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- Eriksson, Johanna, 1991-
(författare)
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Drug absorption in the lungs : studies in the isolated perfused rat lung model combined with physiologically based biopharmaceutics modelling
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pulmonary delivery of drugs is the preferred route of administration for treatment of local lung diseases like asthma and chronic obstructive pulmonary disease. Recently, there has also been increased interest in systemic delivery of drugs via the lungs to avoid problems with low and/or variable gastrointestinal absorption, and as a needle-free alternative for drugs that cannot be ingested. Both the pharmacological and the potentially adverse effects of inhaled drugs depend on the drug’s local and systemic concentrations, which in turn depend on the pulmonary absorption of the drug. Pulmonary drug absorption is governed by the dissolution, permeability, tissue retention, and non-absorptive clearance of the drug in the lungs. Predicting systemic and local exposure is necessary for developing an inhaled drug product, and these predictions can be based on data obtained from both in vitro and ex vivo methods, such as cell lines, solubility measurements, and the isolated perfused lung (IPL) model. Data obtained by these methods can then be used to inform physiologically based biopharmaceutics (PBB) models about drug-specific absorption parameters.The overall aim of this thesis was to increase the mechanistic understanding of pulmonary drug absorption, with a special focus on obtaining and analyzing ex vivo absorption parameters for different inhalation drugs and formulations, and evaluating the predictive power of these parameters in simulations of pulmonary drug absorption. In the first two papers of the thesis, drugs were formulated as solutions, suspensions, and dry powders, and pulmonary absorption of these were measured using the IPL model. The data from these experiments were then analyzed to obtain absorption parameters for each drug using a PBB model. Tissue retention was shown to be an important parameter for describing drug absorption in IPL, and particle wetting was shown to greatly affect the absorption of dry powders. Permeability in IPL correlated well with intrinsic permeability measured in cell monolayers, suggesting that passive transcellular transport is the main transport mechanism in the lungs. In the second two papers, the absorption parameters obtained from IPL data were used to simulate rat and human pulmonary drug absorption. The simulations predicted systemic exposure after inhalation well for both rat and human, suggesting that ex vivo parameters can be used to predict rat in vivo and human plasma concentrations. This thesis deepens our understanding of absorption parameters involved in pulmonary drug absorption, and suggests applications for these parameters in predictions of local and systemic exposure after inhalation.
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- Kim, Jae-Young, et al.
(författare)
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Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution
- 2020
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 640
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Tidskriftsartikel (refereegranskat)abstract
- 3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable-ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array, at an angular resolution of ∼20 μas (at a redshift of z = 0:536 this corresponds to ∼0:13 pc ∼ 1700 Schwarzschild radii with a black hole mass MBH = 8 × 108 M⊙). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation.We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across diffierent imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI "core". This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet.We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of ∼15 c and ∼20 c (∼1:3 and ∼1:7 μas day-1, respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3mm core and the outer jet. The intrinsic brightness temperature of the jet components are ≤1010 K, a magnitude or more lower than typical values seen at ≥7mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths.
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- Selley, Liza, et al.
(författare)
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Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages
- 2020
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Ingår i: Metallomics. - : Royal Society of Chemistry. - 1756-5901 .- 1756-591X. ; 12:3, s. 371-386
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Tidskriftsartikel (refereegranskat)abstract
- Studies have emphasised the importance of combustion-derived particles in eliciting adverse health effects, especially those produced by diesel vehicles. In contrast, few investigations have explored the potential toxicity of particles derived from tyre and brake wear, despite their significant contributions to total roadside particulate mass. The objective of this study was to compare the relative toxicity of compositionally distinct brake abrasion dust (BAD) and diesel exhaust particles (DEP) in a cellular model that is relevant to human airways. Although BAD contained considerably more metals/metalloids than DEP (as determined by inductively coupled plasma mass spectrometry) similar toxicological profiles were observed in U937 monocyte-derived macrophages following 24 h exposures to 4–25 μg ml−1 doses of either particle type. Responses to the particles were characterised by dose-dependent decreases in mitochondrial depolarisation (p ≤ 0.001), increased secretion of IL-8, IL-10 and TNF-α (p ≤ 0.05 to p ≤ 0.001) and decreased phagocytosis of S. aureus (p ≤ 0.001). This phagocytic deficit recovered, and the inflammatory response resolved when challenged cells were incubated for a further 24 h in particle-free media. These responses were abrogated by metal chelation using desferroxamine. At minimally cytotoxic doses both DEP and BAD perturbed bacterial clearance and promoted inflammatory responses in U937 cells with similar potency. These data emphasise the requirement to consider contributions of abrasion particles to traffic-related clinical health effects.
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