Predicting Lung Deposition of Extrafine Inhaled Corticosteroid-Containing Fixed Combinations in Patients with Chronic Obstructive Pulmonary Disease Using Functional Respiratory Imaging: An in Silico Study

Background: Functional respiratory imaging (FRI) is a computational fluid dynamics-based technique using three-dimensional models of human lungs and formulation profiles to simulate aerosol deposition. Methods: FRI was used to evaluate lung deposition of extrafine beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) and extrafine BDP/FF delivered through pressurized metered dose inhalers and to compare results with reference gamma scintigraphy data. FRI combined high-resolution computed tomography scans of 20 patients with moderate-to-severe chronic obstructive pulmonary disease (mean forced expiratory volume in 1 second 42% predicted) with in silico computational flow simulations, and incorporated drug delivery parameters to calculate aerosol airway deposition. Inhalation was simulated using profiles obtained from real-life measurements. Results: Total lung deposition (proportion deposited in intrathoracic region) was similarly high for both products, with mean ± standard deviation (SD) values of 31.0% ± 5.7% and 28.1% ± 5.2% (relative to nominal dose) for BDP/FF/GB and BDP/FF, respectively. Pairwise comparison of the deposition of BDP and FF gave a mean intrathoracic BDP/FF/GB:BDP/FF deposition ratio of 1.10 (p = 0.0405). Mean intrathoracic, central and peripheral deposition ratios for BDP were 1.09 (95% confidence interval [CI]: 1.05-1.14), 0.92 (95% CI: 0.89-0.96), and 1.20 (95% CI: 1.15-1.26), respectively, and for FF were 1.11 (95% CI: 1.07-1.15), 0.94 (95% CI: 0.91-0.98), and 1.21 (95% CI: 1.15-1.27), within the bioequivalence range (0.80-1.25) for intrathoracic and central regions, and slightly exceeding the upper boundary in the peripheral region. Mean ± SD central:peripheral deposition (C:P) was 0.48 ± 0.13 for BDP/FF/GB and 0.62 ± 0.17 for BDP/FF, indicating a higher proportion of drug deposition in the small airways than in the large airways. Conclusion: FRI demonstrated similar deposition patterns for extrafine BDP/FF/GB and BDP/FF, with both having a high lung deposition. Moreover, the deposition patterns of BDP and FF were similar in both products. Furthermore, the C:P ratios of both products indicated a high peripheral deposition, supporting small airway targeting and delivery of these two extrafine fixed combinations, with a small difference in ratios potentially due to mass median aerodynamic diameters

Ultra-low energy scattering of a He atom off a He dimer

We present a new, mathematically rigorous, method suitable for bound state and scattering processes calculations for various three atomic or molecular systems where the underlying forces are of a hard-core nature. We employed this method to calculate the binding energies and the ultra-low energy scattering phase shifts below as well as above the break-up threshold for the three He-atom system. The method is proved to be highly successful and suitable for solving the three-body bound state and scattering problem in configuration space and thus it paves the way to study various three-atomic systems, and to calculate important quantities such as the cross-sections, recombination rates etc.Comment: LaTeX, RevTeX and amssymb styles, 7 pages (25 Kb), 3 table

Glauber theory of initial- and final-state interactions in (p,2p) scattering

We develop the Glauber theory description of initial- and final-state interactions (IFSI) in quasielastic A(p,2p) scattering. We study the IFSI-distortion effects both for the inclusive and exclusive conditions. In inclusive reaction the important new effect is an interaction between the two sets of the trajectories which enter the calculation of IFSI-distorted one-body density matrix for inclusive (p,2p) scattering and are connected with incoherent elastic rescatterings of the initial and final protons on spectator nucleons. We demonstrate that IFSI-distortions of the missing momentum distribution are large over the whole range of missing momentum both for inclusive and exclusive reactions and affect in a crucial way the interpretation of the BNL data on (p,2p) scattering. Our numerical results show that in the region of missing momentum p_{m}\lsim 100-150 MeV/c the incoherent IFSI increase nuclear transparency by 5-10\%. The incoherent IFSI become dominant at p_{m}\gsim 200 MeV/c.Comment: Accepted in Z. Phys.A, Latex, 26 pages, uuencoded 9 figure

Dynamical instabilities of a resonator driven by a superconducting single-electron transistor

We investigate the dynamical instabilities of a resonator coupled to a superconducting single-electron transistor (SSET) tuned to the Josephson quasiparticle (JQP) resonance. Starting from the quantum master equation of the system, we use a standard semiclassical approximation to derive a closed set of mean field equations which describe the average dynamics of the resonator and SSET charge. Using amplitude and phase coordinates for the resonator and assuming that the amplitude changes much more slowly than the phase, we explore the instabilities which arise in the resonator dynamics as a function of coupling to the SSET, detuning from the JQP resonance and the resonator frequency. We find that the locations (in parameter space) and sizes of the limit cycle states predicted by the mean field equations agree well with numerical solutions of the full master equation for sufficiently weak SSET-resonator coupling. The mean field equations also give a good qualitative description of the set of dynamical transitions in the resonator state that occur as the coupling is progressively increased.Comment: 23 pages, 6 Figures, Accepted for NJ

Airway deposition of extrafine inhaled triple therapy in patients with copd: A model approach based on functional respiratory imaging computer simulations

Introduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and nonextrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs. Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition. Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/ VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were <1, indicating greater peripheral than central deposition (0.48 ±0.13, 0.48±0.13 and 0.49±0.13 for BDP, FF and GB, respectively; 1.96±0.84, 0.97±0.34 and 1.20±0.48 for FluF, VI and UMEC, respectively). Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB

Intra-alveolar neutrophil-derived microvesicles are associated with disease severity in COPD

Despite advances in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD), there is a distinct lack of biochemical markers to aid clinical management. Microvesicles (MVs) have been implicated in the pathophysiology of inflammatory diseases including COPD but their association to COPD disease severity remains unknown. We analysed different MV populations in plasma and bronchoalveolar lavage fluid (BALF) taken from sixty-two patients with mild to very severe COPD (51% male; mean age: 65.9 years). These patients underwent comprehensive clinical evaluation (symptom scores, lung function, exercise testing) and the capacity of MVs to be clinical markers of disease severity was assessed. We successfully identified various MV subtype populations within BALF (leukocyte, PMN (polymorphonuclear leukocyte i.e. neutrophil), monocyte, epithelial and platelet MVs) and plasma (leukocyte, PMN, monocyte and endothelial MVs), and compared each MV population to disease severity. BALF neutrophil MVs were the only population to significantly correlate with the clinical evaluation scores including FEV1, mMRC dyspnoea score, 6-minute walk test, hyperinflation and gas transfer. BALF neutrophil MVs, but not neutrophil cell numbers, also strongly correlated with BODE index. We have undertaken, for the first time, a comprehensive evaluation of MV profiles within BALF/plasma of COPD patients. We demonstrate that BALF levels of neutrophil-derived MVs are unique in correlating with a number of key functional and clinically-relevant disease severity indices. Our results show the potential of BALF neutrophil MVs for a COPD biomarker that tightly links a key pathophysiological mechanism of COPD (intra-alveolar neutrophil activation) with clinical severity/outcome