Effect of salmeterol treatment on nitric oxide level in exhaled air and dose–response to terbutaline in children with mild asthma

The aim of this study was to investigate whether regular treatment with inhaled salmeterol modifies the dose–response curve to the inhaled short-acting β₂-agonist terbutaline or affects the concentration of nitric oxide (NO) in exhaled air of children with asthma. Twenty-two children aged 7 to 15 years (mean = 11.6 years) with mild asthma were treated with inhaled 50 μg salmeterol twice daily or placebo for 3 weeks in a randomized double-blind cross-over study. These treatments were followed by treatment with inhaled 200 μg budesonide twice daily for 3 weeks. On the last day of each period, NO level was measured in exhaled air and a cumulative dose–response experiment with terbutaline (cumulative dose: 1,475 μg) was performed. Baseline lung functions after salmeterol treatment were significantly higher than baseline after placebo (P + 0.05). Salmeterol treatment flattened out the dose–response curve to terbutaline such that higher doses of terbutaline were required to produce the same degree of bronchodilation (ED₅₀ for FEV₁ was increased by an estimated factor of 70 (95% CI: 0.8–6307) and ED₅₀ for FEF_25–75 by a factor of 41 (95% CI: 6.7–254); P < 0.05). NO levels were unaffected by salmeterol treatment (12.7 ppb; placebo = 10.7 ppb), but were significantly reduced during budesonide therapy (5.2 ppb; P < 0.001). The corresponding maximal NO levels were 19.5 (placebo), 22.9 (salmeterol), and 9.4 ppb (budesonide). We conclude that 3 weeks treatment with salmeterol does not affect NO levels in exhaled air, but it significantly changes the dose–response curve to terbutaline. Pediatr Pulmonol. 1998; 25:314–321. © 1998 Wiley-Liss, Inc.     

Acute protection against exercise-induced bronchoconstriction by formoterol, salmeterol and terbutaline.

The onset of bronchoprotection as obtained by various beta2-agonists has not been examined in a comparitive study. In this study, the onset of bronchodilation and protection against exercise-induced bronchoconstriction in asthmatics after inhalation of the long-acting beta2-agonists formoterol and salmeterol and the short-acting beta2-agonist terbutaline were measured. Twenty-five subjects with asthma and a history of exercise-induced bronchoconstriction (mean baseline forced expiratory volume in one second (FEV1): 90% predicted; mean fall in FEV1 after exercise: 31% from baseline) were enrolled in this double-blind, double-dummy, placebo-controlled, randomized, four-period crossover study. Exercise challenges were performed on 12 days at either 5, 30, or 60 min after inhalation of a single dose of formoterol (12 microg Turbuhaler), salmeterol (50 microg Diskus), terbutaline (500 microg Turbuhaler) or placebo. Exercise-induced bronchoconstriction (maximum fall in FEV1 or area under the curve) did not differ significantly between terbutaline, formorerol and salmeterol either 5, 30, or 60 min after inhalation of the study medication. In contrast, the onset of bronchodilation was slower after salmeterol compared to terbutaline and formoterol (p<0.05, each), which both showed a similar time course. At all time points between 5 and 60 min, formoterol provided significantly greater bronchodilation than salmeterol (p<0.05). These data indicate that equipotent doses of the bronchodilators salmeterol, formoterol and terbutaline were similarly effective with respect to their short-term protective potency against exercise-induced bronchoconstriction, despite the fact that the time course of bronchodilation was significantly different between the three beta2-agonists.     

beta-Adrenergic receptor polymorphisms and response to salmeterol

RATIONALE: Several studies suggest that patients with asthma who are homozygous for arginine at the 16th position of the beta2-adrenergic receptor may not benefit from short-acting beta-agonists. OBJECTIVES: We investigated whether such genotype-specific effects occur when patients are treated with long-acting beta-agonists and whether such effects are modified by concurrent inhaled corticosteroid (ICS) use. METHODS: We compared salmeterol response in patients with asthma homozygous for arginine at B16 (B16Arg/Arg) with those homozygous for glycine at B16 (B16Gly/Gly) in two separate cohorts. In the first, subjects were randomized to regular therapy with salmeterol while simultaneously discontinuing ICS therapy. In the second, subjects were randomized to regular therapy with salmeterol while continuing concomitant ICS. RESULTS: In both trials, B16Arg/Arg subjects did not benefit compared with B16Gly/Gly subjects after salmeterol was initiated. In the first cohort, compared with placebo, the addition of salmeterol was associated with a 51.4 L/min lower A.M. peak expiratory flow (PEF; p = 0.005) in B16Arg/Arg subjects(salmeterol, n = 12; placebo, n = 5) as compared with B16Gly/Gly subjects (salmeterol, n = 13; placebo, n = 13). In the second cohort, B16Arg/Arg subjects treated with salmeterol and ICS concurrently (n = 8) had a lower A.M. PEF (36.8 L/min difference, p = 0.048) than B16Gly/Gly subjects (n = 22) treated with the same regimen. In addition, B16 Arg/Arg subjects in the second cohort had lower FEV1 (0.42 L, p = 0.003), increased symptom scores (0.2 units, p = 0.034), and increased albuterol rescue use (0.95 puffs/d, p = 0.004) compared with B16Gly/Gly subjects. CONCLUSIONS: Relative to B16Gly/Gly patients with asthma, B16Arg/Arg patients with asthma may have an impaired therapeutic response to salmeterol in either the absence or presence of concurrent ICS use. Investigation of alternate treatment strategies may benefit this group.     

Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma.

There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling, such as the increased subepithelial airway vascularity in patients with asthma. We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids (ICS) (range 200-500 microg twice a day) and 28 normal subjects without asthma as a control population. Subjects underwent bronchoscopy with airway biopsy and subjects with asthma were then randomized to receive supplementary inhaled salmeterol 50 microg twice a day, fluticasone propionate 100 microg twice a day, or placebo for 3 mo in addition to their baseline ICS. Biopsy of the airway was then repeated. The biopsies were analyzed for vascular structures in the subepithelial lamina propria. Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects. We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects (524 +/- 137 vessels/mm2, n = 34 versus 425 +/- 130 vessels/mm2, n = 28; p = 0.004). There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline (before, 535 +/- 153 vessels/mm2 versus after, 400 +/- 142 vessels/mm2; n = 12; p = 0.04). There was no significant change within the fluticasone (n = 11) or placebo (n = 11) treatment groups, but also no significant differences between the groups. Notably, no treatment was associated with increased airway wall vascularity. The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study, which is complementary to the action of ICS on airway vascularity.     

Chronic inhalation of nebulized levalbuterol does not increase mucociliary clearance in healthy subjects

Acute inhalations of beta 2-adrenergic receptor agonists increase mucociliary clearance (MCC). Less is known about the effect of long-term inhalations of these agents on MCC, or cough clearance (CC). We hypothesized that chronic inhalations of nebulized levalbuterol, the R-isomer of albuterol, would enhance MCC and/or CC in healthy subjects, compared to albuterol or placebo. This was a randomized, double-blind, placebo-controlled trial in ten healthy, adult subjects who inhaled nebulized levalbuterol (1.25mg), albuterol (2.5mg), or placebo for 7 days, three times daily. MCC and CC were measured 6-7h after the last dose of drug on the 7th day of treatment. These were quantified from gamma camera images of the lungs following inhalation of an aerosol containing the isotope (99m)technetium. Levalbuterol did not improve MCC or CC. MCC averaged (+/-SD) 12.3+/-8.3%, 9.2+/-4.7% and 10.0+/-9.6% with placebo, albuterol and levalbuterol, respectively. CC averaged 3.9+/-6.8%, 4.9+/-4.3% and 3.8+/-6.4% with placebo, albuterol and levalbuterol, respectively. These results indicate that chronic inhalations of nebulized levalbuterol for 1 week do not increase MCC or CC in healthy subjects, compared to albuterol or placebo.     

A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge

OBJECTIVES: To compare the effects of addition of montelukast or salmeterol to inhaled corticosteroids (ICS) on the response to rescue beta2-agonist use after exercise-induced bronchoconstriction. METHODS: A double-blind, placebo-controlled study was performed at 16 centers in the United States. Patients with asthma (n = 122, ages 15-58) whose symptoms were uncontrolled on Low-dose inhaled fluticasone and who had a history of exercise-induced worsening of asthma were randomized to receive either montelukast (10 mg once daily), salmeterol (50microg twice daily), or placebo for 4 weeks. Standardized spirometry after exercise challenge and beta2-agonist rescue was performed at baseline, week 1 and 4. RESULTS: Maximum achievable forced expiratory volume in 1 s (FEV1) percent predicted after rescue beta2-agonist improved in the montelukast (+1.5%) and placebo (+1.2%) groups at 4 weeks, but diminished in the salmeterol (-3.9%) group (P < 0.001). Although pre-exercise FEV1 was greatest with salmeterol (P = 0.10), patients taking montelukast had significantly greater protection from an exercise-induced decrease in FEV1 than those taking salmeterol (P < 0.001). Both the magnitude and rate of rescue bronchodilation were greater with montelukast compared with salmeterol (P < 0.001). Five minutes after rescue beta2-agonist, 92% of patients taking montelukast and 68% of those taking placebo had recovered to pre-exercise levels, whereas only 50% of those taking salmeterol had recovered to pre-exercise levels. CONCLUSION: In patients whose asthma symptoms remain uncontrolled using ICS, addition of montelukast permits a greater and more rapid rescue bronchodilation with a short-acting beta2-agonist than addition of salmeterol and provides consistent and clinically meaningful protection against exercise-induced bronchoconstriction.     

Effects of a short course of inhaled corticosteroids in noneosinophilic asthmatic subjects

BACKGROUND:

Noneosinophilic asthma has been regarded as a distinct phenotype characterized by a poor response to inhaled corticosteroids (ICS).

OBJECTIVE:

To determine whether noneosinophilic, steroid-naive asthmatic subjects show an improvement in asthma control, asthma symptoms and spirometry after four weeks of treatment with ICS, and whether they further benefit from the addition of a long-acting beta-2 agonists to ICS.

METHODS:

A randomized, double-blind, placebo-controlled, multicentre study comparing the efficacy of placebo versus inhaled fluticasone propionate 250 μg twice daily for four weeks in mildly uncontrolled, steroid-naive asthmatic subjects with a sputum eosinophil count ≤2%. This was followed by an open-label, four-week treatment period with fluticasone propionate 250 μg/salmeterol 50 μg, twice daily for all subjects.

RESULTS:

After four weeks of double-blind treatment, there was a statistically significant and clinically relevant improvement in the mean (± SD) Asthma Control Questionnaire score in the ICS-treated group (n=6) (decrease of 1.0±0.5) compared with the placebo group (n=6) (decrease of 0.09±0.4) (P=0.008). Forced expiratory volume in 1 s declined in the placebo group (−0.2±0.2 L) and did not change in the ICS group (0.04±0.1 L) after four weeks of treatment (P=0.02). The open-label treatment with fluticasone propionate 250 μg/salmeterol 50 μg did not produce additional improvements in those who were previously treated for four weeks with inhaled fluticasone alone.

CONCLUSION:

A clinically important and statistically significant response to ICS was observed in mildly uncontrolled noneosinophilic asthmatic subjects.     

Effects of terbutaline in combination with mannitol on mucociliary clearance.

Beta2-agonists and osmotic agents stimulate mucociliary clearance (MCC) via different mechanisms which could potentially interact. The effects of inhaling terbutaline in combination with mannitol on MCC were investigated in nine healthy (aged 19+/-1 yrs) and 11 mild (aged 21+/-4 yrs) asthmatic subjects. Using 99mTc-sulphur colloid radioaerosol and a gamma camera, MCC was studied on four separate days with each of the following interventions: 1) terbutaline or its placebo inhaled 10 min before mannitol (in random, double blind); 2) terbutaline inhaled 5 min after mannitol; and 3) terbutaline inhaled 10 min before the control for mannitol. Lung images were collected over a period of 120 min postintervention and over 150 min in total. The mannitol-induced increase in clearance was transiently inhibited by terbutaline pretreatment and transiently enhanced when terbutaline was administered after mannitol both in asthmatic and healthy subjects. The order of administration of mannitol and terbutaline did not affect the total clearance of radioactive mucus over 140 min from the start of intervention in both groups. The pathways through which terbutaline and mannitol increase mucociliary clearance may transiently interact in an inhibitory or synergistic way, depending on the order of administration. However, this did not affect the overall increase in mucociliary clearance over 140 min.     

神经生长因子在哮喘患者诱导痰炎性细胞的表达

目的　通过观察神经生长因子 (NGF)在哮喘气道炎性细胞的表达 ,探讨NGF与哮喘气道炎症形成的关系。方法　取 11例哮喘急性发作期、19例哮喘非急性发作期患者及 11例健康对照者的诱导痰 ,其中 12例哮喘非急性发作期患者予丙酸氟替卡松 (ICS)治疗 2周后再取诱导痰。做诱导痰炎性细胞分类计数 ;SP法测诱导痰炎性细胞NGF表达 ;ELISA测其上清中白细胞介素 (IL) 5浓度。结果　 (1)诱导痰巨噬细胞、淋巴细胞、粒细胞NGF表达阳性率哮喘组较健康对照组高 (P值均<0 0 1) ,且急性发作期较非急性发作期高 (P <0 0 1)。急性发作期IL 5水平较非急性发作期和健康对照组高 (P值均 <0 0 1)。 (2 ) 12例非急性发作期患者经ICS治疗后 ,诱导痰巨噬细胞、淋巴细胞、粒细胞NGF表达阳性率及IL 5水平均较治疗前下降 (P值均 <0 0 1)。 (3)巨噬细胞、粒细胞NGF表达阳性率与淋巴细胞相对计数构成比、IL 5水平均呈正相关。结论　哮喘患者气道内巨噬细胞、淋巴细胞和粒细胞NGF表达增加 ,提示NGF可能与哮喘气道炎症的形成有关。     

Effect of ascorbic acid on forearm reactive hyperaemia in patients with hypercholesterolaemia.

BACKGROUND: This study was designed to research the effect of hypercholesterolaemia and ascorbic acid on forearm blood flow (FBF) reactive hyperaemia (RH). Reactive hyperaemia seems to be at least partly endothelium-dependent. Endothelial dysfunction has been described in patients with hypercholesterolaemia, and has been reversed with ascorbic acid administration. METHOD: Forearm blood flow was studied with venous occlusion plethsmography in 26 healthy volunteers and 46 hypercholesterolaemic patients. Hypercholesterolaemic patients were divided into two groups. Group A comprised 25 patients, who received ascorbic acid and group B comprised 21 patients, who received placebo. All subjects underwent measurement of FBF at baseline and during RH (phase A). Forearm blood flow during RH was measured every 15 seconds for three minutes. Subsequently patients in group A received 2 g of ascorbic acid orally in the form of effervescent tablets, and patients in group B received placebo orally in the same form. Forearm blood flow measurements at baseline and during RH were repeated two hours later (phase B). RESULTS: Maximal percent increase of FBF was significantly higher in healthy subjects than in hypercholesterolaemic patients (139.1+/-12.1% versus 73.1+/-11.0% respectively, P<0.05). Duration of RH was smaller in hypercholesterolaemic patients compared to normal subjects (60.9+/-17.1 seconds versus 105.6+/-10.2 seconds, P<0.05). Administration of ascorbic acid but not of placebo increased the duration of RH (69.1+/-11.1 seconds versus 104.1+/-12.2 seconds, P<0.05) but not of peak RH FBF. CONCLUSION: Hypercholesterolaemia seems to impair both the early and late phase of RH. Ascorbic acid improves only the duration of RH, possibly due to its antioxidant effect on endothelium.     

Expiratory flows and airway inflammation in elderly asthmatic patients

Asthma in the elderly is often underrecognized and suboptimally treated, resulting in an increased morbidity and mortality. The characteristics of asthma-related bronchitis and its optimal treatment remain to be determined in this population. We aimed to compare lung function and airway inflammation in elderly and younger asthmatic subjects. Data from two induced sputum databases were analyzed in three groups of asthmatic subjects (18-30 y, n = 136; 31-59 y, n = 385; 60-72 y, n = 172) and one group of healthy elderly subjects (60-89 y, n = 16). Expiratory flows and induced sputum cell counts were analyzed. Airway obstruction was more marked in elderly asthmatics compared with healthy elderly or younger asthmatic subjects (p < 0.01). An increase in sputum neutrophils and a decrease in macrophages and lymphocytes were observed in elderly asthmatics (p < 0.0001). Neutrophil percentages significantly increased with asthma severity in the young and the middle-aged groups, while they remained similar in elderly asthmatics regardless of asthma severity (p < 0.05). Neutrophil percentages weakly correlated with the dose of ICS in all asthmatics (r = 0.17, p < 0.0001). Age and dose of ICS were independent predictors of neutrophil percentage in asthmatic subjects in a regression model (R(2) = 0.12). Asthma in the elderly is associated with a more marked airway obstruction and sputum neutrophilia. Both age and the dose of corticosteroids need to be considered in the interpretation of the clinical relevance of sputum neutrophil count.     

大剂量皮质激素吸入治疗高原地区重症哮喘发作的研究

目的 探讨大剂量皮质激素吸入是否有助于β激动剂对高原地区重症哮喘发作的治疗。方法 采用随机双盲对照方法,将４２例高原地区重症哮喘发作患分为布地奈德组和对照组,每组２１例。两组先吸入特布他林气雾剂２．５ｍｇ,然后布地奈德组 布地奈德气雾１．２ｍｇ,对照组吸入安慰剂。１０ｍｉｎ后各重复１次。所有受试给药前、后检查肺功能、辅助呼吸肌少支,并观察患呼吸困难、哮鸣音变化。后３项依据严重程度计分,平均值     

Tolerance to the protective effect of salmeterol in mild untreated asthmatics

The aim of this study was to assess the distribution of the occurrence of tolerance to the protective effect of salmeterol on allergen challenge in a large sample of asthmatic subjects. We investigated 53 subjects (45 male and eight female), mean age 24+/-8.2 years, with mild intermittent asthma, in stable phase of the disease, never previously treated with regular beta2-agonists. All subjects with a previous positive early airway response (EAR) to a screening allergen challenge underwent, in double blind randomized, cross-over manner, three further allergen challenges: after placebo (T0), after a single dose (50 microg) of inhaled salmeterol (T1), and after regular treatment with inhaled salmeterol (50 microg bid) for 1 week (T2). All subjects showed an EAR after placebo treatment (T0), and were completely protected against EAR by the single dose of salmeterol (T1). After 1-week regular treatment with salmeterol (T2). 24 out of 53 subjects (45%) were still protected, whereas 29 subjects (55%) showed a significant EAR. The distribution of the response to allergen challenge, which was quite homogeneous at T0 and T1, showed considerable heterogeneity at T2. Tolerance to the protective effect of salmeterol on allergen challenge can be observed in a large group of previously untreated mild asthmatic subjects. This phenomenon is heterogeneously distributed, with some subjects still showing a complete protection similar to that obtained after a single dose of salmeterol and others showing a response similar to that obtained after placebo. The reason of this heterogeneity needs to be elucidated.     

Comparable spirometric efficacy of tiotropium compared with salmeterol plus fluticasone in patients with COPD: a pilot study

BACKGROUND: International guidelines recommend the long-acting anticholinergic, tiotropium, or long-acting beta 2-agonists as maintenance therapy in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). The efficacy of long-acting beta(2)-agonists combined with inhaled corticosteroids (ICS) in the treatment of COPD has also been confirmed for severe and very severe COPD, but data comparing tiotropium with the combination of a long-acting beta 2-agonist and an ICS are lacking. METHODS: This 6-week multicentre, randomised, double-blind, triple-dummy pilot study compared the bronchodilator effects of tiotropium 18 microg once daily (n=56) vs. the combination of salmeterol 50 microg plus fluticasone 250 microg twice daily (n=51) in patients with moderate-to-very severe COPD. Serial spirometry was performed over 12h after 6 weeks of treatment. The primary endpoint was forced expiratory volume in 1s (FEV1) area under the curve from 0 to 12h (AUC0-12h) on Day 43. RESULTS: Randomization failed to provide treatment groups with comparable baseline characteristics for smoking history, current smokers, duration of COPD, FEV1, forced vital capacity (FVC) and reversibility. Mean+/-SD FEV1 was 1.31+/-0.47 l in the tiotropium group vs. 1.46+/-0.53 l in the salmeterol plus fluticasone group. Fewer patients in the tiotropium showed a 12% and 200 ml acute increase to short-acting bronchodilators at baseline. However, treatment with tiotropium alone resulted in comparable bronchodilation compared with salmeterol plus fluticasone, as measured by all the spirometric parameters at the end of the 6-week study period. FEV1 AUC0-12h was 1.55+/-0.03 l in the tiotropium group vs. 1.57+/-0.04 l in the salmeterol plus fluticasone groups (p=0.63). Trough (predose) FEV1 was 1.54+/-0.03 l in the tiotropium group vs. 1.46+/-0.03 l in the combination group (p=0.07), and peak FEV(1) was 1.68+/-0.04 l vs. 1.66+/-0.04 l, respectively, (p=0.77). FVC AUC0-12h, trough and peak were also comparable between groups at study end (p>0.05, for all). Further, rescue salbutamol use was similar in the tiotropium and combination groups and both treatment regimens were well tolerated. CONCLUSIONS: Six weeks of treatment with tiotropium resulted in comparable bronchodilation compared with salmeterol plus fluticasone in patients with moderate-to-very severe COPD, despite tiotropium patients having lower lung function and fewer patients considered reversible at baseline. The results of this pilot study will aid planning for further large-scale comparative studies.     

Effect of four-week treatment with oxitropium bromide on lung mucociliary clearance in patients with chronic bronchitis or asthma

The effect of oxitropium bromide on lung mucociliary clearance, pulmonary function and viscoelastic properties of sputum was investigated in 10 asthmatics and 10 chronic bronchitics. A controlled, double-blind, crossover study was performed. Following a baseline (B) measurement the patients were, in a random order, allocated placebo (P) or oxitropium bromide (O; 0.1 mg/puff), administered from metered dose inhalers, which they used for 4 weeks at a dose of 2 puffs t.d.s. This test medication was used in conjunction with their normal medication. At the end of the treatment period the patients were assessed, the treatments were then crossed over and a final assessment made 4 weeks later. The administration of oxitropium bromide resulted in (1) small but statistically significant increases in pulmonary function (less than 10% vs. placebo); (2) increased penetrance of radioaerosol into the lungs (mean +/- SEM alveolar deposition: 35 +/- 3, 26 +/- 3 and 24 +/- 3% for the O, P and B runs respectively; p less than 0.025); (3) no significant change in particle clearance rate from the lungs despite their deeper penetration (mean +/- SEM area under the tracheobronchial clearance curves between 0 and 6 h: 317 +/- 26, 324 +/- 25 and 287 +/- 25%.h for the O, P and B runs respectively; p greater than 0.1); (4) no alteration in sputum production, and (5) no significant changes in apparent viscosity (mean +/- SEM: 640 +/- 162, 446 +/- 79 and 557 +/- 115 mPa.s for the O, P and B runs, respectively; p greater than 0.1) and elasticity (mean +/- SEM: 3,682 +/- 1,383, 1,779 +/- 353 and 2,061 +/- 366 mPa for the O, P and B runs, respectively; p greater than 0.1) of sputum. When the two groups, i.e. the chronic bronchitics and asthmatics, were studied separately, no significant differences in any parameter measured (other than radioaerosol penetrance which was significantly enhanced on oxitropium bromide in chronic bronchitics) were noted between the three assessments.     

A 6-month,placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol

BACKGROUND: Tiotropium, a once-daily anticholinergic, and salmeterol represent two inhaled, long-acting bronchodilators from different pharmacologic classes. A trial was designed to examine the efficacy and safety of both compounds with multiple outcome measures, including lung function, dyspnea, and health-related quality of life (HRQoL) in patients with COPD. METHODS: A 6-month, randomized, placebo-controlled, double-blind, double-dummy, parallel-group study of tiotropium, 18 microg once daily via dry-powder inhaler, compared with salmeterol, 50 microg bid via metered-dose inhaler, was conducted in patients with COPD. Efficacy was assessed by 12-h monitoring of spirometry, transition dyspnea index (TDI), and the St. George's Respiratory Questionnaire (SGRQ). RESULTS: A total of 623 patients participated (tiotropium, n= 209; salmeterol, n = 213; and placebo, n = 201). The groups were similar in age (mean, 65 years), gender (75% men), and baseline FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted, 40 +/- 12% [+/- SD]). Compared with placebo treatment, the mean predose morning FEV(1) following 6 months of therapy increased significantly more for the tiotropium group (0.14 L) than the salmeterol group (0.09 L; p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium was statistically superior to salmeterol (difference, 0.08 L; p < 0.001). Tiotropium improved TDI focal score by 1.02 U compared with placebo (p = 0.01), whereas there was no significant change in TDI focal score with salmeterol (0.24 U). Tiotropium was superior to salmeterol in improving TDI focal score (p < 0.05). At 6 months, the mean improvement in SGRQ total score vs baseline was tiotropium, - 5.14 U (p < 0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs placebo); and placebo, - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo. Both active drugs reduced the need for rescue albuterol (p < 0.0001). CONCLUSIONS: Tiotropium once daily produces superior bronchodilation, improvements in dyspnea, and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD.     

Bronchodilator reversibility, airway eosinophilia and anti-inflammatory effects of inhaled fluticasone in COPD are not related

Background and objective: Bronchodilator reversibility (BDR) is common in smoking‐related COPD, but the airway pathology underlying this has not been described. In particular, it is not known whether BDR is associated with underlying airway eosinophilia and whether BDR is predictive of a better response to inhaled corticosteroid (ICS) treatment. Methods: A double‐blind, placebo‐controlled, randomized 2 : 1 study of fluticasone propionate (FP), 500 µg twice daily versus placebo over 6 months was performed in subjects with mild to moderate COPD. Subjects with a clinical history of asthma were excluded, but not on BDR criteria alone. Induced sputum, BAL and endobronchial biopsies (EBB) were performed in 36 subjects at baseline, and 30 of these provided a second full set of samples (FP, n = 19; placebo, n = 11). Results: Baseline BDR was not related to airway eosinophilia and did not predict response to ICS. Post‐bronchodilator FEV₁ increased in the FP group compared with the placebo group (P = 0.05), and there were within‐treatment group reductions in total symptom scores with FP (P < 0.05). Compared with placebo, FP reduced macrophage numbers but increased neutrophil numbers in EBB (P = 0.01 and P = 0.003, respectively). BAL neutrophil and epithelial cell numbers were also reduced with FP (P = 0.03 for both). There were within‐treatment group reductions in the numbers of EBB mast cells and CD8+ve lymphocytes with FP (P = 0.007). Conclusions: BDR was not related to any particular inflammatory phenotype or any clinical or anti‐inflammatory response to ICS in these subjects with mild to moderate COPD.     

Inhaled mannitol changes the sputum properties in asthmatics with mucus hypersecretion

BACKGROUND AND OBJECTIVES: Most asthmatics with mucus hypersecretion have difficulty in clearing their secretions so that mucus plugs and airway obstruction are commonly present. Inhaled mannitol facilitates clearance of mucus. This study investigated the changes in the physical properties of sputum in response to mannitol in asthmatics with chronic cough and sputum production. METHOD: Sputum was collected from 12 asthmatics (26-73 year), lifelong non-smokers, at baseline, after eformoterol (24 mug) and after mannitol on each of four visits. Inhaled mannitol doses were: 635 mg (Visit 1), 240 mg (Visit 2), 360 mg (Visit 3) and 360 mg in the presence of montelukast (Visit 4). Eformoterol was inhaled before mannitol on each visit to prevent bronchoconstiction. Sputum measurements included viscosity, elasticity, surface tension, contact angle-glass and percentage solids. RESULTS: There were no significant differences between the sputum properties at baseline and after eformoterol. Mannitol (360 mg) reduced the baseline (mean +/- SEM) elasticity from 29.9 +/- 4.5 to 15.1 +/- 1.4 Pa (P < 0.0001), viscosity from 18.4 +/- 3.2 to 8.1 +/- 1.2 Pa (P < 0.0001) at 1 rad/ s, surface tension from 92.1 +/- 2.2 to 81.9 +/- 2.5 mN/m (P < 0.0001), contact angle-glass from 57.5 +/- 3.2 to 49.6 +/- 2.0 degrees (P < 0.0001), and percentage solids from 6.9 +/- 0.7 to 5.7 +/- 0.4% (P < 0.0001). All doses of mannitol reduced the sputum properties similarly and no property was further reduced by montelukast (P > 0.4). CONCLUSION: Inhaled mannitol reduced the viscoelasticity, surface tension, contact angle and the solids content of sputum in asthmatics with chronic cough and sputum production, consistent with the osmotic effect of mannitol causing water efflux in the airway lumen.     

Effects of withdrawal of inhaled steroids in men with severe irreversible airflow obstruction

Inhaled corticosteroid therapy has proven efficacy for asthmatics, but the benefit for patients with chronic obstructive pulmonary disease (COPD) is less well supported. We hypothesized that withdrawal of inhaled steroids in elderly patients with severe irreversible airway obstruction would not lead to a deterioration in respiratory function. We designed a prospective, double-blind, randomized, placebo-controlled, crossover study to follow spirometry, quality of life questionnaire, six-minute (6-min) walk test, and sputum markers of inflammation during a 6-wk placebo treatment period and a 6-wk treatment period with beclomethasone dipropionate (BDP), 336 microg/d. There were 24 men receiving BDP who entered the study; 15 completed the study. Their mean age was 66.9 +/- 1.9 yr, and mean FEV(1) was 1.61 +/- 0.1 L (47% of predicted). There was a significant decrease in the mean FEV(1 )while using the placebo inhaler (1.70 L versus 1.60 L, baseline versus placebo: 95% CI, 0.002 to 0.195; p < 0.05). There was a decrease in the mean percentage change in FEV(1) for the study subjects during the placebo treatment period as compared with the BDP treatment period (-6.28 versus 5.03%, placebo versus BDP: 95% CI, -23.38 to 0.76; p = 0.06). Six-minute walk test results and sputum analysis for cell count and differential were not significantly different during placebo and BDP treatment periods. Borg scale assessment of dyspnea after exercise was increased while using the placebo inhaler as compared with baseline, and decreased during the BDP treatment period. Chronic Respiratory Disease Questionnaire (CRQ) scores revealed no significant difference between placebo and BDP. This study has demonstrated that in elderly patients with severe irreversible airway obstruction, withdrawal of inhaled corticosteroid therapy leads to a deterioration in ventilatory function and increased exercise-induced dyspnea.     

哮喘患者痰液细胞因子和哮嗜酸细胞阳离子蛋白水平及意义

目的 探讨痰中细胞因子、嗜酸细胞阳离子蛋白（ＥＣＰ）水平与哮喘严重程度的关系。方法 采用酶联免疫法及荧光光免疫法对轻（Ｍ组１０例）中、重度（ＭＳ组１５例）哮喘２痰液白细胞介素（ＩＬ）５、肿瘤坏死因子α（ＴＮＦ－α）、可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）、ＥＣＰ水平进行检测。结果 中、重度哮喘患溶液ＩＬ－５（３５ｎｇ／Ｌ以上）、ＴＮＦ－α（Ｍ组为１４９±５９ｎｇ／Ｌ，ＭＳ组为２６７±１４７ｇ／Ｌ