The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics
The effect of the NK2 tachykinin receptor antagonist SR 48968 (saredutant) on neurokinin A-induced bronchoconstriction in asthmatics
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DOI：
10.1183/09031936.98.12010017
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发表时间：
1998-07-01
影响因子：
24.3
通讯作者：
Pauwels, RA
中科院分区：
文献类型：
--
作者：
Van Schoor, J;Joos, GF;Pauwels, RA
吸入神经激肽（NK）A可引起哮喘患者支气管收缩。在离体人气道中，NKA诱导的支气管收缩通过NK 2受体介导，并被SR 48968（一种强效和特异性的非肽类速激肽NK 2受体拮抗剂）抑制。在本研究中，在12例轻度哮喘患者中检查了经口给予SR 48968对NKA诱导的支气管收缩的影响。在筛选日和研究期间，增加NKA浓度（3.3 × 10（-9）至1.0 × 10（-6）mol.mL（-1））吸入，直至1秒用力呼气量（FEV 1）和比气道传导率（sGaw）分别降低至少20%和50%。在研究期间，以双盲、随机、交叉方式摄入100 mg SR 48968或匹配安慰剂，并在给药后1.5和24 h进行NKA激发。NKA的平均（SEM）log 10激发浓度导致FEV 1下降20%（PC 20 FEV 1）为-6.25 SR 48968后（0.20）和-6.75（0.17）安慰剂后（p= 0.05）; NKA的平均log 10激发浓度导致sGaw下降35%（PC 35 sGaw）为-7.02 SR 48968后（0.28）和-7.64（0.19）（p= 0.05），24 h时，平均log 10 PC 20 FEV 1为-6.21 SR 48968组为0.17，安慰剂组为-6.65（0.11）（p= 0.05）;平均log 10 PC 35 sGaw为-6.85 SR 48968后（0.23）和-7.17（0.15）安慰剂后由于每个SR 48968组中多达4名患者未达到PC 20 FEV 1和/或PC 35 sGaw，因此SR 48968与安慰剂之间的差异被低估。经口给予100 mg SR 48968可显著抑制哮喘患者中神经激肽A诱导的支气管收缩，这一发现构成了人类中选择性速激肽受体拮抗剂抑制感觉神经肽诱导的支气管收缩的第一个证据。
Inhalation of neurokinin (NK) A causes bronchoconstriction in patients with asthma. The NKA-induced bronchoconstriction in isolated human airways is mediated via the NK2 receptor and inhibited by SR 48968, a potent and specific nonpeptide tachykinin NK2 receptor antagonist. In the present study, the effect of orally administered SR 48968 on NKA-induced bronchoconstriction was examined in 12 mild asthmatics,On the screening day and during the study periods, increasing concentrations of NKA (3.3x10(-9) to 1.0x10(-6) mol.mL(-1)) were inhaled, until the forced expiratory volume in one second (FEV1) and specific airway conductance (sGaw) decreased by at least 20 and 50%, respectively. During the study periods, 100 mg SR 48968 or matched placebo was ingested in a double-blind, randomized, crossover fashion and NKA provocation was performed at 1.5 and 24 h after dosing.At 15 h, the mean (SEM) log10 provocative concentration of NKA causing a 20% fall in FEV1 (PC20 FEV1) was -6.25 (0.20) after SR 48968 and -6.75 (0.17) after placebo (p=0,05); the mean log10 provocative concentration of NKA causing a 35% fall in sGaw (PC35 sGaw) was -7.02 (0.28) after SR 48968 and -7.64 (0.19) after placebo (p=0,05),At 24 h, the mean log10 PC20 FEV1 was -6.21 (0.17) after SR 48968 and -6.65 (0,11) after placebo (p=0,05); the mean log10 PC35 sGaw was -6.85 (0.23) after SR 48968 and -7.17 (0.15) after placebo (nonsignificant).As PC20 FEV1 and/or PC35 sGaw were not reached in up to 4 patients per SR 48968 group, the differences between SR 48968 and placebo were underestimated.In conclusion, oral treatment with 100 mg SR 48968 caused a significant inhibition of neurokinin A-induced bronchoconstriction in asthmatics, This finding constitutes the first evidence of inhibition of sensory neuropeptide-induced bronchoconstriction by a selective tachykinin receptor antagonist in humans.