Once-daily, single-inhaler indacaterol/mometasone versus twice-daily salmeterol/fluticasone in Asian patients with inadequately controlled asthma: post hoc pooled analysis from PALLADIUM and IRIDIUM studies.

OBJECTIVE: PALLADIUM and IRIDIUM studies demonstrated efficacy and safety of indacaterol/mometasone (IND/MF) versus salmeterol/fluticasone (SAL/FLU). This post hoc analysis of pooled data from PALLADIUM and IRIDIUM studies evaluated efficacy and safety of IND/MF versus SAL/FLU in Asian patients with inadequately controlled asthma. METHODS: Both studies were Phase III, 52-week, randomized, double-blind, active-controlled that included patients with predicted pre-bronchodilator FEV1 (PALLADIUM, ≥50%-<85%; IRIDIUM, <80%), ACQ-7 score ≥1.5. Patients treated with IND/MF high- (150/320 µg) or medium-dose (150/160 µg) or SAL/FLU high-dose (50/500 µg) were included. Lung function, asthma control, and asthma exacerbations were evaluated. RESULTS: In total, 323 patients (IND/MF high-dose, n = 107; IND/MF medium-dose, n = 106, SAL/FLU high-dose, n = 110) were included. IND/MF high-dose showed improvement in trough FEV1 versus SAL/FLU high-dose at Weeks 26 (Δ, 42 mL; 95% CI, -35 to 120 mL), and 52 (Δ, 41 mL; 95% CI, -37 to 120 mL). IND/MF high-dose exhibited numerically greater improvement in ACQ-7 score versus SAL/FLU high-dose at Weeks 26 (Δ, -0.215; 95% CI, -0.385 to -0.044) and 52 (Δ, -0.176; 95% CI, -0.348 to -0.005). Improvements in trough FEV1 and ACQ-7 score were comparable between IND/MF medium-dose and SAL/FLU high-dose. IND/MF high- and medium-dose showed reductions in moderate or severe (45%; 30%), severe (39%; 41%), and all (9%; 25%) exacerbations, respectively, versus SAL/FLU high-dose over 52 weeks. All treatments were well tolerated. CONCLUSIONS: Once-daily, single-inhaler IND/MF high-dose improved lung function with better asthma control, reduced asthma exacerbations with comparable safety versus twice-daily SAL/FLU high-dose. IND/MF medium-dose showed comparable outcomes to SAL/FLU high-dose at a reduced steroid dose.

Indacaterol, glycopyrronium, and mometasone: Pharmacological interaction and anti-inflammatory profile in hyperresponsive airways.

LABA/ICS and LABA/LAMA/ICS combinations elicit beneficial effects in asthma. Specific evidence concerning the impact of combining indacaterol acetate (IND), glycopyrronium bromide (GLY), and mometasone furoate (MF) on human airway hyperresponsiveness (AHR) and airway inflammation is still missing. The aim of this study was to characterize the synergy of IND/MF and IND/GLY/MF combinations, both once-daily treatments for asthma, in hyperresponsive airways. Passively sensitized human medium and small airways were stimulated by histamine and treated with IND/MF (molar ratio: 100/45, 100/90) and IND/GLY/MF (molar ratio: 100/37/45, 100/37/90). The effect on contractility and airway inflammation was tested. Drug interaction was assessed by Bliss Independence equation and Unified Theory. IND/MF 100/90 elicited middle-to-very strong synergistic relaxation in medium and small airways (+≈20-30% vs. additive effect, P < 0.05), for IND/MF 100/45 the synergy was middle-to-very strong in small airways (+≈20% vs. additive effect, P < 0.05), and additive in medium bronchi (P > 0.05 vs. additive effect). IND/GLY/MF 100/37/45 and 100/37/90 induced very strong synergistic relaxation in medium and small airways (+≈30-50% vs. additive effect, P < 0.05). Synergy was related with significant (P < 0.05) reduction in IL-4, IL-5, IL-6, IL-9, IL-13, TNF-α, TSLP, NKA, SP, and non-neuronal ACh, and enhancement in cAMP. IND/MF and IND/GLY/MF combinations synergistically interact in hyperresponsive medium and small airways and modulate the levels of cytokines, neurokinins, ACh, and intracellular cAMP. The concentrations of MF in the combinations modulate the effects in the target tissue.

Dose bridging data for mometasone furoate in once-daily fixed-dose inhaled combinations of mometasone furoate/indacaterol and mometasone furoate/ indacaterol/glycopyrronium in patients with asthma.

Once-daily (o.d.) fixed-dose combinations of mometasone furoate/indacaterol acetate (MF/IND) and mometasone furoate/indacaterol acetate/glycopyrronium bromide (MF/IND/GLY), both delivered via the Breezhaler® device, are approved for the maintenance treatment of asthma. Across these fixed-dose combinations, while the doses of bronchodilators remain the same, the nominal doses of mometasone furoate in micrograms differ. This article presents the steps followed in bridging the mometasone furoate doses at the corresponding dose strengths in the mometasone furoate formulation delivered via the Twisthaler® and mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulations delivered via the Breezhaler®. These were: (i) bridging the mometasone furoate doses in the Twisthaler® (previously approved) to mometasone furoate doses in the Breezhaler®; (ii) bridging the mometasone furoate doses in the Breezhaler® to mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation. Following this stepwise approach, it was determined that mometasone furoate 80 µg o.d. (medium-dose strength) and 160 µg o.d. (high-dose strength) in mometasone furoate/indacaterol acetate/glycopyrronium bromide formulation provided comparable inhaled corticosteroid efficacy to mometasone furoate 160 µg o.d. (medium-dose strength) and 320 µg o.d. (high-dose strength) in the mometasone furoate/indacaterol acetate formulation, respectively. These doses were used in the PLATINUM Phase III clinical program that investigated the efficacy and safety of mometasone furoate/indacaterol acetate and mometasone furoate/indacaterol acetate/glycopyrronium bromide combinations in patients with asthma.

Detection of ADB-BUTINACA Metabolites in Human Urine, Blood, Kidney and Liver.

The N-butyl indazole derivative, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-butyl-1H-indazole-3-carboxamide (ADB-BUTINACA or ADB-BINACA), currently a drug of abuse in Russia, is reported to have a cannabinoid receptor potency and efficacy almost three times higher than JWH-018. ADB-BUTINACA was detected in blood from patients with suspected drug intoxications, as well as in blood, kidney and liver samples collected during postmortem investigations. Using liquid chromatography-time-of-flight-mass spectrometry, a number of ADB-BUTINACA metabolites were tentatively identified in urine samples. These include products of mono- and dihydroxylation, hydroxylation of the N-butyl side chain and dehydrogenation, formation of a dihydrodiol, hydrolysis of the terminal amide group, N-dealkylation of the indazole and a combination of these reactions. The dihydrodiol was found to be the predominant metabolite, with its chromatographic peak area exceeding those of other metabolites by almost an order of magnitude. For the routine analysis of blood, liver and kidney samples, the dihydrodiol and monohydroxylated metabolites along with the parent compound are recommended as target analytes. The same metabolites in free and glucuronidated forms are also recommended for analytical confirmation in urine samples.

The Influence of Argon Cluster Ion Bombardment on the Characteristics of AlN Films on Glass-Ceramics and Si Substrates.

In this paper, the influence of surface modification on the characteristics and properties of AlN thin films on Si and glass-ceramics substrates is investigated. The surface modification was made at various parameters of argon cluster ions. By using XRD and Raman spectroscopy, it was shown that the obtained AlN films have a hexagonal structure with a characteristic direction of texturing along the c axis and slight deviations from it. A comparison of the AlN surface morphology obtained by atomic force microscopy before and after cluster processing was demonstrated. This demonstrated that the cluster ions with low energy per atom (E/N = 10 eV/atom) have a high efficiency of surface smoothing. A decrease in the intensity of the Raman peaks and an increase in their full-width after bombardment with cluster ions were found, which may be caused by a change in the physicochemical state of the surface. The optical properties, the quality of the boundaries, and the distribution map of the thickness of the functional layer of AlN were investigated by the methods of spectral and spatial resolution ellipsometry. By using the cross-sectional SEM, the direction of crystallite texturing was demonstrated. The influence of argon cluster ion bombardment on the stoichiometry of samples was analyzed by EDX spectroscopy. The results obtained demonstrate the efficiency of the cluster ion smoothing of polycrystalline thin films for microelectronics, particularly when creating surface acoustic wave resonators.

Performance Characteristics of Breezhaler® and Aerolizer® in the Real-World Setting.

The evaluation of errors in use with different inhaler devices is challenging to quantify as there are a number of definitions of critical and non-critical errors with respect to inhaler use; in addition, performance characteristics of the device, such as airflow resistance, can also influence effective use in the real-world setting. Repeated observations and checking/correcting inhaler use are essential to optimise clinical effectiveness of inhaled therapy in patients. Breezhaler® is a single unit-dose dry powder inhaler used in chronic obstructive pulmonary disease and in asthma (budesonide) that has low airflow resistance, making it easier for patients of varying disease severities to achieve the inhalation flow rate required for lung deposition of treatment. Similar to Breezhaler®, the Aerolizer® is a single unit-dose dry powder inhaler used in asthma management with low airflow resistance. Studies have shown relatively low rates of critical errors with Breezhaler® and Aerolizer®, with similarities in the critical errors reported; these data on critical errors together with similarities in the usability of Breezhaler® and Aerolizer® further support the functional similarity between the two devices in both asthma and chronic obstructive pulmonary disease. Breezhaler® also has patient-feedback features, including use of a transparent drug capsule that can be checked after inhalation to see it is empty. The low resistance of the dose-confirming Breezhaler® results in less inspiratory effort being required by patients for its effective use, which allows the device to be used effectively across a wide age range of patients and disease severities.

Efficacy of one time per day, single-inhaler indacaterol/glycopyrronium/mometasone in patients with inadequately controlled asthma: post hoc analysis of IRIDIUM study in Asian population.

BACKGROUND AND OBJECTIVE: The 52-week IRIDIUM study demonstrated the efficacy of indacaterol acetate/glycopyrronium bromide/mometasone furoate (IND/GLY/MF) versus IND/MF and salmeterol xinafoate/fluticasone propionate (SAL/FLU) in patients with symptomatic asthma, despite long-acting ß2-agonist/inhaled corticosteroids (LABA/ICS) medium-dose or high-dose, predicted forced expiratory volume in 1 s (FEV1) <80% and at least one exacerbation in the previous year. Here, we present data from a post hoc analysis of the IRIDIUM study in the Asian subpopulation. METHODS: This post hoc analysis evaluated improvements in lung function, asthma control and reduction in asthma exacerbations with IND/GLY/MF medium- (150/50/80 µg) and high-dose (150/50/160 µg) versus IND/MF medium- (150/160 µg) and high-dose (150/320 µg), all one time per day and SAL/FLU high-dose (50/500 µg) two times per day, in Asian patients from the IRIDIUM study. RESULTS: In total, 258 patients (IND/GLY/MF medium-dose, 52; IND/GLY/MF high-dose, 52; IND/MF medium-dose, 51; IND/MF high-dose, 51; SAL/FLU high-dose, 52) were included. IND/GLY/MF medium- and high-dose showed greater improvement in trough FEV1 at week 26 versus respective doses of IND/MF (Δ, 100 mL and 101 mL; both p<0.05, respectively), and SAL/FLU high-dose (Δ, 125 mL; p=0.0189, and 136 mL; p=0.0118, respectively), which were maintained over 52 weeks. Both doses of IND/GLY/MF showed greater improvement in morning and evening peak expiratory flow versus respective doses of IND/MF and SAL/FLU high-dose at week 52. The changes in Asthma Control Questionnaire-7 scores from baseline were comparable in all treatment groups. IND/GLY/MF medium- and high-dose showed greater reductions in severe (34%, 69%), moderate or severe (18%, 54%) and all exacerbations (21%, 34%) compared with SAL/FLU high-dose over 52 weeks. CONCLUSION: One time per day, single-inhaler IND/GLY/MF improved lung function, reduced asthma exacerbations and provided comparable asthma control versus IND/MF and SAL/FLU in Asian patients with inadequately controlled asthma despite LABA/ICS. The results of this analysis were consistent with the overall population in the IRIDIUM study.

Controlling the dynamics of spontaneous emission from quantum dots by photonic crystals.

Control of spontaneously emitted light lies at the heart of quantum optics. It is essential for diverse applications ranging from miniature lasers and light-emitting diodes, to single-photon sources for quantum information, and to solar energy harvesting. To explore such new quantum optics applications, a suitably tailored dielectric environment is required in which the vacuum fluctuations that control spontaneous emission can be manipulated. Photonic crystals provide such an environment: they strongly modify the vacuum fluctuations, causing the decay of emitted light to be accelerated or slowed down, to reveal unusual statistics, or to be completely inhibited in the ideal case of a photonic bandgap. Here we study spontaneous emission from semiconductor quantum dots embedded in inverse opal photonic crystals. We show that the spectral distribution and time-dependent decay of light emitted from excitons confined in the quantum dots are controlled by the host photonic crystal. Modified emission is observed over large frequency bandwidths of 10%, orders of magnitude larger than reported for resonant optical microcavities. Both inhibited and enhanced decay rates are observed depending on the optical emission frequency, and they are controlled by the crystals' lattice parameter. Our experimental results provide a basis for all-solid-state dynamic control of optical quantum systems.

Modelling the Cost-Effectiveness of Indacaterol/Glycopyrronium versus Salmeterol/Fluticasone Using a Novel Markov Exacerbation-Based Approach.

Purpose: Exacerbations drive outcomes and costs in chronic obstructive pulmonary disease (COPD). While patient-level (micro) simulation cost-effectiveness models have been developed that include exacerbations, such models are complex. We developed a novel, exacerbation-based model to assess the cost-effectiveness of indacaterol/glycopyrronium (IND/GLY) versus salmeterol/fluticasone (SFC) in COPD, using a Markov structure as a simplification of a previously validated microsimulation model. Methods: The Markov model included three health states: infrequent or frequent exacerbator (IE or FE; ≤1 or ≥2 moderate/severe exacerbations in prior 12 months, respectively), or death. The model used data from the FLAME study and was run over a 10-year horizon. Cycle length was 1 year, after which patients remained in the same health state or transitioned to another. Analysis was conducted from a Swedish payer's perspective (Swedish healthcare costs, converted into Euros), with incremental costs and quality-adjusted life-years (QALYs) calculated (discounted 3% annually). Results: At all post-baseline timepoints, IND/GLY was associated with more patients in the IE health state and fewer patients in the FE and dead states relative to SFC. Over a 10-year period, IND/GLY was associated with a cost saving of €1,887/patient, an incremental benefit of 0.142 QALYs, and an addition of 0.057 life-years, compared with SFC. Conclusion: This Markov model represents a novel cost-effectiveness analysis for COPD, with simpler methodology than prior microsimulation models, while retaining exacerbations as drivers of disease progression. In patients with COPD with a history of exacerbations in the previous year, IND/GLY is a cost-effective treatment option compared with SFC.

Color control of natural fluorescent proteins by photonic crystals.

The emission of fluorescent proteins inside photonic crystals is studied. It is demonstrated that the apparent emission color of the fluorescent protein can be controlled externally by the photonic crystal. With increasing crystal lattice parameter, the appearance of the proteins turns from orange to red, and suddenly to green. The dramatic color changes agree with the theoretically expected redistribution of light escaping around the stop band of the photonic crystal. Our experiments show the potential of combining biological systems with nanophotonics. This "biophotonic engineering" may be extended to control emission rates and complex Förster energy-transfer systems obtained by protein engineering.

Real-life evaluation of COPD treatment in a Bulgarian population: a 1-year prospective, observational, noninterventional study.

Introduction: This was the first study designed to prospectively evaluate treatment patterns in chronic obstructive pulmonary disease (COPD) and the degree of adherence with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy recommendations in routine clinical practice in Bulgaria. Methods: The study was conducted in an outpatient setting and enrolled patients of both genders, aged >40 years, who were diagnosed with COPD (as per GOLD 2013). Evaluations were performed at baseline and at 6- and 12-month visits. Results: Of the 811 enrolled patients, 719 were assessed and completed the 12-month observation period. Overall, a substantial number of patients experienced moderate airflow limitation (~49% patients, GOLD 2 as per GOLD 2013; mean postbronchodilator forced expiratory volume in 1 second value was ~50% of the predicted value), belonged to GOLD group D (~51% patients), and had COPD assessment test score ≥10 or modified Medical Research Council score ≥2 (~79% patients), and ≤1 exacerbation in the past 1 year (~80% patients). Short-acting ß2-agonists (~63% patients), inhaled corticosteroids/long-acting ß2-agonist fixed-dose combination (~62% patients), and long-acting muscarinic antagonists (~59% patients) were the most frequently used medications at all visits, regardless of severity. High levels of deviation from GOLD recommendations were observed in GOLD groups A and B patients. The deviation comprised high use of inhaled corticosteroid-containing regimens in ~45% and 63% of patients in GOLD groups A and B, respectively. Only 25 (3%) of the 796 patients reported at least one adverse event. Conclusion: The routine clinical practice for COPD in Bulgaria deviates from the GOLD recommendations largely in patients at a low risk (GOLD groups A and B), while the deviation was lesser in those at a higher risk (GOLD groups C and D).