Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics
Benefits from adding the 5-lipoxygenase inhibitor zileuton to conventional therapy in aspirin-intolerant asthmatics
复制标题
DOI：
10.1164/ajrccm.157.4.9707089
复制
发表时间：
1998-04-01
影响因子：
24.7
通讯作者：
Dahlén, SE
中科院分区：
文献类型：
--
作者：
Dahlén, B;Nizankowska, E;Dahlén, SE
从支气管激发研究和抑制白三烯 (LT) 药物的急性作用调查中，我们得出这样的假设：白三烯是阿司匹林不耐受哮喘 (AIA) 气道阻塞和其他症状的重要介质。然而，尚未表明 AIA 受试者对白三烯抑制剂的临床治疗是否有良好反应。因此，在一项双盲安慰剂对照交叉研究中，我们检查了 40 名具有明确特征的 AIA 患者接受白三烯途径抑制剂齐留通（600 mg，每天四次）治疗 6 周的效果。该治疗是在现有疗法的基础上添加的，其中包括除一名患者外的所有患者均使用中至高剂量吸入（平均每日剂量 1,030 微克倍氯米松或布地奈德）或口服糖皮质激素（4 至 25 毫克/天）。除了治疗基线之外，添加安慰剂没有显着影响，表明他们的哮喘保持相对稳定。然而，齐留通治疗后肺功能出现急性和慢性改善，表现为与安慰剂相比，FEV1 较基线增加，以及与安慰剂相比，齐留通治疗的早晚峰值呼气流速 (PEFR) 值更高。尽管齐留通救援支气管扩张剂的使用较少，但仍出现了改善。齐留通还可以减轻鼻功能障碍，这是 AIA 的主要症状之一。在齐留通治疗期间，嗅觉显着恢复，鼻漏减少，鼻塞减少，鼻吸气流量增加。齐留通可小幅但明显地降低支气管对组胺的高反应性，并抑制阿司匹林引起的支气管收缩。齐留通抑制 LTE4 的尿排泄，但不改变气道对吸入 LTD4 的反应性，支持齐留通特异性抑制白三烯生物合成。研究结果表明，白三烯是 AIA 中持续性气道阻塞和慢性鼻功能障碍的重要介质。该研究还表明，与单独使用中到高剂量的糖皮质激素治疗相比，添加白三烯途径抑制剂（例如齐留通）可能会更好地控制哮喘。
From bronchoprovocation studies and investigations of the acute effects of drugs that inhibit leukotrienes (LT), the hypothesis has emerged that leukotrienes are important mediators of airway obstruction and other symptoms in aspirin-intolerant asthma (AIA). However, it has yet not been shown if subjects with AIA respond favorably to clinical treatment with leukotriene inhibitors. Therefore, in a double-blind placebo-controlled crossover study, we examined the effects of 6 wk of treatment with the leukotriene-pathway inhibitor zileuton (600 mg, four times daily) in 40 patients with well-characterized AIA. The treatment was added to existing therapy, which included medium to high doses of inhaled (average daily dose 1,030 mu g of beclomethasone or budesonide) or oral glucocorticosteroids (4 to 25 mg/d) for all but one of the patients. On top of this treated baseline, there were no significant effects of adding placebo, indicating that their asthma was kept relatively stable. However, there was an acute and chronic improvement in pulmonary function after treatment with zileuton, expressed both as increased FEV1 from baseline compared with placebo, and higher morning and evening peak expiratory flow rate (PEFR) values on zileuton treatment compared with placebo. The improvements occurred despite lower use of rescue bronchodilator with zileuton. Zileuton also diminished nasal dysfunction, which is one of the cardinal signs of AIA. There was a remarkable return of smell, less rhinorrhea, and a trend for less stuffiness and higher nasal inspiratory flow during treatment with zileuton. Zileuton caused a small but distinct reduction of bronchial hyperresponsiveness to histamine and inhibited aspirin-induced bronchoconstriction. Zileuton inhibited urinary excretion of LTE4 but did not change airway reactivity to inhaled LTD4, supporting that zileuton specifically inhibited leukotriene biosynthesis. The findings indicate that leukotrienes are important mediators of persistent airway obstruction and chronic nasal dysfunction in AIA. The study also suggests that addition of a leukotriene pathway inhibitor such as zileuton may bring about greater control of asthma than what is achieved by treatment with medium to high doses of glucocorticosteroids alone.