Effects of a leukotriene receptor antagonist on exhaled leukotriene E4 and prostanoids in children with asthma

BACKGROUND: Leukotriene (LT) E(4) and 8-isoprostane concentrations are elevated in exhaled breath condensate in children with asthma. The effects of leukotriene receptor antagonists (LTRAs) on exhaled leukotriene and prostanoids in children with asthma are unknown. OBJECTIVE: (1) To study the effect of montelukast, a LTRA, on exhaled LTE(4), 8-isoprostane, and prostaglandin E(2) in children with asthma and atopic children; (2) to measure exhaled nitric oxide. METHODS: An open-label study with oral montelukast (5 mg once daily for 4 weeks) was undertaken in 17 atopic children with asthma and 16 atopic children without asthma. RESULTS: Pretreatment exhaled LTE(4) (P < .0001) and 8-isoprostane (P < .0001) values were higher in atopic children with asthma than in atopic children without asthma. In atopic children with asthma, montelukast reduced exhaled LTE(4) by 33% (P < .001), and this reduction was correlated with pretreatment LTE(4) values (r = -0.90; P = .0001). Posttreatment exhaled LTE(4) levels in children with asthma were higher than pretreatment LTE(4) values in atopic children without asthma (P < .004). Montelukast had no effect on exhaled LTE(4) in atopic children without asthma (P = .74), or on exhaled 8-isoprostane (atopic children with asthma, P = .94; atopic children without asthma, P = .55) and PGE(2) (atopic children with asthma, P = .56; atopic children without asthma, P = .93) in both groups. In atopic children with asthma, exhaled nitric oxide concentrations were reduced by 27% (P < .05) after montelukast. CONCLUSION: Leukotriene receptor antagonists decrease exhaled LTE(4) in atopic children with asthma. This reduction is dependent on baseline exhaled LTE(4) values. CLINICAL IMPLICATIONS: Measurement of exhaled LTE(4) might help identify children with asthma most likely to benefit from LTRAs.     

Urinary leukotriene E4 and 9α, 11β-prostaglandin F2 concentrations in mild, moderate and severe asthma, and in healthy subjects

BACKGROUND: Airway inflammation in asthma is associated with cysteinyl leukotriene and prostaglandin D(2) production. Measurement of urinary metabolites of these eicosanoids may be useful for monitoring asthma patients. However, the influence of asthma phenotype and severity on basal urinary excretion of these metabolites is unknown. OBJECTIVE: To compare urinary leukotriene (LT)E(4) and 9 alpha, 11 beta-prostaglandin (PG)F(2) concentrations in large groups of mild, moderate and severe asthmatic patients and healthy control subjects. METHODS: Asthma severity, treatment and aspirin sensitivity were assessed by questionnaire in 168 asthmatic patients. Basal LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations were measured in urine samples from these patients and from 175 control subjects using enzyme immunoassays. RESULTS: Urinary LTE(4) was correlated with 9 alpha, 11 beta-PGF(2) in both control subjects and asthmatic patients (P<0.002). Median LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations in patients with severe asthma were significantly reduced compared with mild asthmatic patients (P<0.05 and <0.001, respectively). Urinary 9 alpha, 11 beta-PGF(2), but not LTE(4) was lower in asthmatic patients using inhaled corticosteroids (P<0.02). Multiple regression analysis indicated that urinary 9 alpha, 11 beta-PGF(2) concentration was negatively correlated with asthma severity (P=0.003) and also with % predicted FEV(1) (forced expiratory volume in 1 s) (P=0.005). CONCLUSIONS: Baseline urinary LTE(4) and 9 alpha, 11 beta-PGF(2) concentrations are of limited value in discriminating between patients with different severities of asthma. Reduced urinary LTE(4) and 9 alpha, 11 beta-PGF(2) in patients with severe asthma suggest that direct or indirect effects of high-dose corticosteroid therapy combined with other factors associated with severe asthma may influence eicosanoid production. However, the negative association of urinary 9 alpha, 11 beta-PGF(2) with lung function suggests an adverse effect of chronic PGD(2) production on lung function in asthma, irrespective of severity.     

Urinary leukotriene E4

Measurement of urinary leukotriene E4 (LTE4) is a sensitive and noninvasive method of assaying total body cysteinyl leukotriene production and changes in cysteinyl leukotriene levels in specific microenvironments, such as the airway. Urinary LTE4 measurements can be used as sensitive biomarkers of exposure to asthma triggers, such as air pollution and viral infections. Recent studies suggest the potential of using urinary LTE4 concentrations as predictors of asthma control and markers of susceptibility to treatment with leukotriene receptor antagonists.     

Effect of montelukast on peripheral airflow obstruction in children with asthma.

BACKGROUND: Montelukast is a widely used controller agent in childhood asthma. It is modestly effective in reducing symptoms, decreasing the need for rescue albuterol, and improving forced expiratory volume in 1 second (FEV1). OBJECTIVE: To determine whether montelukast therapy improves peripheral airway obstruction as measured by lung volumes, air trapping, airway resistance (Raw), and specific conductance (Sgaw). METHODS: Twenty-one children aged 9 to 18 years with mild-to-moderate asthma were randomized into a double-blind, placebo-controlled study to receive montelukast (5 or 10 mg) or matching placebo daily for 8 weeks. Symptoms and albuterol use were recorded twice daily, and exhaled nitric oxide measurement, forced oscillometry, spirometry, and body box plethysmography (before and after beta-agonist use) were performed at randomization and at 2, 4, 6, and 8 weeks. Circulating eosinophil counts and serum eosinophil cationic protein (ECP) levels were obtained at randomization and at 8 weeks. RESULTS: Montelukast-treated patients had lower residual volume (P = .05), residual volume-total lung capacity ratio (P = .04), Raw (P = .02), Sgaw (P = .03), and serum ECP levels (P = .02) at 8 weeks compared with those treated with placebo. There was a trend toward reduced daytime and nighttime albuterol use, although the difference did not reach statistical significance. There were no significant differences in FEV1, FEV1-forced vital capacity ratio, exhaled nitric oxide levels, or daytime and nighttime symptom scores between the 2 groups. CONCLUSIONS: Montelukast therapy was associated with less air trapping, hyperinflation, and Raw and better Sgaw compared with placebo. Lower serum ECP levels, a surrogate measure of airway inflammation, were associated with improvements in lung function.     

Leukotriene (LT)‐receptor antagonist is more effective in asthmatic patients with a low baseline ratio of urinary LTE4 to 2,3‐dinor‐6‐keto‐prostaglandin (PG)F1α

BACKGROUND: To test the hypothesis that urinary levels of arachidonic acid metabolites may be a predicting factor of the effects of pranlukast, a selective leukotriene (LT) antagonist, on chronic adult asthma, we investigated the relationship between its clinical efficacy and urinary eicosanoid levels. METHODS: An open, multicenter trial was conducted involving 38 stable moderate and severe asthmatic patients (mean percent predicted FEV1 was 71%). All patients received pranlukast (225 mg twice daily) for 4 weeks after a 2-week run-in period. Urinary levels of LTE4, 11-dehydro-thromboxane (TX) B2, 2,3-dinor-6-keto-prostaglandin (PG) F1alpha, and creatinine were measured in 3-h urine collected on day 1 of the treatment. The responder was defined by an improvement of asthma symptom scores and peak expiratory flow rate (PEFR). RESULTS: One patient was excluded because of an adverse effect, nausea. Thirteen out of 37 subjects were responders and 24 were nonresponders. There were no significant differences in patients' backgrounds and urinary arachidonate levels between the two groups. The urinary LTE4 to 2,3-dinor-6-keto-PGF1alpha ratio in the responder was significantly lower (P=0.01) than that in the nonresponder. In all patients, a significant inverse correlation was revealed between the baseline urinary LTE4/2,3-dinor-6-keto-PGF1alpha ratio and the improvement of PEFR in the morning (r=-0.43, P=0.007). CONCLUSIONS: These data suggested that the urinary ratio of LTE4 to 2,3-dinor-6-keto-PGF1alpha might be one of the predictive markers of the clinical efficacy of this LT-receptor antagonist in asthmatic subjects.     

Leukotriene E(4)-induced persistent eosinophilia and airway obstruction are reversed by zafirlukast in patients with asthma

BACKGROUND: We have shown that inhalation of leukotriene (LT) E 4 contributes to specific recruitment of eosinophils to the airway mucosa in patients with asthma at the time of maximal decrease in airway-specific conductance. OBJECTIVE: We examined the ability of the cysteinyl LT 1 receptor antagonist, zafirlukast, to improve or prevent LT-mediated eosinophilia and airway obstruction in asthma. METHODS: Bronchial biopsies were taken and pulmonary function was measured before and 4 to 6 hours after the dose of inhaled LTE 4 causing a > or =15% fall in FEV 1 at baseline both at week 0 and after 6-week randomly assigned treatment with a high dose of zafirlukast, 80 mg twice daily. RESULTS: Leukotriene E 4 inhalation at week 0 doubled the number of eosinophils in the airway mucosa in 21 of 25 patients with mild asthma, increased the numbers of neutrophils and lymphocytes, and decreased FEV 1 (-17%). Zafirlukast reduced both airway eosinophilia and obstruction in FEV 1 , whereas with a double-blind placebo treatment, the effect of LTE 4 on both parameters persisted for 6 weeks. On repeat LTE 4 inhalation challenge after 6 weeks, zafirlukast treatment prevented further airway eosinophilia and decrease in FEV 1 seen in the placebo group. CONCLUSION: Persistent LTE 4 -induced airway eosinophilia may form the basis of an amplification mechanism for further eosinophil recruitment. Zafirlukast prevents LTE 4 -induced eosinophilic airway inflammation in mild asthma.     

Clinical significance of measurement of urinary leukotriene E4 in asthmatic patients without attack]

To evaluate clinical significance of measurement of urinary leukotriene E4 (LTE4) in asthmatic patients without attack, we measured urinary LTE4 in 68 asthmatic patients without attack and investigated its correlation with severity of asthma, % FEV1, bronchial hyperresponsiveness and peripheral eosinophil counts. Values of urinary LTE4 were significantly higher in the asthmatic patients (113.6 +/- 9.7 pg/mg.cr) than in healthy control subjects (67.8 +/- 4.7, n = 31), and the level of urinary LTE4 was in proportion to the severity of disease. Urinary LTE4 showed significant negative correlation with % FEV1 in atopic patients (Rs = -0.43, p = 0.025, n = 28), which was not recognized in non-atopic patients. Urinary LTE4 showed no significant correlation with bronchial hyperresponsiveness and peripheral eosinophil counts. Our findings suggested that basal LTE4 in urine reflected chronic airway inflammation of asthma.     

Effects of montelukast and beclomethasone on airway function and asthma control

BACKGROUND: Maintaining asthma control is a major objective of therapy. Traditionally, the effectiveness of asthma therapy has been judged primarily by its effect on airway function rather than on multiaspect asthma control. OBJECTIVE: An inhaled corticosteroid and a leukotriene receptor antagonist were compared to determine whether they provided equivalent effects, as judged by days of asthma control. METHODS: In a randomized, multicenter, double-blind, placebo-controlled, parallel-group study, asthmatic patients (n = 782) with FEV(1) percent predicted values of between 50% and 85% and a weekly average beta-agonist use of more than 2 puffs per day were randomized to receive montelukast (10 mg daily), beclomethasone (200 microg twice daily), or placebo treatment for 6 weeks in a double-dummy fashion. We examined the distribution of the primary end point: percentage of days of asthma control. Secondary end points included FEV(1), albuterol use, occurrence of an asthma attack, asthma flare-up, rescue corticosteroid use, sustained asthma control, and adverse experiences. RESULTS: The percentage of days of asthma control was almost identical between the montelukast and beclomethasone groups (98% overlap in the distribution). Montelukast was at least equal to beclomethasone, and both were greater than placebo on the basis of frequency of asthma attacks, asthma flare-ups, and rescue corticosteroid use. Beclomethasone had a greater effect than montelukast and both treatments were better than placebo at improving FEV(1). CONCLUSIONS: Montelukast was as effective as beclomethasone, as judged by indices of clinical control other than FEV(1). When evaluating the outcome of montelukast therapy, FEV(1) might underestimate clinical effectiveness.     

Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma

BACKGROUND: The A to C transversion in the promoter region of the gene encoding leukotriene C4 synthase (LTC4S) is proposed to be associated with the development of aspirin-induced asthma (AIA). OBJECTIVE: We investigated the frequency of the polymorphism in Japanese population and its association with clinical characteristics and cysteinyl leukotriene production. METHODS: Genotyping of LTC4S gene promoter was performed on 60 patients with AIA, 100 patients with aspirin-tolerant asthma (ATA), and 110 control subjects. We assessed the basal levels of urinary LTE4, the increment of urinary LTE4 on venous aspirin challenge, and LTC4S activity in peripheral blood eosinophils. RESULTS: The frequency of the variant C allele was significantly higher in patients with AIA (frequency of allele [q] = 0.192) than in patients with ATA (q = 0.110, P =.042). Variant C-allelic carriers experienced asthma at a significantly younger age (31.8 +/- 2.9 years [mean +/- SEM]) than wild-type A homozygotes (41.3 +/- 2.2 years, P =.007). Basal levels of LTE4 and the increment of urinary LTE4 on venous aspirin challenge did not show a difference between wild-type A homozygotes and variant C-allelic carriers. There was no relationship between the polymorphism and the LTC4S activity in eosinophils, although LTC4S activities were significantly higher in patients with AIA than in patients with ATA. CONCLUSION: Our findings reveal the lack of functionality of the polymorphism in the LTC4S gene, whereas this polymorphism might have some effect on the development of AIA, probably in linkage disequilibrium with another causatively important mutation.     

The challenge procedure influences the extent of allergen-induced urinary excretion of leukotriene E4

BACKGROUND: Cysteinyl-leukotrienes are central mediators in asthma and urinary leukotriene E4 (LTE4) is a reliable marker of their endogenous formation. OBJECTIVE: This study tested the hypothesis that the procedure used for allergen bronchoprovocation influences the bronchoconstrictor response and the amount of LTE4 excreted following allergen challenge. METHODS: Seven atopic asthmatic men underwent two allergen bronchoprovocations 4 weeks apart. The same total dose of allergen was given at both sessions, cumulatively on one occasion and as a single dose at the other session. Urine was collected in hourly samples before and after challenge and LTE4 was measured with previously validated methodology. RESULTS: The mean (+/- SE) drop in FEV1 was not significantly different between the cumulative (29 +/- 2.4%) and the single dose challenge (25 +/- 2.8%). There was a significant increase in post-challenge levels of urinary LTE4 after both sessions. The peak excretion of LTE4 occurred 1 h following the maximal drop in FEV1 for both challenges. However, the post-challenge increase in urinary LTE4 was significantly larger at the cumulative session. In fact, the net increase (post-challenge minus prechallenge) of urinary LTE4 was more than twofold higher after the cumulative session (AUC 0-3 h post-challenge: 46.7 +/- 8.2 vs 22.1 +/- 9.8, P < 0.05). CONCLUSION: The peak excretion of urinary LTE4 occurred within 2 h after the termination of either challenge but the magnitude of urinary excretion of LTE4 was larger when cumulative challenge was performed. The findings are important to consider when designing studies where allergen-induced urinary excretion of LTE4 is an outcome variable.     

Response to montelukast among subgroups of children aged 2 to 14 years with asthma

BACKGROUND: Determining who responds to asthma therapies, particularly leukotriene modifiers, continues to be explored. OBJECTIVE: We sought to identify patient characteristics predictive of response to montelukast. METHODS: We used data from 2 clinical trials in which children with asthma received either montelukast or placebo. Symptoms, beta-agonist use, and unanticipated health resource use caused by asthma were recorded in validated daily diaries for children 2 to 5 (n = 689) and 6 to 14 (n = 336) years old. We defined primary end points of days without asthma in 2- to 5-year-old patients (24 hours without symptoms, beta-agonist use, or asthma attack) and change in percent predicted FEV(1) in 6- to 14-year-old children. Asthma attack was defined by the use of rescue oral corticosteroids or by an unscheduled visit to a medical provider. Patients were grouped according to baseline characteristics, such as family history of asthma, personal history of allergy, frequency of asthma symptoms, eosinophilia, and concomitant use of inhaled corticosteroids or cromolyn. We examined the stratum-specific effects of montelukast on the percentage of days without asthma, change in percent predicted FEV(1), asthma attack, and a variety of secondary symptom and FEV(1) end points. RESULTS: We did not identify characteristics that predicted response to montelukast in either preschool or 6- to 14-year-old children. These findings were consistent across all symptom and FEV(1) outcomes. There was also no differential response to montelukast in either age group when asthma attack was the outcome. CONCLUSION: The patient characteristics studied do not appear to provide an indication of who will benefit most from treatment with montelukast.     

Relationship of exhaled nitric oxide to clinical and inflammatory markers of persistent asthma in children

BACKGROUND: Exhaled nitric oxide (eNO) is a noninvasive test that measures airway inflammation. Insufficient information is available concerning correlations between eNO and biologic, physiologic, and clinical characteristics of asthma in children currently not taking controller medications. OBJECTIVE: The aim of this study was to find correlations between eNO and other characteristics of children with mild to moderate asthma currently not taking medications. METHODS: Children aged 6 to 17 years with mild to moderate persistent asthma, taking only albuterol as needed, were characterized during 2 visits 1 week apart before being randomly assigned into a clinical trial. At the screening visit, online measurements of eNO, spirometry before and after bronchodilator, and biomarkers of peripheral blood eosinophils, serum eosinophil cationic protein, total serum IgE, and urinary leukotriene E4 were obtained. During a week characterization period before randomization, symptoms were recorded on a diary and peak expiratory flows were measured twice daily using an electronic device. At the randomization visit, eNO was repeated followed by a methacholine challenge and aeroallergen skin testing. Correlations and rank regression analyses between eNO and clinical characteristics, pulmonary function, and biomarkers were evaluated. RESULTS: eNO was significantly correlated with peripheral blood eosinophils (r =.51, P <.0001), IgE (r =.48, P <.0001), and serum eosinophil cationic protein (r =.31, P =.0003) but not with urinary leukotriene E4 (r =.16, P =.08). A moderate correlation was found between eNO and the number of positive aeroallergen skin tests (r =.45, P <.0001). eNO did not correlate with FEV1% predicted but was weakly correlated with FEV1/forced vital capacity (r = -.19, P =.032), bronchodilator response (r =.20, P =.023), and FEV1 PC20 methacholine (r = -.31, P =.0005). No significant correlations were found between eNO and clinical characteristics or morning or evening peak expiratory flow measurements. The rank regression analysis demonstrated that 5 variables accounted for an R square of.52 (eosinophils [P <.0001], IgE [P =.0023], age [P <.0001], months of inhaled corticosteroid use in the year before study entry [P =.01], and FEV1 PC20 [P =.0061]). CONCLUSIONS: These findings suggest that eNO provides information about the asthmatic state consistent with information from other markers of inflammation. It is a noninvasive technique that could be used in decisional management of children with asthma.     

Responsiveness to montelukast is associated with bronchial hyperresponsiveness and total immunoglobulin E but not polymorphisms in the leukotriene C4 synthase and cysteinyl leukotriene receptor 1 genes in Korean children with exercise-induced asthma (EIA)

BACKGROUND: As previous studies have shown that cysteinyl leukotrienes are important mediators in exercise-induced bronchoconstriction (EIB), and leukotriene receptor antagonists (LTRAs) such as montelukast have been shown to improve post-exercise bronchoconstrictor responses, we herein investigated whether clinical responsiveness to montelukast was associated with polymorphisms in the genes encoding leukotriene C4 synthase (LTC4S) and cysteinyl leukotriene receptor 1 (CysLTR1) and/or clinical parameters in Korean asthmatic children with EIB. METHODS: The study population consisted of 100 asthmatic children with EIB. The individuals studied were given exercise challenge tests before and after receiving montelukast (5 mg/day) for 8 weeks. Responders were defined as children showing>10% post-treatment improvement in forced expiratory volume in 1 s (FEV1). The LTC4S A(-444)C and CysLTR1 T(+927)C polymorphisms were genotyped by PCR-restriction fragment length polymorphism analysis. RESULTS: Of 100 enrolled children, 68 were classified as responders and 32 were classified as non-responders. No significant association was observed between montelukast responsiveness and LTC4S or CysLTR1 genotype, either alone or in combination. In contrast, montelukast-induced improvement in FEV(1) after exercise was correlated with higher pre-treatment PC20 (methacholine) values (r=0.210, P=0.036) and lower total IgE levels (r=-0.216, P=0.031). CONCLUSIONS: The LTC4S A(-444)C and CysLTR1 T(+927)C genotypes do not appear to be useful for predicting clinical responsiveness to montelukast, whereas bronchial hyperresponsiveness and total IgE appear to predict the degree of montelukast responsiveness in Korean asthmatic children with EIB.     

Once-daily ciclesonide improves lung function and is well tolerated by patients with mild-to-moderate persistent asthma

BACKGROUND: Inhaled corticosteroids are recommended as first-line therapy for persistent asthma. OBJECTIVE: We sought to assess the efficacy and safety of ciclesonide once daily in patients with mild-to-moderate persistent asthma. METHODS: An integrated analysis of 2 identical, multicenter, double-blind, randomized, parallel-group, placebo-controlled trials was conducted. Patients (n = 1015; aged > or =12 years) with mild-to-moderate asthma (FEV1 of 60% to 85% of predicted value) were randomized to ciclesonide 80 microg (CIC80), 160 microg (CIC160), or 320 microg (CIC320), once daily (exactuator doses) in the morning or placebo for 12 weeks. RESULTS: All ciclesonide groups showed significant improvements from baseline to week 12 in FEV1 compared with the placebo group (CIC80, 0.12 L [P = .0007]; CIC160, 0.13 L [P = .0004]; and CIC320, 0.14 L [P < .0001]). Likewise, FEV1 percent predicted, morning and evening peak expiratory flow, 24-hour asthma symptom score, daily albuterol use, and nighttime awakenings were significantly improved in all ciclesonide groups compared with the placebo group. Overall ciclesonide safety profile and rates of oropharyngeal adverse events for all groups were low and similar to those of the placebo group. Fewer ciclesonide-treated patients exhibited asthma-aggravated adverse events, and fewer ciclesonide-treated patients discontinued the study for any reason or because of a lack of efficacy compared with those in the placebo group. No suppression of hypothalamic-pituitary-adrenal-axis function (as assessed by means of 24-hour urinary cortisol levels corrected for creatinine and peak serum cortisol levels after stimulation with low-dose [1 microg] cosyntropin) was observed with any dose of ciclesonide. CONCLUSIONS: In this integrated analysis, ciclesonide once daily administered in the morning is effective and well tolerated.     

Tacrolimus reduces urinary excretion of leukotriene E(4) and inhibits aspirin-induced asthma to threshold dose of aspirin

BACKGROUND: The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE: We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS: Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS: In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION: The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.     

Comparative efficacy and anti-inflammatory profile of once-daily therapy with leukotriene antagonist or low-dose inhaled corticosteroid in patients with mild persistent asthma.

BACKGROUND: Current guidelines advocate the use of preventative anti-inflammatory therapy for mild persistent asthma. OBJECTIVE: We compared the efficacy and anti-inflammatory profiles of a leukotriene receptor antagonist and a low dose of inhaled corticosteroid in patients with mild persistent asthma. METHODS: Twenty-one adult patients with mild asthma received 4 weeks of either once-daily inhaled hydrofluoroalkane triamcinolone acetonide (450 microg/day ex-actuator dose) or oral montelukast (10 mg/day) in a randomized, placebo-controlled, single-blinded crossover study. Measurements were made before and after 2 and 4 weeks of each treatment. RESULTS: At the endpoint (after 4 weeks), triamcinolone and montelukast had improved the primary outcome (provocative dose of methacholine required to produce a 20% fall in FEV(1)) in comparison with placebo (P <.05), there being no difference between the treatments (1.09-fold; 95% CI 0.73 to 1.63). Triamcinolone was better than placebo or montelukast for effects on all other surrogate inflammatory markers (P <.05), including exhaled nitric oxide, blood eosinophils, serum eosinophil cationic protein, plasma intracellular circulating adhesion molecule 1, and plasma E-selectin. Both treatments improved (P <.05) morning and evening peak flow, nighttime beta2-agonist use, and symptoms in comparison with placebo, though triamcinolone was better than montelukast (P <.05) with regard to peak flow. Triamcinolone produced suppression (P <.05) of overnight urinary cortisol/creatinine and serum osteocalcin. CONCLUSION: Once-daily inhaled corticosteroid and leukotriene antagonist improved the primary outcome variable of bronchial hyperresponsiveness to a similar degree.     

Leukotriene D4 receptor blockade inhibits the immediate and late bronchoconstrictor responses to inhaled antigen in patients with asthma.

We have tested the hypothesis that leukotriene D4 (LTD4) receptor activation is involved in the development of antigen-induced bronchoconstriction. In two studies, patients with asthma received infusions of placebo or MK-571, a potent and specific LTD4 receptor antagonist (450 mg or 37.5 mg total dose, respectively). Antigen was inhaled during test-drug administration, and FEV1 was measured for 10 hours after challenge. Urine samples were collected for measurement of LTE4; plasma samples were drawn repeatedly for assay of MK-571. MK-571 infusions inhibited both immediate (0 to 3 hours) and late (3 to 10 hours) asthmatic responses. For the high MK-571 dose, the extent of inhibition, as assessed by the area under the curve of FEV1 versus time was 88% (p = 0.01) and 63% (p = 0.01), for immediate and late responses, respectively. The low MK-571 dose also inhibited both responses but to a minor extent. Mean urinary LTE4 excretion was elevated after antigen challenge and was unaffected by administration of the LTD4 receptor antagonist. The present study demonstrates that MK-571 inhibits antigen-induced asthma in a dose-related fashion; it had not effect on antigen-induced increases in urinary LTE4 excretions. The results suggest that LTD4 receptor activation plays an important role in antigen-induced asthma.     

Bronchial responsiveness to leukotriene D4 is resistant to inhaled fluticasone propionate

BACKGROUND: Inhaled corticosteroids are highly effective in asthma, reducing inflammatory markers and bronchial hyperresponsiveness. Cysteinyl-leukotrienes are major mediators of airway obstruction and display proinflammatory effects. Although the synthesis of leukotrienes is not affected by corticosteroid treatment, the influence of corticosteroids on the leukotriene pathway remains unresolved. OBJECTIVE: We investigated whether or not bronchial responsiveness to leukotriene (LT) D(4) is reduced by fluticasone propionate in subjects with asthma. METHODS: In 13 subjects with mild asthma, inhalation challenges with methacholine and LTD(4) were performed on consecutive days before and after 2 weeks of treatment with inhaled fluticasone 500 mug, twice daily, in a double-blind, randomized, placebo-controlled study with crossover design and 3 weeks of washout between periods. Exhaled nitric oxide was measured as a marker of corticosteroid responsiveness, and baseline urinary LTE(4) concentrations as an index of cysteinyl-leukotriene biosynthesis. RESULTS: Fluticasone produced a significant decrease in methacholine responsiveness, corresponding to 2.6-fold shift in the PD(20) FEV(1), and a significant reduction in the levels of exhaled nitric oxide. By contrast, bronchial responsiveness to LTD(4) in the same subjects was unaffected by fluticasone, as were urinary LTE(4) concentrations. CONCLUSION: These new data indicate that neither the biosynthesis nor the actions of leukotrienes appear to be sensitive to inhaled corticosteroids. CLINICAL IMPLICATIONS: The study provides mechanistic support for the additive therapeutic efficacy of antileukotrienes and inhaled corticosteroids in asthma.     

Exhaled breath condensate cysteinyl leukotrienes are increased in children with exercise-induced bronchoconstriction

BACKGROUND: It is recognized that airway inflammation has a central role in the pathogenesis of asthma, but how it relates to exercise-induced bronchoconstriction (EIB) is not completely understood. OBJECTIVE: The aim of our study was to investigate the relationship between EIB and baseline concentrations of cysteinyl leukotrienes (Cys-LTs) and other inflammatory markers in exhaled breath condensate (EBC). METHODS: EBC was collected, and the fraction of exhaled nitric oxide (FE NO ) was measured in a group of 19 asthmatic children, after which they performed a treadmill exercise test. Fourteen healthy children were enrolled as control subjects. RESULTS: The asthmatic children were divided into the EIB group (decrease in FEV 1 , > or =12%) and the non-EIB group. The EBC was analyzed for the presence of Cys-LTs, leukotriene B 4 , and ammonia. Asthmatic patients with EIB (mean FEV 1 decrease, 23% +/- 3%) had higher Cys-LT concentrations than either asthmatic patients without EIB or control subjects (42.2 pg/mL [median] vs 11.7 pg/mL and 5.8 pg/mL; P < .05 and P < .001, respectively). Ammonia concentrations were lower in both the EIB and non-EIB groups than in control subjects (253.2 microM and 334.6 microM vs 798.4 microM; P < .01 and P < .05, respectively). No difference in EBC leukotriene B 4 levels was found among the 3 groups. Both asthmatic groups had higher FE NO levels than control subjects ( P < .001). EBC Cys-LT ( P < .01; r = 0.7) and FE NO ( P < .05; r = 0.5) values both correlated significantly with the postexercise FEV 1 decrease. CONCLUSION: this study shows that EBC Cys-LT values are higher in asthmatic children with EIB and correlate with the decrease in FEV 1 after exercise. These findings suggest that the pathways of both Cys-LT and nitric oxide are involved in the pathogenesis of EIB.     

Comparison of inhaled salmeterol and oral zafirlukast in patients with asthma

BACKGROUND: Salmeterol, a long-acting beta2 -agonist, and zafirlukast, a leukotriene receptor antagonist, are both indicated for the treatment of asthma in adolescent and adult patients. OBJECTIVE: We sought to compare the effect of 4 weeks of treatment with inhaled salmeterol xinafoate versus oral zafirlukast in the treatment of persistent asthma. METHODS: This was a randomized, double-blind, double-dummy, parallel-group, multicenter clinical trial. Patients, over 80% of whom were on a concurrent inhaled corticosteroid regimen, were treated for 4 weeks with either inhaled salmeterol xinafoate 42 microgram twice daily administered by means of a metered-dose inhaler or oral zafirlukast 20 mg twice daily. The primary efficacy measure was morning peak expiratory flow (PEF); secondary efficacy measures included evening PEF, asthma symptom scores, supplemental albuterol use, nighttime awakenings, sleep symptoms, asthma exacerbations, and FEV1. RESULTS: Both inhaled salmeterol and oral zafirlukast resulted in within-group improvements from baseline in measures of pulmonary function, asthma symptoms, and supplemental albuterol use. Salmeterol treatment resulted in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements, including morning PEF (29.6 vs 13.0 L/min; P 相似文献