FK224 (4 mg) or placebo (P) was administered via metered-dose inhaler 30 min before NKA challenge in a double-blind, crossover manner. The study medication was well tolerated. FK224 had no significant effect on baseline lung function. After P and FK224, NKA caused a comparable concentration-dependent bronchoconstriction. The mean +/- SEM log PC35 sGaw NKA (mol/ml) was -6.04 +/- 0.18 after P and -6.19 +/- 0.23 after FK224 (NS). In conclusion, inhaled FK224 had no effect on baseline lung function and offered no protection against NKA-induced bronchoconstriction in a group of mild asthmatic patients.
速激肽P物质和神经激肽A（NKA）存在于气道感觉神经中，并与哮喘的发病机制有关。FK224是一种环肽速激肽拮抗剂，先前已证明其能抑制豚鼠中速激肽NK-1和NK-2受体介导的气道反应。吸入FK224可预防哮喘患者中缓激肽诱导的支气管收缩和咳嗽。在本研究中，我们检测了10例稳定期哮喘患者中NKA激发试验的可重复性以及吸入FK224对NKA诱导的支气管收缩的影响。在第1天测定基线肺功能和乙酰甲胆碱PC20。在第2天和第3天，通过吸入给予浓度加倍的递增NKA（3.3×10⁻⁹至1.0×10⁻⁶mol/ml），间隔10分钟。在这两天中，NKA均导致气道比传导率（sGaw）和第1秒用力呼气容积（FEV1）呈浓度依赖性下降。第2天的平均值±标准误，NKA使sGaw下降的log PC35（mol/ml）为-6.61±0.10，第3天为-6.57±0.14（无显著差异[NS]）。在第4天和第5天，在NKA激发试验前30分钟，以双盲、交叉方式通过定量吸入器给予FK224（4mg）或安慰剂（P）。研究药物耐受性良好。FK224对基线肺功能无显著影响。给予P和FK224后，NKA均引起了类似的浓度依赖性支气管收缩。给予P后，NKA使sGaw下降的平均±标准误log PC35（mol/ml）为-6.04±0.18，给予FK224后为-6.19±0.23（无显著差异）。总之，在一组轻度哮喘患者中，吸入FK224对基线肺功能无影响，且不能预防NKA诱导的支气管收缩。
