Add-on montelukast in inadequately controlled asthma patients in a 6-month open-label study: The MONtelukast In Chronic Asthma (MONICA) study

SummaryBronchial asthma often remains uncontrolled despite treatment with inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) or both, necessitating additional treatment. Patients ≥18years (n=1681) with mild-to-moderate asthma received oral montelukast 10mg added to ICS or ICS+LABAs, and were followed for 6months in a prospective, open-label observational study. The primary endpoint was change in Asthma Control Test (ACT) score. Secondary endpoints included mini-Asthma Quality-of-Life Questionnaire (mini-AQLQ) and FEV1/PEF. Mean ACT scores improved from 14.6±4.6 (baseline) to 19.4±4.4 (month 6; p<0.0001). Using ACT score categories, the percentage of patients with uncontrolled (57.5%) or poorly controlled (25.0%) asthma at baseline decreased at month 6 (17.6 and 21.7%, respectively); the percentage of patients with well controlled (13.9%) or completely controlled (1.2%) asthma at baseline increased at month 6 (47.5 and 11.4%, respectively). The mini-AQLQ score (mean±SD) improved from 4.0±1.1 to 5.3±1.1 (p<0.0001); FEV1 increased from 2.46±0.89 to 2.60±0.92L (p<0.0001). Treatment with montelukast was generally well tolerated. In patients insufficiently controlled with ICS or ICS+LABAs, daily add-on montelukast improved both asthma control and asthma-related quality of life. Clinicaltrials.gov registry number NCT00802789

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma : results from two phase 3, randomised, double-blind, placebo-controlled trials

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D

Effectiveness of inhaler devices in adult asthma and COPD

Peer reviewedPublisher PD

Kinetic pathways of multi-phase surfactant systems

The relaxation following a temperature quench of two-phase (lamellar and sponge phase) and three-phase (lamellar, sponge and micellar phase) samples, has been studied in an SDS/octanol/brine system. In the three-phase case we have observed samples that are initially mainly sponge phase with lamellar and micellar phase on the top and bottom respectively. Upon decreasing temperature most of the volume of the sponge phase is replaced by lamellar phase. During the equilibriation we have observed three regimes of behaviour within the sponge phase: (i) disruption in the sponge texture, then (ii) after the sponge phase homogenises there is a lamellar nucleation regime and finally (iii) a bizarre plume connects the lamellar phase with the micellar phase. The relaxation of the two-phase sample proceeds instead in two stages. First lamellar drops nucleate in the sponge phase forming a onion `gel' structure. Over time the lamellar structure compacts while equilibriating into a two phase lamellar/sponge phase sample. We offer possible explanatioins for some of these observations in the context of a general theory for phase kinetics in systems with one fast and one slow variable.Comment: 1 textfile, 20 figures (jpg), to appear in PR

Prescription of inhalers in asthma and COPD : Towards a rational, rapid and effective approach

Peer reviewedPublisher PD

The impact of moderate and severe asthma exacerbations on quality of life: a post hoc analysis of randomised controlled trial data

Funder: ALK-Abello A/SAbstract: Background: This paper reports the duration of moderate and severe exacerbations in patients with house dust mite induced allergic asthma and the impact on patients’ quality of life. Methods: Post-hoc analyses were conducted using data collected during a phase III multi-national trial (MT-04) that investigated time to moderate or severe asthma exacerbation among 485 patients during withdrawal from inhaled corticosteroids. Patient diaries were analysed to ascertain duration of exacerbations. The impact on patients’ quality of life was measured by calculating utilities for five health states using the EuroQol-5 Dimension (EQ-5D-3L) and Asthma Quality of Life Questionnaire (AQL-5D). A regression analysis predicted the disutility of moving from ‘well controlled asthma’ to the other four health states: ‘partially controlled asthma’, ‘uncontrolled asthma’, ‘moderate exacerbation’ and ‘severe exacerbation’. Results: Two hundred four patients experienced exacerbations. Moderate and severe exacerbations involved statistically significant reductions in lung function compared to the constant peak expiratory flow observed for patients without exacerbations. Lung function decline occurred for 28 days, decreasing approximately 14 days before an exacerbation followed by a return to baseline over 14 days. Asthma symptoms, the use of short-acting β2-agonists, and frequency of nocturnal awakening all increased, starting 10–14 days before an exacerbation, and returned to baseline within 10–28 days following exacerbations. Compared to ‘well controlled asthma’, the disutility of having a ‘moderate exacerbation’ ranged from − 0.0834 to − 0.0921 (EQ-5D-3L) and from − 0.114 to − 0.121 (AQL-5D); and of having a ‘severe exacerbation’ from − 0.115 to − 0.163 (EQ-5D-3L) and from − 0.153 to − 0.217 (AQL-5D), depending on the length of the observation period. Conclusions: The impact of moderate and severe exacerbations in house dust mite induced allergic asthma extends 14 days before and 28 days after the peak exacerbation event. The impact of exacerbations on patients’ health-related quality of life (HRQoL) continues long after their occurrence

The impact of moderate and severe asthma exacerbations on quality of life: a post hoc analysis of randomised controlled trial data.

Funder: ALK-Abello A/SBACKGROUND: This paper reports the duration of moderate and severe exacerbations in patients with house dust mite induced allergic asthma and the impact on patients' quality of life. METHODS: Post-hoc analyses were conducted using data collected during a phase III multi-national trial (MT-04) that investigated time to moderate or severe asthma exacerbation among 485 patients during withdrawal from inhaled corticosteroids. Patient diaries were analysed to ascertain duration of exacerbations. The impact on patients' quality of life was measured by calculating utilities for five health states using the EuroQol-5 Dimension (EQ-5D-3L) and Asthma Quality of Life Questionnaire (AQL-5D). A regression analysis predicted the disutility of moving from 'well controlled asthma' to the other four health states: 'partially controlled asthma', 'uncontrolled asthma', 'moderate exacerbation' and 'severe exacerbation'. RESULTS: Two hundred four patients experienced exacerbations. Moderate and severe exacerbations involved statistically significant reductions in lung function compared to the constant peak expiratory flow observed for patients without exacerbations. Lung function decline occurred for 28 days, decreasing approximately 14 days before an exacerbation followed by a return to baseline over 14 days. Asthma symptoms, the use of short-acting β2-agonists, and frequency of nocturnal awakening all increased, starting 10-14 days before an exacerbation, and returned to baseline within 10-28 days following exacerbations. Compared to 'well controlled asthma', the disutility of having a 'moderate exacerbation' ranged from - 0.0834 to - 0.0921 (EQ-5D-3L) and from - 0.114 to - 0.121 (AQL-5D); and of having a 'severe exacerbation' from - 0.115 to - 0.163 (EQ-5D-3L) and from - 0.153 to - 0.217 (AQL-5D), depending on the length of the observation period. CONCLUSIONS: The impact of moderate and severe exacerbations in house dust mite induced allergic asthma extends 14 days before and 28 days after the peak exacerbation event. The impact of exacerbations on patients' health-related quality of life (HRQoL) continues long after their occurrence

Neuroglia at the crossroads of homoeostasis, metabolism and signalling: evolution of the concept

Ever since Rudolf Virchow in 1858 publicly announced his apprehension of neuroglia being a true connective substance, this concept has been evolving to encompass a heterogeneous population of cells with various forms and functions. We briefly compare the 19th–20th century perspectives on neuroglia with the up-to-date view of these cells as an integral, and possibly integrating, component of brain metabolism and signalling in heath and disease. We conclude that the unifying property of otherwise diverse functions of various neuroglial cell sub-types is to maintain brain homoeostasis at different levels, from whole organ to molecular