Reid David W, Misso Neil L, Aggarwal Shashi, Thompson Philip J, Johns David P, Walters E Haydn
Respiratory Research Group, Menzies Research Institute, University of Tasmania Hobart, Tasmania, Australia.
J Negat Results Biomed. 2008 May 19;7:3. doi: 10.1186/1477-5751-7-3.
The potential for tolerance to develop to zafirlukast, a cysteinyl leukotriene (CysLT) receptor antagonist (LRA) in persistent asthma, has not been specifically examined.
To look for any evidence of tolerance and potential for short-term clinical worsening on LRA withdrawal. Outcome measures included changes in; airway hyperresponsiveness to inhaled methacholine (PD20FEV1), daily symptoms and peak expiratory flows (PEF), sputum and blood cell profiles, sputum CysLT and prostaglandin (PG)E2 and exhaled nitric oxide (eNO) levels.
A double blind, placebo-controlled study of zafirlukast, 20 mg twice daily over 12 weeks in 21 asthmatics taking beta2-agonists only (Group I), and 24 subjects treated with ICS (Group II).
In Group I, zafirlukast significantly improved morning PEF and FEV1compared to placebo (p < 0.01), and reduced morning waking with asthma from baseline after two weeks (p < 0.05). Similarly in Group II, FEV1 improved compared to placebo (p < 0.05), and there were early within-treatment group improvements in morning PEF, beta2-agonist use and asthma severity scores (p < 0.05). However, most improvements with zafirlukast in Group I and to a lesser extent in Group II deteriorated toward baseline values over 12 weeks. In both groups, one week following zafirlukast withdrawal there were significant deteriorations in morning and evening PEFs and FEV1 compared with placebo (p < or = 0.05) and increased nocturnal awakenings in Group II (p < 0.05). There were no changes in PD20FEV1, sputum CysLT concentrations or exhaled nitric oxide (eNO) levels. However, blood neutrophils significantly increased in both groups following zafirlukast withdrawal compared to placebo (p = 0.007).
Tolerance appears to develop to zafirlukast and there is rebound clinical deterioration on drug withdrawal, accompanied by a blood neutrophilia.
在持续性哮喘中，对半胱氨酰白三烯（CysLT）受体拮抗剂（LRA）扎鲁司特产生耐受性的可能性尚未得到专门研究。
寻找耐受性的证据以及停用LRA后短期临床恶化的可能性。观察指标包括：对吸入乙酰甲胆碱的气道高反应性（PD20FEV1）、每日症状和呼气峰值流速（PEF）、痰液和血细胞谱、痰液CysLT和前列腺素（PG）E2以及呼出一氧化氮（eNO）水平的变化。
一项双盲、安慰剂对照研究，对21名仅服用β2激动剂的哮喘患者（第一组）和24名接受吸入性糖皮质激素（ICS）治疗的受试者（第二组），每日两次服用20 mg扎鲁司特，为期12周。
在第一组中，与安慰剂相比，扎鲁司特显著改善了晨间PEF和FEV1（p < 0.01），并在两周后使晨间哮喘发作次数从基线水平减少（p < 0.05）。同样，在第二组中，与安慰剂相比FEV1有所改善（p < 0.05），并且在治疗组内晨间PEF、β2激动剂使用情况和哮喘严重程度评分在早期有所改善（p < 0.05）。然而，第一组中扎鲁司特带来的大多数改善以及第二组中程度较轻的改善在12周内都向基线值恶化。在两组中，停用扎鲁司特一周后，与安慰剂相比，晨间和夜间PEF以及FEV1均有显著恶化（p ≤ 0.05），并且第二组夜间觉醒次数增加（p < 0.05）。PD20FEV1、痰液CysLT浓度或呼出一氧化氮（eNO）水平没有变化。然而，与安慰剂相比，两组在停用扎鲁司特后血液中性粒细胞均显著增加（p = 0.007）。
似乎会对扎鲁司特产生耐受性，并且停药后临床症状会出现反弹恶化，同时伴有血液中性粒细胞增多。
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