Respiratory epithelium acts as a first line of defence against external stimuli of biological and material origin. Several members of the macrolide class of antibiotics, particularly azithromycin have clinical benefit in the treatment of a range of respiratory diseases, including the ability to reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) (Albert, R.K. et al. NEJM 2011; 365: 689-698), in addition to their antimicrobial activity. We have recently demonstrated that macrolides can enhance epithelial barrier integrity (Aarson, A.J. et al. Respir Res 2019; 20: 129), as well exhibit anti-inflammatory activity, which has prompted us to develop non-antibiotic compounds with similar pharmacological actions, but without antimicrobial activity. EP395 is the lead compound of this new class of compounds we have termed "barriolides" and has recently entered a first time in human (FTIH) study and is expected to enter phase 2 clinical trials in mid-2022. We have now demonstrated that EP395 has significant anti-inflammatory effects in lipopolysaccharide (LPS) and respiratory syncytial virus (RSV)-induced neutrophilia in the lungs of mice. EP395 dose-dependently reduced neutrophil infiltration in LPS and RSV with ED50s of 3.7 (n=10) and 14 µmol/kg/week (n=8), respectively. Correspondingly, concentrations of key inflammatory cytokines, TNFα and IL-6 were also significantly reduced after 2 weeks' pre-treatment, comparable to effects induced by azithromycin and roflumilast. These data support the potential for EP395, to modify diseases involving neutrophilic infiltration and epithelial barrier dysfunction, such as COPD.

Impact of erdosteine on exacerbations in moderate COPD Introduction: Prophylactic treatment with LABA/ICS in moderate COPD affects the number of exacerbations and their treatment (Martinez AJRCCM 2018). Little is known about the effect of antioxidants on exacerbation treatment. We evaluated the effect of erdosteine on exacerbations, antibiotic and oral corticosteroid (OCS) use and health status in moderate COPD. Methods: In this post-hoc analysis of RESTORE study (Dal Negro ERJ 2017), 254 patients with moderate COPD (GOLD 2) received erdosteine 300 mg bid or placebo added to usual therapy for 12 months. We determined antibiotic and OCS use, exacerbation duration and St George’s Respiratory Questionnaire (SGRQ) scores. Subjective COPD severity scores were rated at baseline, 6 and 12 months. A p value <0.05 was considered nominally significant. Results: With erdosteine 43/126 patients exacerbated (7 moderate), compared to 62/128 with placebo (14 moderate). Erdosteine-treated patients with moderate or severe exacerbations took OCS on fewer days compared to placebo (11.4 vs 13.3), required less antibiotics (71.4% vs 85.8%) (p <0.05). Total OCS exposure was significantly less with erdosteine (p<0.05) due to shorter treatment periods (p<0.04). Erdosteine-treated patients who exacerbated showed greater improvements in SGRQ with significantly more reporting a 4 point decrease in total score despite their exacerbation (p<0.001). Similar changes were seen in subjective disease severity scores, regardless of exacerbation severity. Conclusions: In GOLD 2 patients erdosteine decreased the frequency and changed the treatment of exacerbations, lessening their impact. Preventing exacerbations in moderate COPD produces clinically meaningful benefits.

BACKGROUND:There are limited findings from low-powered studies based on few number of subjects with equine asthma. Furthermore, no studies have been performed to assess a meaningful clinically detectable impact of corticosteroids in equine asthma. OBJECTIVES:To assess and compare the clinical effect of inhaled and systemic corticosteroids in equine asthma and identify a quantitative clinical score suitable to assess the Minimal Important Difference (MID), expressed as the Minimally Clinically Detectable Difference (MCDD). STUDY DESIGN:Pair-wise and network meta-analysis. METHODS:Literature searches for studies on corticosteroid therapy in equine asthma were performed. The risk of publication bias was assessed by Funnel plots and Egger's test. The effect on changes in clinical scores vs. control was analysed via random-effects models and Bayesian networks. RESULTS:Corticosteroids significantly improved the clinical condition (Standardised Mean Difference: -1.52, 95% CrI -2.07 to -0.98; P<0.001 vs. control). No difference was detected between inhaled and systemic corticosteroids with regard to the changes in clinical scores (Relative Effect: 0.08, 95% CrI -1.45 to 1.32; P = 0.8). An Improved clinically Detectable Equine Asthma Scoring System (IDEASS) indicated that corticosteroids improved the clinical condition of asthmatic horses by 30% compared with controls (IDEASS value: -2.36, 95% CI -3.39 to -1.33; P<0.001). A one-point change in IDEASS represented the MCDD in equine asthma. MAIN LIMITATIONS:Moderate quality of evidence for systemic corticosteroids. CONCLUSIONS:Inhaled corticosteroids are effective in improving the clinical condition of horses with equine asthma and prevent exacerbations. Systemic corticosteroids should be used only in selected cases with symptomatic airway hyperresponsiveness during exacerbation. IDEASS requires further validation but may represent a suitable approach to rank the level of asthma severity and assess the clinical effect of pharmacotherapy in horses with equine asthma.

The ultra long-acting β2 -adrenoceptor agonist olodaterol plus the ultra long-acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration-Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration-ratio delivered by the currently available fixed-dose combination (1:1). The single agents elicited a significant (p < .05) concentration-dependent reduction in the EFS-induced contractility, that was synergistically improved (CI 0.18) when administered in combination (0.9 logarithms more potent, 24% more effective than the monocomponents). The drugs mixture allowed a reduction in the concentration of olodaterol from ≃1 to ≃2.3 logarithms. A favorable CRI was detected also for tiotropium bromide, whose concentration can be reduced ≃1 logarithm at medium effect levels, remaining positive up to submaximal relaxant effect in the presence of olodaterol. The combination of tiotropium bromide/olodaterol allows the reduction in the concentration of the monocomponents to achieve airway smooth muscle relaxation, thus potentially decreases the risk of adverse events when these drugs are used to treat severe asthmatic horses.

BACKGROUND AND PURPOSETNF-alpha is an inflammatory cytokine implicated in the pathogenesis of asthma and it causes airway inflammation, bronchoconstriction and airway hyperresponsiveness to a number of spasmogens following inhalation.EXPERIMENTAL APPROACHWe compared contractions of guinea pig isolated trachea incubated with saline or TNF-alpha for 1, 2 or 4 days to electrical field stimulation (EFS), 5-HT or methacholine. In addition, we compared bronchoconstriction in anaesthetized guinea pigs 6 h after intratracheal instillation of saline or TNF-alpha to vagal nerve stimulation, i.v. 5-HT or methacholine. Differential counts were performed on the bronchoalvelolar lavage fluid (BALF).KEY RESULTSMaximum contractions to methacholine, 5-HT and EFS were not different between freshly prepared and saline-incubated tissues. Exposure to TNF-alpha concentration-dependently potentiated contractions to 5-HT and EFS, but not methacholine. All contractions were atropine-sensitive, but not hexamethonium-sensitive. 5-HT-evoked contractions were inhibited by ketanserin or epithelial denudation. Only EFS-evoked contractions were tetrodotoxin-sensitive. Vagal stimulation, i.v. 5-HT or MCh caused a significant atropine-sensitive, frequency- and dose-dependent bronchoconstriction and decreased blood pressure similarly in both saline and TNF-alpha pre-treated animals. TNF-alpha potentiated the bronchoconstriction to vagal stimulation and 5-HT, but not MCh. The BALF from saline-treated animals contained predominantly macrophages, whereas that from TNF-alpha-treated animals contained neutrophils.CONCLUSIONS AND IMPLICATIONSTNF-alpha caused airway hyperresponsiveness to nerve stimulation in vivo and increased contractility in vitro. However, responsiveness to MCh was unchanged, suggesting a pre-synaptic action of TNF-alpha on parasympathetic nerves. TNF-alpha-induced airway hyperresponsiveness to 5-HT suggested an increased 5-HT2A receptor-mediated acetylcholine release from epithelial cells.

Nanomedicines for inhalation may have several formulation advantages including improving drug solubility and deposition kinetics. However, there remain many open questions regarding the safety and efficacy of inhaled nanomedicines. Recent studies have shown that drug delivery nanoparticles designed for inhalation therapy and composed of biodegradable, biocompatible materials (e.g. PLGA solid lipid nanoparticles, cationic and anionic PEG-PLA) may have a reduced toxicity compared to poorly soluble, non-biodegradable nanoparticles. However, the formulation components of drug vehicles may have an impact of nanomedicine toxicity in the lung and must be carefully controlled. Further, understanding the biodistribution kinetics of different nanoparticle materials will be crucial in determining both the safety and efficacy of potential nanomedicines for inhalation therapy. This article explores recent advances in the in vivo safely and particokinetic evaluations of inhaled nanomedicines.

Chronic inflammatory diseases (lithe respiratory tract remain a considerable healthcare burden with continuing unmet medical needs despite the availability of well established inhaled therapies. A wide array of new drugs are under development for the treatment of respiratory diseases and this article seeks to illustrate the pre-clinical experimental approaches used for the evaluation of new drugs for the treatment of asthma and COPD, from the identification of a new idea to a clinical proof of concept. The article focuses on the contribution of the Sackler Institute of Pharmacology group at King's College London in the development of new drugs by reviewing the discovery pharmacology and describing the current stage of development of four classes of drugs: phosphodiesterase inhibitors, adenosine receptor antagonists, anti-inflammatory polysaccharides and anti-inflammatory drugs that act on platelets. The close collaborations between industry and academic groups that have facilitated the development of these agents towards new therapies is proposed as an academic model for the development of medicines of the future.