Smith L J, Hanby L A, Lavins B J, Simonson S G
Northwestern University, Chicago, Illinois, USA.
Ann Allergy Asthma Immunol. 1998 Jul;81(1):43-9. doi: 10.1016/S1081-1206(10)63108-0.
Previous studies demonstrated that leukotriene receptor antagonists (LTRAs) are effective in reducing asthma symptoms and the airway response to inhaled leukotriene D4 (LTD4) in asthmatic patients receiving inhaled beta2-agonists alone.
To investigate the efficacy of a single 20-mg dose of the oral LTRA zafirlukast in reducing the airway response to inhaled LTD4 in mild-to-moderate asthmatic patients receiving inhaled beta2-agonists and inhaled corticosteroids (ICS).
In this double-blind, crossover trial, six patients on maintenance ICS (median dose 800 microg/day; range 336 to 1600 microg/day), who had a 20% decrease in FEV1 following inhalation of a maximal concentration of 50 microg/mL LTD4, received either zafirlukast or placebo on each of two study days. Two hours after dosing, patients underwent bronchoprovocation challenges with increasing concentrations of LTD4 (0.1 to 1000 microg/mL) at 10-minute intervals until either the patient's FEV1 decreased by 20% or the maximum concentration of LTD4 was given. Spirometric tests were done just before (baseline) and throughout the challenge phase until the patient's FEV1 returned to within 5% of baseline. Blood samples were collected two hours after dosing to determine plasma concentrations of zafirlukast.
Compared with placebo, zafirlukast produced a 1.82-unit increase in logPC20FEV1 and a 1.88-unit increase in logPD20FEV1, representing a 66-fold higher concentration and a 76-fold higher dose of LTD4, respectively, to produce a 20% decrease in FEV1 (P < .001). Mean time to recovery after challenge was 36.7 versus 51.7 minutes when patients received zafirlukast and placebo, respectively. No correlation between clinical effects and plasma drug levels was observed.
This trial demonstrated that asthmatic patients on maintenance ICS can respond to exogenously administered LTD4 and that zafirlukast reduced the airway response to LTD4 in these patients.
先前的研究表明，白三烯受体拮抗剂（LTRAs）可有效减轻哮喘症状，并降低仅接受吸入β2受体激动剂治疗的哮喘患者对吸入白三烯D4（LTD4）的气道反应。
研究口服20mg剂量的LTRA扎鲁司特对接受吸入β2受体激动剂和吸入性糖皮质激素（ICS）治疗的轻至中度哮喘患者气道对吸入LTD4反应的影响。
在这项双盲、交叉试验中，6名接受ICS维持治疗（中位剂量800μg/天；范围336至1600μg/天）的患者，在吸入最大浓度为50μg/mL的LTD4后FEV1下降20%，在两个研究日分别接受扎鲁司特或安慰剂治疗。给药2小时后，患者每隔10分钟接受递增浓度（0.1至1000μg/mL）的LTD4支气管激发试验，直至患者的FEV1下降20%或给予LTD4的最大浓度。在激发试验前（基线）及整个激发阶段进行肺功能测试，直至患者的FEV1恢复至基线的5%以内。给药2小时后采集血样以测定扎鲁司特的血浆浓度。
与安慰剂相比，扎鲁司特使logPC20FEV1增加1.82个单位，logPD20FEV1增加1.88个单位，分别代表使FEV1下降20%所需的LTD4浓度高66倍、剂量高76倍（P <.001）。接受扎鲁司特和安慰剂治疗的患者激发试验后的平均恢复时间分别为36.7分钟和51.7分钟。未观察到临床疗效与血浆药物水平之间的相关性。
该试验表明，接受ICS维持治疗的哮喘患者对外源性给予的LTD4有反应，且扎鲁司特可降低这些患者对LTD4的气道反应。
