Whelan Glenn J, Blake Kathryn, Kissoon Niranjan, Duckworth Laurie J, Wang Jainwei, Sylvester James E, Lima John J
Centers for Pediatric Pharmacology Research and Pharmacogenetics, Nemours Children's Clinic, Jacksonville, Florida 32207, USA.
Pediatr Pulmonol. 2003 Nov;36(5):413-20. doi: 10.1002/ppul.10385.
Leukotrienes (LT) mediate inflammation in asthma. The fraction of exhaled nitric oxide (FE(NO)) is thought to be a sensitive and reproducible method for assessing airway inflammation in asthmatics and the anti-inflammatory effects of drugs. A number of factors are known to contribute to intrapatient variation in FE(NO) which can confound interpretation. The aims of this study were to characterize the time-course of FE(NO), determine the effect of montelukast on the time-course of FE(NO), and evaluate the influence of the LTC(4) synthase A(-444)C polymorphism on montelukast-evoked changes in FE(NO). Following a 2-week run-in, 7 males and 5 females with asthma, 10-16 years old, received 5 or 10 mg of montelukast or an identical placebo at bedtime for 7 days in double-blind, crossover fashion, followed by a 7-day washout. FE(NO)was quantified every 30 min for 3 or 6 hr at baseline and on days 1, 2, 3, and 7 of treatment. A time-averaged value for FE(NO) was calculated (FE(NO)), and % changes in FE(NO) relative to baseline vs. time following placebo and montelukast were compared. The genotype of the A(-444)C polymorphism was determined by PCR and RFLP. FE(NO) varied markedly as a function of time in each patient. Time-averaged values of FE(NO) (FE(NO)) during placebo and montelukast treatment were similar. Montelukast significantly reduced the slope of the % change in FE(NO) vs. time curve in heterozygotes (n = 4), but not in A/A homozygotes (n = 8). These data suggest that heterozygotes respond better to montelukast compared to A/A homozygotes, at least with respect to changes in FE(NO). We conclude that assessment of inflammation or the anti-inflammatory effects of drugs in asthma based on single determinations of FE(NO) can be misleading. We further conclude that the A(-444)C polymorphism in the LTC(4) synthase gene probably contributes to interpatient variability in montelukast-evoked changes in FE(NO)* and warrants further study.
白三烯（LT）介导哮喘中的炎症反应。呼出一氧化氮分数（FE(NO)）被认为是评估哮喘患者气道炎症及药物抗炎效果的一种敏感且可重复的方法。已知多种因素会导致患者体内FE(NO)的变化，这可能会混淆对结果的解释。本研究的目的是描述FE(NO)的时间进程，确定孟鲁司特对FE(NO)时间进程的影响，并评估白三烯C4合成酶A(-444)C多态性对孟鲁司特引起的FE(NO)变化的影响。在进行为期2周的导入期后，7名年龄在10 - 16岁的男性哮喘患者和5名女性哮喘患者，以双盲、交叉方式在睡前接受5或10毫克孟鲁司特或相同的安慰剂，持续7天，随后是7天的洗脱期。在基线以及治疗的第1、2、3和7天，每30分钟对FE(NO)进行3或6小时的定量。计算FE(NO)的时间平均值（FE(NO)*），并比较安慰剂和孟鲁司特治疗后FE(NO)相对于基线的百分比变化与时间的关系。通过聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）确定A(-444)C多态性的基因型。每位患者的FE(NO)随时间有显著变化。安慰剂和孟鲁司特治疗期间FE(NO)的时间平均值（FE(NO)）相似。孟鲁司特显著降低了杂合子（n = 4）中FE(NO)*百分比变化与时间曲线的斜率，但在A/A纯合子（n = 8）中未降低。这些数据表明，至少就FE(NO)的变化而言，杂合子对孟鲁司特的反应比A/A纯合子更好。我们得出结论，基于单次FE(NO)测定评估哮喘中的炎症或药物的抗炎效果可能会产生误导。我们进一步得出结论，白三烯C4合成酶基因中的A(-444)C多态性可能导致患者间孟鲁司特引起的FE(NO)*变化的差异，值得进一步研究。
