Process development of inhalation powders containing simvastatin loaded liposomes using spray drying technology.

The development of an inhalation powder (IP) for cancer therapy is desired to improve the therapeutic response and patient compliance. The latest studies highlighted that statins, a class of drugs used in hypercholesterolemia, can have anticancer and antiinflammatory properties. Therefore, the aim of the study was to develop an IP containing liposomes loaded with simvastatin using spray drying technology, as well as to investigate the influence of formulation factors on the quality attributes of the IP by means of experimental design. Results highlighted that the composition of liposomes, namely type of phospholipid and cholesterol concentration, highly influences the quality attributes of IP, and the use of optimal concentrations of excipients, i.e. D-mannitol and L-leucine, is essential to preserve the characteristics of liposomes throughout the spray drying process. The in vitro characterization of the optimal IP formulation revealed that the total percentage of released drug is higher from the IP formulation compared to the powder of active substance (53.38 vs. 42.76%) over a period of six hours, and 39.67% of dry particles have a size less than 5 µm, making them suitable for inhalation. As a conclusion, spray drying technology can be effectively used in the development and preparation of IP containing liposomes.

Effects of Spaceflight on Human Skin.

During both short- and long-duration spaceflight, several health problems can occur, including those of the skin. Astronauts in space and after returning to earth experience erythematous, burning, itchy, dry, sensitive, and thinning skin. Other skin problems, such as infections, abrasions, lacerations, delayed wound healing, and accelerated skin aging, are also common. Human skin is an ecosystem composed of a wide range of habitats for bacteria, fungi, and viruses called microbiome, which not only show a strong skin site-specific preference but also serve as microbial fingerprints that are highly unique to individuals. These human skin-associated microorganisms make a substantial contribution to the microbial ecosystems that inhabit the closed environments in space. On the other hand, human skin microbiome is also subject to change during spaceflight, which may lead to skin infections or the flare up of skin diseases. This review highlights some of the interactions between the space environment and the skin.

The effect of oral and nasal breathing on the deposition of inhaled particles in upper and tracheobronchial airways.

The inhalation route has a substantial influence on the fate of inhaled particles. An outbreak of infectious diseases such as COVID-19, influenza or tuberculosis depends on the site of deposition of the inhaled pathogens. But the knowledge of respiratory deposition is important also for occupational safety or targeted delivery of inhaled pharmaceuticals. Simulations utilizing computational fluid dynamics are becoming available to a wide spectrum of users and they can undoubtedly bring detailed predictions of regional deposition of particles. However, if those simulations are to be trusted, they must be validated by experimental data. This article presents simulations and experiments performed on a geometry of airways which is available to other users and thus those results can be used for intercomparison between different research groups. In particular, three hypotheses were tested. First: Oral breathing and combined breathing are equivalent in terms of particle deposition in TB airways, as the pressure resistance of the nasal cavity is so high that the inhaled aerosol flows mostly through the oral cavity in both cases. Second: The influence of the inhalation route (nasal, oral or combined) on the regional distribution of the deposited particles downstream of the trachea is negligible. Third: Simulations can accurately and credibly predict deposition hotspots. The maximum spatial resolution of predicted deposition achievable by current methods was searched for. The simulations were performed using large-eddy simulation, the flow measurements were done by laser Doppler anemometry and the deposition has been measured by positron emission tomography in a realistic replica of human airways. Limitations and sources of uncertainties of the experimental methods were identified. The results confirmed that the high-pressure resistance of the nasal cavity leads to practically identical velocity profiles, even above the glottis for the mouth, and combined mouth and nose breathing. The distribution of deposited particles downstream of the trachea was not influenced by the inhalation route. The carina of the first bifurcation was not among the main deposition hotspots regardless of the inhalation route or flow rate. On the other hand, the deposition hotspots were identified by both CFD and experiments in the second bifurcation in both lungs, and to a lesser extent also in both the third bifurcations in the left lung.

Ultrafine urban particle measurements in Budapest and their airway deposition distribution calculation.

OBJECTIVES: The aim of this study was to provide particle number and mass deposition rates of submicron particles in the human airways as inputs for toxicology and other areas of aerosol science. METHODS: Scanning Mobility Particle Spectrometer was used to measure the number concentrations and size distributions of the ultrafine urban particles during summer and winter in Budapest. The Stochastic Lung Model (SLM) was applied to calculate number and mass deposition rates of the inhaled particles in different anatomical regions of the airways. RESULTS: Our calculations revealed that for the selected days in summer and winter with PM10 values below the health limit 4.7 and 18.4 billion particles deposited in the bronchial region of the lungs. The deposition in the acinar region of the lung was even higher, 8.3 billion particles for the summer day, and 33.8 billion particles for winter day. CONCLUSIONS: Our results clearly demonstrate that large daily numbers of urban UFPs are deposited in the respiratory tract, which may play a key role in the health effects of particulate matter (PM) inhalation. Present results, connecting the ambient exposure parameters with the local burden of the airway epithelium, can be useful inputs of in vitro cell culture experiments. By the combination of urban UFP monitoring and numerical modeling of particle deposition with toxicological studies, the health risks of urban aerosols could be better assessed. The use of UFP data in addition to PM10 and PM2.5 in the epidemiological studies would also be indicated.

Simulation of the effect of mucociliary clearance on the bronchial distribution of inhaled radon progenies and related cellular damage using a new deposition and clearance model for the lung.

Most of the current dosimetry models of inhaled short-lived radon decay products assume uniform activity distributions along the bronchial airways. In reality, however, both deposition and clearance patterns of inhaled radon progenies are highly inhomogeneous. Consequently, a new deposition-clearance model has been developed that accounts for such inhomogeneities and applied together with biophysical models of cell death and cell transformation. The scope of this study was to apply this model which is based on computational fluid and particle dynamics methods, in an effort to reveal the effect of mucociliary clearance on the bronchial distribution of deposited radon progenies. Furthermore, the influence of mucociliary clearance on the spatial distribution of biological damage due to alpha-decay of the deposited radon progenies was also studied. The results obtained demonstrate that both deposition and clearance of inhaled radon progenies are highly non-uniform within a human airway bifurcation unit. Due to the topology of the carinal ridge, a slow clearance zone emerged in this region, which is the location where most of the radio-aerosols deposit. In spite of the slow mucus movement in this zone, the initial degree of inhomogeneity of the activity due to the nonuniform deposition decreased by a factor of about 3 by considering the effect of mucociliary clearance. In the peak of the airway bifurcation, the computed cell death and cell transformation probabilities were lower when considering deposition and clearance simultaneously, compared to the case when only deposition was considered. However, cellular damage remained clustered.

The degree of inhomogeneity of the absorbed cell nucleus doses in the bronchial region of the human respiratory tract.

Inhalation of short-lived radon progeny is an important cause of lung cancer. To characterize the absorbed doses in the bronchial region of the airways due to inhaled radon progeny, mostly regional lung deposition models, like the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection, are used. However, in this model the site specificity of radiation burden in the airways due to deposition and fast airway clearance of radon progeny is not described. Therefore, in the present study, the Radact version of the stochastic lung model was used to quantify the cellular radiation dose distribution at airway generation level and to simulate the kinetics of the deposited radon progeny resulting from the moving mucus layer. All simulations were performed assuming an isotope ratio typical for an average dwelling, and breathing mode characteristic of a healthy adult sitting man. The study demonstrates that the cell nuclei receiving high doses are non-uniformly distributed within the bronchial airway generations. The results revealed that the maximum of the radiation burden is at the first few bronchial airway generations of the respiratory tract, where most of the lung carcinomas of former uranium miners were found. Based on the results of the present simulations, it can be stated that regional lung models may not be fully adequate to describe the radiation burden due to radon progeny. A more realistic and precise calculation of the absorbed doses from the decay of radon progeny to the lung requires deposition and clearance to be simulated by realistic models of airway generations.

Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro-in silico lung deposition results.

Objective: The aim was to study the stability of dry powder inhaler (DPI) formulations containing antibiotic with different preparation ways - carrier-based, carrier-free, and novel combined formulation - and thereby to compare their physicochemical and in vitro-in silico aerodynamical properties before and after storage. Presenting a novel combined technology in the field of DPI formulation including the carrier-based and carrier-free methods, it is the most important reason to introduce this stable formulation for the further development of DPIs. Methods: The structure, the residual solvent content, the interparticle interactions, the particle size distribution and the morphology of the samples were studied. The aerodynamic values were determined based on the cascade impactor in vitro lung model. We tested the in silico behavior of the novel combined formulated samples before and during storage. Results: The physical measurements showed that the novel combined formulated sample was the most favorable. It was found that thanks to the formulation technique and the use of magnesium stearate (MgSt) has a beneficial effect on the stability compared with the carrier-based formulation without MgSt and carrier-free formulations. The results of in vitro and in silico lung models were consistent with the physical results, so the highest deposition was found for the novel combined formulated sample during the storage. Conclusions: It can be established that after the storage a novel combined formulated DPI contained amorphous drug to have around 2.5 µm mass median aerodynamic diameter and nearly 50% fine particle fraction predicted high lung deposition in silico also.

Comparison of airway deposition distributions of particles in healthy and diseased workers in an Egyptian industrial site.

The objective of this study is the prediction and comparison of airway deposition patterns of an industrial aerosol in healthy workers and workers suffering from silicosis. Mass concentrations and related size distributions of particulate matter were measured in the industrial area of Samalut in Minia, Egypt. A novel stochastic lung deposition model, simulating the symptoms of silicosis by chronic bronchial (Br) obstruction and emphysema in the acinar (Ac) region, was applied to compute mass deposition fractions, deposition density, deposition rate and deposition density rate distributions in healthy and diseased workers. In the case of healthy workers, both mass deposition fractions and deposition rates are highest in the first half of the Ac region of the lung, while the corresponding deposition density and deposition density rate distributions exhibit a maximum in the large Br airways. In the case of diseased lungs, bullous emphysema causes a large deposition peak in the region of the bronchioli respiratorii. Regional mass deposition fractions adopt maximum values in the extrathoracic region, except during mouth breathing for bullous emphysema, where Ac deposition can be the most prominent. In general, lung deposition is significantly higher in diseased than in healthy lungs. Indeed, workers suffering from silicosis receive significantly higher Ac doses than healthy workers exposed to the same aerosol. Thus, this illness may progress faster if a diseased worker remains in a strongly polluted area.

A Novel Combined Dry Powder Inhaler Comprising Nanosized Ketoprofen-Embedded Mannitol-Coated Microparticles for Pulmonary Inflammations: Development, In Vitro-In Silico Characterization, and Cell Line Evaluation.

Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.

Comparative study of the inhalation parameters of COPD patients through NEXThaler® and Ellipta® dry powder inhalers.

The deposition of dry powder aerosol drugs depends on the inhalation parameters of the patients through the inhaler. These data are not directly measured in clinical practice. Their prediction based on the routinely measured spirometric data could help in choosing the appropriate device and optimizing the therapy. The aim of this study was to perform inhalation experiments to find correlations between inhalation parameters of COPD patients through two DPI devices and their native spirometric data, gender, age and disease severity. Another goal was to establish relationships between peak inspiratory flows through NEXThaler® and Ellipta® inhalers and their statistical determinants. Breathing parameters of 113 COPD patients were measured by normal spirometry and while inhaling through the two DPIs. Statistical analysis of the measured data was performed. The average values of peak inspiratory flow through the devices (PIFdev) were 68.4 L/min and 78.0 L/min for NEXThaler® and Ellipta®, respectively. PIFdev values were significantly higher for males than for females, but differences upon age, BMI and disease severity group were not significant. PIFdev values correlated best with their native spirometric counterparts (PIF) and linear relationships between them were revealed. Current results may be used in the future to predict the success of inhalation of COPD patients through DPI devices, which may help in the inhaler choice. By choosing the appropriate device-drug pair for each patient the lung dose can be increased and the efficiency of the therapy improved. Further results of the clinical study will be the subject of a next publication.

Simulation of bronchial mucociliary clearance of insoluble particles by computational fluid and particle dynamics methods.

For a correct assessment of health consequences of inhaled aerosols as a function of dose, whether for environmental, occupational or therapeutic agents, knowledge of their deposition distribution in the respiratory tract and subsequent clearance is important. The objective of this study is to model particle clearance at bronchial airway bifurcation level and to analyze the combined effect of deposition and clearance. For this purpose, a numerical model has been implemented. Air and mucus flow fields were computed in a model bronchial airway bifurcation. Inhaled particles with 1 and 10 µm aerodynamic diameters were tracked to determine deposition and clearance patterns. Simulation results revealed the existence of a slow clearance zone around the peak of the airway bifurcation causing delayed clearance of the particles depositing or entering here. Particles clearing up from the deeper airways and crossing the studied bifurcation do not accumulate in this zone, because of their tendency to avoid it. The average residence time of these particles was around 20 min independently of particle size (whether it is 1 or 10 µm). However, as a result of the superposition of deposition and clearance mechanisms, the final spatial distribution of particles deposited primarily in the target bifurcation is size dependent, because deposition is size specific. Although deposition density of particles deposited in the slow clearance area is one-two orders of magnitude higher than the average deposition density, these values are reduced by clearance by the factors of 4-7, depending on the particle size and the surface area of the selected slow clearance zone. In conclusion, although particle deposition is inhomogeneous, clearance can significantly decrease the degree of spatial non-uniformity of the particles. Therefore, for a correct assessment of doses at local levels, it is important to consider both deposition and clearance. Although future research may overwrite some of the model assumptions on the nature of mucus, the authors think that most of the current predictions will hold.

Firework smoke: Impacts on urban air quality and deposition in the human respiratory system.

Particle number concentrations and size distributions resulting from the firework displays held in Budapest, Hungary every year on St. Stephen's Day were studied over a period of seven years. In the year most impacted, the total particle number concentration reached its peak measured level of 369 × 103 cm-3 5 min after the end of the display, and returned to the pre-event state within 45 min. The fireworks increased hourly mean concentrations by a factor of 5-6, whereas the concentrations in the diameter range of 100-1000 nm, in which the magnitude of the increase was the greatest, were elevated by a factor of 20-25. An extra particle size mode at 203 nm was manifested in the size distributions as result of the fireworks. The PM10 mass concentrations at peak firework influence and as 1-h mean increased 123 and 58 times, respectively, relative to the concentration before the display. The smoke was characterised by a relatively short overall atmospheric residence time of 25 min. Spatiotemporal dispersion simulations revealed that there were substantial vertical and horizontal concentration gradients in the firework plume. The affected area made up a large part of the city. Not only the spectators of the display at the venue and nearby areas, but the population located further away downwind of the displays and more distant, large and populous urban quarters were affected by the plume and its fallout. The fireworks increased the deposition rate in the respiratory system of females by a factor of 4, as a conservative estimate. The largest surface density deposition rates were seen in the segmental and sub-segmental bronchi, which represents an excessive risk to health. Compared to adults, children were more susceptible to exposure, with the maximum surface density deposition rates in their case being three times those of adults in the trachea.

Effectiveness and quality of life in lung cancer, pre-, post- and perioperative rehabilitation - A review.

Functional conditions like lung function and exercise capacity are important limiting factors of chest surgery in lung cancer with co-morbidities (chronic obstructive pulmonary disease (COPD) and other chronic respiratory diseases). Pulmonary rehabilitation has a favourable effect on the cardiovascular system, metabolism, respiratory and peripheral muscles and lung mechanics. Our aim was to assess the role of pre-, post- and peri-operative pulmonary rehabilitation in lung cancer in this review. We sought to size up the importance of pulmonary rehabilitation in patients undergoing surgery with or without (neo)adjuvant treatment, radiotherapy, chemotherapy, chemoradiotherapy, major physiological impairments and complications. Searches were performed in PubMed and ClinicalTrials.gov databases using the terms "exercise", "rehabilitation", "small cell lung cancer", "non-small cell lung cancer", "exercise capacity", "chest surgery" and "quality of life" from inception to February 7th, 2022. Pulmonary rehabilitation has been recognized as an effective intervention to reduce lung cancer related symptoms and improve the pulmonary function, lung mechanics, chest kinematics, respiratory- and peripheral muscle function, physical activity and quality of life (QoL) of the patients. In conclusion, this review shows positive, highly encouraging and effective results of pulmonary rehabilitation in terms of the patients' lung function, functional mobility and quality of life. The tools for complex pulmonary rehabilitation have evolved considerably over the past two decades, thus this research has been conducted on a variety of studies about this subject and serves as a synthesis of the systematic and meta-analytic reviews.

Modeling of pulmonary deposition of agents of open and fixed dose triple combination therapies through two different low-resistance inhalers in COPD: a pilot study.

Introduction: Inhalation therapy is a cornerstone of treating patients with chronic obstructive pulmonary disease (COPD). Inhaler devices might influence the effectiveness of inhalation therapy. We aimed to model and compare the deposition of acting agents of an open and a fixed dose combination (FDC) triple therapy and examine their repeatability. Methods: We recruited control subjects (Controls, n = 17) and patients with stable COPD (S-COPD, n = 13) and those during an acute exacerbation (AE-COPD, n = 12). Standard spirometry was followed by through-device inhalation maneuvers using a pressurized metered dose inhaler (pMDI) and a soft mist inhaler (SMI) to calculate deposition of fixed dose and open triple combination therapies by numerical modeling. Through-device inspiratory vital capacity (IVCd) and peak inspiratory flow (PIFd), as well as inhalation time (tin) and breath hold time (tbh) were used to calculate pulmonary (PD) and extrathoracic deposition (ETD) values. Deposition was calculated from two different inhalation maneuvers. Results: There was no difference in forced expiratory volume in 1 s (FEV1) between patients (S-COPD: 42 ± 5% vs. AE-COPD: 35 ± 5% predicted). Spiriva® Respimat® showed significantly higher PD and lower ETD values in all COPD patients and Controls compared with the two pMDIs. For Foster® pMDI and Trimbow® pMDI similar PD were observed in Controls, while ETD between Controls and AE-COPD patients did significantly differ. There was no difference between COPD groups regarding the repeatability of calculated deposition values. Ranking the different inhalers by differences between the two deposition values calculated from separate maneuvers, Respimat® produced the smallest inter-measurement differences for PD. Discussion: Our study is the first to model and compare PD using pMDIs and an SMI as triple combination in COPD. In conclusion, switching from FDC to open triple therapy in cases when adherence to devices is maintanined may contribute to better therapeutic effectiveness in individual cases using low resistance inhalers.

The effect of lung emptying before the inhalation of aerosol drugs on drug deposition in the respiratory system.

The amount of drug depositing in the airways depends, among others, on the inhalation manoeuvre and breathing parameters. The objective of this study was to quantify the effect of lung emptying before the inhalation of drugs on the lung doses. Thirty healthy adults were recruited. Their breathing profiles were recorded while inhaling through six different emptied DPI devices without breathe-out and after comfortable or forced exhalation. The corresponding emitted doses and aerosol size distributions were derived from the literature. The Stochastic Lung Model was used to estimate the deposited doses. In general, forceful exhalation caused increased flow rate and inhaled air volume. Increased flow rate led to the increase of the average lung dose for drugs with positive lung dose-flow rate correlation (e.g. Symbicort®: relative increase of 6.7%, Bufomix®: relative increase of 9.2%). For drugs with negative correlation of lung dose with flow rate (all the studied drugs except the above two) lung emptying caused increased (Foster® by 2.7%), almost unchanged (Seebri®, Relvar®, Bretaris®) and also decreased (Onbrez® by 6.6%) average lung dose. It is worth noting that there were significant inter-individual differences, and lung dose of each drug could be increased by a number of subjects. In conclusion, the change of lung dose depends on the degree of lung emptying, but it is also inhaler and drug specific. Forceful exhalation can help in increasing the lung dose only if the above specificities are taken into account.

The effect of exhalation before the inhalation of dry powder aerosol drugs on the breathing parameters, emitted doses and aerosol size distributions.

Airway deposition of aerosol drugs is highly dependent on the breathing manoeuvre of the patients. Though incorrect exhalation before the inhalation of the drug is one of the most common mistakes, its effect on the rest of the manoeuvre and on the airway deposition distribution of aerosol drugs is not explored in the open literature. The aim of the present work was to conduct inhalation experiments using six dry powder inhalers in order to quantify the effect of the degree of lung emptying on the inhalation time, inhaled volume and peak inhalation flow. Another goal of the research was to determine the effect of the exhalation on the aerodynamic properties of the drugs emitted by the same inhalers. According to the measurements, deep exhalation before drug inhalation increased the volume of the inhaled air and the average and maximum values of the inhalation flow rate, but the extent of the increase was patient and inhaler specific. For different inhalers, the mean value of the relative increase in peak inhalation flow due to forceful exhalation was between 15.3 and 38.4% (min: Easyhaler®, max: Breezhaler®), compared to the case of normal (tidal) exhalation before the drug inhalation. The relative increase in the inhaled volume was between 36.4 and 57.1% (min: NEXThaler®, max: Turbuhaler®). By the same token, forceful exhalation resulted in higher emitted doses and smaller emitted particles, depending on the individual breathing ability of the patient, the inhalation device and the drug metered in it. The relative increase in the emitted dose varied between 0.2 and 8.0% (min: Foster® NEXThaler®, max: Bufomix® Easyhaler®), while the relative enhancement of fine particle dose ranged between 1.9 and 30.8% (min: Foster® NEXThaler®, max: Symbicort® Turbuhaler®), depending on the inhaler. All these effects and parameter values point toward higher airway doses due to forceful exhalation before the inhalation of the drug. At the same time, the present findings highlight the necessity of proper patient education on the importance of lung emptying, but also the importance of patient-specific inhaler-drug pair choice in the future.

Effects of hygroscopic growth of ambient urban aerosol particles on their modelled regional and local deposition in healthy and COPD-compromised human respiratory system.

Total, regional and local deposition fractions of urban-type aerosol particles with diameters of 50, 75, 110 and 145 nm were modelled and studied in their dry state and after their hygroscopic growth using a Stochastic Lung Model and a Computational Fluid and Particle Dynamics method. Healthy subjects and patients with severe chronic obstructive pulmonary disease (COPD) were considered. The hygroscopic growth factors (HGFs) adopted were determined experimentally and represent a real urban-type environment. The hygroscopic growth of particles resulted in decrease of the deposition fractions in all major parts of the healthy respiratory system and the extent of the deposited fractions was rising monotonically with particle size. In the extrathoracic (ET) region, the relative decrease was between 7% and 13%. In the lungs the deposition decreased by 11-16%. The decrease of deposition fraction due to hygroscopic growth was more accentuated in the conductive airways (up to 25%) and less pronounced towards the terminal airways. The spatial distribution of the deposited particles remained highly inhomogeneous with some areas containing thousands times more particles than the average number of particles per unit surface area. For COPD patients, the hygroscopic growth produced similar deposition alterations in the ET region than for healthy subjects. In the conductive airways, however, the particle growth caused a substantial relative decrease in the deposition fractions. In contrast, the relative depositions of hygroscopic particles increased in the acinar region.

Do we really target the receptors? Deposition and co-deposition of ICS-LABA fixed combination drugs.

Fixed dose combinations of aerosolized bronchodilators and steroids are routinely used in current asthma and COPD management. As spatial distribution of their receptors within the human airways is different, it is a challenging task to deliver the right drug component to the right receptor. The aim of this work was to apply numerical methods to analyse the airway deposition distribution of two inhalation corticosteroid (ICS) - long-acting beta-agonist (LABA) combination drugs in comparison with the distribution of the corresponding receptors. Our results revealed that different combination drugs exhibit different co-deposition patterns depending on the aerodynamic properties of their components. While ICS and LABA components of Symbicort® Turbuhaler® had similar deposition efficiencies in the same airway generation throughout the whole respiratory tract, the steroid component of Relvar® Ellipta® had up to 25% higher deposition than its bronchodilator component in the large bronchi and up to 40% lower deposition in the deeper airways. Present results highlight the need for extensive research to elucidate whether each drug component should deposit according to its receptor distribution or similar deposition distribution patterns of the components should be attained to benefit from the synergistic effects documented in the open literature. Once this aspect clarified, the next step will be to tailor the aerodynamic properties of each component of combination drugs to yield the desired deposition distribution in the lungs.

Modeling of nursing care-associated airborne transmission of SARS-CoV-2 in a real-world hospital setting.

Respiratory transmission of SARS-CoV-2 from one older patient to another by airborne mechanisms in hospital and nursing home settings represents an important health challenge during the COVID-19 pandemic. However, the factors that influence the concentration of respiratory droplets and aerosols that potentially contribute to hospital- and nursing care-associated transmission of SARS-CoV-2 are not well understood. To assess the effect of health care professional (HCP) and patient activity on size and concentration of airborne particles, an optical particle counter was placed (for 24 h) in the head position of an empty bed in the hospital room of a patient admitted from the nursing home with confirmed COVID-19. The type and duration of the activity, as well as the number of HCPs providing patient care, were recorded. Concentration changes associated with specific activities were determined, and airway deposition modeling was performed using these data. Thirty-one activities were recorded, and six representative ones were selected for deposition modeling, including patient's activities (coughing, movements, etc.), diagnostic and therapeutic interventions (e.g., diagnostic tests and drug administration), as well as nursing patient care (e.g., bedding and hygiene). The increase in particle concentration of all sizes was sensitive to the type of activity. Increases in supermicron particle concentration were associated with the number of HCPs (r = 0.66; p < 0.05) and the duration of activity (r = 0.82; p < 0.05), while submicron particles increased with all activities, mainly during the daytime. Based on simulations, the number of particles deposited in unit time was the highest in the acinar region, while deposition density rate (number/cm2/min) was the highest in the upper airways. In conclusion, even short periods of HCP-patient interaction and minimal patient activity in a hospital room or nursing home bedroom may significantly increase the concentration of submicron particles mainly depositing in the acinar regions, while mainly nursing activities increase the concentration of supermicron particles depositing in larger airways of the adjacent bed patient. Our data emphasize the need for effective interventions to limit hospital- and nursing care-associated transmission of SARS-CoV-2 and other respiratory pathogens (including viral pathogens, such as rhinoviruses, respiratory syncytial virus, influenza virus, parainfluenza virus and adenoviruses, and bacterial and fungal pathogens).

Effect of site-specific bronchial radon progeny deposition on the spatial and temporal distributions of cellular responses.

Inhaled short-lived radon progenies may deposit in bronchial airways and interact with the epithelium by the emission of alpha particles. Simulation of the related radiobiological effects requires the knowledge of space and time distributions of alpha particle hits and biological endpoints. Present modelling efforts include simulation of radioaerosol deposition patterns in a central bronchial airway bifurcation, modelling of human bronchial epithelium, generation of alpha particle tracks, and computation of spatio-temporal distributions of cell nucleus hits, cell killing and cell transformation events. Simulation results indicate that the preferential radionuclide deposition at carinal ridges plays an important role in the space and time evolution of the biological events. While multiple hits are generally rare for low cumulative exposures, their probability may be quite high at the carinal ridges of the airway bifurcations. Likewise, cell killing and transformation events also occur with higher probability in this area. In the case of uniform surface activities, successive hits as well as cell killing and transformation events within a restricted area (say 0.5 mm(2)) are well separated in time. However, in the case of realistic inhomogeneous deposition, they occur more frequently within the mean cycle time of cells located at the carinal ridge even at low cumulative doses. The site-specificity of radionuclide deposition impacts not only on direct, but also on non-targeted radiobiological effects due to intercellular communication. Incorporation of present results into mechanistic models of carcinogenesis may provide useful information concerning the dose-effect relationship in the low-dose range.