| 1. |
- Dhanani, Jayesh A, et al.
(författare)
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A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models
- 2018
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic.
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| 2. |
- Dhanani, Jayesh A., et al.
(författare)
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Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
- 2019
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Ingår i: Anesthesiology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0003-3022 .- 1528-1175. ; 131:2, s. 344-355
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Tidskriftsartikel (refereegranskat)abstract
- Editors PerspectiveWhat We Already Know about This Topic For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity What This Article Tells Us That Is New In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P amp;lt; 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P amp;lt; 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P amp;lt; 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P amp;lt; 0.001). Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.
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| 3. |
- Dhanani, Jayesh A, et al.
(författare)
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Recovery rates of combination antibiotic therapy using in vitro microdialysis simulating in vivo conditions
- 2018
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Ingår i: Journal of pharmaceutical analysis. - : Elsevier BV. - 2214-0883 .- 2095-1779. ; 8:6, s. 407-412
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Tidskriftsartikel (refereegranskat)abstract
- Microdialysis is a technique used to measure the unbound antibiotic concentration in the interstitial spaces, the target site of action. In vitro recovery studies are essential to calibrating the microdialysis system for in vivo studies. The effect of a combination of antibiotics on recovery into microdialysate requires investigation. In vitro microdialysis recovery studies were conducted on a combination of vancomycin and tobramycin, in a simulated in vivo model. Comparison was made between recoveries for three different concentrations and three different perfusate flow rates. The overall relative recovery for vancomycin was lower than that of tobramycin. For tobramycin, a concentration of 20µg/mL and flow rate of 1.0µL/min had the best recovery. A concentration of 5.0µg/mL and flow rate of 1.0µL/min yielded maximal recovery for vancomycin. Large molecular size and higher protein binding resulted in lower relative recoveries for vancomycin. Perfusate flow rates and drug concentrations affected the relative recovery when a combination of vancomycin and tobramycin was tested. Low perfusate flow rates were associated with higher recovery rates. For combination antibiotic measurement which includes agents that are highly protein bound, in vitro studies performed prior to in vivo studies may ensure the reliable measurement of unbound concentrations.
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| 4. |
- Berghauser Pont, Meta, 1972, et al.
(författare)
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Quantitative comparison of cities : Distribution of street and building types based on density and centrality measures
- 2017
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Ingår i: Proceedings - 11th International Space Syntax Symposium, SSS 2017. - : Instituto Superior Tecnico, Departamento de Engenharia Civil, Arquitetura e Georrecursos. - 9789729899447 ; 2, s. 44.1-44.18
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Konferensbidrag (refereegranskat)abstract
- It has been argued that different urban configurations-planned vs. organic, treelike vs. grid like-perform differently when it comes to the intensity and distribution of pedestrian flows, built density and land uses. However, definitions of urban configurations are often rather abstract, ill-defined and at worse end in fixed stereotypes hiding underlying spatial complexity. Recent publications define morphological typologies based on quantitative variables (e.g. Barthelemy, 2015; Serra, 2013a; Gil et al., 2012; Berghauser Pont and Haupt, 2010) and solve some of these shortcomings. These approaches contribute to the discussion of types in two ways: firstly, they allow for the definition of types based on multiple variables in a precise and repeattable manner, enabling the study of large samples and the comparison between both cities and regions; secondly, they frame design choices in terms of types without being fixed and so open up for design explorations where the relation between the variables can be challenged to propose new types. This paper explores the typologies defined by Serra (2013a) and Berghauser Pont and Haupt (2010) further, as these target two of the most important morphological entities of urban form, namely the street network and the building structure. The purpose is to gain a better understanding of how types are composed and distributed within and across different cities. The method is based on GIS and statistical modeling of four cities to allow for a comparative analysis of four cities: Amsterdam, London, Stockholm and Gothenburg. For the street network, we process the Road-Centre-line maps to obtain a clean network model, then run segment angular analysis to calculate the space syntax measures of betweenness at different metric radii, defining the "centrality palimpsest" (Serra, 2013a). For the building structure, we process elevation data to obtain building height, then run accessible density analysis for all building density metrics (FSI, GSI, OSR, L) using the Place Syntax Tool (Berghauser Pont and Marcus, 2014). The street and building types are defined using cluster analysis (unsupervised classification), following a similar approach to Serra (2013a). The result is a typology of street ('paths') and building types ('places'), with different profiles of centrality and density across scales. The spatial distribution and frequency of these types across the four cities gives an objective summary of their spatial structure, identifying common as well as unique traits.
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| 5. |
- Berghauser Pont, Meta, 1972, et al.
(författare)
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The spatial distribution and frequency of street, plot and building types across five European cities
- 2019
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Ingår i: Environment and Planning B-Urban Analytics and City Science. - : SAGE Publications. - 2399-8083 .- 2399-8091. ; 46:7, s. 1226-1242
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Tidskriftsartikel (refereegranskat)abstract
- Typologies have always played an important role in urban planning and design practice and formal studies have been central to the field of urban morphology. These studies have predominantly been of a historical-qualitative nature and do not support quantitative comparisons between urban areas and between different cities, nor offer the precise and comprehensive descriptions needed by those engaged in urban planning and design practice. To describe contemporary urban forms, which are more diffuse and often elude previous historic typologies, systematic quantitative methods can be useful but, until recently, these have played a limited role in typo-morphological studies. This paper contributes to recent developments in this field by integrating multi-variable geometric descriptions with inter-scalar relational descriptions of urban form. It presents typologies for three key elements of urban form (streets, plots and buildings) in five European cities, produced using statistical clustering methods. In a first instance, the resulting typologies contribute to a better understanding of the characteristics of streets, plots and buildings. In particular, the results offer insight into patterns between the types (i.e. which types are found in combination and which not) and provide a new large scale comparative analysis across five European cities. To conclude, a link between quantitative analysis and theory is established, by testing two well-known theoretical propositions in urban morphology: the concept of the burgage cycle and the theory of natural movement.
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| 6. |
- Dhanani, Jayesh, et al.
(författare)
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Antimicrobial chemotherapy and lung microdialysis: a review
- 2010
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 1872-7913 .- 0924-8579. ; 36:6, s. 491-500
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Forskningsöversikt (refereegranskat)abstract
- Pneumonia is a form of lung infection that may be caused by various micro-organisms. The predominant site of infection in pneumonia is debatable. Advances in the fields of diagnostic and therapeutic medicine have had a less than optimal effect on the outcome of pneumonia and one of the many causes is likely to be inadequate antimicrobial concentrations at the site of infection in lung tissue. Traditional antimicrobial therapy guidelines are based on indirect modelling from blood antimicrobial levels. However, studies both in humans and animals have shown the fallacy of this concept in various tissues. Many different methods have been employed to study lung tissue antimicrobial levels with limited success, and each has limitations that diminish their utility. An emerging technique being used to study the pharmacokinetics of antimicrobial agents in lung tissue is microdialysis. Development of microdialysis catheters, along with improvement in analytical techniques, has improved the accuracy of the data. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied. These studies generally suggest that this technique is a safe and effective way of assessing the pharmacokinetics of antimicrobial agents in lung tissue. Further descriptive studies need to be conducted to study the pharmacokinetics and pharmacodynamics of different antimicrobial classes in lung tissue. Data emanating from these studies could inform decisions for appropriate dosing schedules of antimicrobial agents in pneumonia. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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