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Sökning: WFRF:(Friberg Sven)

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  • Bouchene, Salim, 1984-, et al. (författare)
  • A Whole-Body Physiologically Based Pharmacokinetic-Pharmacodynamic (WBPBPK-PD) Model for Colistin in Critically Ill Patients
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • Objectives: Colistin is used as a salvage therapy for multidrug-resistant Gram-negative bacterial infections and administered as a prodrug, colistimethate sodium (CMS). Characterizing distribution of colistin at the site of infection is important to optimize bacterial killing. The aims of this analysis were (i) to apply a whole-body physiologically based pharmacokinetic (WPBPK) model structure to describe the pharmacokinetics (PK) of CMS and colistin in critically ill patients and (ii) to predict colistin concentration-time courses and bacterial killing in target tissues combining the WBPBPK model with a semi-mechanistic pharmacokinetic-pharmacodynamic (PKPD) model.Methods: 27 critically ill patients treated with colistin were included in the analysis. A WBPBPK model previously developed in rat was applied to describe CMS and colistin PK data. The model was used to predict tissue concentrations in lungs, skin, blood and kidneys to drive a semi-mechanistic PKPD model on a wild-type (ATCC 27853) or a meropenem-resistant (AUR552) clinical strain P. aeruginosa to predict bacterial killing following the original dosing regimen and by replacing the original initial dose with a loading dose of 9MU.Results: The plasma data were reasonably well described by the WBPBPK model for both CMS and colistin with a slight overprediction at the 1st occasion.  High exposure was predicted in kidneys comparable to what had been predicted in previous studies, in rat and healthy subjects. Bacterial load was quickly cleared for both the ATCC 27853 and ARU552 strains in all tissues and at a higher extend in kidney tissue, for all dosing scenarios.Conclusion: The WPBPK model was able to adequately describe the PK of CMS and colistin in critically ill patients. The combination of the predicted PK profiles in tissues of interest with a PKPD model was able to predict the bactericidal effect of colistin at target sites.
  • Bouchene, Salim, 1984-, et al. (författare)
  • Application of a whole-body physiologically based pharmacokinetic model to describe the plasma and urine disposition of colistin and colistin methanesulfonate (CMS) in healthy volunteers
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • Objectives: The primary aim of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model to describe CMS and colistin disposition in human plasma and urine. The secondary aim of this analysis was to use the WBPBPK model to predict CMS and colistin tissue distribution in typical individuals with different pathophysiological changes and receiving different dosing regimens.Methods: Twelve healthy males were included in the analysis. They received a single dose of 80 mg CMS (1 million unit) through a 1-h intravenous infusion. Venous blood was collected between 0 and 18 h post dose. Fractionated urine samples were collected between 0 and 24 h after dose. A WBPBPK model initially developed in rat was further detailed with the addition of a specific urinary tract (UT) model. The Kp values of CMS and colistin were estimated for all tissues using experimental Kp prior values from rat tissue homogenates.Results: The model adequately described CMS and colistin concentrations over time in plasma and in urine. A shared first order elimination rate constant was estimated to depict the hydrolysis of CMS in plasma and tissues. A separate hydrolysis rate constant for CMS was estimated in urine, and was lower than in plasma and tissues. A shared non-renal elimination rate constant of colistin was estimated in plasma and in tissues. CMS and colistin disposition in urine was well characterized by the UT model. The tubular reabsorption of colistin was best described by a saturable model estimating the colistin affinity constant, KM. Non-specific binding of colistin in the UT lumen was accounted for using a linear relationship.Conclusion: The WBPBPK developed in this study characterized plasma and urine PK of CMS and colistin in human well. This model was used as a new framework to predict colistin exposure in the tissues of interest under different physiological conditions. The model can be easily refined when new data are available and can be combined to PKPD models to increase the understanding of the concentration-effect relationship at target sites.
  • Bouchene, Salim, et al. (författare)
  • Development of a Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin methanesulfonate (CMS) in Rat
  • ????
  • Tidskriftsartikel (refereegranskat)abstract
    • Colistin is a polymyxin antibiotic which is used to treat patients infected with multidrug resistant Gram negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WBPBPK) model in rat for colistin and its prodrug, CMS. The Kp prior values of colisin and CMS used in the WBPBPK model were either measured ex vivo in rat tissue homogenates or calculated using an in silico model. The PK parameters were estimated fitting plasma concentrations from rats receiving an i.v. bolus of CMS. In the WBPBPK model, the tissue distribution was assumed to be well-stirred and perfusion-limited. Three scenarios were investigated: estimating the Kp values using in silico Kp prior values (I), estimating the Kp values using the Kp prior values from ex vivo experiments (II) and fixing the Kp values to the experimental ex vivo Kp values (III). The WBPBPK model well described CMS and colistin plasma concentration-time profiles. Colistin Kp values in kidneys were higher than in the other tissues. The predicted concentrations in tissue were highest for kidneys and brain which might be due to a high affinity for these tissues and/or active transport processes that remain poorly elucidated. The clearance estimates of CMS and colistin were in agreement with previously reported values in the literature. The model developed in this study might be a valuable tool in drug development to understand the disposition of colistin or new polymyxin candidates as well as to guide for optimal dosing regimens.
  • Bouchene, Salim, 1984-, et al. (författare)
  • Development of an interspecies whole-body physiologically based pharmacokinetic (WBPBPK) model for colistin methanesulfonate (CMS) and colistin in five animal species and evaluation of its predictive ability in human
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • Background and purposeColistin is a last-line antibiotic administered as the prodrug colistin methanesulfonate (CMS) for the treatment of multidrug resistant Gram-negative bacterial infections. Whole-body physiologically based pharmacokinetic (WBPBPK) models are valuable tools to understand and characterize drug disposition, predict tissue distribution and interpret exposure-response relationship. The aim of this work was to develop a WBPBPK model for colistin and CMS in five animal species and evaluate the utility of the model for predicting colistin and CMS disposition in human.MethodsA nonlinear mixed-effects WBPBPK model previously developed in rats was extended to describe CMS and colistin plasma data of animals from 5 different species (40 mice, 6 rats, 3 rabbits, 3 baboons and 2 pigs) that had received single doses of CMS. CMS renal clearance and hydrolysis to colistin were allometrically scaled based on glomerular filtration rate (GFR) and tissue volumes, respectively. For the non-renal colistin clearance, three scaling models were evaluated: volume based allometric scaling, volume and maximum lifespan potential (MLP) based allometric scaling, and estimation of specie-specific parameters. Tissue concentrations were predicted for all species. The WBPBPK model was then used to predict human plasma concentrations, which were compared to observed human plasma PK data extracted from literature.ResultsThe description of the plasma PK of CMS and colistin in mice, rats, rabbits, baboons and pigs was satisfactory. The volume and MLP based allometric scaling of the non-renal clearance of colistin was best at characterizing colistin concentration-time course, even if a misprediction remained in pigs. In human however, allometric scaling without MLP was closest to the observed data, with satisfactory prediction of the CMS plasma profiles and a slight overprediction of colistin plasma PK profiles.ConclusionsInterspecies WBPBPK models were developed to describe the disposition of CMS and colistin across five animal species and human plasma concentrations of CMS and colistin were predicted in the right ranges.
  • Enfors, Sven-Olof, et al. (författare)
  • Physiological responses to mixing in large scale bioreactors
  • 2001
  • Ingår i: Journal of Biotechnology. - 0168-1656. ; 85:2, s. 175-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Escherichia coli fed-batch cultivations at 22 m(3) scale were compared to corresponding laboratory scale processes and cultivations using a scale-down reactor furnished with a high-glucose concentration zone to mimic the conditions in a feed zone of the large bioreactor. Formate accumulated in the large reactor, indicating the existence of oxygen limitation zones. It is suggested that the reduced biomass yield at large scale partly is due to repeated production/reassimilation of acetate from overflow metabolism and mixed acid fermentation products due to local moving zones with oxygen limitation. The conditions that generated mixed-acid fermentation in the scale-down reactor also induced a number of stress responses, monitored by analysis of mRNA of selected stress induced genes. The stress responses were relaxed when the cells returned to the substrate limited and oxygen sufficient compartment of the reactor. Corresponding analysis in the large reactor showed that the concentration of mRNA of four stress induced genes was lowest at the sampling port most distant from the feed zone. It is assumed that repeated induction/relaxation of stress responses in a large bioreactor may contribute to altered physiological properties of the cells grown in large-scale bioreactor. Flow cytometric analysis revealed reduced damage with respect to cytoplasmic membrane potential and integrity in cells grown in the dynamic environments of the large scale reactor and the scale-down reactor.
  • Friberg, Anders, et al. (författare)
  • Recognition of the Main Melody in a Polyphonic Symbolic Score using Perceptual Knowledge
  • 2009
  • Ingår i: Journal of New Music Research. - 0929-8215. ; 38:2, s. 155-169
  • Tidskriftsartikel (refereegranskat)abstract
    • It is in many cases easy for a human to identify the main melodic theme when listening to a music example. Melodic properties have been studied in several research projects, however, the differences between properties of the melody and properties of the accompaniment (non-melodic) voices have not been addressed until recently. A set of features relating to basic low-level statistical measures were selected considering general perceptual aspects. A new 'narrative' measure was designed intended to capture the amount of new unique material in each voice. The features were applied to a set of scores consisting of about 250 polyphonic ringtones consisting of MIDI versions of contemporary pop songs. All tracks were annotated into categories such as melody and accompaniment. Both multiple regression and support vector machines were applied on either the features directly or on a Gaussian transformation of the features. The resulting models predicted the correct melody in about 90% of the cases using a set of eight features. The results emphasize context as an important factor for determining the main melody. A previous version of the system has been used in a commercial system for modifying ring tones.
  • Friberg, Bertil, 1950-, et al. (författare)
  • One-year prospective three-center study comparing the outcome of a "soft bone implant" (prototype Mk IV) and the standard Brånemark implant.
  • 2003
  • Ingår i: Clinical implant dentistry and related research. - 1523-0899. ; 5:2, s. 71-7
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Oral implant treatment ad modum Brånemark has been used for decades in the rehabilitation of edentate and partially dentate patients. Posterior jaw regions frequently exhibit bone of poor texture, and it is often difficult to obtain primary stability. Thus, it may prove beneficial to deviate from the original protocol and to use implants with a modified design, for example, with a slightly tapered geometry. PURPOSE: The purpose of the investigation was to compare the early behavior of a modified (prototype Mk IV, Brånemark System, Nobel Biocare AB, Gothenburg, Sweden; test) implant with that of the standard Brånemark implant (control) in regions of mainly type 4 bone. MATERIALS AND METHODS: Three Swedish centers participated, and a total of 44 patients were treated with oral implants for 39 maxillas and 5 mandibles. The study focused on the most distal right and left implant sites (88 implants), which were randomized to receive either a test or a control implant. Various parameters were recorded, such as registered insertion torque (OsseoCare), Nobel Biocare AB), wobbling during insertion, primary and secondary stability (as measured with resonance frequency), and marginal bone loss. The implants were followed up for 1 year. RESULTS: The test implant more frequently required a higher insertion torque and showed a significantly higher primary stability than the control implant. This difference in stability leveled out over time, and test and control implants exhibited similar secondary stability at abutment operation and at the 1-year visit. Wobbling during insertion was rarely recorded for either of the implant designs. The 1-year cumulative success rate was 93.1% for test implants and 88.4% for control implants. CONCLUSIONS: The modified implant design resulted in an increased primary stability, which may be important when placing implants in jaw regions of type 4 bone. However, independent of the achieved primary stability, successful implants tended to approach similar secondary stability in the two designs tested.
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