Effects of pranlukast, a leukotriene receptor antagonist, on airway inflammation in mild asthmatics.

To determine the anti-inflammatory actions of pranlukast, a cysteinyl leuklotriene receptor antagonist, we measured exhaled nitric oxide (NO) concentrations and eosinophil ratio in induced sputum of three groups of mild asthmatics (n = 30): treated with bronchodilators alone, with bronchodilators and inhaled steroid (beclomethasone dipropionate; 400 microg/day), and bronchodilators and pranlukast (450 mg/day). Pranlukast (450 mg/day) reduced the eosinophil ratio in the induced sputum significantly (p < 0.01) without a major effect on the concentration of exhaled NO. Pranlukast also increased values of peak expiratory flow significantly (p < 0.05). Pranlukast may be useful for mild asthmatics, in part through its ability to suppress eosinophilic airway infiltration.     

Clinical effects of long-term administration of pranlukast, a leukotriene receptor antagonist, on adult patients with bronchial asthma]

Eighty-one adult patients with bronchial asthma who suffered asthmatic episodes in spite of treatment with 400 mg/day of BDP were placed on pranlukast therapy for 4 weeks. Group I, which showed a 5% or greater increase in PEFR, continued oral pranlukast medication for an additional two years. Those patients who did not show an increase of 5% or greater in PEFR after 4 weeks of pranlukast therapy were instructed to continue the medication for another year. Group II, which exhibited a 5% or greater increase in PEFR after a one-year period continued medication for one more year. Medication was suspended for Group III, which failed to show improvement in PEFR after one year, and the group was placed under observation for the following year. Group I improved significantly in PEFR and exhibited a reduction in the frequency of b2 inhalation, the number of night visits to a medical facility, the amount of steroids inhaled, and the quantity of oral steroids given at regular intervals; and the Group I peripheral eosinophil count, serum ECP level, and FEV1.0 ameliorated. After one year, Group II also showed significant improvement in PEFR and a reduction in both the peripheral eosinophil count and the serum ECP level. This group's PEFR continued to improve after two years. One year after medication was suspended, Group III showed a significant increase in the number of night visits to a medical facility and a rise in the serum ECP level. These findings indicated the efficacy of pranlukast.     

Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model

Background

Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic–polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration.

Markers of airway inflammation and airway hyperresponsiveness in patients with well-controlled asthma.

In steroid-naive asthmatics, airway hyperresponsiveness correlates with noninvasive markers of airway inflammation. Whether this is also true in steroid-treated asthmatics, is unknown. In 31 stable asthmatics (mean age 45.4 yrs, range 22-69; 17 females) taking a median dose of 1,000 microg inhaled corticosteroids (ICS) per day (range 100-3,600 microg x day(-1)), airway responsiveness to the "direct" agent histamine and to the "indirect" agent mannitol, lung function (forced expiratory volume in one second (FEV1), forced vital capacity (FVC), peak expiratory flow (PEF)), exhaled nitric oxide (eNO), and number of inflammatory cells in induced sputum as a percentage of total cell count were measured. Of the 31 subjects, 16 were hyperresponsive to mannitol and 11 to histamine. The dose-response ratio (DRR: % fall in FEV1/cumulative dose) to both challenge tests was correlated (r=0.59, p=0.0004). However, DRR for histamine and DRR for mannitol were not related to basic lung function, eNO, per cent sputum eosinophils and ICS dose. In addition, NO was not related to basic lung function and per cent sputum eosinophils. In clinically well-controlled asthmatics taking inhaled corticosteroids, there is no relationship between markers of airway inflammation (such as exhaled nitric oxide and sputum eosinophils) and airway responsiveness to either direct (histamine) or indirect (mannitol) challenge. Airway hyperresponsiveness in clinically well-controlled asthmatics appears to be independent of eosinophilic airway inflammation.     

The role of cysteinyl leukotrienes in the pathogenesis of asthma: Clinical study of leukotriene antagonist pranlukast for 1 year in moderate and severe asthma

Clinical studies have shown that pranlukast (Ono Pharmaceutical Co., Osaka, Japan) is effective for mild and moderate asthma. However, it is not well known that pranlukast is also effective on moderate and severe persistent asthma in the long term. We studied the effect of pranlukast on moderate and severe asthmatics by evaluating the change of peak expiratory flow (PEF) and therapeutic scores for 1 year before and during pranlukast therapy. We gave pranlukast 225 mg twice daily orally to 25 patients who were receiving more than 400 micrograms/day beclomethasone inhalation and beta 2 stimulant inhalation with or without oral corticosteroid. Pranlukast increased PEF more than 10 L/min in 14 patients in the first 4 weeks. In these 14 patients, 10 patients continued to monitor PEF and kept asthma diaries for 1 year. We compared the data for 1 year before and during the pranlukast therapy. During the pranlukast therapy, PEF significantly increased, puffs of beta 2 stimulant inhalation significantly decreased. The incidence of oral corticosteroid rescue therapy reduced, and the mean daily dose of oral corticosteroid decreased; however, they were not statistically significant. During treatment with pranlukast, no side effect was observed. From these results, we suggest that pranlukast is effective for more than half of the moderate and severe persistent asthmatics, and that the effectiveness continues for more than 1 year.     

Effect of losartan, a type 1 angiotensin II receptor antagonist, on bronchial hyperresponsiveness to methacholine in patients with bronchial asthma

It is unclear whether angiotensin II receptors are involved in bronchial hyperresponsiveness in asthmatic patients. We examined the effect of losartan, a specific angiotensin II type 1 (AT1) receptor antagonist, on bronchial responsiveness to inhaled methacholine in eight patients with stable asthma. Bronchial responsiveness to methacholine, assessed as the concentration of methacholine producing a 20% fall in FEV(1) (PC(20)-FEV(1)) and a 35% fall in standardized partial expiratory flow at 40% of FVC (PC(35)-PEF(40)), was measured on two occasions 2 wk apart. Losartan (50 mg once a day) or a placebo was orally administered for 1 wk before methacholine provocation test in a double-blind, randomized, crossover fashion. Although the PC(20)-FEV(1) values after placebo (2.037 [geometric standard error of the mean, GSEM = 0.210] mg/ml) and losartan (2.098 [GSEM, 0.239] mg/ml) were identical (p = 0.840), the geometric mean PC(35)-PEF(40) values significantly (p = 0.034) increased from 0.258 (GSEM, 0.156) mg/ml with placebo to 0.456 (GSEM, 0.186) mg/ml with losartan. We conclude that AT1 receptors are involved in bronchial hyperresponsiveness in asthmatic patients. This is the first report demonstrating the involvement of AT1 receptors in bronchial asthma.     

Clinical effects of pranlukast, an oral leukotriene receptor antagonist, in mild-to-moderate asthma: a 4 week randomized multicentre controlled trial

OBJECTIVE: Leukotriene antagonists are increasingly used in asthma management. Pranlukast is a new, orally active, selective inhibitor of CysLt1 leukotriene receptor. The present clinical trial was performed to study the effect and safety of pranlukast in mild-to-moderate asthma. METHODOLOGY: A randomized, double-blind, placebo-controlled, parallel group study was performed in eight medical centres in Korea. Mild-to-moderate asthma patients who had been treated with beta2-agonists and/or inhaled corticosteroids were studied. The patients' symptoms were evaluated by asthma diary and twice-daily peak flow monitoring. RESULTS: Of the 206 patients enrolled, 197 were eligible for analysis. The pranlukast group (n = 98) showed statistically significant improvement in asthma symptoms, including asthma attack rate, daily living score, and morning and evening asthma scores. Pranlukast significantly reduced the consumption of beta2-agonist. Compared with the placebo group, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) were not significantly higher in the pranlukast group. Morning and evening peak expiratory flow (PEF) were significantly increased after pranlukast treatment at weeks 2 and 4 (380.8 +/- 10.1 L/min at baseline, 394.5 +/- 10.1 at week 2, 396.3 +/- 10.4 at week 4). There were no serious adverse reactions. CONCLUSION: Pranlukast, an oral leukotriene antagonist, was well tolerated and was effective for the management of mild-to-moderate asthma.     

The position of pranlukast, a cysteinyl leukotriene receptor antagonist, in the long-term treatment of asthma. 5-year follow-up study

BACKGROUND: Adverse effects, tachyphylaxis, and the position of pranlukast, a cysteinyl leukotriene receptor antagonist, in asthma treatment have not been fully established. OBJECTIVES AND METHODS: To address these questions, adverse effects and long-term efficacy of pranlukast were evaluated in 82 patients [28 patients with moderate asthma (group I), 27 with severe persistent asthma not on oral corticosteroid (OCS; group II) and 27 with severe persistent asthma on OCS (group III)] at 4 and 16 weeks. In the following, pranlukast was either withdrawn 1 year after the start of therapy, or if that was not possible due to reappearance of symptoms, the dose of OCS or inhaled corticosteroid (ICS) was reduced. The efficacy of pranlukast was evaluated during 5 years by peak expiratory flow rate (PEFR), and symptom and treatment scores. RESULTS: Adverse reactions appeared in 4 patients (4.9%; diarrhea, dizziness and leg edema). The mean improvement in PEFR on week 16 was 18.5 +/- 2.3, 18.8 +/- 3.2, and 15.2 +/- 3.8% in groups I-III, respectively (p < 0.01, for all groups). However, increases in PEFR in 29 of 72 patients (40.3%) were less than 15%. Pranlukast could not be withdrawn in 28 of 42 responders (66.7%), but their dose of ICS was reduced by 363 +/- 97 microg/day (group II) and that of OCS by 3.4 +/- 0.7 mg/day (group III). Tachyphylaxis was not recognized during the 5-year period. CONCLUSION: Pranlukast is safe when taken for up to 5 years, and is effective irrespective of asthma severity. In the majority of patients with persistent asthma, pranlukast may help to control the disease in the long term.     

Combination therapy with a long-acting beta-agonist and a leukotriene antagonist in moderate asthma

RATIONALE: Long-acting beta-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well. OBJECTIVE: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma. Methods and MEASUREMENTS: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure. MAIN RESULTS: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity. CONCLUSIONS: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.     

The effects of a specific tachykinin receptor antagonist FK-224 on ozone-induced airway hyperresponsiveness and inflammation

Abstract We have demonstrated previously that tachykinin depletion by capsaicin prevented the ozone-induced airway hyperresponsiveness and the bronchial wall oedema in guinea pigs. To further clarify the role of neurogenic inflammation in ozone-induced airway hyperresponsiveness, we investigated the effects of a specific tachykinin receptor antagonist (FK-224) in guinea pigs. Animals were anaesthetized, tracheostomized and mechanically ventilated. Total pulmonary resistance (R_L) was calculated from transpulmonary pressure and box flow in a plethysmograph. Airway responsiveness was assessed by determining the provocative concentration of histamine aerosol that increased R_L to twice the baseline value (PC₂₀₀). Animals were injected with either FK-224 (10 mg/kg, dissolved in 0.2 mL/kg DMSO) or vehicle (0.2 mL/kg DMSO) intravenously, then pre-ozone PC₂₀₀ was determined. Following this measurement, animals were exposed to 3 ppm ozone for 60 min. Immediately after exposure, the histamine dose response curve was evaluated again. Bronchoalveolar lavage (BAL) was performed in animals treated with FK-224 or vehicle. In animals treated with vehicle, ozone exposure caused significant decrease in PC₂₀₀ and moderate increase in neutrophils in BAL fluid. FK-224 pre-treatment significantly inhibited ozone-induced hyperresponsiveness. Neutrophils in BAL fluid did not significantly increase after ozone exposure in animals treated with FK-224. By contrast, the degree of epithelial desquamation did not differ significantly between the two groups. We conclude that neurogenic inflammation caused by tachykinin release may be responsible for ozone-induced bronchial hyperresponsiveness, and that tachykinins may play a role in the initiation of airway inflammation.     

Roles of hyperresponsiveness and airway inflammation in bronchial asthma

Bronchial hyperresponsiveness is one important feature of bronchial asthma, and evidence has been accumulated that airway inflammation contributes to the specific airway response in asthmatic patients. Increase in airway responsiveness following viral infection, exposure to allergen, ozone or chemical sensitizers supports the evidence for a link between hyperresponsiveness and airway inflammation. However, as only some respiratory tract infections induce an increase in hyperresponsiveness, and patients with chronic bronchitis and cystic fibrosis have less airway hyperresponsiveness than asthmatics, airway inflammation is considered to be only one of many factors contributing to the hyperresponsiveness of asthmatic airways.     

半胱氨酰白三烯受体拮抗剂对成人哮喘的临床疗效观察

目的 系统观察半胱氨酰白三烯（CysLTs）受体拮抗剂安可来在不同严重程度哮喘患者中的疗效及其安全性。方法 117例成人哮喘患者,其中轻度哮喘62例,中度哮喘34例,重度哮喘21例。口服安可来20mg,2次／d,持续服用4周。结果 轻、中、重度哮喘患者口服安可来后日间及夜间症状计分、液间憋醒次数、吸入β2－受体激动剂用量及肺功能指标包括FEV1（轻度患者除外）、PEFRam、PEFRpm均有显著改善,与安可来相关的可颖药物发生不良反应5例（4％）,症状轻微,无需特别处理。结论 安可来对各种严重程度哮喘均具有缓解哮喘症状及改善肺功能的作用,且具有服用方便、副作用少、耐受性好的优点。     

Montelukast, a leukotriene receptor antagonist, in combination with loratadine, a histamine receptor antagonist, in the treatment of chronic asthma

BACKGROUND: Montelukast sodium, a potent, oral, specific leukotriene-receptor antagonist, has demonstrated clinical efficacy in the treatment of chronic asthma. Loratadine, a selective histamine type 1 (H(1))-receptor antagonist, has demonstrated antiallergic properties. Leukotriene-receptor antagonists given concomitantly with H(1)-receptor antagonists have been shown to have additive effects in the prevention of bronchospasm in antigen-challenge models. OBJECTIVE: To determine whether montelukast plus loratadine provides improved efficacy to montelukast alone in the treatment of chronic asthma. METHODS: The efficacy of montelukast alone vs montelukast-loratadine was studied in a 10-week, multicenter, randomized, double-blind, 2 x 2 crossover study. After a 2-week placebo run-in period, patients received montelukast sodium (10 mg) plus loratadine (20 mg), or montelukast sodium (10 mg) plus placebo once daily for 2 weeks. After a 2-week placebo washout period, patients were crossed over to receive 2 weeks of the other active treatment regimen, followed by another 2-week placebo washout period. RESULTS: Montelukast given concomitantly with loratadine caused significant improvement in percentage of change from baseline in forced expiratory volume in 1 second (FEV(1)) compared with montelukast alone (13.86% vs 9.72%; P =.001). The average additional effect of loratadine (least square mean difference in percentage of change from baseline in FEV(1)) was 4.15% (95% confidence interval, 1.65%-6.65%). Key secondary end points (mean daily beta-agonist use, daytime and nighttime symptom scores, morning and evening peak expiratory flow rate, and the Patient Global Evaluation) all showed significant improvement with montelukast-loratadine (P<.05). CONCLUSION: Montelukast-loratadine significantly improved end points of asthma control during a 2-week treatment period.     

Effect of an NK1/NK2 receptor antagonist on airway responses and inflammation to allergen in asthma

RATIONALE: The tachykinins substance P and neurokinin A (NKA) are implicated in the pathophysiology of asthma. Objective: We tested the safety, tolerability, and pharmacologic and biological efficacy of a tachykinin NK(1)/NK(2) receptor antagonist, AVE5883, in patients with asthma in two double-blind, placebo-controlled crossover studies. METHODS: The pharmacologic efficacy of a single inhaled dose (4.8 mg) of AVE5883 was tested against inhaled NKA in 20 patients with asthma. Subsequently, we studied the biological efficacy of the pharmacologically effective dose on inhaled allergen in a multiple-dose trial (4.8 mg three times per day, 9 d) in 12 patients with asthma with dual responses to inhaled house dust mite. On Day 8, an allergen challenge was conducted, and airway response was measured by FEV(1) until 9 hours postallergen. Exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and induced sputum were performed on Days 1, 7, and 9. RESULTS: AVE5883 had a bad taste, and transient bronchospasm occurred in some subjects. A single inhaled dose shifted the dose response to NKA by 1.2 doubling doses. Pretreatment with multiple doses of AVE5883 enhanced the allergen-induced early and late airway responses. There were no significant differences in the allergen-induced changes in exhaled NO, provocative concentration of methacholine bromide causing a 20% fall in FEV(1), and sputum cell differentials between placebo and AVE5883. CONCLUSIONS: Despite its demonstrated pharmacologic activity against inhaled NKA, multiple doses of AVE5883 increased the allergen-induced airway responses without affecting markers of airway hyperresponsiveness and airway inflammation. Our data question the prominent role of neurogenic inflammation in asthma and, consequently, the therapeutic potential of dual tachykinin antagonists.     

Differences in airway cytokine profile in severe asthma compared to moderate asthma

BACKGROUND: Some studies of severe asthma suggest that persistence or alteration in the pattern of inflammation may be associated with the severity of the disease. Whether there are differences in the expression of the principal cytokines and chemokines relevant to eosinophilic and neutrophilic inflammation in the airway tissues of severe compared to moderate asthmatics has not been determined. The aim of this study was to compare the patterns of expression of representative T-helper (Th) type 1 (interferon [IFN]-gamma) and Th-2 cytokines (interleukin [IL]-4, IL-5) and the neutrophil- and eosinophil-associated chemokines (IL-8 and eotaxin) in the airway tissues of patients with severe and moderate asthma. METHODS: Subjects with severe asthma (n = 24) and a comparison moderate asthma group (n = 26) were assessed using spirometry, induced sputum, exhaled nitric oxide, and bronchial biopsy. The expression of proteins of interest in the epithelium and subepithelium of the airway wall was examined by immunocytochemistry. RESULTS: Subjects with severe asthma were more symptomatic, had a lower FEV(1), and had more sputum neutrophilia (p = 0.007) and eosinophilia (p = 0.001). Exhaled nitric oxide was similar between groups. IL-8 and IFN-gamma expression were increased and IL-4 expression was decreased in severe asthma compared to moderate disease (p < 0.001 for each comparison). Eotaxin and IL-5 expression did not differ between the groups. CONCLUSION: Patients with severe asthma have increases in neutrophils and eosinophils in the sputum, and differ in airway cytokine/chemokine expression from moderate asthmatics. Excess neutrophilia may be explained by increased expression of IL-8, but differences in eosinophilia do not appear to be associated with IL-5 and eotaxin expression.     

扎鲁司特对支气管哮喘患者的疗效评价

目的　观察白三烯受体拮抗剂———扎鲁司特对轻、中度哮喘缓解期患者的疗效及其对气道炎症和气道高反应性的影响。方法　将 36例轻、中度哮喘缓解期患者随机分为 2组 :扎鲁司特组 2 2例 ,口服扎鲁司特 2 0mg,2次 /d ,加吸吸入型 β2 肾上腺素能受体激动剂 (喘乐宁气雾剂 ,每喷 10 0μg) ,按需使用 ;对照组 14例 ,按需使用喘乐宁气雾剂。疗程均为 4周。治疗前后观察日间哮喘症状评分、夜间憋醒次数、吸入喘乐宁的使用量 ,测定肺功能和气道反应性 ,同时测血清嗜酸细胞阳离子蛋白 (ECP)、肿瘤坏死因子 (TNF)α及白细胞介素 (IL) 8。结果　 (1)扎鲁司特组患者治疗后日间哮喘症状评分下降 [治疗前为 (1 7± 0 7)分 ,治疗后为 (1 1± 0 8)分 ;P <0 0 1],夜间憋醒次数减少 [治疗前为(1 1± 0 9)次 /晚 ,治疗后为 (0 6± 0 7)次 /晚 ;P <0 0 1],吸入喘乐宁的使用量减少 [治疗前为 (3 6±1 2 )喷 /d ,治疗后为 (2 4± 1 1)喷 /d ;P <0 0 1];(2 )肺功能 :1秒钟用力呼气容积升高 [治疗前为(2 15± 0 42 )L ,治疗后为 (2 41± 0 6 3)L ;P <0 0 1],最大呼气流速峰值升高 [治疗前为 (4 5 8± 1 2 2 )L/s ,治疗后为 (5 19± 1 2 6 )L/s ;P <0 0 5 ];(3)气道反应性 :起始呼吸阻力下降 [治疗前为 (6