Formoterol attenuates neutrophilic airway inflammation in asthma

STUDY OBJECTIVES: Airway neutrophil levels are increased in patients with severe asthma and during asthma exacerbations. Long-acting beta2-agonists (LABAs), such as formoterol, reduce the number of asthma exacerbations. While beta2-agonists may affect neutrophil function in vitro, it is uncertain whether they have effects on neutrophilic inflammation in asthmatic patients in vivo. DESIGN: In a double-blind randomized crossover study, we evaluated the effects of 4 weeks of treatment with formoterol (Turbuhaler), 24 microg bid, compared to placebo on sputum neutrophil numbers and interleukin (IL)-8 levels in asthmatic patients. Therapy with budesonide (administered via Turbuhaler), 400 microg bid for 4 weeks, was added at the end as a "gold standard" antiinflammatory effect comparison. PATIENTS: We studied 15 steroid-na?ve nonsmoking patients who ranged from 19 to 51 years of age and had mild persistent asthma. RESULTS: Formoterol therapy significantly reduced sputum IL-8 levels and neutrophil numbers compared to placebo. There was a significant correlation between the reduction in sputum IL-8 levels and the number of neutrophils, indicating that formoterol may attenuate neutrophilic airway inflammation by inhibiting IL-8 production. CONCLUSIONS: Our data suggest that the LABA formoterol reduces neutrophilic airway inflammation in patients with mild asthma and that this might be beneficial in preventing asthma exacerbations.     

Circadian variations in theophylline concentrations and the treatment of nocturnal asthma

The nocturnal worsening of asthma is a common problem that can be difficult to treat. Two different sustained-release theophylline preparations were used to determine (1) if the serum theophylline concentrations (STC) depend on the type and dosing schedule of the preparation, (2) the relationship between STC and the circadian variations in asthma, and (3) the effect of STC on sleep quality and respiratory patterns during the night. In 16 subjects with nocturnal asthma, the STC were significantly higher during the daytime on twice-daily versus once-daily theophylline preparations given at 7 P.M., but the FEV1 values were similar. During the night, the STC were significantly higher with the once-daily regimen, and the awakening FEV1 value was also improved (p less than 0.05). All polysomnographic variables were similar between the two preparations, except that with the once-daily preparation there was a decreased number of hypopneas (p less than 0.05) and fewer minutes below an oxygen saturation of 90% (p less than 0.05). We conclude that patients with nocturnal asthma need their treatment focused on the nocturnal portion of the circadian cycle and that higher STC during this critical time period are beneficial without interfering with sleep quality.     

夜间哮喘发病机制及特殊治疗的研究进展

夜间哮喘是哮喘的一种普遍现象和重要临床类型。夜间哮喘的患者主要表现为哮喘控制不佳、睡眠质量下降及白天嗜睡,严重影响患者生活质量并增加了哮喘的死亡率。因此,探求夜间哮喘的发病机制,在治疗上根据其夜间变化规律调整相应的给药时间和剂量,具有重要意义。     

Value of a daily dose of theophylline in the treatment of nocturnal asthma

The authors report the results obtained with one single daily dose of 10 mg/kg of a long-acting theophylline preparation administered in the evening to asthmatic patients previously treated with the same dose twice a day. Twenty-seven patients presenting with airway obstruction reversible by beta-stimulants entered the study; their mean FEV1 value was 57% of the expected value, and diffuse sibilances were present; paroxysmal attacks occasionally occurred, particularly at night. No significant difference was found between the two dosage regimens with regard to symptomatic improvement, adjuvant drug consumption, and plasma theophylline levels 12 hours after the evening dose. The classical side-effects of theophylline therapy were not increased by the once-a-day regimen. It is concluded that one dose of theophylline per day is effective in the treatment of nocturnal asthma.     

Airways inflammation in nocturnal asthma

Nocturnal asthma is a frequent problem, but the mechanism is unclear. We investigated the possibility that airways inflammation occurred during the night. Bronchoalveolar lavage fluid was analyzed in asthmatic patients with (n = 7) and without nocturnal asthma (n = 7) at 1600 and 0400 h. The nocturnal asthma group had an increase in the total leukocyte count (24.0 +/- 7.0 to 41.1 +/- 9.9 x 10(4) cells/ml, p less than 0.05), neutrophils (1.1 +/- 0.6 to 3.7 +/- 1.5 x 10(4) cells/ml, p less than 0.05), and eosinophils (0.5 +/- 0.1 to 1.7 +/- 0.7 x 10(4) cells/ml, p less than 0.05) from 1600 to 0400 h. Cellular components for the non-nocturnal asthma group did not change. Between groups, the 1600-h cells were similar. At 0400 h the nocturnal asthma group had significantly higher total leukocyte, neutrophil, eosinophil, lymphocyte, and epithelial cell counts. For all subjects, the overnight fall in peak expiratory flow rates was correlated to the change in neutrophils (r = 0.54, p less than 0.05) and eosinophils (r = 0.77, p less than 0.05). We conclude that the nocturnal worsening of asthma has an associated cellular inflammatory response that is not seen in patients without overnight decrements in lung function. This inflammatory response together with epithelial damage may be important factors in the etiology of nocturnal asthma.     

Airway-parenchyma uncoupling in nocturnal asthma

Airway flow resistance is well known to be dependent upon lung volume. The rise in lung volume that occurs in asthma is therefore thought to be an important mechanism that defends airway patency. The purpose of the current study was to investigate the interdependence or mechanical coupling between airways and lung parenchyma during the inflammatory processes that occur in the patient with nocturnal asthma. Five patients with documented nocturnal asthma were studied in both a vertical and a horizontal body plethysmograph. Lung volume was altered with continuous negative pressure as applied to the chest wall with a poncho cuirass in different postures and during sleep. We found during the awake phase that an increase in lung volume decreased lower pulmonary resistance (Rlp); however, within 30 min of sleep onset, functional residual capacity (FRC) fell and Rlp rose more than would be expected for the fall in FRC. Restoring FRC to presleep values either at an early (half-hour) or a late (3-h) time point did not cause Rlp to significantly fall. A second phase of the study showed that the loss of Rlp dependence on lung volume was not due to the assumption of the supine posture. Indirect measurements of lung compliance were consistent with a stiffening of the lung. We conclude that with sleep there is an immediate uncoupling of the parenchyma to the airway, resulting in a loss of interdependence that persists throughout sleep and may contribute to the morbidity and mortality associated with nocturnal asthma.     

Formoterol protects against platelet-activating factor-induced effects in asthma.

Platelet-activating factor (PAF) is an inflammatory mediator that provokes neutropaenia, bronchoconstriction and gas exchange defects due to exudation of bulk plasma within the airways. While the inhibitory effects of short-acting beta2-agonists on PAF-induced disturbances have been consistently shown, those of long-acting beta2-agonists are less convincing. To further explore the mechanisms involved in PAF challenge in asthma, 12 patients (forced expiratory volume in one second, 90 +/- 4% predicted) were investigated 2 h after inhaled formoterol (18 microg), in a double-blind, placebo-controlled, crossover design following PAF (18 microg) inhalation. Compared with the placebo, at 5 min, premedication with formoterol reduced PAF-induced cough and dyspnoea, and attenuated increased respiratory system resistance (by 67%) and arterial deoxygenation (by 50%). Likewise, ventilation-perfusion (V'A/Q') inequality improved, as reflected by the dispersion of pulmonary blood flow (by 63%) and an overall index of V'A/Q' heterogeneity (by 71%). In contrast, PAF-induced facial flushing, neutropaenia and subsequent rebound neutrophilia remained unchanged. The improvement in gas exchange abnormalities shown after platelet-activating factor in patients with asthma pretreated with formoterol at the recommended clinical dose may reflect, in addition to its class effects, an anti-exudative effect of formoterol in the airways.     

布地耐德/福莫特罗和布地耐德治疗轻、中度持续性哮喘的药物经济学分析

目的 采用随机、对照方法观察布地耐德/福莫特罗和布地耐德治疗的轻、中度持续性哮喘患者的临床药物经济学分析.方法 收集40例轻、中度持续性哮喘患者,将其随机分为布地耐德/福莫特罗组(160 μg/4.5 μg,2吸/次,bid),单用布地耐德组(200 μg,2吸/次,bid)各20例,随访12周后的成功治疗周、无症状日和未累及天数的平均成本-效果比以及增量效果比,并进行敏感度分析.结果 经过治疗后,成功治疗周、无症状日和未累及天数的比例,布地耐德/福莫特罗组高于单用布地耐德组(P＜0.05).成功治疗周、无症状日和未累及天数的平均成果-效果比布地耐德/福莫特罗组高于单用布地耐德组(P＜0.05),且受价格影响不大.结论 布地耐德/福莫特罗在治疗轻、中度哮喘患者更经济有效.     

Nasal CPAP in nonapneic nocturnal asthma

Nasal CPAP has been shown to improve nocturnal asthma in those patients with associated sleep apnea. We studied seven nonapneic, nonsnoring asthmatics to determine the effect of CPAP in this patient population. On the CPAP night vs the baseline night, there was a significant worsening of sleep architecture. This included increased awake time and decreased REM sleep. For the group, the overnight decrement in FEV1 was not improved. Of interest, two patients did have a marked improvement in FEV1 associated with improved oxygen saturation on the CPAP night. These individuals were restudied only on supplemental oxygen. This intervention also improved the overnight FEV1 and allowed the patients to have better sleep compared to the CPAP night. We concluded that CPAP is associated with disrupted sleep architecture in nonapneic asthmatics and nocturnal oxygen desaturation may play a role in the development of nocturnal asthma.     

Formoterol Turbuhaler as reliever medication in patients with acute asthma.

The aim of this study was to compare the efficacy and safety of formoterol versus salbutamol as reliever medication in patients presenting at an emergency dept with acute asthma. A randomised, double-blind, double-dummy, parallel group study was performed in four Australian emergency treatment centres. The study included a total of 78 adult patients (mean baseline forced expiratory volume in one second (FEV1) 1.83 L; 59% predicted) with acute asthma. Based on the expected dose equivalence of formoterol Turbuhaler 4.5 microg (delivered dose) and salbutamol pressurised metered-dose inhaler 200 microg (metered dose), patients received a total of formoterol Turbuhaler 36 microg (delivered) or salbutamol pressurised metered-dose inhaler with spacer 1,600 microg (metered), divided into two equal doses at 0 and 30 min. FEV1, peak expiratory flow and systemic beta2-agonist effects were monitored for 4 h. The primary variable was FEV1% pred at 45 min. At 45 min, mean increases in FEV1 expressed in % pred were 6.6% and 9.3%, respectively, with a small adjusted mean difference in favour of salbutamol (3.0%, 95% confidence interval -2.0-8.0). Transient increases in systemic beta2-agonist effects occurred predominantly with salbutamol, although no significant treatment differences were observed. Eight patients discontinued due to adverse events. In this study of patients presenting at emergency depts with acute asthma, formoterol Turbuhaler 36 microg was well tolerated and, as rescue therapy, had an efficacy that was not different from that of salbutamol pressurised metered-dose inhaler with spacer 1,600 microg in the number of patients studied.     

The pharmacokinetics of uniphyllin in nocturnal asthma

Three consecutive doses of approximately 10 mg/kg of a once daily slow-release theophylline preparation (Uniphyllin) were given at 22.00 hours to 15 patients with nocturnal asthma who were recovering from an acute exacerbation of their asthma. Twenty-four hour plasma theophylline profiles were obtained after the first and third doses. Following the first dose, the mean peak level was 12.5 mg/litre, mean time to peak was 8.1 hours and mean apparent elimination half-life was 6.6 hours. Pharmacokinetic data were similar following the third dose. In nocturnal asthma, Uniphyllin should be given at about 20.00 hours to coincide peak levels with the time of maximum airflow obstruction.     

Gastro-oesophageal reflux and nocturnal asthma

Gastro-oesophageal (GO) reflux is believed to be a possible cause of nocturnal asthma. The aim of this study was to see if there is any correlation between the incidence of GO-reflux at night and nocturnal asthma. Thirty-seven adult patients with a history of nocturnal asthma for more than one hundred days a year and of reflux disease were evaluated using 24 h pH-monitoring of the oesophagus and measurement of peak expiratory flow (PEF) rate every hour when awake. Half of the patients suffered from severe GO-reflux at night, whilst the other half had no nocturnal reflux. Respiratory symptoms and inhalation of beta-2 agonists were recorded during the night and PEF was recorded when the patients awoke in the morning. A significant correlation was found between reflux at night and the degree of bronchial obstruction in the early morning, but not between night-time reflux and nocturnal respiratory symptoms. It would appear that GO-reflux in most asthmatics is neither a strong nor immediate trigger factor in nocturnal asthma, although it does seem to influence bronchial obstruction during the night as was demonstrated by a low morning-PEF value.     

Effects of a combined treatment theophylline and tulobuterol on nocturnal chronic asthma

The efficacy of a bronchodilator combination therapy (a slow-release xanthine derivative plus an oralβ ₂-mimetic—tulobuterol) in the treatment of nocturnal asthma attacks was compared to the efficacy of a monotherapy using a xanthine derivative alone.     

Diagnosis and therapy of nocturnal asthma

The bronchial tonus depends on circadian oscillations like all other organ functions. The tendency to increased nocturnal bronchoconstriction in some asthmatic subjects is well known. The reasons of such individual variations are different concentrations of cortisol, adrenaline, histamine, cAMP in serum as well as imbalance between vagal and sympathetic interactions. In practice, the early diagnosis of severe nocturnal bronchial constriction is important for prevention of asthma attacks and status asthmaticus. We report on our circadian measurements of airway resistance (Ros) or peak-flow. By adequate therapy an improvement of the individual bronchial tolerance could be achieved, however the biorhythm remained unchanged. Measurements of airway resistance at 2 a.m. were significantly improved by therapy, as was the mean level measurements during 4-hourly readings. High dose bedtime or slow release theophylline decreased the number of nocturnal asthma attacks.     

Factors related to the nocturnal worsening of asthma

The nocturnal worsening of asthma is a very common problem, yet little is known about the relationships between the nocturnal worsening and daytime lung function, methacholine bronchial responsiveness, the degree of the circadian variability in bronchial responsivity, and the nocturnal sleep pattern. This study demonstrates in 20 asthmatic patients that the overnight fall in the peak expiratory flow rates (PEFR) is related to the severity of daytime airflow limitation (r = 0.73, p less than 0.001) and daytime bronchial responsiveness (r = 0.48, p less than 0.05). In individuals with larger overnight decrements in PEFR, bronchial responsivity at 0400 h is so great that normal saline inhalation alone can produce a greater than 20% fall in the FEV1. Sleep quality and sleep staging are not correlated to the change in the PEFR. Thus, the overnight decrement in asthmatic lung function is related to the daytime severity of asthma as determined by daytime measurements of airflow limitation and bronchial responsiveness as well as the circadian variation in bronchial responsivity.     

Two aminophylline preparations in nocturnal asthma.

In a double-blind trial the effects of aminophylline suppositories and slow-release aminophylline tablets were compared with similar placebo preparations in nine patients whose complaint was asthma which woke them from sleep at night. Forced expired volume in one second (FEV1) was measured in each patient at three-hourly intervals from 1900 hours to 0700 hours on four separate nights, the preparation being administered immediately after the 2200 hour measurement. On the nights when a placebo was administered the FEV1 showed a statistically significant fall between 1900 and 0400 hours. Aminophylline had a statistically highly significant effect in reducing or preventing this fall, suppositories and tablets being equally effective in this single-dose study.     

夜间哮喘发病的自由基机理研究

目的探讨夜间哮喘发病与自由基的关系。方法应用细胞化学发光分析技术动态检测夜间哮喘淋巴细胞发光强度（Ｌｙ－ｃｌ）和多形核白细胞发光强度（ＰＭＮ－ｃｌ）的变化；同时检测全血谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）活力和血浆丙二醛（ＭＤＡ）浓度。结果夜间哮喘患者Ｌｙ－ｃｌ及ＰＭＮ－ｃｌ次日２∶００时较当日１４∶００时增强（Ｐ＜０．０１），与对照组比较差异有显著性（Ｐ＜０．０１）；而ＧＳＨ－Ｐｘ活力下降（Ｐ＜０．００１），ＭＤＡ含量增高（Ｐ＜０．０１）。结论夜间哮喘患者外周血自由基代谢具有明显的昼夜差异，提示体内淋巴细胞（Ｌｙ）及多形核白细胞（ＰＭＮ）活化而释放的过多活性氧以及由于抗氧化功能的受损而产生的脂质过氧化反应（ＬＰＯ）可能是夜间哮喘发病的重要机制之一