Boot Johan D, de Haas Sanne, Tarasevych Svetlana, Roy Christine, Wang Lin, Amin Dilip, Cohen Judith, Sterk Peter J, Miller Barry, Paccaly Anne, Burggraaf Jacobus, Cohen Adam F, Diamant Zuzana
Centre for Human Drug Research, Zernikedreef 10 2333 CL, Leiden, The Netherlands.
Am J Respir Crit Care Med. 2007 Mar 1;175(5):450-7. doi: 10.1164/rccm.200608-1186OC. Epub 2006 Dec 14.
The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma.
We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies.
The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9.
AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883.
Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.
速激肽P物质和神经激肽A（NKA）与哮喘的病理生理学有关。
在两项双盲、安慰剂对照的交叉研究中，我们测试了速激肽NK(1)/NK(2)受体拮抗剂AVE5883在哮喘患者中的安全性、耐受性以及药理和生物学疗效。
在20例哮喘患者中，测试了单次吸入剂量（4.8毫克）的AVE5883对吸入NKA的药理疗效。随后，我们在一项多剂量试验（每天3次，每次4.8毫克，共9天）中，研究了该药理有效剂量对12例对吸入屋尘螨有双重反应的哮喘患者吸入变应原的生物学疗效。在第8天进行变应原激发试验，并通过第1秒用力呼气量（FEV(1)）测量气道反应直至变应原激发后9小时。在第1、7和9天检测呼出一氧化氮（NO）、使FEV(1)下降20%的溴化乙酰甲胆碱激发浓度以及诱导痰。
AVE5883有不良味道，一些受试者出现短暂支气管痉挛。单次吸入剂量使对NKA的剂量反应向右移动1.2个加倍剂量。多剂量AVE5883预处理增强了变应原诱导的早期和晚期气道反应。在安慰剂和AVE5883之间，变应原诱导的呼出NO变化、使FEV(1)下降20%的溴化乙酰甲胆碱激发浓度以及痰液细胞分类均无显著差异。
尽管已证明AVE5883对吸入NKA具有药理活性，但多剂量AVE5883增加了变应原诱导的气道反应，而不影响气道高反应性和气道炎症标志物。我们的数据对神经源性炎症在哮喘中的重要作用提出了质疑，因此也对双重速激肽拮抗剂的治疗潜力提出了质疑。
