Inhaled corticosteroids (ICS) are used to reduce the rate of COPD exacerbations (EX). Debate continues over use of blood eosinophils (EOS) to predict ICS response, with some suggesting a cut-off of ≥2% (Pascoe S et al. Lancet Respir Med 2015;3:435 – 42). In the WISDOM study (NCT00975195), this response was driven by patients with higher EOS levels (≥4% or ≥300 cells/µL) (Watz H et al. Lancet Respir Med 2016;4:390 – 8]).

Les antécédents d’exacerbation (AE) sont des données importantes dans la classification GOLD. Toutefois, la relation entre les (AE) et la mortalité est moins claire. Nous avons étudié les relations entre les (AE) et la mortalité dans les données de l’étude (TIOSPIR™). Déterminer si AE (≥ 1 exacerbation l’année précédant l’inclusion), et l’utilisation de CSI à l’inclusion influence la mortalité des patients atteints de BPCO. Cette analyse post-hoc a comparé la mortalité toutes causes et les exacerbations entre quatre sous-groupes de patients caractérisés par l’utilisation de CSI à l’inclusion et AE, avec un ajustement pour le VEMS post-BD, le tabagisme et l’utilisation concomitante de β2-agoniste longue durée d’action (LABA) à l’inclusion. Les caractéristiques à l’inclusion telles que l’âge, indice de masse corporelle, le sexe, le tabagisme, et les antécédents de maladie cardiaque étaient comparables entre les sous-groupes. Les patients avec un AE avaient un risque plus élevé de décès (délai jusqu’à l’événement fatal) par rapport aux patients sans AE. Les augmentations observées dans les sous-groupes avec l’utilisation de CSI (risque relatif [RR] : 1,31) et sans CSI (HR : 1,26) étaient comparables. Le risque d’exacerbation (délai de première exacerbation) était augmenté chez les patients avec AE (avec et sans utilisation de CSI). Chez les patients atteints de BPCO dans l’étude TIOSPIR™, un antécédent d’exacerbation l’année précédant l’inclusion augmentait le risque de décès et le risque d’exacerbation indépendamment de l’utilisation de CSI.

Background: Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases.

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Seed and colleagues suggest that the excipient benzalkonium chloride in the Respimat mist inhaler might partly explain the differences seen between placebo and the Respimat inhaler.1 The hypothesis is unfounded for three reasons. Firstly, the placebo in clinical trials with tiotropium Respimat was identical to the active treatment except for the lack of the active chemical entity. …

This study compared the bronchodilator effects of tiotropium, formoterol and both combined in chronic obstructive pulmonary disease (COPD). A total of 71 COPD patients (mean forced expiratory volume in one second (FEV1) 37% predicted) participated in a randomised, double-blind, three-way, crossover study and received tiotropium 18 microg q.d., formoterol 12 microg b.i.d. or both combined q.d. for three 6-week periods. The end-points were 24-h spirometry (FEV1, forced vital capacity (FVC)) at the end of each treatment, rescue salbutamol and safety. Compared with baseline (FEV1 prior to the first dose in the first period), tiotropium produced a significantly greater improvement in average daytime FEV1 (0-12 h) than formoterol (127 versus 86 mL), while average night-time FEV1 (12-24 h) was not different (tiotropium 43 mL, formoterol 38 mL). The most pronounced effects were provided by combination therapy (daytime 234 mL, night-time 86 mL); both differed significantly from single-agent therapies. Changes in FVC mirrored the FEV1 results. Compared with both single agents, daytime salbutamol use was significantly lower during combination therapy (tiotropium plus formoterol 1.81 puffs.day(-1), tiotropium 2.41 puffs x day(-1), formoterol 2.37 puffs x day(-1)). All treatments were well tolerated. In conclusion, in chronic obstructive pulmonary disease patients, tiotropium q.d. achieved a greater improvement in daytime and comparable improvement in night-time lung function compared with formoterol b.i.d. A combination of both drugs q.d. was most effective and provided an additive effect throughout the 24-h dosing interval.

Inhaled antimuscarinics, often called anticholinergics in clinical medicine, are established as first line bronchodilators in COPD. Tiotropium has been developed as a new generation antimuscarinic following ipratropium. Tiotropium is a specific, highly potent antimuscarinic, demonstrating very slow dissociation from muscarinic receptors. Dissociation from M2-receptors is faster than from M3 or m1, which in functional in vitro studies, appeared as kinetic receptor subtype selectivity of m3 and m1 over M2. The high potency and slow receptor dissociation found its clinical correlate in significant and long lasting bronchodilatation and bronchoprotection in patients with COPD and asthma. In asthma, protection against methacholine challenge exceeded the study period of 48 hours. In COPD, bronchodilatation of about 80% of the plateau was demonstrated after the first dose. Following chronic once daily inhalation for 28 days, the improvement in pulmonary function was sustained and there was a further increase in peak effects, but more importantly a rising baseline, achieving steady state within 2 weeks. Tiotropium achieves very stable long lasting effects with comparatively low variation of bronchodilatation between peak and trough (the level before the next administration). Stable 24 hour effectiveness profiles the compound as the first once daily bronchodilator. Clinical correlates of kinetic receptor subtype selective blockade remain to be shown. Plasma levels of tiotropium at trough are in the low pg/ml range and are unlikely to explain the sustained effectiveness in the airways. Slow dissociation from muscarinic receptors is likely to be responsible for the long duration of action.