Tolerability Profiles of Leukotriene Receptor Antagonists and Long-Acting β2-Adrenoceptor Agonists in Combination with Inhaled Corticosteroids for Treatment of Asthma: A Review

Inhaled corticosteroids, long-acting β₂-adrenoceptor agonists, and leukotriene receptor antagonists are widely used for treatment of asthma. Inhaled corticosteroids are recommended as first-line therapy, whereas long-acting β₂-adrenoceptor agonists and leukotriene receptor antagonists are indicated as add-on therapy in patients not adequately controlled with corticosteroids alone. A number of studies have investigated the efficacy of combinations of these drugs in asthma, but several issues concerning the safety of these treatments are highly debated. This review provides a critical appraisal of the tolerability profiles of long-acting β₂-agonists and leukotriene receptor antagonists used in combination with inhaled corticosteroids for the treatment of asthma.     

Comparison of Mometasone Furoate Dry Powder Inhaler and Fluticasone Propionate Dry Powder Inhaler in Patients with Moderate to Severe Persistent Asthma Requiring High-Dose Inhaled Corticosteroid Therapy: Findings from a Noninferiority Trial

Background. Inhaled corticosteroids (ICSs) are one of the suggested first-line therapies for patients with persistent asthma of moderate severity. Methods: The efficacy and safety of mometasone furoate (MF) 400 μg twice daily (BID) and fluticasone propionate (FP) 500 μ g BID administered for 12 weeks via dry powder inhaler (DPI) were compared in a noninferiority trial, in adults with moderate-to-severe persistent asthma. The primary variable was the change from baseline in am peak expiratory flow rate (PEFR). pm PEFR, forced expiratory volume in 1 second (FEV₁), asthma symptoms, rescue medication use, response to therapy, exacerbation rates, and adverse events were also assessed. Results. The lower bound of 95% CIs for treatment differences in the primary variable ranged from 2.6% to 5.6% throughout the 12-week study and were within the prespecified noninferiority range. No significant between-group differences were observed in lung function, rescue medication use, response to therapy, exacerbation rates, or adverse events. At most of the weeks assessed, there were no between-group differences in asthma symptoms. Most adverse events were mild-to-moderate. Conclusion. MF-DPI 400 μ g BID was therapeutically equivalent to FP-DPI 500 μ g BID in patients with moderate-to-severe persistent asthma.     

Salivary IgA and Oral Candidiasis in Asthmatic Patients Treated with Inhaled Corticosteroid

Background. Inhaled corticosteroids are used for the treatment of bronchial asthma. Systemic side effects are rare, but local problems, such as oral candidiasis, can occur. Only a proportion of patients encounter this problem, and the mechanism of oral candidiasis induced by inhaled corticosteroids remains obscure. According to reports in immunodeficient patients, oral candidiasis is related to deficiencies in topical immunity, such as salivary IgA. Objectives. We evaluated differences in salivary IgA between asthmatics in whom Candida was detected or not detected from the pharynges, respectively. Methods. Saliva was collected from 18 healthy controls and 37 asthmatic patients treated with inhaled corticosteroids. The amounts of total IgA and the Candida-specific IgA of the saliva were measured. Fungal culture of the pharyngeal wall was also performed. Results. There were no differences in salivary total IgA and Candida-specific IgA between healthy controls and culture-negative asthmatic patients. Salivary total IgA of Candida-positive asthmatic patients was significantly lower than that of Candida-negative patients. However, there was no difference in Candida-specific IgA levels between these two groups. Conclusions. Our results suggest that inhaled corticosteroids can potentially decrease salivary total IgA but that host factors are also important in the development of oral candidiasis.     

5岁以下儿童支气管哮喘诊断和治疗的挑战及应对策略

肺功能检查对5岁以下儿童支气管哮喘（简称哮喘）诊断的不可靠性以及缺少明确哮喘标记物。导致该年龄段儿童哮喘诊断困难，其诊断主要依赖于症状、是否存在哮喘危险因素以及治疗的反应性。儿童哮喘系列指南对于5岁以下儿童哮喘长期治疗推荐使用吸人型糖皮质激素（ICS）和白三烯调节剂。但是，我们亦要重视ICS和白三烯调节剂持续或间歇治疗对5岁以下儿童哮喘治疗存在的一些“阴性”结果。针对5岁以下儿童哮喘，临床实践过程之中在选择合适治疗方案，需要考虑患儿疾病严重程度、为间歇性喘息抑或持续性喘息、是否哮喘预测指数阳性等因素。     

Anti-inflammatory pharmacotherapy for wheezing in preschool children

Accumulating evidence indicates that there are at least two phenotypes of wheezing in preschool years with distinct natural history. Frequent wheezing in the first 3 years of life with risk factors for asthma (e.g., eczema, maternal asthma) predicts symptoms in older age, while infrequent viral-associated wheezing without risk factors for asthma has a benign prognosis. This systematic review summarizes evidence on the use of anti-inflammatory medications in preschool children with wheezing. Literature search was performed using Medline and the Cochrane Library. Retrieved articles were critically appraised. Episodic use of high-dose inhaled corticosteroids (>1,600 mcg/day of beclomethasone) may ameliorate severity of intermittent viral-associated wheezing. Maintenance inhaled corticosteroids can control symptoms in children with frequent wheezing associated with risk factors for asthma. Inhaled corticosteroids do not alter the natural history of wheezing even when started early in life and could have a negative impact on linear growth rate. Short courses of oral corticosteroids have been proposed as an effective measure to control exacerbations of symptoms although there is little evidence supporting their use. Some studies support the administration of non-steroidal anti-inflammatory medications (leukotriene pathway modifiers, cromones, methylxanthines) for mild frequent wheezing. Maintenance inhaled corticosteroids is the most effective measure for controlling frequent wheezing in preschool children, especially when accompanied by risk factors for asthma. This treatment does not affect the natural history of wheezing, although deceleration of linear growth rate is the most commonly recognized systemic adverse effect.     

Treating the patient with asthma.

Treatment of patients with asthma, although straight-forward, is a challenge. The treatment is prolonged, often for life, and must be taken regularly. For low-income countries, the treatment must be efficient and feasible. Two drugs are indicated: one to reduce the inflammation and one to relieve the airflow obstruction. The treatment and its goals need to be explained to the patient with asthma and to family members, as the success of treatment is dependent on their cooperation. The medications that reduce inflammation are corticosteroids. Inhaled beclomethasone 250 microg per puff is indicated for every patient who has persistent asthma. The medication recommended for relief of airflow obstruction is inhaled salbutamol/100 microg per puff. A four-step approach to treatment is indicated, starting with the dose of medication indicated by the degree of severity of the asthma, and periodically adjusted. When the condition improves and remains stable for at least 3 months, the dose of medication may be reduced to fit the grade of severity assessed at that time. In the event the condition worsens, the treatment is increased stepwise. This approach to treatment has every promise to improve the life and health of patients with asthma.     

Step-up and step-down treatments for optimal asthma control in children and adolescents

Objective: To review therapeutic options for stepwise management of pediatric asthma in the context of this population’s unique needs such as potential effects of asthma, treatments, or both on growth and psychosocial development, and caregiver involvement. Data sources and study selection: We conducted PubMed searches to identify relevant articles then reviewed resultant articles, guidelines for asthma management in children, and articles from personal files. Results: Stepwise management of asthma, similar to adults, is recommended for children in current global and US guidelines. Treatment may be stepped up or stepped down temporarily or long-term based on response over time. Inhaled corticosteroids remain the recommended treatment for persistent childhood asthma and any potential small effects on growth are considered relatively minor compared with their benefit. Controller medication options for patients <18?years old are limited, especially for Global Initiative for Asthma Steps 2–5. The long-acting antimuscarinic antagonist tiotropium (Steps 4/5, patients aged ≥12?years) and in certain circumstances (Step 5), anti-immunoglobulin E (aged ≥6?years) and interleukin-5 antibodies (aged ≥12?years) are newer treatment options. Tiotropium is indicated in the United States and Europe for patients ≥6?years old. Stepping down treatment, which is recommended but infrequently practiced, can maintain symptom control and minimize adverse events while substantially reducing costs. Patient education and better monitoring remain important for self-management and optimum outcomes. Conclusion: A need exists to target individual treatment goals for children with asthma by using step-up and step-down approaches to maximize treatment benefits and minimize potential adverse effects.     

Tolerability Profiles of Leukotriene Receptor Antagonists and Long-Acting β2-Adrenoceptor Agonists in Combination with Inhaled Corticosteroids for Treatment of Asthma: A Review

Inhaled corticosteroids, long-acting β₂-adrenoceptor agonists, and leukotriene receptor antagonists are widely used for treatment of asthma. Inhaled corticosteroids are recommended as first-line therapy, whereas long-acting β₂-adrenoceptor agonists and leukotriene receptor antagonists are indicated as add-on therapy in patients not adequately controlled with corticosteroids alone. A number of studies have investigated the efficacy of combinations of these drugs in asthma, but several issues concerning the safety of these treatments are highly debated. This review provides a critical appraisal of the tolerability profiles of long-acting β₂-agonists and leukotriene receptor antagonists used in combination with inhaled corticosteroids for the treatment of asthma.     

Managing a variable disease

Asthma varies in severity over time; consequently, treatment regimens must be sufficiently flexible to be adjusted when necessary. At present, inhaled corticosteroids (ICS) remain the cornerstone of asthma therapy and optimal treatment strategies must consider total daily dose and dosing frequency. The dose responsiveness to ICS varies for different indices of asthma. Symptoms and lung function respond readily to low-dose ICS and the dose-response curve is relatively flat. In contrast, the prevention of asthma exacerbations displays a more pronounced dose-response relationship. In mild asthma, once-daily dosing with budesonide is as effective as twice-daily dosing. However, in moderate-to-severe asthma, four-times daily dosing is better than twice-daily dosing for obtaining maximal benefit with minimal side effects. A flexible treatment regimen, consisting of low-dose maintenance treatment combined with high dose and frequently dosed ICS at the earliest sign of an exacerbation, has been shown to be effective. This could be achieved using a single inhaler combination product if the beta(2)-agonist moiety allows for the same flexibility in dosing. Formoterol, with its wide dose range, rapid onset and long duration of effect, has the pharmacological features that permit this versatile, flexible dosing. As a result, Symbicort would seem to offer the flexibility required in a single inhaler for maintenance and reliever purposes in the management of this variable disease.     

Strategies for the management of asthma

Abstract The aims of treating patients with asthma are to relieve symptoms, to prevent symptoms and exacerbations, and to prevent long-term deterioration in lung function. It is the role of medical practitioners to inform the patient what asthma is, and to develop a plan to achieve the aims for the individual, recognizing that asthma is frequently a chronic, lifelong disease. Most patients can be diagnosed, assessed for severity and causes, and treated in primary care practices, however sometimes help from an asthma clinic or a specialist is required. The most important management decision is to determine whether the patient needs inhaled corticosteroids; subsequently, decisions about dose, duration and method of delivery of treatment can be tailored to the individual depending on the preferences and social conditions of the patient. The aim of this article is to present the latest strategies for the management of asthma and the simplest methods for their implementation. Important new strategies include careful assessment of the severity; the immediate introduction of a plan that is tailored for the individual and aimed at the possible reversing of the disease; detailed instructions for management of exacerbations and the combined use of inhaled corticosteroids with a long-acting bronchodilator. It is becoming clear that these strategies obviate dependence on oral corticosteroids in newly diagnosed asthmatic patients. Furthermore, relatively low doses of inhaled corticosteroids can be used to maintain good control if used in conjunction with other therapies. The role of newly developed antagonists to leukotrienes is not yet known but it may well be useful in mild asthma and in special forms of the disease, such as those sensitive to aspirin. In the future, the most important strategy will be to prevent the disease.     

Effects of corticosteroids on lung function in asthma and chronic obstructive pulmonary disease

Both oral and inhaled corticosteroids have clinically significant effects on symptoms, exacerbations, health status, and lung function in asthma, and to a lesser extent in chronic obstructive pulmonary disease (COPD). Change in FEV(1) does not correlate well with functional tests in COPD and may not be the best measure of response to treatment. Inhaled corticosteroids may be beneficial when added to a beta-agonist for treatment of acute asthma, and the efficacy of oral corticosteroids in this setting is well established. Oral corticosteroids inconsistently improve lung function in stable outpatients with COPD. Individual inhaled corticosteroids do not have a marked effect, but the combination of fluticasone propionate and salmeterol and the combination of budesonide plus formoterol seem to improve FEV(1) over treatment with the individual components. In addition, there is convincing evidence for the use of systemic corticosteroids during acute exacerbations of COPD. Some evidence suggests that patients with COPD who respond to corticosteroids have eosinophilic inflammation and other attributes of an asthma phenotype.     

Causative and contributive factors to asthma severity and patterns of medication use in patients seeking specialized asthma care

STUDY OBJECTIVES: (1) To assess the prevalence of specific factors considered causative or contributive to asthma in a population of patients seen in a specialized asthma clinic, and to determine whether any of these factors were associated with more severe disease; and (2) to assess the utilization of inhaled steroids by asthma severity in this population and compare it with published guidelines of the National Heart, Lung, and Blood Institute (NHLBI). DESIGN, SETTING, AND PATIENT POPULATION: We conducted a retrospective chart review of new patients seen in a specialized asthma treatment center over a 2.5-year period and recorded the prevalence of 14 causative or contributive factors, the severity of asthma, and the intensity of treatment with inhaled corticosteroids in each patient. Patients were grouped as mild asthma vs moderate/severe asthma and compared by chi(2) analysis and stepwise logistic regression to determine whether certain factors were associated with more severe asthma. MEASUREMENTS AND RESULTS: The average number of factors recorded was 2.9 +/- 1.8 in the mild group (+/- SD) and 3.5 +/- 1.6 in the moderate/severe asthma group. This difference was statistically significant (p = 0.014). Increasing age, male gender, symptomatic gastroesophageal reflux disease (GERD), and chronic sinusitis were independently associated with more severe asthma. Suboptimal use of inhaled corticosteroids was more common in patients with mild persistent asthma, but suboptimal dosing of inhaled corticosteroids was equally common in mild and moderate/severe asthma. No relationship was found between allergen sensitization combined with exposure to cats, dogs, dust mite, or molds and more severe asthma. CONCLUSIONS: This study confirms earlier studies showing that symptomatic GERD and chronic sinusitis are important comorbid conditions in patients with asthma, both being associated with greater asthma severity. This study further shows that the doses of inhaled corticosteroids used for treatment of asthma fall short of NHLBI guidelines in the majority of patients regardless of asthma severity.     

Inhaled Corticosteroids for Asthma: Common Clinical Quandaries

This narrative review provides evidence-based explanations to some of the common clinical concerns regarding inhaled corticosteroids. Inhaled corticosteroids are the treatment of choice for a newly diagnosed asthmatic patient. Better results are obtained when treatment is initiated as soon as the diagnosis is made. Asthma control can be achieved and maintained in most patients with a low or moderate dose of inhaled corticosteroid administered in two daily doses. Longer duration of treatment provides more sustained benefits than treatment that is intermittent and for short periods of time. The clinical benefits can be observed within 24 hours of commencing treatment and may be more pronounced in patients with an eosinophilic bronchitis. Inhaled corticosteroids provide additional benefit when used in conjunction with prednisone in acute severe asthma. Low doses do not have clinically deleterious side effects on the bones, growth, eye, or hypothalamo-pituitary-adrenal-axis. However, they do not normalize lung function and prevent structural changes in the airway wall in all asthmatic patients.     

Effect of corticosteroids on exacerbations of asthma and chronic obstructive pulmonary disease

Periodic exacerbations of disease severity, which may lead to hospitalization, are a characteristic feature of asthma and chronic obstructive pulmonary disease (COPD), becoming more prevalent as disease severity increases. Oral corticosteroids increase the rate of resolution of these episodes in both diseases. Inhaled corticosteroids are much less effective at conventional doses and are not recommended as a primary treatment for exacerbations of either disease. Maintenance therapy with inhaled corticosteroids significantly reduces the chance that a further exacerbation will occur in asthma. In general, increasing doses of inhaled corticosteroids are more effective than placebo therapy in preventing exacerbations, at least until patients become persistently symptomatic and regular users of inhaled corticosteroid therapy. Thereafter, the gains from doubling the dose of inhaled corticosteroid maintenance therapy are modest and generally inferior to those that result from adding other antiinflammatory or bronchodilator agents to the treatment regime. The reduction in the incidence of exacerbations with inhaled corticosteroids, compared with placebo, ranges from 15 to 20% in COPD versus almost 50% in severe asthma. However, given the impact of exacerbations on overall quality of life in COPD, even this modest reduction is likely to be clinically important.     

Reassessment of Theophylline Use for Severe Asthma Exacerbation: Is It Justified in Critically Ill Hospitalized Patients?

In the 1990s, numerous double-blind, randomized, placebo-controlled trials revealed that theophylline therapy offered no benefit to inhaled beta₂ agonists and systemic corticosteroids in the treatment of patients hospitalized for asthma exacerbations. Routine use of theophylline in patients hospitalized for asthma is no longer advocated due to the potential for serious adverse effects and lack of benefit. However, the question remains whether this drug adds any benefits in critically ill patients who are being admitted to an intensive care unit. Two recent pediatric studies suggest that theophylline therapy may have a role in the management of patients with impending respiratory failure who have failed aggressive treatment with inhaled beta₂ agonists, systemic corticosteroids, and inhaled ipratropium. If a patient has failed to respond adequately to high-dose routine therapies, theophylline should be initiated by a clinician who is competent in dosing, monitoring serum concentrations, and assessing factors that modify clearance of this high-risk drug. Further clinical research is needed to verify the value of theophylline in adults and children with severe asthma exacerbations and impending respiratory failure.     

支气管哮喘患者吸入性糖皮质激素疗效与基因多态性研究进展

支气管哮喘(简称哮喘)是一种多基因疾病。吸入性糖皮质激素是哮喘治疗的一线药物,但哮喘患者吸入性糖皮质激素的疗效则各有不同,本文就哮喘患者吸入性糖皮质激素疗效与基因多态性关系的研究进展作一综述。     

The dose-response relationship of inhaled corticosteroids in asthma

Inhaled corticosteroids are the only class of asthma medication that can reduce symptoms, improve lung function, reduce the frequency of severe exacerbations, including hospital and ICU admissions, and decrease the risk of mortality. The therapeutic dose range for all clinical outcome measures in adults is 100 to 1000 ώg/d of beclomethasone dipropionate or budesonide, or 50 to 500 ώg/d of fluticasone propionate. Doses in excess of this range are not recommended for routine use because they are likely to increase the risk of systemic side-effects without further major improvement in efficacy. The recommendations are qualified by the recognition that there is considerable individual variability in the response to inhaled corticosteroids in asthma, which would suggest that some patients might obtain greater benefit at higher doses, just as some might obtain maximum benefit at lower doses.     

Initial corticosteroid therapy for asthma

PURPOSE OF REVIEW: This review examines the commencement of maintenance pharmacotherapy for asthma: inhaled corticosteroids alone or in combination with long-acting beta2 agonists. RECENT FINDINGS: A systematic review of randomized controlled trials has examined the starting dose of inhaled corticosteroids (high, moderate, low) and the dose regimen (step down versus constant) in asthma. There was no significant difference in key asthma outcomes for step down compared with a constant inhaled corticosteroid dose. There was no significant difference between high or moderate dose inhaled corticosteroid groups (n=11) for morning peak expiratory flow, symptoms and rescue medication use. There may be a benefit from high-dose inhaled corticosteroids for airway hyperresponsiveness. There was a significant improvement in peak expiratory flow and nocturnal symptoms in favour of a moderate inhaled corticosteroid dose compared with low-dose treatment. Long-acting beta2 agonists combined with inhaled corticosteroids as initial asthma therapy has been examined in a systematic review of nine randomized controlled trials. Inhaled corticosteroids combined with long-acting beta2 agonists led to significant improvements in forced expiratory volume in 1 s, morning peak expiratory flow, symptom score and symptom-free days but no difference in exacerbations requiring oral corticosteroids. A randomized controlled trial of patients with uncontrolled asthma found a benefit of escalating doses of salmeterol/fluticasone compared with fluticasone on asthma control. SUMMARY: Initial inhaled corticosteroid therapy should begin with a constant, moderate dose. Initial therapy with long-acting beta2 agonist and inhaled corticosteroids achieves superior improvement in symptoms and lung function, and at a quicker rate than inhaled corticosteroids alone. There is no benefit in terms of reduced exacerbations unless an escalating inhaled corticosteroid dose strategy is used.     

Inhaled Corticosteroids versus Leukotriene Antagonists as First-Line Therapy for Asthma

Inhaled corticosteroids are the most effective anti-inflammatory drugs for asthma. Leukotriene receptor antagonists are a new class of anti-inflammatory drugs that have the advantage of oral administration and the potential for better compliance compared with inhaled corticosteroids. This article summarizes evidence from randomized controlled trials, comparing the efficacy and tolerability of inhaled corticosteroids with those of leukotriene receptor antagonists in patients with persistent asthma. The evidence derived from a systematic review of randomized controlled trials confirms that patients treated with inhaled corticosteroids of chlorofluorocarbon-propelled beclomethasone 400 mug/day or fluticasone propionate 200 mug/day have better asthma control than those treated with oral leukotriene receptor antagonists. More specifically, treatment with inhaled corticosteroids is associated with 65% fewer exacerbations requiring systemic corticosteroids, greater improvement in spirometry and symptoms, fewer night-time awakenings and less use of rescue beta(2)-adrenoceptor agonists. This review does not identify any difference in short-term safety between inhaled corticosteroids and leukotriene receptor antagonists. Although adverse effects typically associated with inhaled corticosteroids (such as growth suppression, osteopenia, and adrenal suppression) were not measured, preventing a fair comparison of the safety profile on long-term use.In conclusion, the scientific evidence does not support the substitution of leukotriene receptor antagonists for low doses of inhaled corticosteroids, which should remain first-line therapy for asthma control.     

Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.