Long-acting Beta2-adrenergic Agonist Research Articles

Cost-effectiveness of triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate compared with dual therapy for the treatment of chronic obstructive pulmonary disease (COPD) in Canada

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with significant economic and societal burden in Canada. For patients whose symptoms remain uncontrolled with dual therapies including long-acting muscarinic antagonists (LAMA)/long-acting beta2-adrenergic agonists (LABA) or inhaled corticosteroids (ICS)/LABA, step-up to triple-therapy with ICS/LAMA/LABA is recommended. Budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) is an ICS/LAMA/LABA therapy with demonstrated efficacy compared to dual therapies in pivotal phase 3 trials (ETHOS and KRONOS). OBJECTIVES The objectives of this study were to conduct a cost-utility analysis to compare BGF with dual therapies (ICS/LABA and LAMA/LABA) for patients with COPD requiring escalation to triple therapy. METHODS A Markov cohort-based cost-utility analysis was conducted over a 30-year time horizon from a public payer perspective, to compare costs and outcomes in patients with COPD requiring escalation from dual therapy to triple therapy. The analysis was based on data from the ETHOS trial, Canadian administrative data, and published sources. Health states were characterized by forced expiratory volume (FEV1) severity and exacerbations (none, moderate, severe). RESULTS Over a 30-year time horizon in probabilistic analysis across several scenario analyses, BGF was associated with modest but consistent benefits to overall costs ($40,406 total for BGF, $40,685 for LAMA/LABAs and $43,261 for ICS/LABAs), as well as life years and quality-adjusted life year (QALYs) gained compared to dual therapies (8.7 total QALYs for BGF triple therapy, 8.5 for LAMA/LABAs and 8.4 for ICS/LABAs). CONCLUSIONS From a Canadian public healthcare perspective, BGF is associated with both cost-savings and improved health benefits compared with dual therapies for maintenance treatment of COPD patients at risk of exacerbations. These results may help to inform optimal decision-making.

Perfil de un paciente con enfermedad obstructiva crónica tratado con la combinación de un agonista β2 adregénico de acción prolongada y un corticoide inhalado en un dispositivo presurizado en la práctica clínica habitual: estudio ARIES

Background and objectiveThe study aimed to describe the profile of patients with stable chronic obstructive pulmonary disease (COPD) and maintenance treatment with a long-acting beta2-adrenergic agonist and an inhaled corticosteroid (LABA/ICS) in a pressurised device (pMDI), and to assess the quality of life (HRQoL). Materials and methodsObservational, multicentre, cross-sectional study in routine clinical practice, conducted in 50 sites in Spain. 390 patients aged ≥ 40 years, treated with LABA/ICS in a pMDI device for at least the previous 3 months before the inclusion, were assessed. Demographic and clinical data were collected from medical records and patient-reported COPD Assessment Test (CAT). ResultsThe patients analysed in the study were mostly male (71.3%); 84.9% in GOLD 2-3 groups; and 32.6% and 38.2% of participants with dyspnoea grade 1 and 2 according to the modified Medical Research Council (mMRC) scale, respectively. The mean CAT questionnaire score (standard deviation [SD]) was 16.3 (8.4). ConclusionsThe profile of the patients treated with LABA/ICS in a pMDI device is mainly male, with no or low comorbidities, moderate-severe functional severity, and mild-moderate dyspnoea. Patients reported a medium impact on their quality of life.

Prediction of pharmacokinetic parameters of inhaled indacaterol formulation in healthy volunteers using physiologically-based pharmacokinetic (PBPK) model

BackgroundInhaled formulations are the first choices for treating asthma and chronic obstructive pulmonary disease (COPD), attracting the increasing investment and development in the pharmaceutical industry. Both the equivalence of local and systemic exposures need to be considered when assessing the equivalence of generic inhaled drugs, which has become a dilemma in the development of generic inhaled drugs. There is an urgent need for reliable methods such as physiologically-based pharmacokinetic (PBPK) model to assist in the development of inhaled drugs. MethodTo test the strategy that in silico simulation is an effective tool in developing inhaled products and further assessing their clinically feasibility, a long-acting beta2-adrenergic agonists indacaterol, which was referred as the first-line therapy for patient with COPD, was selected as a tool drug. The PBPK model was established and the predicted plasma concentration curve was obtained by inputting the physicochemical properties of indacaterol and adjusting model parameters. The accuracy of simulation was verified by an alignment with the actual data. The main factor affecting PK in vivo was investigated by parameter sensitivity analysis. The biological equivalent size of indacaterol was investigated by virtual bioequivalence analysis. ResultsThe models of indacaterol after intravenous and oral administration were established and confirmed, and used as a background for PBPK model of inhaled administration. All those models showed favorable stability and applicability. Appropriate lung deposition was generated in the PBPK model, and the predicted plasma profile of indacaterol was consistent with the clinical actual observation values. Particle size is the most important factor affecting the PK of indacaterol in vivo. Furthermore, virtual bioequivalence simulation exhibited statistically comparable results between the particle size fluctuates in the range of 3.5–6.5 μm and baseline levels (D90 = 5 μm). ConclusionsThe PBPK model can simulate the pharmacokinetics and lung deposition of indacaterol, which will be a powerful tool to assist the development of inhaled drugs.

Chemocentric Informatics Analysis: Dexamethasone Versus Combination Therapy for COVID-19.

COVID-19 is a biphasic infectious disease with no approved vaccine or pharmacotherapy. The first drug that has shown promise in reducing COVID-19 mortality in severely-ill patients is dexamethasone, a cheap, well-known anti-inflammatory glucocorticoid, approved for the treatment of inflammatory conditions including respiratory diseases such as asthma and tuberculosis. However, about 80% of COVID-19 patients requiring oxygenation, and about 67% of patients on ventilators, are not responsive to dexamethasone therapy mainly. Additionally, using higher doses of dexamethasone for prolonged periods of time can lead to severe side effects and some patients may develop corticosteroid resistance leading to treatment failure. In order to increase the therapeutic efficacy of dexamethasone in COVID-19 patients, while minimizing dexamethasone-related complications that could result from using higher doses of the drug, we applied a chemocentric informatics approach to identify combination therapies. Our results indicated that combining dexamethasone with fast long-acting beta-2 adrenergic agonists (LABAs), such as formoterol and salmeterol, can ease respiratory symptoms hastily, until dexamethasone’s anti-inflammatory and immunosuppressant effects kick in. Our studies demonstrated that LABAs and dexamethasone (or other glucocorticoids) exert synergistic effects that will augment both anti-inflammatory and fibronectin-mediated anticoagulant effects. We also propose other alternatives to LABAs that are supported by sound systems biology evidence, such as nitric oxide. Other drugs such as sevoflurane and treprostinil interact with the SARS-CoV-2 interactome and deserve further exploration. Moreover, our chemocentric informatics approach provides systems biology evidence that combination therapies for COVID-19 will have higher chances of perturbing the SARS-CoV-2 human interactome, which may negatively impact COVID-19 disease pathways.

Bioequivalence studies of inhaled indacaterol maleate in healthy Chinese volunteers under gastrointestinal non-blocking or blocking with concomitant charcoal administration

BackgroundIndacaterol is one of the long-acting beta2-adrenergic agonists, referred as first-line monotherapy for Chronic obstructive pulmonary disease since 2011. Generic products are encouraged to benefit the large COPD patients in China, in which can provide more choices association with reduced cost and improve the quality of patient life. ObjectiveThe three-part study consists of two independent cohorts of thirty-six subjects, aimed to evaluate the bioequivalence (BE) of two indacaterol formulations in gastrointestinal (GI) absorption charcoal-block or non-block conditions. One pilot study performed in six healthy subjects to determine the blocking effect of a new charcoal-based regimen on GI absorption after orally inhalation of indacaterol. MethodsTwo BE studies were conducted with a randomized, open-label, 2-period crossover design in two independent 36-healthy-subject cohorts, equivalence in systemic and lung deposition was assessed after inhalation of a single dose of 150 μg indacaterol (test or reference formulation) alone or concomitant administration of charcoal. The charcoal-based regimen was improved by optimizing the dose and number of doses, and its blocking efficacy against GI absorption was assessed in a pilot study. Six healthy subjects received 9 g charcoal 10 min before, immediately after and 2 h after indacaterol (3 g/100 ml water × 3 times). Blood collected at predetermined time points up to 72 h. Plasma indacaterol concentrations were determined using HPLC-MS/MS. Pharmacokinetics parameters were calculated with non-compartment analysis. Equivalences were concluded if the 90% confidence interval (CI) for test: reference of Cmax and AUC0-t fell within the limits of 0.8–1.25. ResultsIndacaterol was undetectable in plasma samples in pilot study. The T/R ratio of the geometric mean Cmax and AUC0-t was 109.9% (90% CI, 106.1–113.8%) and 104.8% (90% CI, 101.5–108.1%) for charcoal-block subjects and 105.4% (90% CI, 99.8% ~ 111.3%), and 101.0% (90% CI, 97.7%–104.4%) for non-block subjects. No serious adverse events were reported. ConclusionsThe results showed that 150 μg indacaterol (+/− 9 g charcoal) was well tolerated in all subjects. The two formulations are bioequivalent in terms of the rate and absorption both in charcoal-block and non-block conditions. The improved charcoal-based regimen demonstrated to be effective and fully blockade of GI absorption of indacaterol.

Pediatric asthma: Principles and treatment.

Approximately one-half of children with asthma present with symptoms before 3 years of age. The typical history describes recurrent episodes of wheezing and/or cough triggered by a viral upper respiratory infection (URI), activity, or changes in weather. When symptoms occur after a viral URI, children with asthma often take longer than the usual week to fully recover from their respiratory symptoms. Wheezing and coughing during exercise or during laughing or crying, and episodes triggered in the absence of infection suggest asthma. A trial of bronchodilator medication should show symptomatic improvement. The goal of asthma therapy is to keep children "symptom free" by preventing chronic symptoms, maintaining lung function, and allowing for normal daily activities. Avoidance of triggers identified by a history, such as second-hand cigarette smoke exposure, and allergens identified by skin-prick testing can significantly reduce symptoms. According to the 2007 National Asthma Education and Prevention Program (NAEPP) report, if impairment symptoms are present for >2 days/week or 2 nights/month, then the disease process is characterized as persistent, and, in all age groups, inhaled corticosteroids (ICS) are recommended as the preferred daily controller therapy. Montelukast is approved for children ages ≥ 12 months and is often used for its ease of daily oral dosing. Long-acting beta-2 adrenergic agonists should only be used in combination with an ICS. For more-severe or difficult-to-control phenotypes, biologic therapy has been developed, which targets the type of inflammation present.

The Role of Guaifenesin in the Management of Chronic Mucus Hypersecretion Associated with Stable Chronic Bronchitis: A Comprehensive Review.

Chronic obstructive pulmonary disease is the third leading cause of death and disease burden worldwide. It includes a spectrum of diseases including chronic bronchitis which is characterized by overproduction, hypersecretion and decreased elimination of mucus. Chronic bronchitis has numerous clinical consequences, including predisposition to lower respiratory tract infections, accelerated decline in lung function, increased exacerbation rate and decreased health-related quality of life. Although the inflammatory mechanisms responsible for mucus cell metaplasia in chronic obstructive pulmonary disease and stable chronic bronchitis are poorly understood, the main goals of therapy are to decrease mucus hypersecretion by controlling inflammation and to increase mucus clearance. Non-pharmacological measures include smoking cessation and chest physiotherapy. Pharmacological interventions include expectorants and mucolytics together with long-acting beta2-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics. Guaifenesin is an expectorant that is thought to increase hydration and decrease viscosity of mucus leading to improved clearance of accumulated secretions from the upper and lower airway. Although guaifenesin has a Food and Drug Administration Over-the-Counter (OFC) Monograph indication to "help loosen phlegm (mucus) and thin bronchial secretions in patients with stable chronic bronchitis," there is limited published evidence of either mechanism of action or clinical efficacy in this disease state. Here we review the pathophysiology and consequences of chronic mucus hypersecretion and examine the evidence for the use of guaifenesin in patients with stable chronic bronchitis.

The Impact of Twice-Daily Indacaterol/Glycopyrrolate on the Components of Health-Related Quality of Life and Dyspnea in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease.

Chronic cough, dyspnea, and excessive sputum production, the characteristic symptoms of chronic obstructive pulmonary disease (COPD), can negatively affect patients' health-related quality of life (HRQoL). The fixed-dose combination of a long-acting beta2-adrenergic agonist and a long-acting muscarinic antagonist (LABA/LAMA) have been shown to improve HRQoL and COPD symptoms as measured by the St George's Respiratory Questionnaire (SGRQ) and the Transition Dyspnea Index (TDI) total scores. However, the impact of a LABA/LAMA on the individual components of HRQoL and dyspnea with daily activities is unknown. Secondary analysis of pooled data from 2 replicate, phase 3, 12-week, randomized, placebo, and active-controlled trials of twice-daily indacaterol/glycopyrrolate (IND/GLY) were analyzed. Change from baseline in HRQoL and dyspnea was measured by SGRQ and TDI, respectively. Total and component scores were evaluated using linear mixed models. Logistic regression was used to analyze the proportion of patients achieving minimum clinically important difference. Study outcomes were further explored in patient subgroups. A total of 2038 patients from FLIGHT1/FLIGHT2 studies were evaluated. IND/GLY significantly improved SGRQ component scores (symptoms [-7.3], activity [-3.6], and impacts [-5.0]); all P < 0.001 compared with placebo. IND/GLY also significantly improved symptoms scores compared with IND and GLY (-3.5 and -3.7, respectively; both P < 0.001). Patients treated with IND/GLY also had significant improvements in TDI component scores compared with placebo: functional impairment (0.48), magnitude of task (0.61), and magnitude of effort (0.54); all P < 0.001. All component scores were significantly higher for IND/GLY compared with IND and GLY (P ≤ 0.002 for all). Twice-daily IND/GLY significantly improved total scores as well as components of HRQoL and dyspnea in patients with COPD. These data demonstrate multiple clinical benefits of LABA/LAMA maintenance therapy in the COPD population. ClinicalTrials.gov: NCT01727141 and NCT01712516.

Clinical and economic evaluation of using fixed dose dual bronchodilator combination tiotropiumolodaterol in patients with chronic obstructive pulmonary disease

The paper is devoted to the problem of clinical efficacy and pharmacoeconomic evaluation of Spiolto Respimat. The results of clinical trials prove that Spiolto Respimat in patients with COPD improves spirometric values, symptoms of dyspnea and health-related quality of life, compared with placebo, tiotropium bromide (5 μg) and olodaterol (5 μg). According to conducted in European countries pharmacoeconomic analysis «cost-utility» therapy with Spiolto Respimat results in quality-adjusted life-year gained comparing to tiotropium bromide (5 μg). Also Spiolto Respimat is an effective option of COPD therapy comparing to the other combinations of long-acting muscarinic antagonist – long-acting beta2-adrenergic agonist.

BRONCHIAL ASTHMA THERAPY IN SMART-REGIME: STUDIES IN REAL CLINICAL PRACTICE

Despite considerable progress in development of effective therapeutic means, numerous studies are indicative of the insufficient BA control level resulting in reduction of patient life quality as well as to the high risk of disease exacerbations. The major therapeutic approach aimed at achievement of control and reduction of damage from disease is anti-inflammatory therapy based on modern inhalation glucocorticosteroids (IGCC) complemented if required by long-acting beta-2-adrenergic agonists (LABA).

Olodaterol: Once-daily inhalation spray for COPD

FDA has approved olodaterol (Striverdi Respimat—Boehringer Ingelheim), a once-daily inhalation spray to treat airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. The long-acting beta-adrenergic agonist (LABA), delivered via a propellant-free inhaler, helps the muscles around the airways in the lungs stay relaxed to prevent symptoms.

Long-acting beta2-adrenergic agonist in pediatric and adolescent asthma patients, 2003–2011

Objectives: To evaluate changes in the dispensing patterns of long-acting beta2-adrenergic agonist (LABA) in pediatric and adolescent asthma patients in relation to multiple Food and Drug Administration (FDA) regulatory activities from 2003 to 2011. Methods: We estimated LABA dispensing to pediatric asthma patients across three periods: 2003–2004 (after the first labeling change), 2005–2009 (after regulatory activities in 2005 and before 2010 LABA labeling change) and 2010–2011 (after 2010 LABA labeling change), using the IMS Health Plan Claims database. We estimated dispensing patterns over time for single-ingredient (SI) LABA and fixed-dose combination (FDC) of inhaled corticosteroid (ICS) and LABA (FDC-ICS/LABA). We also evaluated prior use of non-LABA asthma-control medication (ACM) before LABA initiation. Results: Of the 147 862 pediatric and adolescent asthma patients who initiated a LABA during the entire study period, the majority (96%) were FDC-ICS/LABA initiators. The proportion of SI-LABA among any LABA initiators was small and declined (9%, 4% and 2%, trend test p < 0.001) for the three periods. Among the patients who initiated, the proportions with prior use of an ACM (1–90 days prior) were 35%, 36% and 39% for the three periods. Conclusions: The significant decline in the proportion of SI-LABA initiation over these years is consistent with FDA’s recommendations. However, the favorable trend cannot be solely attributed to FDA activities as changes to clinical practice guidelines, and media publicity may have played a role. Investigating the reasons for the low ACM use before LABA initiation may inform approaches to further improve appropriate use of LABA in young asthma patients.

The effect of omalizumab on small airway inflammation as measured by exhaled nitric oxide in moderate-to-severe asthmatic patients

Measurement of fractional nitric oxide concentration in exhaled breath (FENO) is a simple, noninvasive method to evaluate eosinophilic airway inflammation. Nitric oxide (NO) arising from peripheral small airways/alveoli (alveolar NO concentration [CalvNO]) can be estimated using multiple flow rates and a two-compartment model of the airways and alveoli. Omalizumab, a monoclonal anti-IgE antibody, is approved for the treatment of allergic asthma and also has been shown to decrease FENO levels. This study investigates the effects of omalizumab, when added to an inhaled corticosteroid (ICS) ± long-acting beta-adrenergic agonist (LABA) treatment, on peripheral small airway/alveolar inflammation reflected by FENO measurements at higher flow rates. We hypothesized that compared with placebo, omalizumab would decrease CalvNO levels in asthmatic patients on ICS ± LABA. Forty-two patients with moderate-to-severe asthma were randomly assigned 2:1 to either omalizumab (n = 29) or placebo treatment (n = 13) for 16 weeks. Selection criteria included moderate-to-severe asthmatic patients on an ICS ± LABA, positive skin test to one or more perennial allergen, screening FENO of >13 ppb, and a baseline IgE of 30-700 IU/mL. FENO measured at multiple flow rates was used to calculate CalvNO over the course of 16 weeks. FENO levels decrease with increasing flow rates (p < 0.05 repeated measures ANOVA) but no differences between the placebo and treatment groups in overall CalvNO levels or in the changes of CalvNO with time were found. Omalizumab did not lower the CalvNO, which could have been caused by the initial low CalvNO in this asthmatic population. The model used may not be completely sufficient and/or sensitive enough to detect small changes in CalvNO.

Umeclidinium–vilanterol: First once-daily dual bronchodilator for COPD

Umeclidinium–vilanterol: First once-daily dual bronchodilator for COPD

Assessment of asthma control: The SERENA study

Several studies suggest that many asthmatic subjects have uncontrolled asthma. The control of asthma is now considered the major goal of therapy. to ascertain the level of asthma control, by Asthma Control Test (ACT), in "real-life" clinical practice and the potential risk factors for uncontrolled disease in patients treated with inhaled corticosteroids (ICS) and long-acting beta-adrenergic agonists (LABA). SERENA is a multi-centre, cross-sectional, 6-month observational, non-interventional study carried out in 16 Pulmonary Units in Italy. Asthmatic outpatients aged over 18, undergoing treatment with ICS at medium-high daily doses associated with LABA, were enrolled. The patients were divided in 3 subgroups according to the level of asthma control by ACT score (25:controlled; 20-24:partly controlled; <20: uncontrolled). Out of a total of 548 patients, 396 met the inclusion criteria. Only 9.1% of patients had asthma controlled, while partly controlled and uncontrolled asthma accounted for 39.6% and 51.3% respectively. The mean age was 54.5 ± 15.8 and the mean duration of asthma was 16.1 ± 14.1 years. There were more females than males (63% vs 37%) and females had highest prevalence of uncontrolled asthma (63.1%). The mean values of FEV1% predicted were lower in the uncontrolled group (p < 0.001). The percentage of patients with at least 1 exacerbation, unscheduled visit and/or admissions was lower in controlled (22.2%, 8.3%, 8.3%) than in partly controlled (50%, 38.6%, 9.2%) and uncontrolled (83.2%, 66.2%, 27.8%) groups (p < 0.0001). The multivariate ordinal logistic regression analysis identified female sex, FEV1 and exacerbations as the strongest independent factors associated with the uncontrolled disease. This study highlights the importance in clinical practice of a periodic assessment by a validated asthma control instrument and exacerbations/health care contacts during previous year. Clinicians should be aware that a significant proportion of patients can have uncontrolled asthma, despite regular pharmacological treatment.

Fluticasone furoate and vilanterol: Combination drug for COPD

Fluticasone furoate and vilanterol inhalation powder (Breo Ellipta— GlaxoSmithKline, Theravance) has received FDA approval as the fi rst long-term, once-daily drug for maintenance treatment of airfl ow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. The product combines fl uticasone furoate, an inhaled corticosteroid, and vilanterol, a long-acting beta-2 adrenergic agonist (LABA). Together these

Characterization of Long-Acting Beta2-Adrenergic Agonists Utilization in Asthma Patients

Objective. Because of the serious safety risks, Food and Drug Administration (FDA) has recommended that long-acting beta2-adrenergic agonists (LABAs) be reserved for patients whose asthma cannot be adequately managed with asthma control medication. The objective of the study is to assess prescribing patterns for LABAs prior to the FDA’s drug safety communication issued on 2 June 2010. Methods. Data were extracted from IMS Health Plan Claims database for asthma patients who had a new LABA therapy during 2005–2009. The proportion of LABA incident episodes preceded by inhaled corticosteroid (ICS) or leukotriene receptor antagonists (LTRAs) was examined. The medication–concurrent ratio (MCR), defined as the ratio of overlapping therapy days of single-ingredient (SI) LABAs and non-LABA products to the total days of SI LABAs, was calculated. Four criteria were used to estimate poorly controlled asthma prior to LABA initiation. Results. Of the 228 047 asthma patients, fixed-dose combination (FDC) LABAs were used by the majority of patients (96%). Prior use of ICS or LTRAs was observed in 64% and 31% of SI and FDC LABA incident episodes, respectively. The median MCR for SI LABAs was 62%. Approximately half of the patients met at least one criterion for poorly controlled asthma prior to LABA use. Conclusions. Substantial proportion of patients was prescribed LABAs without prior use of ICS or LTRAs, or other indicators of poor asthma control. These findings suggest that asthma guidelines were not entirely followed in clinical practice during the study period.

Myocardial Ischemia Associated with Clenbuterol Abuse: Report of Two Cases

BackgroundClenbuterol is an orally administered long-acting beta-2 adrenergic agonist closely related to albuterol that, in recent years, has become a substance of abuse in the bodybuilding and athletic community. ObjectivesWe report two cases of acute myocardial ischemia associated with clenbuterol abuse in two healthy young male body builders. Case ReportTwo male bodybuilders, ages 18 and 22 years, presented to the Emergency Department with palpitations, nausea, vomiting, chest pain, diaphoresis, and tachycardia shortly after ingesting clenbuterol. Both patients experienced prolonged sinus tachycardia that, in one patient, was relatively resistant to both beta- and calcium channel blockade. Both patients were found to have elevated troponin levels, the first patient as high as 4.71 ng/mL (normal<0.04 ng/mL). Further investigation revealed normal coronary arteries at catheterization and normal cardiac magnetic resonance imaging in the first patient, and normal echocardiograms for both patients. The tachycardia gradually resolved and both patients recovered uneventfully. The etiology of cardiac ischemia in these patients is uncertain. ConclusionsEmergency physicians should be aware of the clinical presentation of clenbuterol abuse and overdose, and the possibility of related cardiac ischemia and rhythm disturbances. Suggested treatment includes intravenous fluids, oxygen, aspirin, beta-blockers, and benzodiazepines, although efficacy remains unproven.

Tiotropium is non-inferior to salmeterol in maintaining improved lung function in b16-arg/arg patients with asthma

Background The efficacy and safety of inhaled long-acting beta-2 adrenergic agonists (LABA) in asthmatic patients with the B16-Arg/Arg genotype has been questioned, and the use of anti-muscarinics proposed as an alternative in patients not controlled on inhaled steroids (ICS). Objective We compare the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to ICS in B16-Arg/Arg patients with asthma not controlled by ICS alone. Methods In a double-blind, double-dummy, placebo-controlled trial, after a 4‑week run-in on 50μg b.i.d. MDI salmeterol, 388 asthma patients were randomised 1:1:1 to 16 weeks treatment with Respimat ® tiotropium 5μg q.d. evening, MDI salmeterol 50μg b.i.d., or placebo. Patients aged 18‑67 years demonstrated reversibility to bronchodilators and were uncontrolled on regular ICS (400‑1000 μg budesonide/equivalent). ICS regimes were maintained throughout the trial. Mean weekly morning PEF before randomisation was 358±115.7 L/min (range: 80.3‑733.0). Results Changes in weekly PEF from the last week of run-in to the last week of treatment (primary endpoint: ∆PEF) were -3.9±4.87 L/min (n=128) for tiotropium and ‑3.2±4.64 L/min (n=134) for salmeterol, and were superior to placebo (‑24.6±4.84 L/min; n=125; P<0.05). Tiotropium was non-inferior to salmeterol (estimated difference: −0.78 L/min; 95% CI: −13.096, 11.53; P=0.002, α level 0.025, 1‑sided, non-inferiority delta=20 L/min). Tiotropium and salmeterol were numerically superior to placebo in some patient-reported secondary outcomes. Adverse events were comparable across treatments. Conclusion Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. Safety profiles were comparable.

Characterization of a Long Acting Smooth Muscle Myosin Inhibitor, CK‐2125927, as a Novel Therapeutic Mechanism for Bronchodilation

Smooth muscle myosin is a mechanochemical enzyme that hydrolyzes ATP to generate mechanical force; ultimately all signaling pathways that modulate smooth muscle tone converge on the regulation of this motor protein. We previously showed that a novel smooth muscle myosin inhibitor, CK‐2019165, inhibited the methacholine‐induced bronchoconstriction in rat models with a short duration of action (~ 2 hours). Here we describe the discovery and characterization of a long acting smooth muscle myosin inhibitor for bronchodilation. Using high throughput screening, we identified and subsequently optimized a class of selective inhibitors of smooth muscle myosin. These compounds potently inhibit the smooth muscle myosin ATPase (IC50≤ 30 nM). An optimized member of this series, CK‐2125927,, inhibited calcium‐induced contraction of skinned rat tail artery in a concentration dependent manner with an IC50 of ~ 1 μM. CK‐2125927 induced concentration‐dependent relaxation of methacholine‐pre‐constricted rat tracheal rings with an EC50 of ~ 1 μM. Further, CK‐2125927 (10 μM) completely inhibited electrical field stimulation‐induced constriction of guinea pig tracheal rings with a 50% recovery time of &gt; 6 hours, a duration comparable to the long‐acting beta‐adrenergic agonist salmeterol. Together these data suggest CK‐2125927 is a long‐acting smooth muscle myosin inhibitor that may provide a novel therapeutic approach for the treatment of diseases where bronchoconstriction plays a role, such as asthma and COPD.