Asthma Drug Therapy Research Articles

Comparison and review of international guidelines for treating asthma in children.

Asthma, the most common chronic disease, is characterized by airway inflammation and airflow obstruction. The World Health Organization estimates that approximately 300 million people worldwide have asthma, 30% of whom are pediatric patients. Asthma is a major cause of morbidity that can lead to hospitalization or death in severe pediatric cases. Therefore, it is necessary to provide children with objective and reliable treatment according to consistent guidelines. Several institutes, such as the Global Institute for Asthma, National Heart, Lung, and Blood Institute, British Thoracic Society, Japanese Society of Pediatric Allergy and Clinical Immunology, and Korean Academy of Asthma, Allergy, and Clinical Immunology have published and revised asthma guidelines. However, since recommendations differ among them, confusion persists regarding drug therapy for pediatric asthma patients. Additionally, some guidelines have changed significantly in recent years. This review investigated the latest changes in each guideline, compared and analyzed the recommendations, and identified the international trends in pediatric asthma drug therapy. The findings of this review may aid determinations of the future direction of the Korean guidelines for childhood asthma.

Analysis of drug therapy for bronchial asthma

The review considers the main groups of drugs used to treat bronchial asthma depending on the severity of the disease. The mechanisms of action and effectiveness of taking anti-asthma drugs, their combinations and side effects are covered in detail. Particular attention is paid to targeted therapy with biological drugs, the action of which is aimed at reducing the allergic and inflammatory response in patients with severe asthma. This approach to therapy allows to change the natural course of the disease, reduce airway inflammation without side effects associated with glucocorticosteroids. The review of the current available drug therapies may be useful to clinicians in selecting appropriate strategies for the asthma treatment.

A Comparative Study of Montelukast and Salbutamol in Bronchial Asthma

Current asthma drug therapy is highly effective, having evolved from naturally occurring substances via logical pharmaceutical developments. Pharmacology has played an important role in the development of asthma drugs, and several key experimental findings have been published in this journal. Understanding the pharmacology of effective drug therapies has also taught us a lot about the mechanisms underlying asthma. 2-Adrenoceptor agonists, which evolved from catecholamines in the adrenal medulla, are the most effective bronchodilators, whereas corticosteroids, which evolved from catecholamines in the adrenal cortex, are by far the most effective controllers of the underlying inflammatory process in the airways. A combination inhaler containing a long-acting 2-agonist and a corticosteroid - an improved form of adrenal gland extract - is the current "gold standard" of asthma therapy. Theophylline, a dietary methyl xanthine, and chromoglycate, a plant-derived substance, have both been widely utilized in the treatment of asthma, but their molecular mechanisms are still unknown. Pharmacology has been crucial in enhancing natural products to create effective, long-lasting, and secure asthma medications, but it has faced difficulties in developing new classes of anti-asthma treatments. Leukotriene antagonists, the only brand-new type of anti-asthma therapy established in the previous 30 years, are less efficient than currently available medications. Corticosteroids are less successful than new, more focused medicines that target particular cytokines, but more focused medications run the risk of having side effects that may not be tolerable. Pharmacology, not molecular genetics, appears to be the most likely direction for future advancements in asthma treatment.

Potential cellular endocrinology mechanisms underlying the effects of Chinese herbal medicine therapy on asthma

Asthma is a complex syndrome with polygenetic tendency and multiple phenotypes, which has variable expiratory airflow limitation and respiratory symptoms that vary over time and in intensity. In recent years, continuous industrial development has seriously impacted the climate and air quality at a global scale. It has been verified that climate change can induce asthma in predisposed individuals and that atmospheric pollution can exacerbate asthma severity. At present, a subset of patients is resistant to the drug therapy for asthma. Hence, it is urgent to find new ideas for asthma prevention and treatment. In this review, we discuss the prescription, composition, formulation, and mechanism of traditional Chinese medicine monomer, traditional Chinese medicine monomer complex, single herbs, and traditional Chinese patent medicine in the treatment of asthma. We also discuss the effects of Chinese herbal medicine on asthma from the perspective of cellular endocrinology in the past decade, emphasizing on the roles as intracellular and extracellular messengers of three substances—hormones, substances secreted by pulmonary neuroendocrine cells, and neuroendocrine-related signaling protein—which provide the theoretical basis for clinical application and new drug development.

Pharmacoeconomic analysis of bronchial asthma prophylaxis in adults and children with allergic rhinitis by means of sublingual allergen-specific immunotherapy

BACKGROUND: Allergic rhinitis is the most common chronic allergic disease worldwide, and bronchial asthma (BA) is one of the most severe complications of allergic rhinitis. Clinical studies reported that sublingual allergen-specific immunotherapy can reduce the incidence of bronchial asthma in children and adults. However, allergen-specific immunotherapy is rather expensive and is not reimbursed by the state, which transfers the cost of this therapy to patients.
 AIMS: To evaluate the cost-effectiveness of allergen-specific immunotherapy in children and adults with allergic rhinitis and/or allergic rhinoconjunctivitis
 MATERIALS AND METHODS: The study hypothesized based on study results by Devillier P. et al. in 2019, to which the incidence of asthma was 13.7% and 17.0% in the sublingual allergen-specific immunotherapy + symptomatic therapy and the symptomatic therapy group, respectively (odds ratio: 0.776, 95% confidence interval [0.622; 0.968]). Pharmacoeconomic study based on decision tree model. Costs taken into account are the following: allergen-specific immunotherapy, symptomatic therapy, diagnostics, and routine follow-up visits due to bronchial asthma, outpatient bronchial asthma drug therapy, and hospitalization due to bronchial asthma. The modeling horizon was 5 years, including 2 years of allergen-specific immunotherapy therapy and 3 years of follow-up.
 RESULTS: The cost per patient when using allergen-specific immunotherapy in combination with symptomatic therapy was 166,711.93 rubles, whereas with symptomatic therapy was 101,700.35 rubles. The cost-effectiveness ratio for allergen-specific immunotherapy in combination with symptomatic therapy was 193,177.20 rubles per 1 prevented case of asthma, whereas 122,530.55 rubles for symptomatic therapy for 1 prevented case of bronchial asthma. Thus, the cost of 1 averted bronchial asthma case when using allergen-specific immunotherapy in combination with symptomatic therapy is 57.7% higher than with symptomatic therapy. The cost-benefit analysis result revealed that the incremental cost-utility ratio for an additional year of life adjusted for its quality when performing sublingual allergen-specific immunotherapy in combination with symptomatic therapy compared with symptomatic therapy alone in children and adults was 567,365.48 rubles, which is less than the calculated willingness to pay threshold (RUB 2,248,898.50).
 CONCLUSIONS: The comparison results of the cost of 1 added quality adjusted life years and willingness to pay threshold concluded that sublingual allergen-specific immunotherapy in combination with symptomatic therapy compared to symptomatic therapy alone is potentially cost-effective in children and adults with allergic rhinitis.

Mechanisms of non-type 2 asthma.

Non-type 2 inflammation (Non-T2)-mediated asthma is difficult to define due to lack of signature biomarkers. It exists in the absence of T2-high or eosinophilic inflammation and includes neutrophilic and paucigranulocytic subtypes. Several cell types and cytokines, including Th1, Th17, IL-6, and IL-17, contribute to mechanisms of non-T2 asthma. Neutrophil extracellular traps (NETs) and inflammasome activation likely play a role in severe neutrophilic asthma. Several mechanisms lead to uncoupling of airway hyperresponsiveness and remodeling from airway inflammation in paucigranulocytic asthma. Recent research on transcriptomics and proteomics in non-T2 asthma is discussed in this review. Investigations of specific drug therapies for non-T2 asthma have been disappointing, and remain an important area for future clinical studies.

Disagreement between guidelines regarding the third step of asthma drug therapy for school-age children

With the help of a routine clinical case, we highlighted the difference between two of the best asthma guidelines available at the time regarding therapeutic suggestions for the so-called “third step” for school-age asthmatic children.We have analyzed the scientific evidence that each of the two guidelines brings to support their position.Finally, we have motivatedly solved the clinical scenario.However, the question of disagreement between two guidelines remains unresolved. This can lead to unjustified differences in the management of schoolchildren with persistent asthma.

Impact of a population-based asthma management program in France (Sophia Asthme): A matched controlled before-and-after quasi-experimental study using the French health insurance database (SNDS).

Sophia Asthme (SA) is a chronic disease management program of the French national health insurance for adult patients with asthma. We evaluated the early impact of this intervention. We conducted a matched controlled, before-and-after quasi-experimental study within the French Health Insurance Database (Système National Des Données de Santé [SNDS]). The SA program was implemented in a set of 18 Départements in France and targeted 18- to 44-year-old subjects, with at least two reimbursement dates for asthma drug therapy during the 12-month period prior to program targeting. Change in outcomes was assessed from the "before program" period (January-December 2014) to the "after program implementation" period (March 2015-February 2016) in the program group (eligible to SA program in the 18 Départements) and in the matched controlled group. The main outcome measure was the before-after change in proportion of subjects with a controllers/(controllers+relievers) ratio greater than 50%. Of the 99 578 subjects of the program group, 9225 (9.3%) actually participated in SA program. The program had no significant impact on the proportion of subjects with a ratio greater than 50%. However, subjects exposed to SA program were significantly more likely to be dispensed controller medications (OR = 1.04; 95% CI, 1.01-1.07) and to sustain their use of these medications (OR = 1.08; 95% CI, 1.05-1.12). We did not demonstrate any significant impact of the program on the primary outcome. The modest yet encouraging findings of this early evaluation suggest the need for reformulation of the program and its evaluation.

DP2 antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment.

Increased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation and contributes to asthma-associated morbidity and mortality. No current drug therapy for asthma is known to affect airway smooth muscle mass. Although there is increasing evidence that prostaglandin D2 type 2 receptor (DP2) is expressed in airway structural and inflammatory cells, few studies have addressed the expression and function of DP2 in airway smooth muscle cells. We report that the DP2 antagonist fevipiprant reduced airway smooth muscle mass in bronchial biopsies from patients with asthma who had participated in a previous randomized placebo-controlled trial. We developed a computational model to capture airway remodeling. Our model predicted that a reduction in airway eosinophilia alone was insufficient to explain the clinically observed decrease in airway smooth muscle mass without a concomitant reduction in the recruitment of airway smooth muscle cells or their precursors to airway smooth muscle bundles that comprise the airway smooth muscle layer. We experimentally confirmed that airway smooth muscle migration could be inhibited in vitro using DP2-specific antagonists in an airway smooth muscle cell culture model. Our analyses suggest that fevipiprant, through antagonism of DP2, reduced airway smooth muscle mass in patients with asthma by decreasing airway eosinophilia in concert with reduced recruitment of myofibroblasts and fibrocytes to the airway smooth muscle bundle. Fevipiprant may thus represent a potential therapy to ameliorate airway remodeling in asthma.

The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma.

Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective.Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice.Methods:BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined.Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3+CD4+ Th2 and CD4+RORγt+ Th17 cells in the lungs of the allergic mice.Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation.

Expression of vitamin D receptor in bronchial asthma and its bioinformatics prediction.

Vitamin D receptors (VDRs) are associated with the occurrence and development of asthma. The aim of the present study was to analyze the secondary structure and B-cell and T-cell epitopes of VDR using online prediction software and aid in the future development of a highly efficient epitope-based vaccine against asthma. Blood samples were collected from peripheral blood of asthmatic children. Reverse transcription quantitative-polymerase chain reaction (RT-qPCR) was performed to detect the expression of VDR in the peripheral blood. Mouse models of asthma were established. Hematoxylin and eosin staining was performed to observe the pathological alterations of the lungs of mice. Immunohistochemistry, western blot analysis and RT-qPCR were performed to detect the expression of VDR in the lungs of asthmatic mice. Online prediction software immune epitope database and analysis resource, SYFPEITHI and linear epitope prediction based on propensity scale and support vector machines were used to predict the B-cell and T-cell epitopes and the RasMol and 3DLigandSite were used to analyze the tertiary structure of VDR. RT-qPCR demonstrated that VDR expression in the peripheral blood of asthmatic children was decreased. Immunohistochemistry, western blotting and RT-qPCR demonstrated that VDR expression also decreased in the lungs of mouse models of asthma. VDR B-cell epitopes were identified at 37–45, 88–94, 123–131, 231–239, 286–294 and 342–350 positions of the amino acid sequence and VDR T-cell epitopes were identified at 125–130, 231–239 and 265–272 positions. A total of six B-cell epitopes and three T-cell epitopes for VDR were predicted by bioinformatics, which when validated, may in the future aid in immunological diagnosis and development of a targeted drug therapy for clinical asthma.

New and emerging drug treatments for severe asthma.

Asthma is a common chronic inflammatory condition of the airways affecting over 300 million people world-wide. In 5%-10% of cases, it is severe, with disproportionate healthcare resource utilization including costs associated with frequent exacerbations and the long-term health effects of systemic steroids. Characterization of inflammatory pathways in severe asthma has led to the development of targeted biological and small molecule therapies which aim to achieve disease control while minimizing corticosteroid-associated morbidity. Herein, we review currently licensed agents and those in development, and speculate how drug therapy for severe asthma might evolve and impact on clinical outcomes in the near future.

Factors Affecting Drug Compliance in Paediatric Asthma

Introduction: Childhood asthma is an immensely important chronic disease in children with increasing prevalence worldwide. Inhaled corticosteroids and bronchodilators are the key drugs in asthma therapy.Material and Methods: Compliance of childhood asthma was assessed at a tertiary care centre to find out the percentage of compliant Vs noncompliant patients and the reasons for the latter. If the patient had attended at least nine visits (> 75%) the previous year he was labelled compliant and those with less than six visits (<50%) were put in the non-complaint group.Results: Of the 374 patients attending the asthma clinic, 60 were randomly selected for the study of which 53 finally participated. In this study the compliance was 47% and gender predilection did not affect compliance. The distance a patient had to commute to reach the hospital and the mother’s education did not have any influence on the compliance. Older asthmatics exhibited better compliance in our study.Conclusion: Forty percent of our patients were compliant to regular use of prescribed medicine. Older age of the patients and care giver`s awareness about asthma were the two factors which are statistically significant in compliance with drug therapy in asthma. Gender of the patient, academic qualification and distance from the hospital did not have a significant effect on compliance.

Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea.

BackgroundContinuous positive airway pressure (CPAP) in asthma patients with concomitant obstructive sleep apnea syndrome (OSAS) seems to have a favorable impact on asthma, but data are inconsistent due to methodological limitations of previous studies.MethodsProspective, multicenter study. We examined asthma outcomes after 6 months of CPAP in 99 adult asthma patients (mean age 57 years) with OSAS (respiratory disturbance index ≥20). Asthma control and quality of life were assessed with the Asthma Control Questionnaire (ACQ) and the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), respectively. Data were analyzed by intention‐to‐treat basis.ResultsThe mean ± SD score of the ACQ decreased from 1.39 ± 0.91 at baseline to 1.0 ± 0.78 at 6 months (P = 0.003), the percentage of patients with uncontrolled asthma from 41.4% to 17.2% (P = 0.006), and the percentage of patients with asthma attacks in the 6 months before and after treatment from 35.4% to 17.2% (P = 0.015). The score of the mAQLQ increased from 5.12 ± 1.38 to 5.63 ± 1.17 (P = 0.009). There were also significant improvements in symptoms of gastroesophageal reflux and rhinitis, bronchial reversibility, and exhaled nitric oxide values (all P < 0.05). No significant changes were observed in drug therapy for asthma or their comorbidities nor in the patients’ weight.ConclusionsAsthma control (both actual and future risk), quality of life, and lung function improved after starting continuous positive airway pressure in asthmatics with moderate to severe obstructive sleep apnea syndrome.

Patients' perspectives and preferences in the choice of inhalers: the case for Respimat(®) or HandiHaler(®).

Poor inhaler technique hampers the efficacy of drug therapy in asthma and chronic obstructive pulmonary disease. Not only does this affect individual patient care, but it also impacts on the wider health care economics associated with these conditions. Treatment guidelines recommend a systematic approach to drug class selection; however, standardization of inhaler selection is currently difficult owing to the complexity of the interaction between the inhaler device and the patient. Specifically, individual patient preference can influence how successful a treatment is overall. This article reviews inhaler devices from the patient perspective, with a particular focus on the dry powder inhaler HandiHaler® and Respimat® Soft Mist™ Inhaler. It discusses factors that influence device preference and treatment compliance and reviews tools that can aid health care professionals to better match inhaler devices to individual patients’ needs.

Ani9, A Novel Potent Small-Molecule ANO1 Inhibitor with Negligible Effect on ANO2.

Anoctamin1 (ANO1)/transmembrane protein 16A (TMEM16A), a calcium-activated chloride channel (CaCC), is involved in many physiological functions such as fluid secretion, smooth muscle contraction, nociception and cancer progression. To date, only a few ANO1 inhibitors have been described, and these have low potency and selectivity for ANO1. Here, we performed a high-throughput screening to identify highly potent and selective small molecule inhibitors of ANO1. Three novel ANO1 inhibitors were discovered from screening of 54,400 synthetic small molecules, and they were found to fully block ANO1 channel activity with an IC50 < 3 μM. Electrophysiological analysis revealed that the most potent inhibitor, 2-(4-chloro-2-methylphenoxy)-N-[(2-methoxyphenyl)methylideneamino]-acetamide (Ani9), completely inhibited ANO1 chloride current with submicromolar potency. Notably, unlike previous small-molecule ANO1 inhibitors identified to date, Ani9 displayed high selectivity for ANO1 as compared to ANO2, which shares a high amino acid homology to ANO1. In addition, Ani9 did not affect the intracellular calcium signaling and CFTR chloride channel activity. Our results suggest that Ani9 may be a useful pharmacological tool for studying ANO1 and a potential development candidate for drug therapy of cancer, hypertension, pain, diarrhea and asthma.

Persistence with inhaled corticosteroids reduces the risk of exacerbation among adults with asthma: A real-world investigation.

Real-world evidence suggests that persistence with inhaled corticosteroids (ICS), the mainstay of asthma drug therapy, is generally poor. The effect of persistence with ICS on the risk of asthma exacerbation was addressed in a population-based study. The cohort of 2335 beneficiaries of the National Health Service provided by the Italian Region of Lombardy, aged 18-40 years and newly treated with ICS during 2005-2008, was followed from their first ICS dispensation until 2010. Discontinuation of treatment with ICS and starting oral corticosteroid therapy during follow-up were respectively regarded as proxies of poor persistence with asthma medication and asthma exacerbation (outcomes). A proportional hazards model was fitted to identify predictors of ICS discontinuation. Case-crossover and case-case-time-control designs and conditional logistic regressions were used to estimate the association between persistence with ICS and asthma exacerbation. Cumulative incidences of discontinuation were 36%, 57% and 78% at 6 months, 1 year and 5 years, respectively. Predictors of poor persistence were female gender, use of antibiotics during follow-up, absence of use of short-acting beta-agonists prior to and after starting treatment with ICS and starting and maintaining ICS monotherapy during follow-up. The odds ratios of asthma exacerbation (and 95% confidence intervals) associated with ICS exposure during the current period, contrasted with exposure during the reference period, were 0.4 (0.2, 0.9) and 0.3 (0.1, 1.0) from case-crossover and case-case-time-control estimates, respectively. Persistence with ICS treatment in adults with asthma reduces the risk of exacerbation in the real-life setting.

Systematic review of models used in economic analyses in moderate-to-severe asthma and COPD

Background:Respiratory diseases exert a substantial burden on society, with newer drugs increasingly adding to the burden. Economic models are often used, but seldom reviewed.Purpose:To summarize economic models used in economic analyses of drugs treating moderate-to-severe/very severe asthma or chronic obstructive pulmonary disease (COPD).Methods:This study searched Medline and Embase from inception to the end of February 2015 for cost-effectiveness/utility analyses that examined at least one drug against placebo, another drug, or other standard therapy in asthma or COPD. Two reviewers independently searched and extracted data with differences adjudicated via consensus discussion. Data extracted included model used and its qualities, validation methods, treatments compared, disease severity, analytic perspective, time horizon, data collection (pro- or retrospective), input rates and sources, costs and sources, planned sensitivity analyses, criteria for cost-effectiveness, reported outcomes, and sponsor.Results:This study analyzed 53 articles; 14 (25%) on asthma and 39 (75%) COPD. Markov models were commonly used for both asthma and COPD-related economic evaluations. Relatively few studies validated their model. For asthma-related studies, 10 examined inhaled corticosteroids and nine studied omalizumab. Placebo or standard therapy was the comparison in 11 studies and active drugs in the remainder.Conclusions:Few studies include validation of their models. Furthermore, controversy concerning some results was uncovered in this study, which needs to be avoided in the future.

Assessment of inhalation technique and predictors of incorrect performance among patients of chronic obstructive pulmonary disease and asthma

Background: Poor inhalation technique is responsible for decreasing the efficacy of topical drug therapy in asthma and chronic obstructive pulmonary disease (COPD). Certain steps of the inhalation technique are erred most often and if ascertained, can be rectified leading to an overall improvement in the technique. The predictors for poor use can also be marked. Methods: Inhaler technique for pressurised metered dose inhalers (pMDI), pressurised metered dose inhaler with spacer and dry powder inhaler (DPI) was assessed in one hundred and five patients who fulfilled the inclusion and exclusion criteria and were enrolled in this study. Inhaler technique was assessed using an ERAS/ISAM Task force report based scores and the lung function using pulmonary function test (PFT).The technique was re-assessed and scored after a period of three months along with the assessment of the lung function by PFT. Results: The mean of ERS/ISAM task force report based score for evaluation of the techniques of inhalation increased from 5.79±2.58 to 8.23±2.41 (p<0.0001) after intervention. The most commonly committed error in the inhalation technique was in step number eight, ten and four by patients using pMDI, pMDI with spacer and DPI, respectively. The faulty technique being the dependent variable/outcome could be explained 16% by the type of inhaler used (r2 = 0.1607) and this is statistically significant (p<0.0001), thus the type of inhaler used was a predictor of poor use. Conclusions: Inhaler techniques improved with systematic training and there was a trend towards improvement in lung function, hence the clinical condition.

Past, Present and Future Therapeutics of Asthma: A Review

The therapeutic history of asthma is divided into a period before and after the advent of inhaled corticosteroids (ICS). Before the advent of ICS, bronchodilators such as β2‐agonists and anti‐cholinergic agents were the main drugs used for asthma therapies. ICS were firstly launched in the market in 1978. Their effectiveness and safety have been recognized over time. Consequently, ICS were positioned as gold standard drugs for asthma therapy in the 1980s in Europe and North America and in the late 1990s in Japan. This review addresses the paradigm shift of the drug therapy for asthma.