| 1. |
- Bake, Björn, 1939, et al.
(författare)
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Exhaled Particles After a Standardized Breathing Maneuver
- 2017
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 30:4, s. 267-273
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Tidskriftsartikel (refereegranskat)abstract
- Background: Particles in exhaled air (PEx) provide samples of respiratory tract lining fluid from small airways and offer a new opportunity to monitor pathological changes. The exhaled particles are produced by reopening of closed small airways and contain surfactant. The amount of PEx varies by orders of magnitude among subjects. A standardized breathing pattern reduces the variation, but it remains large and the reasons are unknown. The aim of the present study was to assess to what extent sex, age, body size, and spirometry results explain the interindividual variation of PEx among healthy middle-aged subjects. Methods: The PExA((R)) instrument was used to measure PEx in 126 healthy middle-aged nonsmoking subjects participating in the European Respiratory Community Health Survey (ERCS-III). The subjects performed a standardized breathing maneuver involving expiration to residual volume, a breath-hold of 3 seconds, a full inspiration, and then a full expiration into the PExA instrument. PEx number concentrations were expressed per exhalation and per exhaled liter. Age and anthropometric and spirometric variables were analyzed as potential predictors. Results: PEx/L was consistently and negatively associated to lung size-related variables and accordingly lower in men than in women. PEx/Exhalation was similar in women and men. Increasing age was associated with increasing PEx. Reference equations are presented based on age, weight, and spirometry variables and independent of sex. These predictors explained 28%-29% of the interindividual variation. Conclusions: The interindividual variation of PEx after a standardized breathing maneuver is large and the considered predictors explain a minor part only.
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| 4. |
- Boger, Elin, et al.
(författare)
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Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling Accurately Predicts the Better Bronchodilatory Effect of Inhaled Versus Oral Salbutamol Dosage Forms
- 2018
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Ingår i: Journal of Aerosol Medicine. - : MARY ANN LIEBERT, INC. - 1941-2711 .- 1941-2703. ; 31:0, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Predicting local lung tissue pharmacodynamic (PD) responses of inhaled drugs is a longstanding challenge related to the lack of experimental techniques to determine local free drug concentrations. This has prompted the use of physiologically based pharmacokinetic (PBPK) modeling to potentially predict local concentration and response. A unique opportunity for PBPK model evaluation is provided by the clinical PD data for salbutamol, which in its inhaled dosage form (400g), produces a higher bronchodilatory effect than in its oral dosage form (2mg) despite lower drug concentrations in blood. The present study aimed at evaluating whether inhalation PBPK model predictions of free drug in tissue would be predictive of these observations.Methods: A PBPK model, including 24 airway generations, was parameterized to describe lung, plasma, and epithelial lining fluid concentrations of salbutamol administered intratracheally and intravenously to rats (100nmol/kg). Plasma and lung tissue concentrations of unbound (R)-salbutamol, the active enantiomer, were predicted with a humanized version of the model and related to effect in terms of forced expiratory volume in 1 second (FEV1).Results: In contrast to oral dosing, the model predicted inhalation to result in spatial heterogeneity in the target site concentrations (subepithelium) with higher free drug concentrations in the lung as compared with the plasma. FEV1 of inhaled salbutamol was accurately predicted from the PK/PD relationship derived from oral salbutamol and PBPK predictions of free concentration in airway tissue of high resistance (e.g., 6th generation).Conclusion: An inhalation PBPK-PD model was developed and shown predictive of local pharmacology of inhaled salbutamol, thus conceptually demonstrating the validity of PBPK model predictions of free drug concentrations in lung tissue. This achievement unlocks the power of inhalation PBPK modeling to interrogate local pharmacology and guide optimization and development of inhaled drugs and their formulations.
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| 6. |
- Elihn, Karine, et al.
(författare)
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Cellular Dose of Partly Soluble Cu Particle Aerosols at the Air-Liquid Interface Using an In Vitro Lung Cell Exposure System
- 2013
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Ingår i: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 26:2, s. 84-93
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is currently a need to develop and test in vitro systems for predicting the toxicity of nanoparticles. One challenge is to determine the actual cellular dose of nanoparticles after exposure. Methods: In this study, human epithelial lung cells (A549) were exposed to airborne Cu particles at the air-liquid interface (ALI). The cellular dose was determined for two different particle sizes at different deposition conditions, including constant and pulsed Cu aerosol flow. Results: Airborne polydisperse particles with a geometric mean diameter (GMD) of 180nm [geometric standard deviation (GSD) 1.5, concentration 10(5) particles/mL] deposited at the ALI yielded a cellular dose of 0.4-2.6 mu g/cm(2) at pulsed flow and 1.6-7.6 mu g/cm(2) at constant flow. Smaller polydisperse particles in the nanoregime (GMD 80 nm, GSD 1.5, concentration 10(7) particles/mL) resulted in a lower cellular dose of 0.01-0.05 mu g/cm(2) at pulsed flow, whereas no deposition was observed at constant flow. Exposure experiments with and without cells showed that the Cu particles were partly dissolved upon deposition on cells and in contact with medium. Conclusions: Different cellular doses were obtained for the different Cu particle sizes (generated with different methods). Furthermore, the cellular doses were affected by the flow conditions in the cell exposure system and the solubility of Cu. The cellular doses of Cu presented here are the amount of Cu that remained on the cells after completion of an experiment. As Cu particles were partly dissolved, Cu (a nonnegligible contribution) was, in addition, present and analyzed in the nourishing medium present beneath the cells. This study presents cellular doses induced by Cu particles and demonstrates difficulties with deposition of nanoparticles at the ALI and of partially soluble particles.
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| 12. |
- Hamm, Gregory R., et al.
(författare)
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Revealing the Regional Localization and Differential Lung Retention of Inhaled Compounds by Mass Spectrometry Imaging
- 2020
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Ingår i: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 33:1, s. 43-53
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Tidskriftsartikel (refereegranskat)abstract
- Background: For the treatment of respiratory disease, inhaled drug delivery aims to provide direct access to pharmacological target sites while minimizing systemic exposure. Despite this long-held tenet of inhaled therapeutic advantage, there are limited data of regional drug localization in the lungs after inhalation. The aim of this study was to investigate the distribution and retention of different chemotypes typifying available inhaled drugs [slowly dissolving neutral fluticasone propionate (FP) and soluble bases salmeterol and salbutamol] using mass spectrometry imaging (MSI).Methods: Salmeterol, salbutamol, and FP were simultaneously delivered by inhaled nebulization to rats. In the same animals, salmeterol-d(3), salbutamol-d(3), and FP-d(3) were delivered by intravenous (IV) injection. Samples of lung tissue were obtained at 2- and 30-minute postdosing, and high-resolution MSI was used to study drug distribution and retention.Results: IV delivery resulted in homogeneous lung distribution for all molecules. In comparison, while inhalation also gave rise to drug presence in the entire lung, there were regional chemotype-dependent areas of higher abundance. At the 30-minute time point, inhaled salmeterol and salbutamol were preferentially retained in bronchiolar tissue, whereas FP was retained in all regions of the lungs.Conclusion: This study clearly demonstrates that inhaled small molecule chemotypes are differentially distributed in lung tissue after inhalation, and that high-resolution MSI can be applied to study these retention patterns.
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| 14. |
- Holmgren, Helene, 1981, et al.
(författare)
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Influence of film dimensions on film droplet formation.
- 2012
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Ingår i: Journal of aerosol medicine and pulmonary drug delivery. - : Mary Ann Liebert Inc. - 1941-2703 .- 1941-2711. ; 25:1, s. 47-53
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Aerosol particles may be generated from rupturing liquid films through a droplet formation mechanism. The present work was undertaken with the aim to throw some light on the influence of film dimensions on droplet formation with possible consequences for exhaled breath aerosol formation. Methods: The film droplet formation process was mimicked by using a purpose-built device, where fluid films were spanned across holes of known diameters. As the films burst, droplets were formed and the number and size distributions of the resulting droplets were determined. Results: No general relation could be found between hole diameter and the number of droplets generated per unit surface area of fluid film. Averaged over all film sizes, a higher surface tension yielded higher concentrations of droplets. Surface tension did not influence the resulting droplet diameter, but it was found that smaller films generated smaller droplets. Conclusions: This study shows that small fluid films generate droplets as efficiently as large films, and that droplets may well be generated from films with diameters below 1mm. This has implications for the formation of film droplets from reopening of closed airways because human terminal bronchioles are of similar dimensions. Thus, the results provide support for the earlier proposed mechanism where reopening of closed airways is one origin of exhaled particles.
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| 15. |
- Holmgren, Helene, 1981, et al.
(författare)
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Relation Between Humidity and Size of Exhaled Particles
- 2011
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 24:5, s. 253-260
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Tidskriftsartikel (refereegranskat)abstract
- Background: Aerosol particles are generated in human airways, and leave the body with exhaled air. These particles may carry indicators of various lung conditions. To fully utilize the information provided by endo- genously produced exhaled particles, it is important to understand their formation mechanism and physical properties. The scope of this work was to measure number size distributions of exhaled aerosol particles at various surrounding relative humidities (RH) in order to gain some knowledge of the size distribution at the point of particle generation. Methods: Number size distributions of exhaled particles were measured at various RHs, using an optical particle counter. Breathing with airway closure was employed. Results: A relation between particle volume and RH was fitted to experimental data and used to predict how exhaled droplets behave at RHs not easily accessible by experiments. The diameter of an exhaled particle is reduced by a factor of 0.42 when the RH is changed from 99.5 to 75% at 309 K. Calculations also show that the droplets are concentrated solutions near saturation at 75% RH. Conclusions: It is concluded that the particles are supersaturated liquid particles, rather than crystalline solids, in ambient air with RH below 75%. A size distribution related to the aerosol at the moment of formation is given. A successful detailed formation mechanismshould be able to accommodate the size distribution predicted at 99.5%RH.
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| 18. |
- Löndahl, Jakob, et al.
(författare)
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Measurement Techniques for Respiratory Tract Deposition of Airborne Nanoparticles: A Critical Review.
- 2014
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2703 .- 1941-2711. ; 27:4, s. 229-254
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Forskningsöversikt (refereegranskat)abstract
- Abstract Determination of the respiratory tract deposition of airborne particles is critical for risk assessment of air pollution, inhaled drug delivery, and understanding of respiratory disease. With the advent of nanotechnology, there has been an increasing interest in the measurement of pulmonary deposition of nanoparticles because of their unique properties in inhalation toxicology and medicine. Over the last century, around 50 studies have presented experimental data on lung deposition of nanoparticles (typical diameter≤100 nm, but here≤300 nm). These data show a considerable variability, partly due to differences in the applied methodologies. In this study, we review the experimental techniques for measuring respiratory tract deposition of nano-sized particles, analyze critical experimental design aspects causing measurement uncertainties, and suggest methodologies for future studies. It is shown that, although particle detection techniques have developed with time, the overall methodology in respiratory tract deposition experiments has not seen similar progress. Available experience from previous research has often not been incorporated, and some methodological design aspects that were overlooked in 30-70% of all studies may have biased the experimental data. This has contributed to a significant uncertainty on the absolute value of the lung deposition fraction of nanoparticles. We estimate the impact of the design aspects on obtained data, discuss solutions to minimize errors, and highlight gaps in the available experimental set of data.
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| 19. |
- Muala, Ala, et al.
(författare)
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Respiratory Tract Deposition of Inhaled Wood Smoke Particles in Healthy Volunteers
- 2015
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Ingår i: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 28:4, s. 237-246
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Tidskriftsartikel (refereegranskat)abstract
- Background: Respiratory tract deposition of air pollution particles is a key to their adverse health effects. This study was aimed to determine the size-resolved deposition fraction (DF) of sooty wood smoke particles in the lungs of healthy subjects. The type of wood smoke investigated is typical for household air pollution from solid fuels, which is among the largest environmental health problems globally.Methods: Twelve healthy volunteers inhaled diluted wood smoke from incomplete soot-rich combustion in a common wood stove. The DF of smoke particles (10–500 nm) was measured during three 15-min exposures in each subject during spontaneous breathing. Lung function was measured using standard spirometry.Results: The total DFs by particle number concentration were 0.34±0.08. This can be compared with DFs of 0.21–0.23 in healthy subjects during previous experiments with wood pellet combustion. For particle mass, the total DFs found in this study were 0.22±0.06. DF and breathing frequency were negatively correlated as expected from model calculations (p<0.01).Conclusions: The DF of the investigated sooty wood smoke particles was higher than for previously investigated particles generated during more efficient combustion of biomass. Together with toxicological studies, which have indicated that incomplete biomass combustion particles rich in soot and polycyclic aromatic hydrocarbons (PAHs) are especially harmful, these data highlight the health risks of inadequate wood combustion.
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| 21. |
- Rissler, Jenny, et al.
(författare)
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A Methodology to Study Impactor Particle Reentrainment and a Proposed Stage Coating for the NGI.
- 2009
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Ingår i: Journal of Aerosol Medicine and Pulmonary Drug Delivery. - : Mary Ann Liebert Inc. - 1941-2703 .- 1941-2711. ; 22:3, s. 309-316
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background: Mass-weighted aerodynamic particle-size distribution (APSD) is a key attribute for pharmaceutical products developed to deliver drugs to or through the lungs. In development and quality control, APSD is primarily determined using multistage cascade impactors. For impactor techniques, particle reentrainment is critical because it may lead to an overestimation of the respirable fraction. To avoid reentrainment, the collection surfaces need to be coated with a suitable material. Methods: In this study a method was developed to test flow dependence of particle reentrainment in the Next Generation Pharmaceutical Impactor (NGI) at flow rates ranging from 20 to 80 L/min, and was used to test three coating materials: glycerol coating, aqueous coating with, and without soaked filter paper. Uncoated cups were also tested. In the experimental setup a Vilnius Aerosol Generator generated a flow-independent dry powder aerosol, consisting of micronized insulin. Results: The glycerol coating was not well suited to reduce particle reentrainment at flows >/=40 L/min. The soaked filter paper coating was found to give nearly the same particle size distributions regardless of flow and was therefore judged to be the best of those tested. Using liquid only, without the filter paper, gave the same particle size distributions as soaked filter paper for flows /=60 L/min particle reentrainment increased with flow. However, for most applications liquid coating reduced particle reentrainment to an extent at which further reduction was irrelevant. Particle reentrainment was prevalent for uncoated cups at all flow rates tested. Conclusions: This study shows the advantage of using a stable and flow-independent aerosol generation method to examine particle reentrainment at various flows through the NGI. For insulin dry powder, the use of an aqueous solution as cup coating, preferably with a filter, reduced particle reentrainment to a minimum. The results were confirmed in a study with a DPI.
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| 22. |
- Sedaghat, Mohammad Hadi, et al.
(författare)
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Nanoparticle Diffusion in Respiratory Mucus Influenced by Mucociliary Clearance : A Review of Mathematical Modeling
- 2023
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Ingår i: Journal of Aerosol Medicine. - : Mary Ann Liebert Inc. - 1941-2711 .- 1941-2703. ; 36:3, s. 127-143
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Forskningsöversikt (refereegranskat)abstract
- Background: Inhalation and deposition of particles in human airways have attracted considerable attention due to importance of particulate pollutants, transmission of infectious diseases, and therapeutic delivery of drugs at targeted areas. We summarize current state-of-the art research in particle deposition on airway surface liquid (ASL) influenced by mucociliary clearance (MCC) by identifying areas that need further investigation. Methodology: We aim to review focus on governing and constitutive equations describing MCC geometry followed by description of mathematical modeling of ciliary forces, mucus rheology properties, and numerical approaches to solve modified time-dependent Navier-Stokes equations. We also review mathematical modeling of particle deposition in ASL influenced by MCC, particle transport in ASL in terms of Eulerian and Lagrangian approaches, and discuss the corresponding mass transport issues in this layer. Whenever required, numerical predictions are contrasted with the pertinent experimental data. Results: Results indicate that mean mucus and periciliary liquid velocities are strongly influenced by mucus rheological characteristics as well as ciliary abnormalities. However, most of the currently available literature on mucus fiber spacing, ciliary beat frequency, and particle surface chemistry is based on particle deposition on ASL by considering a fixed value of ASL velocity. The effects of real ASL flow regimes on particle deposition in this layer are limited. In addition, no other study is available on modeling nonhomogeneous and viscoelastic characteristics of mucus layer on ASL drug delivery. Conclusion: Simplification of assumptions on governing equations of drug delivery in ASL influenced by MCC leads to imposing some limitations on numerical results.
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