The effects of long-acting β2-agonists plus inhaled corticosteroids for early reversibility in patients with airway obstruction

Background

Salbutamol, as a short-acting β2-agonist, was popularly used in the past for detection of reversibility in patients with airway obstruction when it was the only drug available in the treatment of airway obstruction. Today, the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids are the first choice of therapy, with or without the presence of reversibility, in patients with airway obstruction. We aimed to compare the efficacy of salbutamol and long acting β2-agonists plus inhaled glucocorticoids for early reversibility test in patients with airway obstruction.

Methods

Symptomatic patients (cough, dyspnea, and/or wheezing) with airway obstruction according to pulmonary function testing (FEV1/FVC value less than 70% of expected) who had never used bronchodilators before or had not received short- or long-acting inhaled bronchodilator therapy within the most recent 12 hours were evaluated. Reversibility measurements were made by administering the combination of long-acting β2-agonists (LABA) and inhaled glucocorticoids after 15 minutes.

Results

A total of 90 patients were evaluated. The mean age of patients was 57.3±17.7 (range, 8-88) years and the male-to-female ratio was 69/21. The baseline pulmonary function test results were mean FVC; 2,747±1,181 mL and 74.7%±21.4%, mean FEV1; 1,716±825 mL and 57.5%±19.0%, mean FEV1/FVC; 61.4%±7.4%. The bronchodilator drugs given before reversibility testing were as salmeterol/fluticasone (FTC/SAL), formoterol/budesonide (BUD/FOR), beclomethasone dipropionate/formoterol (BDP/FOR) and salbutamol (SLB) in 24, 22, 24 and 20 patients, respectively. The reversibility was positive in 33 (36.7%) patients. The absolute change and percentage of change in mean FEV1 were 206±252 mL, 13.2%±16.6% for FTC/SAL group, 273±201 mL, 14%±8% for BUD/FOR group, 240±151 mL, 18.7%±15.9% for BUD/FOR groupand 171±116 mL, 13.3%±11.8% for SLB group. There was no statistically significant for reversibilty results between LABAs/inhaledsteroids and SLB group. And the patients with positivere versibility test were significantly higher in both of BUD/FOR and BDP/FOR groups than SLB group.

Conclusions

We think that performance of an early reversibility test using the combination of a LABA and an inhaled corticosteroid for treatment would enhance both the education of the patient in using the device and the reliability of the drug. And, we suggest that: “you should make the reversibility test with Long-Acting β2-Agonists plus Inhaled Corticosteroids which used in treatment of obstructive lung diseases”.KEY WORDS : Salmeterol/fluticasone, formoterol/budesonide, beclomethasone dipropionat/formoterol, salbutamol, pulmonary function test, reversibility     

The evolution of β2-agonists

β-agonists have been widely used in the treatment of asthma for many years. Although concerns have been expressed over their safety, based largely upon epidemics of increased mor tality in asthmatics associated with high doses of isoprenaline in the 1960s and fenoterolin the 1970s and 1980s, the specific β₂-agonists are vital drugs in asthma management. The short-acting β₂-agonists have an important prophylactic role in the prevention of exercise-induced bronchoconstriction, and are essential in the emergency treatment of severe asthma. However, little if any benefit seems to be derived from regular use of short-acting β₂-agonists and regular or frequent use can increase the:severity of the condition. The development of β₂-agonists with long-acting properties, such as salmeterol and formoterol, has provided advantages over short-acting β-agonists, such as prolonged bronchodilation, reduced day-and night-time symptoms and improved quality of sleep, and has reduced the requirement for short-acting β₂-agonists as relief medication. Both drugs are well tolerated and, when added to inhaled corticosteroids, produce greater improvement in lung function than increased steroid dose alone. Because of its rapid onset of action, formoterol also has the potential to be used for as-needed bronchodilator therapy in asthma.     

Elevated blood lactate in COPD exacerbations associates with adverse clinical outcomes and signals excessive treatment with β2-agonists

Background and Objective

Raised blood lactate secondary to high dose β₂-agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and β₂-agonist treatments during AECOPD.

Methods

Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, β₂-agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with β₂-agonist dosages.

Results

Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV₁ (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative β₂-agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01).

Conclusion

Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of β₂-agonists. Raised lactate may indicate excessive β₂-agonist treatment and should now be investigated as a possible biomarker.     

Meta-analysis: Anticholinergics, but not β-agonists, reduce severe exacerbations and respiratory mortality in COPD

BACKGROUND: Anticholinergics and β2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD). OBJECTIVE: To assess the safety and efficacy of anticholinergics and β2-agonists in COPD. DESIGN: We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or β2-agonist use compared with placebo or each other in patients with COPD. MEASUREMENTS: We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event. RESULTS: Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. β2-Agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with β2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of β2-agonist to anticholinergic use did not improve any clinical outcomes. CONCLUSION: Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while β2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and β2-agonists may be associated with worsening of disease control.     

Comparison between montelukast and tiotropium as add-on therapy to inhaled corticosteroids plus a long-acting β2-agonist in for patients with asthma

Objective: Asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS) alone or with ICS plus a long-acting β₂-agonist (LABA). The recommended alternative is the addition of either montelukast or tiotropium. The aim of this study was to compare the effects of montelukast and tiotropium on airway inflammation and remodeling in persistent asthma. Methods: Eighty-seven patients with asthma were treated with budesonide and formoterol (640/18?μg); then, the patients were randomly allocated to three groups to receive oral montelukast (10?mg/day), inhaled tiotropium (5?μg/day), or no add-on to the maintenance therapy for 48 weeks. Fractional exhaled nitric oxide (FeNO) and pulmonary function were measured, and quantitative computed tomography was performed. Results: Compared to the maintenance therapy, add-on montelukast significantly decreased FeNO (p?<?0.05) and improved airflow obstruction (p?<?0.05), whereas airway dimensions remained unchanged. Changes in FeNO were significantly correlated with changes in FEV₁ (r?=??0.71, p?<?0.001). In contrast, the addition of tiotropium significantly decreased airway wall area corrected for body surface area (WA/BSA) (p?<?0.05), decreased wall thickness (T/√BSA) (p?<?0.05) and improved airflow obstruction (p?<?0.05) with no change in FeNO. Changes in WA/BSA and T/√BSA were significantly correlated with the change in percentage predicted FEV₁ (r?=??0.84, p?<?0.001 and r?=??0.59, p?<?0.01, respectively). Conclusions:Adding either montelukast or tiotropium to ICS/LABA may provide additive benefits with respect to the pulmonary function and airway inflammation or remodeling in patients with asthma.     

A comparison of the efficacy of long-acting β2-agonists: eformoterol via Turbohaler® and salmeterol via pressurized metered dose inhaler or Accuhaler®, in mild to moderate asthmatics

Four hundred and sixty nine patients were randomized to receive either 12 μg bd of eformoterol (Oxis^®, Astra Pharmaceuticals Ltd., Kings Langley, U.K.) delivered via Turbohaler^® or 50 μg bd salmeterol (Serevent^®, Glaxo-Wellcome Ltd., Uxbridge, U.K.) via either the Accuhaler^® (Glaxo-Wellcome Ltd.) or pressurized metered dose inhaler (pMDI, Glaxo-Wellcome Ltd.) for 8 weeks. This was followed by a 4-week cross-over period when patients who had received salmeterol in the previous 8 weeks were given eformoterol and patients who had received eformoterol were given either salmeterol via the Accuhaler^® or pMDI to assess patient device and treatment preference.For the primary efficacy variable, the increase in peak expiratory flow (PEF) rate from run-in to 8 weeks, similar significant improvements were seen in all three treatment groups. Eformoterol Turbohaler^® (FT) achieved a greater increase in morning PEF than salmeterol Accuhaler^® (SA) from randomisation to 4 weeks; the increase shown in the eformoterol Turbohaler^® group was 28·91 min⁻¹ compared to 19·91 min⁻¹ for the salmeterol Accuhaler^® group. The addition of eformoterol Turbohaler^® 12 μg bd, to patients' existing asthma therapy was found to have a significantly more beneficial effect on the severity of patients' daytime asthma symptoms than had salmeterol Accuhaler^® 50 μg bd (P=0·014). Eformoterol Turbohaler^® reduced the severity of daytime asthma symptoms by 42% after only 4 weeks of treatment. The patients in the eformoterol Turbohaler^® treated group experienced a higher percentage of days when they were symptom-free and did not use their short-acting bronchodilator to relieve symptoms (32·8, 24·1 and 28·0% in the FT, SA and SM groups, respectively). At 8 weeks there were no significant differences in any of these variables between the three groups.Patients in all the treatment groups gained an additional 1-1·5 nights undisturbed by asthma per week. The changes in sleep disturbance were not significantly different between the three treatment groups.In addition to the therapeutic benefits provided by eformoterol Turbohaler^® the device (Turbohaler^®) was the significant preference of patients given both Turbohaler^® and pMDI (P=0·0168) and was also considered to be significantly more convenient to carry around than the Accuhaler^® (P<0·0001). No other differences were found between the three devices.The results of this study demonstrate that the addition of a long-acting β₂-agonist is an effective tool for achieving the goals of asthma treatment. Eformoterol via the Turbohaler^® is at least as effective as salmeterol via either the Accuhaler^® or the pMDI in achieving these goals.     

The role of autophagy in β-cell lipotoxicity and type 2 diabetes

Autophagy, a ubiquitous catabolic pathway involved in both cell survival and cell death, has been implicated in many age-associated diseases. Recent findings have shown autophagy to be crucial for proper insulin secretion and β-cell viability. Transgenic mice lacking autophagy in their β-cells showed decreased β-cell mass and suppressed glucose-stimulated insulin secretion. Several studies showed that stress can stimulate autophagy in β-cells: the number of autophagosomes is increased in different in vivo models for diabetes, such as db/db mice, mice fed high-fat diet, pdx-1 knockout mice, as well as in in vitro models of glucotoxicity and lipotoxicity. Pharmacological and molecular inhibition of autophagy increases the susceptibility to cell stress, suggesting that autophagy protects against diabetes-relevant stresses. Recent findings, however, question these conclusions. Pancreases of diabetics and β-cells exposed to fatty acids show accumulation of abnormal autophagosome morphology and suppression of lysosomal gene expression suggesting impairment in autophagic turnover. In this review we attempt to give an overview of the data generated by others and by us in view of the possible role of autophagy in diabetes, a role which depending on the conditions, could be beneficial or detrimental in coping with stress.     

Is the increase in bronchial responsiveness or FEV1 shortly after cessation of beta2-agonists reflecting a real deterioration of the disease in allergic asthmatic patients? A comparison between short-acting and long-acting beta2-agonists

Regular use of beta2-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased forced expiratory volume in 1 sec (FEV1). It has been suggested that these possible detrimental effects are not a real deterioration of the disease, but that it might be only a transient (rebound) effect shortly after discontinuing this regular use. Moreover, these effects are thought to occur especially during short-acting and not during long-acting beta2-agonists use. The aim of this study was to invest gate whether a rebound effect (a pharmacological deterioration effect diminishing after several hours) in FEV1 and PC20 (concentration of histamine causing a 20% fall in FEV1 with regard to baseline) occurred after cessation of regular use of beta2-agonists, and whether this occurred both after short-acting and long-acting beta2-agonists. Allergic asthmatic patients (n = 134) were randomly allocated to the use of a short-acting (salbutamol), a long-acting beta2-agonist (formoterol) or placebo for 12 weeks (double-blind, double-dummy). No other asthma medication was allowed, including inhaled corticosteroids. At the start and every 4 weeks later FEV and PC20 were measured, each time at least 12 h after the last doses of study medication, which is in the possible rebound period. To investigate whether a (transient) rebound effect occurred, parameters were additionally measured at least 72 h later after discontinuation of the study medication. After 12 weeks of short-acting beta2-agonist use, a drop was seen in FEV1 from 85.6 (+/- 2.21)% predicted to 78.8 (+/- 2.9)% predicted, measured 15 h (median) after the last doses of medication. This was significantly different compared to placebo. When measured 168 h (median) later FEV1 recovered to 85.5 (+/- 2.4)% predicted, comparable to baseline. PC20 decreased with -1.17 (+/- 0.44) doubling dose after 12 weeks of short-acting beta2-agonist use, measured 15 h after the last doses of medication, which was significantly different compared to placebo. However, 168 h later PC20 recovered slightly with +0.55 (+/- 0.34) doubling dose, but this value was still lower compared to placebo. In contrast, during long-acting beta2-agonist and placebo use no significant changes were seen. In conclusion, the use of short-acting beta2-agonists resulted in a transient (rebound) effect in FEV while the effects on PC20 may point to a real deterioration of the disease. Long-acting beta2-agonist and placebo use showed no changes.We conclude that a mono-therapy of short-acting and not of long-acting beta2-agonists might have deleterious effects in asthma.     

Dual dopamine D2 receptor and β2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease: the pre-clinical rationale

This paper describes the rationale for the development of dual dopamine D₂-receptor and β₂-adrenoceptor agonists as potential treatments for the symptoms of chronic obstructive pulmonary disease (COPD). The putative involvement of pulmonary sensory afferent nerves in mediating the key COPD symptoms of breathlessness, cough and excess sputum production is outlined and the hypothesis that activation of D₂-receptors on such nerves would modulate their activity is developed. This premise was tested, in a range of animal models, using the first of a novel class of dual dopamine D₂-receptor and β₂-adrenoceptor agonists, sibenadet HCI (Viozan™, AR-C68397AA). In the course of these studies it was demonstrated that sibenadet, through activation of D₂-receptors, inhibited discharge of rapidly adapting receptors and was effective in reducing reflex-induced tachypnoea, mucus production and cough in the dog. Sibenadet, through its activation of β₂-adrenoceptors, was also shown to be an effective bronchodilator with a prolonged duration of action following topical administration to the lungs. These studies also indicated that sibenadet had a wide therapeutic ratio with respect to expected undesirable side-effects such as emesis and cardiovascular disturbances. These results provided a compelling rationale for the initiation of a clinical development programme with sibenadet for the treatment of COPD.