Use of CompEx in eosinophilic patients with severe, uncontrolled asthma on benralizumab.

Background: CompEx Asthma, a composite end-point for asthma exacerbations, captures clinically relevant, diary-based acute worsening events (AWEs) (defined as deterioration in daily peak expiratory flow concurrent with deterioration in asthma symptoms and/or rescue therapy use) and severe exacerbations (SevEx) (defined by American Thoracic Society/European Respiratory Society guidelines). We hypothesised that CompEx and SevEx would show similar benralizumab treatment effects and correlations to blood eosinophil counts in patients with severe asthma.

Methods: This analysis of pooled 12-month data from two phase 3 studies included patients aged ≥16 years with severe, uncontrolled asthma who were randomised to benralizumab 30 mg or placebo.

Diuron and its metabolites induce mitochondrial dysfunction-mediated cytotoxicity in urothelial cells.

In the environment, or during mammalian metabolism, the diuron herbicide (3-(3,4-dichlorophenyl)-1,1-dimethylurea) is transformed mainly into 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous research suggests that such substances are toxic to the urothelium of Wistar rats where, under specific exposure conditions, they may induce urothelial cell degeneration, necrosis, hyperplasia, and eventually tumors. However, the intimate mechanisms of action associated with such chemical toxicity are not fully understood.

Physical activity end-points in trials of chronic respiratory diseases: summary of evidence.

Background: Physical activity contributes to improving respiratory symptoms. However, validated end-points are few, and there is limited consensus about what is a clinically meaningful improvement for patients. This review summarises the evidence to date on the range of physical activity end-points used in COPD, asthma and idiopathic pulmonary fibrosis (IPF) whilst evaluating their appropriateness as end-points in trials and their relation to patients' everyday life.

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD.

The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD.

Background: Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol placebo and an active comparator treatment for moderate-to-severe COPD.

Methods: This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.

Complexity of design in early phase respiratory clinical trials; evaluating impact of primary endpoints and sponsor size.

Asthma and COPD represent most of the clinical trials in the respiratory area. The Primary Endpoint (PE) defines how trials are conducted. We hypothesised that small and mid-sized pharmaceutical companies may be innovative in the selection of their trial endpoints, to be time- and cost-effective.

Impact of season and geography on CompEx Asthma: a composite end-point for exacerbations.

Background: CompEx Asthma, a novel composite end-point combining severe exacerbations (SevEx) with asthma-worsening events, was recently developed. Further characterisation of CompEx Asthma is needed to illustrate the applicability of this end-point. The objective was to evaluate CompEx Asthma as a rate end-point to determine how seasonal and geographical factors impact this novel outcome.

INEXAS: A Phase 2 Randomized Trial of On-demand Inhaled Interferon Beta-1a in Severe Asthmatics.

Background: Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti-viral cytokine, interferon (IFN)-β, during URTI, could prevent these exacerbations.

Objective: To evaluate the efficacy of on-demand inhaled IFN-β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI.

COPDCompEx: A novel composite endpoint for COPD exacerbations to enable faster clinical development.

Background: Frequency of moderate and severe chronic obstructive pulmonary disease exacerbations is an important endpoint in clinical trials, but makes them large and lengthy when powered to evaluate it. We aimed to develop a composite endpoint (COPDCompEx) that could predict treatment effect on exacerbations, enabling the design of shorter early phase clinical trials requiring fewer patients.

Methods: In this post hoc analysis, data from 20 randomized controlled trials were used to develop and test COPDCompEx.

Natural Products from Endophytic Fungi Associated with Rubiaceae Species.

This review presents the chemical diversity and pharmacological properties of secondary metabolites produced by endophytic fungi associated with various genera of Rubiaceae. Several classes of natural products are described for these endophytes, although, this study highlights the importance of some metabolites, which are involved in antifungal, antibacterial, anti-protozoal activities; neurodegenerative diseases; cytotoxic activity; anti-inflammatory and antioxidant activity; and hyperglycemic control.

Profile of Enterobacteria Resistant to Beta-Lactams.

A serious emerging problem worldwide is increased antimicrobial resistance. Acquisition of coding genes for evasion methods of antimicrobial drug mechanisms characterizes acquired resistance. This phenomenon has been observed in Enterobacteriaceae family.

Mutagenic, genotoxic and cytotoxic studies of invasive corals Tubastraea coccinea and Tubastraea tagusensis.

The high diversity of species in the marine environment gives rise to compounds with unique structural patterns not found as natural products in other systems and with great potential for pharmacological, cosmetic and nutritional use. The genus Tubastraea (Class Anthozoa, Order Scleractinia, Family Dendrophylliidae) is characterized as a hard coral without the presence of zooxanthellae. In species of this genus alkaloids derived from the compound aplysinopsin with pharmacological activity are known.

A novel endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of randomised controlled trials.

Background: Occurrence of severe asthma exacerbations are the cornerstone of the evaluation of asthma management, but severe asthma exacerbations are rare events. Therefore, trials that assess drug efficacy on exacerbations are done late in clinical development programmes. We aimed to establish an endpoint capturing clinically relevant deteriorations (diary events) that, when combined with severe exacerbations, create a composite outcome (CompEx).

A relation between TGF-β and mast cell tryptase in experimental emphysema models.

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by emphysema and/or chronic bronchitis. The aim of this study was to investigate the effect of cigarette smoke exposure on mast cells and mast cell function in vitro and in vivo in order to get further insight in the role of mast cells in the pathogenesis of emphysema. Cigarette smoke conditioned medium (CSM) induced the expression of mast cell tryptase (MMCP-6) in primary cultured mast cells.

Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury.

The 18 glycosyl hydrolase family of chitinases is an ancient gene family that is widely expressed from prokaryotes to eukaryotes. In mammals, despite the absence of endogenous chitin, a number of chitinases and chitinase-like proteins (C/CLPs) have been identified. However, their roles have only recently begun to be elucidated.

Chitin particles are multifaceted immune adjuvants.

Rationale: Chitin is a ubiquitous polysaccharide in fungi, insects, allergens, and parasites that is released at sites of infection. Its role in the generation of tissue inflammation, however, is not fully understood.

Objectives: We hypothesized that chitin is an important adjuvant for adaptive immunity.

Novel biomarkers in asthma: chemokines and chitinase-like proteins.

Purpose Of Review: Allergic asthma is a frequent lung disease in Western civilizations and is characterized by airway inflammation and tissue remodeling. Without early diagnosis and specific treatment, asthma results in a loss of lung function, impaired quality of life and the risk to die from uncontrolled asthma attacks. Thus, there is a need for specific biomarkers to detect asthma as soon as possible and to initiate the correct clinical treatment.

Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis.

Mouse breast regression protein 39 (BRP-39; Chi3l1) and its human homologue YKL-40 are chitinase-like proteins that lack chitinase activity. Although YKL-40 is expressed in exaggerated quantities and correlates with disease activity in asthma and many other disorders, the biological properties of BRP-39/YKL-40 have only been rudimentarily defined. We describe the generation and characterization of BRP-39(-/-) mice, YKL-40 transgenic mice, and mice that lack BRP-39 and produce YKL-40 only in their pulmonary epithelium.

Acidic mammalian chitinase regulates epithelial cell apoptosis via a chitinolytic-independent mechanism.

Acidic mammalian chitinase (AMCase) is produced during and plays an important role in the pathogenesis of Th2-mediated diseases and antiparasite responses. However, the effector responses of AMCase in these settings have not been adequately defined and the relationship(s) between its chitinolytic and other biologic properties have not been investigated. In these studies, we demonstrate that AMCase protects airway epithelial cells from Fas ligand- and growth factor withdrawal-induced apoptosis.

Chitin is a size-dependent regulator of macrophage TNF and IL-10 production.

Chitin is a ubiquitous polysaccharide in fungi, insects, and parasites. We hypothesized that chitin is a size-dependent regulator of innate immunity. To test this hypothesis, we characterized the effects of chitins of different sizes on murine bronchoalveolar or peritoneal macrophages.

Chitin regulation of immune responses: an old molecule with new roles.

Chitin, the second most abundant polysaccharide in nature, is commonly found in lower organisms such as fungi, crustaceans, and insects, but not in mammals. Although the non-specific anti-viral and anti-tumor activities of chitin/chitin derivatives were described two decades ago, the immunological effects of chitin have been only recently been addressed. Recent studies demonstrated that chitin has complex and size-dependent effects on innate and adaptive immune responses including the ability to recruit and activate innate immune cells and induce cytokine and chemokine production via a variety of cell surface receptors including macrophage mannose receptor, toll-like receptor 2 (TLR-2), and Dectin-1.

Acidic mammalian chitinase is secreted via an ADAM17/epidermal growth factor receptor-dependent pathway and stimulates chemokine production by pulmonary epithelial cells.

Acidic mammalian chitinase (AMCase) is expressed in an exaggerated fashion in epithelial cells at sites of pulmonary T helper cell type 2 inflammation and plays important roles in the pathogenesis of anti-parasite and asthma-like responses. However, the mechanisms that control epithelial cell AMCase secretion and its effector responses have not been adequately defined. To address these issues, we used in vivo and in vitro experimental systems to define the pathways of epithelial AMCase secretion and its epithelial regulatory effects.

TLR-2 and IL-17A in chitin-induced macrophage activation and acute inflammation.

Chitin is a ubiquitous polysaccharide in fungi, insects, and parasites. To test the hypothesis that chitin is an important immune modulator, we characterized the ability of chitin fragments to regulate murine macrophage cytokine production in vitro and induce acute inflammation in vivo. In this study, we show that chitin is a size-dependent stimulator of macrophage IL-17A production and IL-17AR expression and demonstrate that these responses are TLR-2 and MyD88-dependent.

Marked stem cell factor expression in the airways of lung transplant recipients.

Background: Airways repair is critical to lung function following transplantation. We hypothesised that the stem cell factor (SCF) could play a role in this setting.

Methods: We studied 9 lung transplant recipients (LTx recipients) during their first year postgraft, and evaluated SCF mRNA expression in bronchial biopsy specimens using on-line fluorescent PCR and SCF protein levels in bronchoalveolar lavage (BAL) and serum using ELISA.