Pharmaceutical treatment status of patients with COPD in the community based on medical Internet of Things: a real-world study.

This study aimed to investigate the real-world standardisation and adherence of medical treatment regimens in patients with chronic obstructive pulmonary disease (COPD) in the community for making future management strategy. The follow-up data and treatment information of patients with COPD, which were collected through the Management Information Center of COPD (MICCOPD) in 21 community health service centres in Songjiang District, a countryside region of Shanghai. Concordance between the pharmaceutical treatment plan and recommendation of 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report during the follow-up management period, as well as the medication adherence by patients,were analysed. Out of the 2044 patients diagnosed with COPD, 814 patients (39.8%) who had an initial record of medication use were found to meet the inclusion criteria. The most common medication regimens were long-acting beta-agonist plus inhaled corticosteroids (35.9%) and oral bronchodilators (41.9%). Among these 814 patients, 45.7%, 38.0%, 31.6% and 14.6% adhered to the treatment after 6, 12, 18 and 24 months of follow-up, respectively. The concordance rate with the regimens recommended by the 2017 GOLD guidelines was 35.5% at baseline, 35.5% at 6 months, 32.7% at 12 months, 35.4% at 18 months and 37% at 24 months. The compliance and guideline consistency rates of patients with COPD in the community under the management of general practitioners need to be improved. Enhancing general practitioner proficiency in the prevention and management of COPD and increasing patient awareness of the condition, are crucial standardising and improving adherence to initial and follow-up COPD treatments.

Reducing short-acting beta-agonist use in asthma: Impact of national incentives on prescribing practices in England and the findings from SENTINEL Plus early adopter sites.

Short-acting beta-agonist (SABA) over-use in asthma is harmful for patients and the environment. The Investment and Impact Fund (IIF) 2022/2023 financially rewarded English primary care networks that achieved specific targets, including reducing SABA over-use (RESP-02) and lowering the mean carbon footprint per salbutamol inhaler prescribed (ES-02). SENTINEL Plus is a co-designed quality improvement package that aims to improve asthma outcomes and reduce asthma's environmental impact by addressing SABA over-use. We investigated the impact of (i) the IIF incentives and (ii) SENTINEL Plus implementation on asthma prescribing. Using Openprescribing.net data, we demonstrate that IIF 2022-2023 had no significant impact on the total number of SABA prescribed in England (25,927,252 during 12-months pre- and 25,885,213 12-months post-IIF; 0.16% decrease; p=NS), but lower carbon footprint SABA inhaler use increased (Salamol™ prescribing increased from 5.1% to 19% of SABA prescriptions, p < 0.01). In contrast, SENTINEL Plus sites significantly reduced SABA prescribing post-implementation (5.43% decrease, p < 0.05).

Pharmacological treatment of asthma in Sweden from 2005 to 2015.

OBJECTIVE: Despite access to effective therapies many asthma patients still do not have well-controlled disease. This is possibly related to underuse of inhaled corticosteroids (ICS) and overuse of short-acting ß2-agonists (SABA). Our aim was to investigate longitudinal trends and associated factors in asthma treatment. METHODS: Two separate cohorts of adults with physician-diagnosed asthma were randomly selected from 14 hospitals and 56 primary health centers in Sweden in 2005 (n = 1182) and 2015 (n = 1225). Information about symptoms, maintenance treatment, and use of rescue medication was collected by questionnaires. Associations between treatment and sex, age, smoking, education, body mass index (BMI), physical activity, allergic asthma, and symptom control were analyzed using Pearson's chi2-test. Odds ratios (ORs) were calculated using logistic regression. RESULTS: Maintenance treatment with ICS together with long-acting ß2-agonists (LABA) and/or montelukast increased from 39.2% to 44.2% (p = 0.012). The use of ICS + LABA as-needed increased (11.1-18.9%, p < 0.001), while SABA use decreased (46.4- 41.8%, p = 0.023). Regular treatment with ICS did not change notably (54.2-57.2%, p = 0.14). Older age, former smoking, and poor symptom control were related to treatment with ICS + LABA/montelukast. In 2015, 22.7% reported daily use of SABA. A higher step of maintenance treatment, older age, obesity, shorter education, current smoking, allergic asthma, low or very high physical activity, and a history of exacerbations were associated with daily SABA use. CONCLUSIONS: The use of ICS + LABA both for maintenance treatment and symptom relief has increased over time. Despite this, the problem of low use of ICS and high use of SABA remains.

Evidence of off-label inhalation therapy on pediatric asthma practice in Japan.

BACKGROUND: In Japan, many asthma inhalers do not have formal approval for use in the pediatric population because of the lack of domestic data. In real-world settings, however, numerous off-label medications are prescribed. Currently, the nature of off-label prescriptions of asthma inhalers on pediatric patients in Japan remains unclear. METHODS: Using public open-source national medical claims data, we investigated the real-world descriptive epidemiology of off-label prescriptions for asthma inhalers for pediatric patients. We obtained the number of off-label prescriptions of formulations for patients aged 0-14 years from anonymously summarized prescription data for a 7-year period starting from April 2014. The actual prescription numbers and their chronology over time were then analyzed. RESULTS: In 2019, 143,439 asthma inhalers were used off label in children and adolescents. Overall, 96.1% were inhaled corticosteroids (ICSs) or long-acting beta stimulants (LABAs), and 3.9% were high-dose ICS. Of ICSs and LABAs, 18.8% were off-label prescriptions. The total number of off-label ICS/LABA prescriptions and their percentage relative to the overall formulations gradually decreased but a notable disparity was observed among inhaler types. CONCLUSIONS: There was a surprisingly large number of off-label prescriptions of asthma inhalers in the pediatric population in Japan. The proper use of ICSs/LABAs and expansion of insurance coverage should be advocated to reduce off-label use.

Repurposing of carvedilol to alleviate bleomycin-induced lung fibrosis in rats: Repressing of TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions.

Idiopathic pulmonary fibrosis (IPF) is the most widely studied interstitial lung disease. IPF eventually leads to respiratory insufficiency, lung cancer, and death. Carvedilol (CAR) is a third-generation ß-adrenergic receptor antagonist with an α1-blocking effect. CAR demonstrates antifibrotic activities in various experimental models of organ fibrosis. AIMS: This work is designed to explore the possible alleviating effects of CAR on bleomycin (BLM)-induced lung fibrosis in rats. MAIN METHODS: The BLM rat model of lung fibrosis was achieved by intratracheal delivery of a single dose of 5 mg/kg of BLM. Seven days following BLM injection, either prednisolone or CAR was orally administered at doses of 10 mg/kg once daily for 21 days to the rats. The actions of CAR were evaluated by lung oxidant/antioxidant parameters, protein concentration and total leucocyte count (TLC) in bronchoalveolar lavage fluid (BALF), fibrosis regulator-related genes along with the coexistent lung histological changes. KEY FINDINGS: CAR effectively decreased lung malondialdehyde level, increased superoxide dismutase activity, declined both protein concentration and TLC in BALF, downregulated TGF-ß1/α-SMA/Smad2/3 and STAT3 gene expressions, and repaired the damaged lung tissues. SIGNIFICANCE: CAR conferred therapeutic potential against BLM-induced lung fibrosis in rats, at least in part, to its antioxidant, anti-inflammatory, and antifibrotic activities. CAR could be utilized as a prospective therapeutic option in patients with lung fibrosis in clinical practice.

Pharmacological Treatments for Congenital Myasthenic Syndromes Caused by COLQ Mutations.

BACKGROUND: Congenital myasthenic syndromes (CMS) refer to a series of inherited disorders caused by defects in various proteins. Mutation in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) is the second-most common cause of CMS. However, data on pharmacological treatments are limited. OBJECTIVE: In this study, we reviewed related reports to determine the most appropriate pharmacological strategy for CMS caused by COLQ mutations. A literature review and meta-analysis were also performed. PubMed, MEDLINE, Web of Science, and Cochrane Library databases were searched to identify studies published in English before July 22, 2022. RESULTS: A total of 42 studies including 164 patients with CMS due to 72 different COLQ mutations were selected for evaluation. Most studies were case reports, and none were randomized clinical trials. Our meta-analysis revealed evidence that ß-adrenergic agonists, including salbutamol and ephedrine, can be used as first-line pharmacological treatments for CMS patients with COLQ mutations, as 98.7% of patients (74/75) treated with ß-adrenergic agonists showed positive effects. In addition, AChEIs should be avoided in CMS patients with COLQ mutations, as 90.5% (105/116) of patients treated with AChEIs showed either no or negative effects. CONCLUSION: (1) ß-adrenergic agonist therapy is the first pharmacological strategy for treating CMS with COLQ mutations. (2) AChEIs should be avoided in patients with CMS with COLQ mutations.

Assessment of Drug Usage Pattern among Bronchial Asthma Patients in a Tertiary Care Teaching Hospital, Tamilnadu: A Cross-sectional Study.

BACKGROUND: Asthma is a chronic inflammatory disease of the small airways. Chronic inflammation often causes hyper responsiveness of airways with wheezing, breathing difficulty, cough and chest tightness. OBJECTIVE: The present study aimed to evaluate the drug usage pattern of anti-asthma drugs among asthma patients. METHODS: The present study was a prospective, observational cross-sectional study carried out among 422 outpatients being treated at the respiratory medicine department, SRM Medical College Hospital and Research Centre. Data regarding the prescribing indicators and patient indicators were collected from the patients' prescription slips and entered in the preformed proforma. Prescribing indicators were taken into consideration in evaluating the rationality of prescriptions. RESULTS: In the present study, 49% of patients were between the age group of 20-40 years. Genderwise distribution showed 58.05% of males and 41.95% of females. A family history of asthma was seen in 68% of the study population. The present study reported smoking among 51% and tobacco chewing in 21% of the study population. Low economic strata were observed in 77.9% of the study population. According to asthma grading, 65.8% were in the mild intermittent, and 25% were in the mild persistent group. Patients were on ß2 agonists (35.4%) and corticosteroids (32%). The most commonly used fixed drug combination was a short-acting ß2 agonist with corticosteroid (40.5%). A total of 68% of drugs were used by the inhalational route and 29% by the oral route. CONCLUSION: The findings showed that, the most frequently prescribed drug was a short-acting ß2 agonist with corticosteroid in a fixed-dose combination via inhalational route.

Ractopamine residues in meat might reduce the risk of type 2 diabetes.

Background: The overall prevalence of diabetes in the world has risen substantially in the past several decades, so have complications and mortalities associated with it. Aim: Prevention strategies for diabetes thus become an urgent public health need for reducing the burden of diabetes. Methods: Ractopamine, a ß1/2-adrenergic receptor agonist, has been approved for use in finishing swine, cattle, and turkey in countries where meat exporting brings tremendous economic benefits. This leanness enhancer is recently found to be a full agonist at trace amine-associated receptor 1 also. A thorough literature review was performed to assess possible effects of ractopamine on glucose metabolism. Results: Activating ß-adrenoceptor could lead to glucose-lowering effects independent of insulin while activation on trace amine-associated receptor 1 induces an incretin-like signaling on insulin-secreting pancreatic ß-cells. Conclusion: Accordingly, it is hypothesized that long-term consuming meat containing ractopamine might lower the risk of type 2 diabetes.

Antiasthmatic Compounds Targeting ß2-Adrenergic Receptor from Perilla frutescens Improved Lung Inflammation by Inhibiting the NF-κB Signaling Pathway.

Asthma is a highly prevalent and heterogeneous chronic respiratory disease and is often treated with inhaled corticosteroids or in combination with a ß2-adrenergic receptor (ß2-AR) agonist. However, around 5% of asthma remains uncontrolled, and more effective antiasthmatic drugs with known mechanisms are in high demand. Herein, we immobilized ß2-AR on the polystyrene amino microsphere surface in a one-step fashion. The successful immobilization of ß2-AR was verified by scanning electron microscopy and chromatographic analysis. We screened rosmarinic acid (RA) as the bioactive compound targeting ß2-AR in Perilla frutescens (L.) Britton by mass spectroscopy. The binding constant between RA and ß2-AR was determined to be 2.95 × 104 M-1 by adsorption energy distribution and frontal analysis. The antiasthmatic effect and mechanism of RA were examined on a murine model of allergic asthma induced by ovalbumin (OVA) and aluminum hydroxide. The results showed that RA significantly reduced lung inflammatory cell numbers, the production of Th2 cytokines, and the secretion of total IgE, OVA-specific IgE, and eotaxin. The decreased inflammatory cell infiltration and mucus hypersecretion were associated with the inhibition of the NF-κB signaling pathway. Moreover, the mRNA expression levels of AMCase, CCL11, CCR3, Ym2, and E-selectin in the lung tissues were effectively reduced. It is the first time that RA was proven to target ß2-AR and be effective in counteracting allergic airway inflammation via the NF-κB signaling pathway. Therefore, the immobilized ß2-AR preserves the potential in screening antiasthmatic compounds from herbal medicine, and RA can be developed as an effective agent for the treatment of allergic asthma.

Enhanced efficacy of formoterol-montelukast salt in relieving asthma features and in preserving ß2-agonists rescue therapy.

Adrenergic ß2-agonists represent a mainstay in asthma management. Their chronic use has been associated with decreased bronchoprotection and rebound hyperresponsiveness. Here we investigate on the possible therapeutic advantage of a pharmacological association of ß2-agonists with montelukast, a highly selective leukotriene receptor antagonist, in modulating bronchial reactivity and controlling asthma features. The study has been conducted in vitro and in vivo and also takes advantage of the synthesis of a salt that gave us the possibility to simultaneously administer in vivo formoterol and montelukast (MFS). In vitro studies demonstrate that montelukast (1) preserves ß2-agonist response in isolated bronchi by preventing homologous ß2-adrenoceptor desensitization; (2) reduces desensitization by modulating ß2-receptor translocation in bronchial epithelial cells. In vivo studies demonstrate that sensitized mice receiving formoterol or montelukast display a significant reduction in airway hyperresponsiveness, but the ß2-agonist relaxing response is still impaired. Allergen challenge causes ß2 heterologous desensitization that is further increased by treatment in vivo with formoterol. Conversely MFS not only inhibits airway hyperresponsiveness but it rescues the ß2-agonist response. Histological analysis confirms the functional data, demonstrating an enhanced therapeutic efficiency of MSF in controlling also pulmonary metaplasia and lung inflammation. MFS is efficacious also when sensitized mice received the drug by local administration. In conclusion, the data obtained evidenced a therapeutic advantage in the association of ß2-agonists with montelukast in the control of asthma-like features and a better rescue bronchodilation response to ß2-agonists.

Screening for Chronic Obstructive Pulmonary Disease: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in the US. Objective: To conduct a targeted systematic review to update the evidence on the effectiveness of screening for COPD and the treatment of COPD to inform the US Preventive Services Task Force (USPSTF) update of the 2016 recommendation statement on COPD screening. Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, and CINAHL for relevant studies published between January 1, 2015, to January 22, 2021; surveillance through March 25, 2022. Study Selection: English-language studies of screening in individuals who do not recognize or report respiratory symptoms; studies of treatment in persons with mild or moderate, or minimally symptomatic, COPD. Data Extraction and Synthesis: Two reviewers independently appraised the articles and extracted relevant data from fair- or good-quality studies; no quantitative synthesis was conducted. Main Outcomes and Measures: COPD-related morbidity or mortality, measures of health-related quality of life, and adverse events. Results: The review included no trials on the effectiveness of screening, 3 trials or analyses (n = 20 058) of pharmacologic treatment published since 2015, 13 trials (n = 3657) on nonpharmacologic interventions, and 2 large observational studies (n = 243 517) addressing the harms of pharmacologic treatment published since 2015. The results from the clinical trials of pharmacologic therapy are consistent with the previous review supporting the USPSTF that bronchodilators with or without inhaled corticosteroids can reduce COPD exacerbations and tiotropium can improve health-related quality of life in adults with moderate COPD. Overall, there was no consistent benefit observed for any type of nonpharmacologic intervention across a range of patient outcomes. None of the included treatment trials that reported adverse effects found significant harms. Two large observational studies in a screen-relevant population demonstrated an association of the initiation of a long-acting muscarinic antagonist or long-acting beta agonist with the risk of a serious cardiovascular event in treatment-naïve patients and an association of inhaled corticosteroids use with the risk of developing diabetes. Conclusions and Relevance: The findings of this targeted evidence update are generally consistent with the findings of the previous systematic review supporting the 2016 USPSTF recommendation. Evidence of pharmacologic treatment was still largely limited to persons with moderate airflow obstruction, and there was no consistent benefit observed for a range of nonpharmacologic interventions in mild to moderate COPD or in minimally symptomatic persons with COPD.

Treatment persistence and exacerbations in patients with asthma initiating treatment with inhaled corticosteroids and beta-adrenergic agonists: retrospective cohort study.

OBJECTIVE: To determine treatment persistence and exacerbations in patients initiating inhaler treatment with fixed-dose combinations of inhaled corticosteroids/long-acting beta-2-adrenergic agonists (ICS/LABA) for the treatment of asthma. DESIGN: Retrospective observational study conducted by review of electronic medical records (database: Fundación RediSS). SETTING: Retrospective cohort study. The follow-up period was 1 year. PARTICIPANTS: The study included patients aged ≥18 years who started treatment with ICS/LABA and met the inclusion/exclusion criteria. MAIN OUTCOMES AND MEASURES: The study groups were fluticasone propionate/salmeterol (FP/SAL), beclomethasone/formoterol (BDP/FORM), budesonide/formoterol (BUD/FORM), fluticasone furoate/vilanterol (FF/VI) and fluticasone propionate/formoterol (FP/FORM). The main measurements were persistence, medication possession ratio (MPR) and exacerbations. Statistical significance was established as p<0.05. RESULTS: In total, 3203 patients were recruited for the study. By groups, 31.1% FP/SAL, 28.6% BDP/FORM, 25.0% BUD/FORM, 8.2% FF/VI and 7.0% FP/FORM. The mean age was 52.2 years, 60.8% were female and 44.9% had persistent-moderate asthma. Treatment persistence was 61.7% (95% CI 60.0% to 63.4%) and by study group it was FP/SAL: 60.7%, BDP/FORM: 61.2%, BUD/FORM: 60.3%, FF/VI: 66.7% and FP/FORM: 67.6% (p=0.046). MPR by study group was FP/SAL: 74.3%, BDP/FORM: 73.8%, BUD/FORM: 74.6%, FF/VI: 79.4% and FP/FORM: 80.6% (p=0.028). The mortality rate was 2.9%. By treatment group, exacerbations were FP/SAL: 21.9% (95% CI 19.3% to 24.5%), BDP/FORM: 22.2% (95% CI 19.5% to 24.9%), BUD/FORM: 22.8% (95% CI 19.9% to 25.7%), FF/VI: 17.9% (95% CI 14.9% to 20.7%) and FP/FORM: 16.0% (95% CI 12.2% to 19.3%), p=0.036. CONCLUSIONS: Patients undergoing treatment with FP/FORM and FF/VI versus FP/SAL, BDP/FORM and BUD/FORM were associated with greater treatment adherence (persistence, MPR) and lower rates of exacerbations. However, further studies will be needed to strengthen the consistency of the results.

Therapeutics effects of inhaled magnesium sulfate combined with adrenergic beta-2 agonist on children with acute asthma: Systematic review and meta-analysis.

AIM: To review the evidence on the effectiveness of inhaled magnesium sulfate (MgSO4) combined with beta-2 (B2) agonist as compared to inhaled B2 agonist alone in treating pediatric patients with moderate to severe asthma attacks METHODS: The search was conducted on five electronic databases namely the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, PubMed, Science Direct, and Google Scholar. RESULTS: Eight trials were included in the review. All studies involved a total of 1585 children aged 2-17 years with moderate to severe asthma attacks. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials. Three studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on vital signs revealed no effect of inhaled MgSO4 on vital signs (SMD -0.11, 95% CI 0.27-0.04, p = 0.16, I2 = 68%). Two studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on asthma severity score (ASS) revealed no effect of inhaled MgSO4 on ASS (SMD 0.22, 95% CI 0.01-0.44, Z = 2.01, p = 0.04, I2 = 88%). Two studies that assessed the effect of inhaled MgSO4 as adjunctive therapy on peak expiratory flow rate (PEFR) revealed a large effect of B2 agonist alone on PEFR (SMD 2.02, 95% CI 0.83-3.2, p < 0.001, I2 = 98%). CONCLUSION: This review does not support the use of inhaled MgSO4 as adjunctive therapy to B2 agonist for asthmatic children.

Use of short-acting beta agonists in the treatment of asthma across five European countries.

Commentary on: Janson C, Menzies-Gow A, Nan C, et al SABINA: an overview of short-acting ß2-agonist use in asthma in European countries. Adv Ther 2020;37:1124-35.Series co-ordinator: Dr Teck Khong, DTB Associate Editor Clinical Pharmacology, St George's, University of London, UK.

Epinephrine (adrenaline) compared to selective beta-2-agonist in adults or children with acute asthma: a systematic review and meta-analysis.

BACKGROUND: International asthma guidelines recommend against epinephrine (adrenaline) administration in acute asthma unless associated with anaphylaxis or angio-oedema. However, administration of intramuscular epinephrine in addition to nebulised selective ß2-agonist is recommended for acute severe or life-threatening asthma in many prehospital guidelines. We conducted a systematic review to determine the efficacy of epinephrine in comparison to selective ß2-agonist in acute asthma. METHODS: We included peer-reviewed publications of randomised controlled trials (RCTs) that enrolled children or adults in any healthcare setting and compared epinephrine by any route to selective ß2-agonist by any route for an acute asthma exacerbation. The primary outcome was treatment failure, including hospitalisation, need for intubation or death. RESULTS: Thirty-eight of 1140 studies were included. Overall quality of evidence was low. Seventeen studies contributed data on 1299 participants to the meta-analysis. There was significant statistical heterogeneity, I2=56%. The pooled Peto's OR for treatment failure with epinephrine versus selective ß2-agonist was 0.99 (0.75 to 1.32), p=0.95. There was strong evidence that recruitment age group was associated with different estimates of the odds of treatment failure; with studies recruiting adults-only having lower odds of treatment failure with epinephrine. It was not possible to determine whether epinephrine in addition to selective ß2-agonist improved outcomes. CONCLUSION: The low-quality evidence available suggests that epinephrine and selective ß2-agonists have similar efficacy in acute asthma. There is a need for high-quality double-blind RCTs to determine whether addition of intramuscular epinephrine to inhaled or nebulised selective ß2-agonist improves outcome. PROSPERO REGISTRATION NUMBER: CRD42017079472.

Disease burden and treatment adherence among children and adolescent patients with asthma.

OBJECTIVE: To assess asthma burden and medication adherence in a US de-identified patient level claims database. METHODS: This retrospective observational study used the IQVIA PHARMETRICS PLUS database to identify patients aged 5-17 years, diagnosed with asthma between 01/01/2012-09/30/2017 (asthma cohort), and those initiating treatment with twice-daily inhaled corticosteroids (ICS) or twice-daily ICS/long-acting beta2 agonists (LABA) (treatment cohorts; index date = first dispensing). Patient characteristics, asthma medication, and healthcare resource utilization were assessed over a 12-month baseline period. Treatment cohort endpoints were assessed in a 12-month follow-up period, including: adherence using proportion of days covered (PDC); persistence (no gap >45 days between dispensings). RESULTS: The asthma cohort included 186,868 patients (112,689 children, mean age 7.9 years; 74,179 adolescents, mean age 14.3 years). During baseline, 34.5% used ICS or ICS/LABA, 24% used oral corticosteroids, 11.1% had ≥1 asthma-related emergency department visit, 2.2% had ≥1 asthma-related hospitalization. Among treatment cohorts, 47,276 and 10,247 patients initiated twice-daily ICS and ICS/LABA, respectively (mean ages: 9.9; 12.5 years). Mean PDC adherence to twice-daily ICS and ICS/LABA was 30% and 34% at 6 months (PDC ≥0.8: 4.3%; 6.1%); 21% and 24% at 12 months (PDC ≥0.8: 1.8%; 2.8%). Persistence with twice-daily ICS and ICS/LABA was 10.1% and 14.2% at 6 months; 5.6% and 8.0% at 12 months. CONCLUSIONS: A large disease burden and unmet need exist among US children/adolescent asthma patients, evidenced by low use of, and poor adherence to, ICS-containing medication, the notable proportion of oral corticosteroid users, and higher-than-expected asthma-related emergency department and hospitalization rates.

Novel pharmacological therapies for the treatment of bronchial asthma.

Asthma has long been recognized as a chronic inflammatory disease of the airways, often in response to inhaled allergens prompting inappropriate activation of the immune response involving a range of cells including mast cells, Th2 lymphocytes and eosinophils alongside a wide range of inflammatory mediators. First-line therapy for treatment of persistent asthma involves the use of inhaled corticosteroids (ICS) in combination with inhaled ß2-agonists enabling both the control of the underlying airways inflammation and a reduction of airway hyperresponsiveness. However, many patients remain symptomatic despite high-dose therapy. Therefore, there is a continued unmet clinical need to develop specifically new anti-inflammatory therapies for patients with asthma, either as an add-on therapy to ICS or as replacement monotherapies. The success of fixed dose combination inhalers containing both a bronchodilator and an anti-inflammatory drug has also led to the development of "bifunctional" drugs which are molecules specifically designed to have two distinct pharmacological actions based on distinct pharmacophores. In this review we will discuss these different pharmacological approaches under development for the treatment of bronchial asthma and the available preclinical and clinical data.

Optimizing drug inhibition of IgE-mediated anaphylaxis in mice.

BACKGROUND: Administering allergens in increasing doses can temporarily suppress IgE-mediated allergy and anaphylaxis by desensitizing mast cells and basophils; however, allergen administration during desensitization therapy can itself induce allergic responses. Several small molecule drugs and nutraceuticals have been used clinically and experimentally to suppress these allergic responses. OBJECTIVES: This study sought to optimize drug inhibition of IgE-mediated anaphylaxis. METHODS: Several agents were tested individually and in combination for ability to suppress IgE-mediated anaphylaxis in conventional mice, FcεRIα-humanized mice, and reconstituted immunodeficient mice that have human mast cells and basophils. Hypothermia was the readout for anaphylaxis; therapeutic efficacy was measured by degree of inhibition of hypothermia. Serum mouse mast cell protease 1 level was used to measure extent of mast cell degranulation. RESULTS: Histamine receptor 1 (HR1) antagonists, ß-adrenergic agonists, and a spleen tyrosine kinase (Syk) inhibitor were best at individually inhibiting IgE-mediated anaphylaxis. A Bruton's tyrosine kinase (BTK) inhibitor, administered alone, only inhibited hypothermia when FcεRI signaling was suboptimal. Combinations of these agents could completely or nearly completely inhibit IgE-mediated hypothermia in these models. Both Syk and BTK inhibition decreased mast cell degranulation, but only Syk inhibition also blocked desensitization. Many other agents that are used clinically and experimentally had little or no beneficial effect. CONCLUSIONS: Combinations of an HR1 antagonist, a ß-adrenergic agonist, and a Syk or a BTK inhibitor protect best against IgE-mediated anaphylaxis, while an HR1 antagonist plus a ß-adrenergic agonist ± a BTK antagonist is optimal for inhibiting IgE-mediated anaphylaxis without suppressing desensitization.