DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of the epithelial cytokine thymic stromal lymphopoietin. The efficacy, safety and oral corticosteroid-sparing potential of tezepelumab are being investigated in two ongoing, phase 3, randomized, double-blind, placebo-controlled studies (NAVIGATOR [NCT03347279] and SOURCE [NCT03406078]). DESTINATION (NCT03706079) is a long-term extension (LTE) of these studies. METHODS: DESTINATION is a randomized, double-blind, placebo-controlled LTE study in adults (18-80 years old) and adolescents (12-17 years old) with severe, uncontrolled asthma who are receiving treatment with medium- or high-dose inhaled corticosteroids plus at least one additional controller medication with or without oral corticosteroids. The study population will comprise patients who complete the 52- and 48-week NAVIGATOR and SOURCE studies, respectively. Patients who were randomized to receive tezepelumab 210 mg every 4 weeks (Q4W) in either predecessor study will continue to receive this regimen for 1 year; those who were previously randomized to receive placebo will be re-randomized (1:1) to receive either tezepelumab 210 mg Q4W or placebo for 1 year. Patients will receive their prescribed controller medications throughout DESTINATION and study physicians will have the opportunity to down- or up-titrate dosage of these medications, if appropriate. The primary objective is to evaluate the long-term safety and tolerability of tezepelumab over 104 weeks (inclusive of the treatment period of either predecessor study). The secondary objective is to assess the long-term effect of tezepelumab on asthma exacerbations. Patients recruited from SOURCE will be followed up post-treatment for 12 weeks. Patients recruited from NAVIGATOR who complete 100 weeks of tezepelumab treatment will be eligible for either 12 weeks of follow-up or a 36-week extended follow-up during which the clinical benefit of tezepelumab after treatment cessation will be investigated. DISCUSSION: DESTINATION will evaluate the long-term safety, tolerability and efficacy of tezepelumab versus placebo with continued dosing for up to 2 years. DESTINATION will also evaluate the clinical effect of tezepelumab after treatment cessation. This LTE study aims to elucidate the long-term safety implications of receiving tezepelumab and to assess its potential long-term treatment benefits in patients with severe, uncontrolled asthma. TRIAL REGISTRATION: NCT03706079 (ClinicalTrials.gov). Registered 15 October 2018.

Hydrophobic ion pair loaded self-emulsifying drug delivery system (SEDDS): A novel oral drug delivery approach of cromolyn sodium for management of bronchial asthma.

The aim of the present study is to develop a self-emulsifying drug delivery system (SEDDS) for the hydrophobic ion pair (HIP) complex of cromolyn sodium (CS), in order to enhance its intestinal absorption and biological activity. Two ion pairing agents (IPAs) were investigated: hexadecyl pyridininum chloride (HPC) and myristyl trimethyl ammonium bromide (MTAB). The optimum binding efficiency for complexation between investigated IPAs and CS was observed at a molar ratio of 1.5:1, where CS binding efficiency was found to be 76.10 ± 2.12 and 91.37 ± 1.73% for MTAB and HPC, respectively. The two prepared complexes exhibited a significant increase in partition coefficient indicating increased lipophilicity. The optimized CS-HIP complex was incorporated into SEDDS formulations. SEDDS formulations F2 (40% oleic acid, 40% BrijTM98, 20% propylene glycol) and F3 (25% oleic acid, 50% BrijTM98, 25% propylene glycol) exhibited nanometric droplet diameters with monodisperse distribution and nearly neutral zeta potential values. Ex vivo intestinal permeation study, using the non-everted gut sac technique, revealed a significantly higher cumulative amount of permeated drug, after 2 h, for F2 and F3 (53.836 and 77.617 µg/cm2, respectively) compared to 8.649 µg/cm2 for plain CS solution. The in vivo evaluation of plain CS solution compared to F2 and F3 was conducted in an ovalbumin sensitization-induced bronchial asthma rat model. Lung function parameters (tidal volume and peak expiratory flow), biochemical parameters (interleukin-5, immunoglobulin-E, myeloperoxidase and airway remodelling parameters) were assessed in addition to histopathological examination. The results indicated the superiority of F3 followed by F2 compared to plain CS solution for prophylaxis of bronchial asthma in rats.

Pediatric use of omalizumab for allergic asthma.

INTRODUCTION: Severe pediatric asthma is associated with significant morbidity as well as with a high economic burden. It represents a heterogeneous disease with multiple clinical phenotypes. Currently, physicians are facing the challenge to provide a 'personalized medicine approach', which is tailored to the diverse pathomechanisms underlying clinical presentations. Three main endotypes of airway inflammation have been described in children with severe asthma. While neutrophilic and paucigranulocytic inflammatory patterns are quite uncommon in childhood, type Th2 inflammation asthma with elevated IgE is the most prevalent in pediatric asthma. Considering the pivotal role of IgE in type Th2 inflammation asthma, the blockade of IgE using anti-IgE therapy represents a potent therapeutic option for severe pediatric asthma in children. AREAS COVERED: This review aims to focus on the role of omalizumab as a treatment option in pediatric patients (aged six years and above) with severe allergic asthma. EXPERT OPINION: The clinical efficacy and safety of omalizumab for the treatment of pediatric asthma is well documented in clinical trials and observational studies. Further studies are still required to characterize the potential benefit of anti-IgE therapy in airway remodeling, identify additional biomarkers of clinical response and address current unmet needs, including the limit on omalizumab use in children younger than six years.

Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs.

BACKGROUND: Asthma is a heterogeneous disease characterized by chronic airway inflammation. Long non-coding RNA can act as competing endogenous RNA to mRNA, and play significant role in many diseases. However, there is little known about the profiles of long non-coding RNA and the long non-coding RNA related competing endogenous RNA network in asthma. In current study, we aimed to explore the long non-coding RNA-microRNA-mRNA competing endogenous RNA network in asthma and their potential implications for therapy and prognosis. METHODS: Asthma-related gene expression profiles were downloaded from the Gene Expression Omnibus database, re-annotated with these genes and identified for asthma-associated differentially expressed mRNAs and long non-coding RNAs. The long non-coding RNA-miRNA interaction data and mRNA-miRNA interaction data were downloaded using the starBase database to construct a long non-coding RNA-miRNA-mRNA global competing endogenous RNA network and extract asthma-related differentially expressed competing endogenous RNA network. Finally, functional enrichment analysis and drug repositioning of asthma-associated differentially expressed competing endogenous RNA networks were performed to further identify key long non-coding RNAs and potential therapeutics associated with asthma. RESULTS: This study constructed an asthma-associated competing endogenous RNA network, determined 5 key long non-coding RNAs (MALAT1, MIR17HG, CASC2, MAGI2-AS3, DAPK1-IT1) and identified 8 potential new drugs (Tamoxifen, Ruxolitinib, Tretinoin, Quercetin, Dasatinib, Levocarnitine, Niflumic Acid, Glyburide). CONCLUSIONS: The results suggested that long non-coding RNA played an important role in asthma, and these novel long non-coding RNAs could be potential therapeutic target and prognostic biomarkers. At the same time, potential new drugs for asthma treatment have been discovered through drug repositioning techniques, providing a new direction for the treatment of asthma.

Regulatory T Cells in Severe Persistent Asthma in the Era of Monoclonal Antibodies Target Therapies.

Asthma is an immunoinflammatory disease characterized by bronchial hyper-reactivity to different external stimuli. New monoclonal target treatments have been developed, but few studies have investigated the role of regulatory T cells in severe asthma and the modulatory effect of biological therapy on regulatory T cell functions. Their dysfunction may contribute to the development and exacerbation of asthma. Here we review the recent literature on the potential immunological role of regulatory T cells in the pathogenesis of severe asthma. The analysis of the role of regulatory T cells was performed in terms of functions and their possible interactions with mechanisms of action of the novel treatment for severe asthma. In an era of biological therapies for severe asthma, little data is available on the potential effects of what could be a new therapy: monoclonal antibody targeting of regulatory T cell numbers and functions.

Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs.

The G protein-coupled cysteinyl leukotriene receptor CysLT1R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT1R antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLT1R bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue-coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.

Extracellular polysaccharide produced by Chlorella vulgaris - Chemical characterization and anti-asthmatic profile.

Microalgae are the lowest plant organisms producing a wide range of metabolites that make them interesting organisms for industrial applications. Cultivation of green microalgal species Chlorella vulgaris resulted a significant production of extracellular polysaccharide (EPS). Preliminary chemico-spectroscopic studies on EPS revealed its molecular profile, a complex primary structure consisting of six monosaccharide units occurring in both furano and pyrano forms, a high sugar binding variability and the presence of partially methylated derivatives of some sugar constituents. Biological activity tests showed that EPS caused significant bronchodilatory, anti-inflammatory and antitussive effects in test animals. Chlorella EPS appears to be a promising agent for the prevention of chronic airway inflammation, which is the basic pathogenic mechanism of many respiratory diseases, including bronchial asthma.

Important roles of CD32 in promoting suppression of IL-4 induced immune responses by a novel anti-IL-4Rα therapeutic antibody.

Asthma is characterized by airway hyperresponsiveness and inflammation, as well as underlying structural changes to the airways. Interleukin-4 (IL-4) is a key T-helper type 2 (Th2) cytokine that plays important roles in the pathogenesis of atopic and eosinophilic asthma. We developed a novel humanized anti-IL-4Rα antibody that can potently inhibit IL-4/IL-13-mediated TF-1 cell proliferation. Using monocytes isolated from human peripheral blood mononuclear cells (PBMCs), we revealed a critical role of CD32 in modulating the immune responses of monocytes in response to blockade of IL-4Rα signaling pathway. We, therefore, devised a new strategy to increase the efficacy of the anti-IL-4Rα monoclonal antibody for the treatment of asthma and other atopic diseases by co-engaging CD32 and IL-4Rα on monocytic cells by choosing IgG classes or Fc mutations with higher affinities for CD32. The antibody with selectively enhanced affinity for CD32A displayed superior suppression of IL-4-induced monocytes' activities, including the down-regulation of CD23 expression. Intriguingly, further analysis demonstrated that both CD32A and CD32B contributed to the enhancement of antibody-mediated suppression of CD23 expression from monocytes in response to blockade of IL-4Rα signaling. Furthermore, inhibition of IgE secretion from human PBMC by the antibody variants further suggests that the complex allergic inflammation mediated by IL-4/IL-4Rα signaling might result from a global network where multiple cell types that express multiple FcγRs are all involved, of which CD32, especially CD32A, is a key mediator. In this respect, our study provides new insights into designing therapeutic antibodies for targeting Th2 cytokine-mediated allergic pathogenesis.

The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation.

Asthma is characterised by chronic airway inflammation, airway obstruction and hyper-responsiveness. The inflammatory cascade in asthma comprises a complex interplay of genetic factors, the airway epithelium, and dysregulation of the immune response.Prostaglandin D2 (PGD2) is a lipid mediator, predominantly released from mast cells, but also by other immune cells such as TH2 cells and dendritic cells, which plays a significant role in the pathophysiology of asthma. PGD2 mainly exerts its biological functions via two G-protein-coupled receptors, the PGD2 receptor 1 (DP1) and 2 (DP2). The DP2 receptor is mainly expressed by the key cells involved in type 2 immune responses, including TH2 cells, type 2 innate lymphoid cells and eosinophils. The DP2 receptor pathway is a novel and important therapeutic target for asthma, because increased PGD2 production induces significant inflammatory cell chemotaxis and degranulation via its interaction with the DP2 receptor. This interaction has serious consequences in the pulmonary milieu, including the release of pro-inflammatory cytokines and harmful cationic proteases, leading to tissue remodelling, mucus production, structural damage, and compromised lung function. This review will discuss the importance of the DP2 receptor pathway and the current understanding of its role in asthma.

Selection of a Ligand-Binding Neutralizing Antibody Assay for Benralizumab: Comparison with an Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Cell-Based Assay.

Assessment of anti-drug antibodies (ADAs) for neutralizing activity is important for the clinical development of biopharmaceuticals. Two types of neutralizing antibody (NAb) assays (competitive ligand-binding assay [CLBA] and cell-based assay [CBA]) are commonly used to characterize neutralizing activities. To support the clinical development of benralizumab, a humanized, anti-interleukin-5 receptor α, anti-eosinophil monoclonal antibody, we developed and validated a CLBA and a CBA. The CLBA and CBA were compared for sensitivity, drug tolerance, and precision to detect NAbs in serum samples from clinical trials. The CLBA was more sensitive (27.1 and 37.5 ng/mL) than the CBA (1.02 and 1.10 µg/mL) in detecting NAbs to benralizumab for the polyclonal and monoclonal ADA controls, respectively. With the same polyclonal ADA control, the CLBA detected 250 ng/mL of ADA in the presence of 100 ng/mL of benralizumab, whereas the CBA detected 1.25 µg/mL of ADA in the presence of 780 ng/mL of benralizumab. In 195 ADA-positive samples from 5 studies, 63.59% (124/195) and 16.9% (33/195) were positive for NAb as measured by the CLBA and the CBA, respectively. ADA titers were strongly correlated (Pearson's correlation coefficient r = 0.91; n = 195) with CLBA titers. Moreover, the CLBA titer correlated with CBA percentage inhibition in the CBA-positive samples (Spearman's coefficient r = 0.50; n = 33). Our data demonstrated advantages of the CLBA in various aspects and supported the choice of the CLBA as a NAb assay for the phase III trials.

Predictive Performance of Physiologically Based Pharmacokinetic (PBPK) Modeling of Drugs Extensively Metabolized by Major Cytochrome P450s in Children.

The accuracy of physiologically based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old, has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for 10 drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol), and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group. PBPK models reasonably predicted the pharmacokinetics of desloratadine, diclofenac, itraconazole, lansoprazole, montelukast, ondansetron, sufentanil, theophylline, and tramadol across all age groups. Collectively, 58 out of 67 predictions were within 2-fold and 43 out of 67 predictions within 1.5-fold of observed values. Developed PBPK models can reasonably predict exposure in children age 1 month and older for an array of predominantly CYP metabolized drugs.

Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis.

For decades in China, the Yin-Huang-Qing-Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway.

Low-Molecular-Weight Heparin-Coated and Montelukast-Filled Inhalable Particles: A Dual-Drug Delivery System for Combination Therapy in Asthma.

Montelukast, a cysteinyl leukotriene type 1 receptor antagonist, exhibits secondary anti-inflammatory properties when used at higher concentrations. Low-molecular-weight heparin (LMWH) evokes pronounced anti-inflammatory effects by interrupting leukocyte adhesion and migration. We hypothesized that inhalable particles containing montelukast plus LMWH release both drugs in a sustained fashion and protect the lungs against allergen-induced inflammation. Large porous particles of montelukast and LMWH were prepared using a double-emulsion-solvent-evaporation method. Montelukast was first encapsulated in copolymer-based particles using polyethylenimine as a porosigen; the resulting particles were then coated with LMWH. The particles were evaluated for physicochemical properties, respirability, and release profiles. The anti-inflammatory effect of the optimized formulation was studied in ovalbumin-sensitized asthmatic Sprague Dawley rats. The optimized large porous particles had a diameter of 10.3 ± 0.7 µm, exhibited numerous surface indentations and pores, showed acceptable drug entrapment efficiency (66.8% ± 0.4% for montelukast; 91.7% ± 0.8% adsorption efficiency for LMWH), demonstrated biphasic release patterns, and escaped the uptake by the rat alveolar macrophages. The number of infiltrating inflammatory cells in asthmatic rat lungs, treated with dual-drug particles, was >74% fewer than in untreated asthmatic rat lungs. Similarly, the airway walls of asthmatic animals treated with dual-drug particles were 3-fold thinner than those of untreated asthmatic animals (p < 0.001). The optimized formulation protects lungs against methacholine-induced airway hyper-reactivity. Overall, this study demonstrates the feasibility of loading 2 drugs, montelukast and LMWH, into an inhalable particulate system and establishes that this novel combination therapy produces sustained drug release and elicits a robust anti-inflammatory response in the lungs.

European drug market entries 2015 with new mechanisms of action.

In this article, we consider the new drugs approved for the European market in 2015. We present a summary of the new mechanisms of action introduced and highlight three new mechanisms of action with a potentially high future impact: PCSK9 inhibition (alirocumab (Praluent®) and evolocumab (Repatha®)) for hypercholesterolaemia, neprilysin inhibition (sacubitril in combination with valsartan (Entresto®)) for heart failure, and interleukin-5 inhibition (mepolizumab (Nucala®)) for asthma.

Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients.

BACKGROUND: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(™)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(™)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid. METHODS: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients. RESULTS: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA. CONCLUSIONS: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD).

Structural and Physical Basis for Anti-IgE Therapy.

Omalizumab, an anti-IgE antibody, used to treat severe allergic asthma and chronic idiopathic urticaria, binds to IgE in blood or membrane-bound on B lymphocytes but not to IgE bound to its high (FcεRI) or low (CD23) affinity receptor. Mutagenesis studies indicate overlapping FcεRI and omalizumab-binding sites in the Cε3 domain, but crystallographic studies show FcεRI and CD23-binding sites that are far apart, so how can omalizumab block IgE from binding both receptors? We report a 2.42-Šomalizumab-Fab structure, a docked IgE-Fc/omalizumab-Fab structure consistent with available experimental data, and the free energy contributions of IgE residues to binding omalizumab, CD23, and FcεRI. These results provide a structural and physical basis as to why omalizumab cannot bind receptor-bound IgE and why omalizumab-bound IgE cannot bind to CD23/FcεRI. They reveal the key IgE residues and their roles in binding omalizumab, CD23, and FcεRI.

Stress Tolerance of Antibody-Poly(Amino Acid) Complexes for Improving the Stability of High Concentration Antibody Formulations.

The stabilization of antibodies in aqueous solution against physical stress remains a problematic issue for pharmaceutical applications. Recently, protein-polyelectrolyte complex (PPC) formation using poly(amino acids) was proposed to prepare antibody formulation in a salt-dissociable precipitated state without protein denaturation. Here, we investigated the stabilization effect of PPC of therapeutic antibodies with poly-l-glutamic acid on agitation and thermal stress as forms of mechanical and non-mechanical stress, respectively. The precipitated state of PPC prevented the inactivation and aggregation induced by agitation. Similar results were obtained using the suspension state of PPC, but the stabilizing effects were slightly inferior to those of the PPC precipitate. PPC precipitate and PPC suspension prevented heat-induced inactivation of the antibodies, but showed little effect on heat-induced aggregation. Thus, PPC is a new candidate as a simple storage method for antibodies in aqueous solution, as an alternative state for freeze-drying.

Fluticasone furoate/vilanterol: a review of its use in patients with asthma.

Fluticasone furoate/vilanterol (Relvar(®)) is a once-daily, fixed combination of an inhaled corticosteroid (ICS) and a long-acting ß2-adrenoreceptor agonist (LABA), delivered via a dry powder inhaler (Ellipta(®)). It is approved for the treatment of asthma in the EU and Japan, and is the first once-daily ICS/LABA to be available for this indication. Fluticasone furoate is an enhanced-affinity glucocorticoid receptor agonist, with potent anti-inflammatory activity. Vilanterol produces rapid and prolonged bronchodilation. In phase III trials in adolescents and adults with various levels of asthma uncontrolled on ICS and/or ICS/LABA, fluticasone furoate/vilanterol 100/25 or 200/25 µg once daily (approved dosages in the EU) significantly improved pulmonary function compared with placebo or equivalent dosages of fluticasone furoate alone (in some trials) or fluticasone propionate. In similar trials, fluticasone furoate/vilanterol 100/25 µg once daily was as effective as fluticasone propionate/salmeterol 250/50 µg twice daily in improving pulmonary function and significantly reduced the risk of severe asthma exacerbation relative to fluticasone furoate alone. In clinical trials, fluticasone furoate/vilanterol was generally well tolerated with fewer than 15 % of patients experiencing treatment-related adverse events, the most common of which were oral/oropharyngeal candidiasis, dysphonia, extrasystoles and cough. The tolerability profile of fluticasone furoate/vilanterol was generally similar to that of fluticasone propionate/salmeterol. Thus, fluticasone furoate/vilanterol is an effective and generally well tolerated ICS/LABA option for the treatment of uncontrolled asthma.

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals.

Bronchial asthma is a heterogeneous, complex, chronic inflammatory and obstructive pulmonary disease driven by various pathways to present with different phenotypes. A small proportion of asthmatics (5-10%) suffer from severe asthma with symptoms that cannot be controlled by guideline therapy with high doses of inhaled steroids plus a second controller, such as long-acting ß2 agonists (LABA) or leukotriene receptor antagonists, or even systemic steroids. The discovery and characterization of the pathways that drive different asthma phenotypes have opened up new therapeutic avenues for asthma treatment. The approval of the humanized anti-IgE antibody omalizumab for the treatment of severe allergic asthma has paved the way for other cytokine-targeting therapies, particularly those targeting interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17, and IL-23 and the epithelium-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin. Knowledge of the molecular basis of asthma phenotypes has helped, and continues to help, the development of novel biologicals that target a diverse array of phenotype-specific molecular targets in patients suffering from severe asthma. This review summarizes potential therapeutic approaches that are likely to show clinical efficacy in the near future, focusing on biologicals as promising novel therapies for severe asthma.

In vitro microsomal hepatic metabolism of antiasthmatic prototype LASSBio-448.

In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl- LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4-dimethoxyphenyl and 1,3- benzodioxole subunits, respectively, in agreement with the in silico prediction using MetaSite Program. The development of a reproducible analytical methodology for the major metabolites by using HPLC-MS showed that both reactions require NADPH generating system and appeared to be catalyzed by cytochrome P450 (CYP). The identification of which isoenzyme was involved in the oxidative metabolism of LASSBio-448 was carried out by pre-incubations with the selective inhibitors sulfaphenazole (CYP2C9), quinidine (CYP2D6), furafylline (CYP1A2), p-nitrophenol (CYP2E1), ticlopidine (CYP2C19) and ketoconazole (CYP3A4). CYP1A2, CYP2C19 and CYP3A4 were demonstrated to be involved in the oxidative biotransformation of LASSBio-448.