New perspectives in pharmacological treatment of mild persistent asthma

Until the relationship between symptoms, lung function tests, airway inflammation, airway hyper-responsiveness (AHR), exacerbations and remodelling is clarified, regular treatment seems to enable a greater disease control than on-demand therapy in most patients with mild persistent asthma. Current guideline classification based on disease severity remains a cornerstone in asthma management. However, the heterogeneity of asthma, the growing emphasis on subphenotypes, including molecular phenotypes identified by -omics technologies, and their possible implications in terms of different asthma severity, progression and therapeutic response, are changing current asthma treatment mainly based on disease severity classification to a pharmacological strategy more focused on the individual patient.     

孟鲁司特纳治疗小儿轻、中度持续性哮喘分析

目的研究孟鲁司特纳治疗小儿轻、中度持续性哮喘的效果。方法根据双盲随机分组原则将2016年8月～2017年7月本院接收的轻、中度持续性哮喘患儿104例分为对照组(常规对症治疗)和观察组(加用孟鲁司特纳治疗),每组52例。将两组的临床效果、实验室指标、肺功能指标、不良反应发生情况、复发情况进行比对。结果观察组轻、中度持续性哮喘患儿的临床总有效率、治疗后的IL-12、FEV1高于对照组(P 0.05),治疗后的IL-4、Ig E水平以及复发率低于对照组(P 0.05);治疗后的肺功能指标明显优于治疗前(P 0.05),两组均无明显不良反应发生。结论孟鲁司特纳应用于小儿轻、中度持续性哮喘治疗中安全有效。     

孟鲁斯特治疗小儿轻中度持续哮喘的临床疗效

目的探讨孟鲁斯特治疗小儿轻中度持续性哮喘的临床效果。方法选取2012年5月～2013年7月收治的轻中度持续哮喘患儿98例,随机分为两组,对照组46例患儿给予布地奈德气雾剂进行常规治疗,观察组52例在对照组常规治疗的基础上,再给予口服孟鲁斯特钠片进行治疗。比较两组患儿的治疗效果。结果观察组患儿的临床总有效率为94．2％,显著高于对照组的76．1％,差异有统计学意义（P〈0．05）;经治疗跟踪观察,对照组患儿嗜酸性粒细胞及血清IgE水平均显著高于观察组,差异具有统计学意义（P〈0．05）。结论孟鲁司特在治疗小儿轻中度持续性哮喘时效果显著。     

Daily versus intermittent corticosteroids for the treatment of mild persistent asthma

Asthma is a chronic disease of the airways in which inflammation causes bronchial hyper-reactivity and attacks of wheezing, dyspnea and chest tightness that are triggered by various agents. It requires both acute treatment of the paroxistical respiratory symptoms with reliever medications and maintenance treatment, which is aimed at achieving an optimal disease control and consists of controller medications with regimens and dosages that are tailored according to disease severity. Inhaled steroids represent the main controller medication and are recommended to be given even in mild asthma on a daily basis in order to improve lung function, reduce asthma exacerbations and symptoms, and improve the quality of life. Intermittent regimens could also be used and the currently discussed study compares these two regimens in terms of clinical efficacy.     

采用布地奈德与孟鲁司特治疗儿童轻度持续性哮喘的效果比较

目的比较布地奈德与孟鲁司特治疗儿童轻度持续性哮喘的临床疗效。方法选择2016年6月~2017年6月在我院诊断治疗的儿童轻度持续性哮喘患儿80例为研究对象,随机分为布地奈德组与孟鲁司特组各40例。布地奈德组给予吸入用布地奈德混悬液治疗,孟鲁司特组给予孟鲁司特片口服。比较治疗前、治疗后血EOS水平及呼出气一氧化氮(Fe No)水平,日间症状评分与夜间症状评分。结果两组治疗后日间症状评分与夜间症状评分显著低于治疗前,差异有统计学意义(P<0.05)。两组治疗后血EOS水平显著低于治疗前,差异有统计学意义(P<0.05);治疗后布地奈德组血EOS水平显著低于孟鲁司特组,差异有统计学意义(P<0.05)。布地奈德组治疗后Fe No水平显著低于治疗前,差异有统计学意义(P<0.05);治疗后布地奈德组Fe No水平显著低于孟鲁司特组,差异有统计学意义(P<0.05)。结论布地奈德与孟鲁司特治疗儿童轻度持续性哮喘均能有效改善临床症状,但布地奈德能降低嗜酸性粒细胞水平以及Fe No水平。     

Beclomethasone dipropionate versus budesonide inhalation suspension in children with mild to moderate persistent asthma

Inhaled steroids are the most effective long-term treatment of persistent asthma but many children are unable to use correctly the available inhalers. Administration of nebulized corticosteroids has some advantages over the administration with pressurised metered-dose inhalers (pMDls). The objective of this multicenter randomised study was to compare the efficacy and tolerability of nebulized corticosteroids in paediatric patients with asthma. 127 patients aged > or = 6 and < or = 14 years with a diagnosis of mild to moderate persistent asthma (PEFR % predicted > 50% and < 85%) and positive response to the reversibility test were randomized. The patients were assigned by randomisation to one of the two treatment groups (4 weeks): beclomethasone dipropionate (BDP) 800 microg/daily b.i.d. (n = 66) or budesonide (BUD) 1000 microg/daily b.i.d. (n = 61) both administered by nebulizer. The primary efficacy end point was the final mean of PEFR measured at clinical visit (clinic PEFR). In the BDP group clinic PEFR increased from 177.5 +/- 80 L/min to 246.6 +/- 84.2 L/min (p < 0.001 vs baseline), while in the BUD group the increase was from 180.4 +/- 77.8/min to 260.9 +/- 84.1 L/min (p < 0.001 vs baseline) (NS between treatments). FEV1 (% predicted) increased from 77.8% to 92.7% (p < 0.001 vs baseline) and from 74.1% to 95.9% (p < 0.001 vs baseline) in BDP and BUD group respectively (NS between treatments). Patients reduced the use of salbutamol rescue medication by 76% and 81% in BDP and BUD group respectively (p < 0.001 vs baseline, NS between treatments). 4 patients in the BDP group and 2 in the BUD group reported adverse events (AEs). AEs were mild to moderate and never there was the need to discontinue the treatments. In conclusion the results of this study demonstrate that both BDP (800 microg/daily) and BUD (1000 microg/daily) administered by nebulization are effective and with a acceptable safety and tolerability profile.     

Part III: Location of asthma inflammation and the distal airways: clinical implications

Accumulating evidence suggests that the airway inflammation and remodeling characteristic of asthma occur not only in the central airways, but also in the distal lung and the lung parenchyma. The distal airways are increasingly being recognized as important sites of airflow obstruction. Research indicates that distal inflammation may play a crucial role in airway hyperresponsiveness, nocturnal asthma, and spontaneous exacerbations of asthma symptoms. Although the effectiveness of inhaled corticosteroids in improving asthmatic symptoms and preventing exacerbations is well established, the ability of conventional formulations to reach the distal airways is limited. The impaired ability of these formulations to reach the distal airways may contribute to the observation that inhaled corticosteroids do not always provide adequate control of asthma symptoms. Newer formulations of inhaled corticosteroids that use hydrofluoroalkane (HFA) propellants in solution have greater access to the distal airways and produce beneficial changes in lung function. Due to their highly targeted delivery systems, newer HFA-based formulations have the potential to effectively treat asthma at reduced doses.     

Pharmacokinetic drug evaluation of mepolizumab for the treatment of severe asthma associated with persistent eosinophilic inflammation in adults

Introduction: Mepolizumab is a humanized monoclonal antibody that binds to and inactivates IL-5. It is available as a subcutaneous preparation. The practical application of mepolizumab is as an add-on therapy in the treatment of severe eosinophilic asthma.

Areas covered: This article was created from a comprehensive literature search with information taken from meta-analyses, systematic reviews, and clinical trials of adults. The articles that have been selected evaluate the use of mepolizumab and its role in eosinophilic asthma.

Expert opinion: Mepolizumab is significantly more effective than placebo in reducing exacerbations and need for systemic corticosteroids in severe eosinophilic asthma. There is a lack of head to head studies comparing mepolizumab to other monoclonal anti-IL-5 inhibitors in severe eosinophilic asthma. Post marketing surveillance revealed risk of anaphylaxis that is below 1%.     

体重指数对轻度持续性哮喘儿童吸入布地奈德的疗效影响

目的：进一步探讨了解体重指数对轻度持续性哮喘儿童吸入布地奈德治疗效果的影响。方法：选取本院儿科在2009年1月～2011年1月收治的66例轻度持续性哮喘儿童患者,将所有患儿随机分为3组,正常体重者一组、超重者一组、肥胖者一组,均给予患儿布地奈德吸入治疗,观察所有患儿的肺功能FEV1的差异。结果：3组哮喘患儿在治疗前后其FEV1指标比较,差异有统计学意义（P〈0.05）,治疗后较治疗前FEV1明显增加。肥胖组患儿FEV1增加量和正常体重患儿的增加值比较,差异有统计学意义（P〈0.05）,前者的增加值小于后者的增加值。结论：肥胖因素可能影响布地奈德的治疗效果。     

Flow cytometry of sputum: assessing inflammation and immune response elements in the bronchial airways

Background: The evaluation of sputum leukocytes by flow cytometry (FCM) is an opportunity to assess characteristics of cells residing in the central airways, yet it is hampered by certain inherent properties of sputum including mucus and large amounts of contaminating cells and debris.

Objective: To develop a gating strategy based on specific antibody panels in combination with light scatter properties for flow cytometric evaluation of sputum cells.

Methods: Healthy and mild asthmatic volunteers underwent sputum induction. Manually selected mucus “plug” material was treated with dithiothreitol, filtered and total leukocytes acquired. Multicolor FCM was performed using specific gating strategies based on light scatter properties, differential expression of CD45 and cell lineage markers to discriminate leukocytes from squamous epithelial cells and debris.

Results: The combination of forward scatter and CD45 expression reliably segregated sputum leukocytes from contaminating squamous epithelial cells and debris. Overlap of major leukocyte populations (neutrophils, macrophages/monocytes) required the use of specific antibodies (e.g. CD16, CD64, CD14, HLA-DR) that differentiated granulocytes from monocytes and macrophages. These gating strategies allowed identification of small populations of eosinophils, CD11c+ myeloid dendritic cells, B-cells and natural killer cells.

Conclusions: Multicolor FCM can be successfully applied to sputum samples to identify and characterize leukocyte populations residing on the surfaces of the central airways.

Clinical relevance: This research describes detailed methods to overcome difficulties associated with FCM of sputum samples, which previously has been lacking in the literature. FCM of sputum samples can provide valuable information on inflammation and immunological response elements in the bronchial airways for both clinical diagnostic and research applications and can be a useful tool in inhalation toxicology for assessing health effects of inhaled environmental pollutants.     

Exhaled breath condensate in asthma: from bench to bedside

The need for non-invasive assessment of airway inflammation is imperative, since inflammatory airway diseases, such as asthma and COPD, are characterized by variation in their clinical presentation throughout their course. Exhaled breath condensate (EBC) collection represents a rather appealing method that can be used to conveniently and noninvasively collect a wide range of volatile and non-volatile molecules from the respiratory tract, without affecting airway function or inflammation. Although promising, EBC is currently used only as a research tool, due to the lack of appropriate standardization and the absence of reference values. A large number of mediators of inflammation, oxidative and nitrosative stress, including adenosine, ammonia, hydrogen peroxide, isoprostanes, leukotrienes, prostanoids, nitrogen oxides, peptides and cytokines, have been studied in EBC. This review focuses mainly on the presentation of the above biomarkers in asthma as well as on the effect of various factors on their concentrations. Concentrations of such mediators have been shown to be related to the underlying asthma and its severity and to be modulated by therapeutic interventions. Despite the encouraging positive results up-to-date, the introduction of EBC in everyday clinical practice requires the work-out of some methodological pitfalls, the standardization of EBC collection, and finally the identification of a reliable biomarker which is reproducible, has normal values and provides information for the underlying inflammatory process and the response to treatment. So far none of the parameters studied in EBC fulfils the aforementioned requirements.     

(R)-salbutamol in the treatment of asthma and chronic obstructive airways disease

INTRODUCTION: Asthma and chronic obstructive pulmonary disease (COPD) are inflammatory disorders that have an increasing prevalence and associated morbidity and mortality. β(2)-adrenoceptor agonists (β(2)-agonists) act by stimulating the β(2)-adrenoceptor present on airway smooth muscle and other cells in the airway, resulting in bronchodilatation. β(2)-agonists are among the most commonly used drugs in the world and remain pivotal in the treatment of symptoms in patients with asthma and COPD. Salbutamol is a chiral drug with (R)- and (S)- isomers. Almost all β(2)-agonists that are used at present are racemic mixtures of (R)- and (S)-salbutamol. AREAS COVERED: In this review the authors show that (R)-salbutamol alone (generically known as levosalbutamol) provides beneficial β(2)-agonist effects at a cellular level and in experimental models of airways disease. In addition the authors demonstrate that (S)-salbutamol opposes the desirable effects of (R)-salbutamol and can actually cause features of asthma and COPD in vitro and in experimental asthma. EXPERT OPINION: Despite this strong body of experimental evidence, (R)-salbutamol has not shown consistent superiority over (S)- or racemic salbutamol in human asthma or COPD.     

Ciclesonide in persistent asthma: the evidence of its therapeutic value

INTRODUCTION: Asthma, a respiratory disease associated with airway inflammation and hyperresponsiveness, is one of the most prevalent chronic diseases worldwide affecting both children and adults. Inhaled corticosteroids are considered to be the cornerstone of asthma management. Ciclesonide, an airway-activated inhaled corticosteroid, has been developed for the management of persistent asthma. Its once-daily administration and airway activation may be advantageous in the treatment of asthma. AIMS: The purpose of this article is to review the place in therapy of ciclesonide in the management of patients with persistent asthma based on the available clinical evidence. EVIDENCE REVIEW: The available evidence indicates that ciclesonide has an effect on pulmonary function (forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow), as well as producing improvements in patient-reported symptoms that are equivalent to those achieved with other inhaled corticosteroids. A few studies have focused on health-related quality of life and have demonstrated a positive effect with ciclesonide treatment. Its pharmacokinetic profile may offer advantages in terms of adverse effects, both local and systemic, although most of the data come from 12-week studies. PLACE IN THERAPY: The current evidence shows that ciclesonide offers another alternative among inhaled corticosteroids, with the potential for fewer adverse effects. The unique pharmacokinetic profile of ciclesonide allows once-daily administration and the airway activation of the drug appears to confer clinical benefit in the treatment of asthma. Its lack of systemic adverse effects make it a viable option for pediatric use.     

Racemic salbutamol and levosalbutamol in mild persistent asthma: A comparative study of efficacy and safety

Aim:

The effect of monotherapy with racemic salbutamol and levosalbutamol on symptoms, quality of life, and pulmonary function has been assessed and compared in mild persistent asthma.

Materials and Methods:

A randomized, open, parallel clinical study was conducted on 60 patients of mild persistent asthma. After baseline assessments, salbutamol was prescribed to 30 patients and levosalbutamol to another 30 for 4 weeks. The efficacy variables were change in asthma symptom scoring, pulmonary function test, and Mini Asthma Quality of Life Questionnaire (MiniAQLQ) scoring. At follow-up, the patients were re-evaluated and analyzed by statistical tools.

Results:

Shortness of breath (P<0.001), chest tightness (P=0.033), wheeze (P=0.01), cough (P=0.024), and overall asthma symptom score (P<0.001) were significantly decreased in the levosalbutamol group in comparison to the salbutamol group. Results of MiniAQLQ revealed that improvement in symptoms (P=0.018), activity limitations (P=0.03), environmental stimuli (P=0.013)-related scoring and overall MiniAQLQ scoring (P<0.001) was statistically significant in the levosalbutamol group. Percentage reversibility of forced expiratory volume at one second (P=0.034), forced vital capacity (P=0.029), peak expiratory flow rate (P=0.0003) was found to be superior in the levosalbutamol group.

Conclusion:

Levosalbutamol was found to be superior compared to recemic salbutamol in mild persistent asthma.KEY WORDS: Asthma symptom score, levosalbutamol, mild persistent asthma, miniAQLQ, pulmonary function test, salbutamol     

芝麻素抗哮喘炎症作用研究

目的观察芝麻素抗哮喘作用,并探讨其可能的作用机制。方法 40只♂清洁级BALB/c小鼠,随机分为正常组、哮喘组、芝麻素低剂量组、芝麻素高剂量组和地塞米松组。体外卵清蛋白(OVA)诱导建立哮喘模型,ELISA和Western blot方法检测芝麻素对支气管炎肺泡灌洗液(BALF)和肺组织白细胞介素-4、5、13(IL-4、5、13)、干扰素-γ(IFN-γ)表达的影响。HE染色观察肺部炎症变化,Western blot方法检测IκBα磷酸化和NF-κB活化。结果哮喘组与正常组相比,炎症细胞计数、IL-4、IL-5、IL-13水平增高,而IFN-γ的表达明显降低(P<0.05),IκBα磷酸化和NF-κB核转位明显增加(P<0.05);芝麻素高剂量组明显降低炎症细胞计数、IL-4、IL-5、IL-13水平,提高IFN-γ的表达(P<0.05),同时抑制IκBα磷酸化和NF-κB核转位(P<0.05)。结论芝麻素通过抑制NF-κB激活,减轻哮喘炎症反应。     

Nerve growth factor and its receptors in asthma and inflammation

Nerve growth factor (NGF) is a high molecular weight peptide that belongs to the neurotrophin family. It is synthesized by various structural and inflammatory cells and activates two types of receptors, the TrkA (tropomyosin-receptor kinase A) receptor and the p75^NTR receptor, in the death receptor family. NGF was first studied for its essential role in neuronal growth and survival. Recent reports indicate that it may also help mediate inflammation, especially in the airways. Several studies in animals have reported that NGF may induce bronchial hyperresponsiveness, an important feature of asthma, by increasing sensory innervation. It may also induce migration and activation of inflammatory cells, which infiltrate the bronchial mucosa, and of structural cells, including epithelial, smooth muscle cells and pulmonary fibroblasts. Increased NGF expression and release is observed in asthma patients after bronchial provocation with allergen. Taken together, the data from the literature suggest that NGF may play a role in inflammation, bronchial hyperresponsiveness and airway remodelling in asthma and may help us to understand the neuro-immune cross-talk involved in chronic inflammatory airway diseases.     

Once-daily inhaled corticosteroids in mild to moderate asthma: improving acceptance of treatment

Despite the established efficacy of inhaled corticosteroids in improving lung function in asthma, there has not been a corresponding improvement in morbidity and mortality associated with the disease, which, in part, may result from non-compliance with the prescribed regimen. The reasons for this are many and varied, but an important measure in improving the level of compliance in asthma patients is simplification of the treatment regimen, which may be achieved by reducing the dose frequency and improving the ease of administration. In clinical trials designed to determine whether a reduction in dose frequency to once daily is associated with similar efficacy to that with more frequent administration, a number of studies have shown that once-daily administration of inhaled corticosteroids in both adults and children is as effective in controlling asthma as twice-daily administration of the same dosage, both when given as initial therapy in corticosteroid-na?ve patients and in patients already receiving an inhaled corticosteroid. The drug for which most evidence to support a dosage change from twice-daily to once-daily therapy currently exists is budesonide, though limited evidence with other inhaled corticosteroids such as beclomethasone dipropionate, fluticasone propionate and flunisolide also supports once-daily use. Despite the larger single dosage with once-daily budesonide therapy, there has been no evidence in clinical trials of a greater incidence of local adverse effects such as hoarseness, throat irritation or oropharyngeal candidosis, and no evidence of adrenal suppression or growth retardation. Since compliance is an important factor that can affect the success or failure of asthma therapy, a reduction in the frequency of administration to once daily offers the potential advantage of improved compliance with treatment and hence better control of asthma. In the short term clinical trials conducted to date, patient preferences have favoured the once-daily regimen over twice-daily administration. When combined with other (e.g. educational) measures to improve patient compliance, a switch from twice-daily (or more frequent) administration to once-daily inhaled corticosteroid therapy seems likely to be beneficial in improving the long term outcome of treatment.     

Metabolic alterations in the sera of Chinese patients with mild persistent asthma: a GC-MS-based metabolomics analysis

Aim:

To character the specific metabolomics profiles in the sera of Chinese patients with mild persistent asthma and to explore potential metabolic biomarkers.

Methods:

Seventeen Chinese patients with mild persistent asthma and age- and sex-matched healthy controls were enrolled. Serum samples were collected, and serum metabolites were analyzed using GC-MS coupled with a series of multivariate statistical analyses.

Results:

Clear intergroup separations existed between the asthmatic patients and control subjects. A list of differential metabolites and several top altered metabolic pathways were identified. The levels of succinate (an intermediate in tricarboxylic acid cycle) and inosine were highly upregulated in the asthmatic patients, suggesting a greater effort to breathe during exacerbation and hypoxic stress due to asthma. Other differential metabolites, such as 3,4-dihydroxybenzoic acid and phenylalanine, were also identified. Furthermore, the differential metabolites possessed higher values of area under the ROC curve (AUC), suggesting an excellent clinical ability for the prediction of asthma.

Conclusion:

Metabolic activity is significantly altered in the sera of Chinese patients with mild persistent asthma. The data might be helpful for identifying novel biomarkers and therapeutic targets for asthma.     

Conquering airways inflammation in the 21st century

This year's edition of the biennial meeting Conquering Airways Inflammation in the 21(st) Century was held September 11-13, 2000, in London. The meeting was devoted to understanding basic mechanisms of airway inflammation, the assessment of the therapeutic impact of existing treatments and the clinical potential of novel therapeutic targets, now and into the 21st century.