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  • 1651.
    Wegler, Christine
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Ölander, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lundquist, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Global variability analysis of mRNA and protein concentrations across and within human tissues2020Inngår i: NAR genomics and bioinformatics, ISSN 2631-9268, Vol. 2, nr 1, artikkel-id lqz010Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genes and proteins show variable expression patterns throughout the human body. However, it is not clear whether relative differences in mRNA concentrations are retained on the protein level. Furthermore, inter-individual protein concentration variability within single tissue types has not been comprehensively explored. Here, we used the Gini index for in-depth concentration variability analysis of publicly available transcriptomics and proteomics data, and of an in-house proteomics dataset of human liver and jejunum from 38 donors. We found that the transfer of concentration variability from mRNA to protein is limited, that established ‘reference genes’ for data normalization vary markedly at the protein level, that protein concentrations cover a wide variability spectrum within single tissue types, and that concentration variability analysis can be a convenient starting point for identifying disease-associated proteins and novel biomarkers. Our results emphasize the importance of considering individual concentration levels, as opposed to population averages, for personalized systems biology analysis.

  • 1652.
    Wegler, Christine
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala University.
    Ölander, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Wisniewski, Jacek R
    Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
    Lundquist, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zettl, Katharina
    Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany.
    Åsberg, Anders
    Department of Pharmacy, University of Oslo, Oslo, Norway.
    Hjelmesæth, Jøran
    Morbid Obesity Centre, Department of Medicine, Vestfold Hospital Trust, Tønsberg, Norway.
    Andersson, Tommy B
    DMPK, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Global expression variability of proteins across and within human tissuesInngår i: Artikkel i tidsskrift (Annet vitenskapelig)
  • 1653.
    Weiss, Frederik
    et al.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Hammer, Helen S.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Klein, Kathrin
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;Univ Tubingen, Dept Clin Pharmacol, Tubingen, Germany.
    Planatscher, Hannes
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Zanger, Ulrich M.
    Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany;Univ Tubingen, Dept Clin Pharmacol, Tubingen, Germany.
    Norén, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Wegler, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Joos, Thomas O.
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Poetz, Oliver
    Univ Tubingen, NMI Nat & Med Sci Inst, Markwiesenstr 55, D-72770 Reutlingen, Germany;SIGNATOPE GmbH, Reutlingen, Germany.
    Direct Quantification of Cytochromes P450 and Drug Transporters-A Rapid, Targeted Mass Spectrometry-Based Immunoassay Panel for Tissues and Cell Culture Lysates2018Inngår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 46, nr 4, s. 387-396Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The quantification of drug metabolizing enzymes and transporters has recently been revolutionized on the basis of targeted proteomic approaches. Isotope-labeled peptides are used as standards for the quantification of the corresponding proteins in enzymatically fragmented samples. However, hurdles in these approaches are low throughput and tedious sample prefractionation steps prior to mass spectrometry (MS) readout. We have developed an assay platform using sensitive and selective immunoprecipitation coupled with mass spectrometric readout allowing the quantification of proteins directly from whole cell lysates using less than 20,000 cells per analysis. Peptide group-specific antibodies (triple X proteomics antibodies) enable the enrichment of proteotypic peptides sharing a common terminus. These antibodies were employed to establish a MS-based immunoassay panel for the quantification of 14 cytochrome P450 (P450) enzymes and nine transporters. We analyzed the P450 enzyme and transporter levels in genotyped liver tissue homogenates and microsomes, and in samples from a time course induction experiment in human hepatocytes addressing different induction pathways. For the analysis of P450 enzymes and transporters only a minute amount of sample is required and no prefractionation is necessary, thus the assay platform bears the potential to bridge cell culture model experiments and results from whole organ tissue studies.

  • 1654.
    Welch, Ken
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Ek, Ragnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Strømme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Comparative Drug Release Measurements in Limited Amounts of Liquid: A Suppository Formulation Study2006Inngår i: Current Drug Delivery, ISSN 1567-2018, E-ISSN 1875-5704, Vol. 3, nr 3, s. 299-306(8)Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel method for the investigation of drug formulations in limited liquid volumes is presented. The experimental setup consists of a measurement cell containing an absorbent sponge cloth placed between two parallel electrodes. Conductivity measurements are used to monitor the drug release from the dosage form. By varying the amount of water contained in the absorbent cloth surrounding the dosage form, it is possible to measure the drug release performance of the dosage form in very limited amounts of water. The method was employed to test four different tablet formulations consisting of the model drug NaCl incorporated in excipient matrices of hard fat, polyethylene glycol, microcrystalline cellulose and a mixture of microcrystalline cellulose and croscarmellose sodium (Ac-Di-Sol). The drug release rates of the different formulations in limited water volumes differed markedly from the release rates in an excess of water. Whereas the release rates from all tablet types in an excess of water showed only minor differences among the tablet types, the release rates from the tablets formulated with disintegrating e

  • 1655.
    Welin-Berger, K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergenståhl, B.
    Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase2000Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 200, nr 2, s. 249-260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The stability of submicron emulsions of different local anesthetic/analgesic substances was investigated in the presence and absence of different hydrophobic excipients (ripening inhibitors). Ostwald ripening was believed to be the underlying mechanism for the instability of these emulsions. In the absence of ripening inhibitors, the mean droplet size of the emulsions increased from 100 nm to about 4-5 microm within an hour of manufacture. The addition of a small amount of a second component of lower solubility to the disperse phase decreased the rate of Ostwald ripening, producing good stability of the emulsions. The efficiency of the ripening inhibitors was directly proportional to their solubility in the disperse phase, i.e. the water. The lower the solubility, the more effective the stabilization of the emulsions. The experimentally observed rates of increase in droplet size in the emulsions were closely correlated with those predicted according to the Liftshitz-Slezov-Wagner (LSW) theory.

  • 1656.
    Welin-Berger, K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Neelissen, J.A.M.
    Bergenståhl, B.
    The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound2001Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 13, nr 3, s. 309-318Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The objective of this study was to investigate the possibility of developing a topical cream that allows maximum release rate of the active compound while having suitable consistency, i.e., sufficient apparent plasticity. A submicron (o/w) emulsion containing a model compound was investigated in the presence and absence of different polymers: sodium carboxymethylcellulose (CMC), Carbopol 934P (C934), polyethylene glycol 400 (PEG400) and polyethylene glycol 4000 (PEG4000). Various concentrations of the polymers were used in order to produce different rheological behaviours. The amount of drug passing through the membrane was measured as a function of time, using static diffusion cells with either Silastic sheeting 500-1 or guinea pig skin as membrane. The emulsion without polymer was used as reference. Rheological measurements were performed, giving the viscosity and the apparent yield stress of the formulations. Furthermore, theoretical values for diffusion coefficients and diffusion pathways were estimated and compared with the experimental data to discuss different diffusion models. Gelling polymers have been shown to produce an increase in the macroviscosity, thus inhibiting the diffusion of the oil droplets in the formulation without affecting the molecular diffusion. However, we suggest that when a compound of limited solubility is emulsified, the intact oil droplets contribute to the transport of the compound through the formulation. Thus, both release and permeation rates are decreased as the apparent yield stress, i.e., the macroviscosity of the formulation, is increased sufficiently by addition of gelling polymers.

  • 1657.
    Welin-Berger, K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Neelissen, J.A.M.
    Emanuelsson, B.M.
    Björnsson, M.A.
    Gjellan, K.
    In vitro-in vivo correlation in man of a topically applied local anesthetic agent using numerical convolution and deconvolution2003Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 92, nr 2, s. 398-406Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to evaluate the relevance of the in vitro permeation method used at our laboratory in predicting in vivo dermal and transdermal absorption. Two different emulsions, a submicron oil-in-water (o/w) emulsion and a semisolid water-in-oil (w/o) emulsion, containing a model compound were investigated. The in vitro permeation rate of the compound from these emulsions was measured using static diffusion cells with human skin as membrane. The emulsions were allowed to remain in contact with the skin in the donor chamber for 15, 60, and 240 min. The study was monitored for 240 min and the steady state flux was calculated. The systemic concentration of the compound was measured in vivo as a function of time after dermal application to healthy volunteers with 15 and 60 min of application. A short-lasting i.v. infusion study in healthy volunteers was used to simulate the i.v. bolus dose. Numerical convolution was used to predict the in vivo plasma concentration of the compound while the in vivo absorption rate of the compound was estimated using numerical deconvolution. To establish correlation, the predicted in vivo flux was compared with the corresponding observed in vitro parameter after adjusting for the lag time. No major differences were seen in the systemic plasma levels between the two emulsions, which is in close agreement with the steady state flux measured in vitro. A linear correlation representing a point-to-point relationship was established for each of the investigated formulations and application times. The longer application time was predicted more accurately for both emulsions.

  • 1658.
    Welin-Berger, K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Neelissen, J.A.M.
    Engblom, J.
    Physicochemical interaction of local anesthetics with lipid model systems: Correlation with in vitro permeation and in vivo efficacy2002Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 81, nr 1-2, s. 33-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In dermal/transdermal drug administration stratum corneum (SC) is often the rate-limiting step. Furthermore, the intercellular lipid domain of SC is nowadays widely accepted as the major contributor to the skin barrier. The current work investigates whether the difference in the level of topical efficacy of local anesthetic compounds correlates with the type of interaction between the drug and the intercellular lipids of SC. Therefore, local anesthetics of varying topical efficacy were evaluated with respect to their effect on the morphology of various model lipid systems using small and wide angle X-ray diffraction (SWAXD) and differential scanning calorimetry (DSC). The model lipids used were glyceryl monooleate, sphingomyelin and lipids isolated from human SC. Furthermore, partitioning into isolated human SC as well as permeation through isolated human SC and human tape-stripped skin were investigated in vitro. The results indicate that local anesthetics may act as their own permeation enhancers by increasing the degree of hydrocarbon chain fluidity of the intercellular lipids. Eventually these interactions may induce non-lamellar reversed types of liquid crystalline structures locally in SC, which further facilitate the drug mobility. The large difference in topical efficacy of the investigated local anesthetics could not be explained simply by looking at their effect on the phase behavior of lipid model systems. Despite the similarities in physicochemical properties of these substances, the in vitro skin permeability differed markedly (AD>EMLA>lidocaine>prilocaine>sameridine). Thus, it was concluded that sufficient drug permeability over SC is essential to obtain local anesthesia by blocking the superficial nociceptors.

  • 1659.
    Welin-Berger, Katayoun
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Formulations, Release and Skin Penetration of Topical Anesthetics2001Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis describes certain critical aspects of the development of semisolid topical anesthetic formulations requiring a fast onset of action. Furthermore, local anesthetics were investigated regarding their phase interaction with membrane lipids.

    A new long acting and topically effective local anesthetic/analgesic agent, isopropyl-methyl-[2-(3-propoxyphenoxy)-ethyl]-amine (amino diether, AD), was used as the model compound. The nonionized form of AD is liquid oil at room temperature with low water solubility. A submicron o/w emulsion with Newtonian flow property was prepared with AD as the disperse phase. The kinetic stability of this emulsion was increased to prevent Ostwald ripening by addition of small amounts of a hydrophobic excipient to the disperse phase. The emulsion allowed a high in vitro release and permeation rate of AD as well as a sufficient in vivo efficacy.

    To achieve a plastic property, hydrophilic polymers were added to the o/w emulsion resulting in a significant reduction of the release and permeation rate of AD. In order to avoid the addition of these polymers, a semisolid w/o emulsion was evaluated with AD as the continuous phase. The inherent plastic property of this formulation allows sufficient skin adhesion. Furthermore, the release and permeation rate of AD from this formulation is comparable to that of the Newtonian submicron o/w emulsion. A close correlation between the in vitro permeation studies and the in vivo human plasma profiles was observed using the convolution/deconvolution

    method.

    Furthermore, x-ray and calorimetric data indicated that local anesthetics are able to interact with skin lipids both by increasing the chain fluidity of the crystalline lipids and by probably producing phase inversions in the grain borders of the stratum corneum lipid multilayers. It was also shown that this lipid interaction was not directly correlated with the different levels of skin permeation and/or topical efficacy of the investigated compounds.

    Delarbeid
    1. Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase
    Åpne denne publikasjonen i ny fane eller vindu >>Inhibition of Ostwald ripening in local anesthetic emulsions by using hydrophobic excipients in the disperse phase
    2000 (engelsk)Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 200, nr 2, s. 249-260Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The stability of submicron emulsions of different local anesthetic/analgesic substances was investigated in the presence and absence of different hydrophobic excipients (ripening inhibitors). Ostwald ripening was believed to be the underlying mechanism for the instability of these emulsions. In the absence of ripening inhibitors, the mean droplet size of the emulsions increased from 100 nm to about 4-5 microm within an hour of manufacture. The addition of a small amount of a second component of lower solubility to the disperse phase decreased the rate of Ostwald ripening, producing good stability of the emulsions. The efficiency of the ripening inhibitors was directly proportional to their solubility in the disperse phase, i.e. the water. The lower the solubility, the more effective the stabilization of the emulsions. The experimentally observed rates of increase in droplet size in the emulsions were closely correlated with those predicted according to the Liftshitz-Slezov-Wagner (LSW) theory.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89450 (URN)10.1016/S0378-5173(00)00395-1 (DOI)10867255 (PubMedID)
    Tilgjengelig fra: 2001-10-03 Laget: 2001-10-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    2. The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound
    Åpne denne publikasjonen i ny fane eller vindu >>The effect of rheological behaviour of a topical anaesthetic formulation on the release and permeation rates of the active compound
    2001 (engelsk)Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 13, nr 3, s. 309-318Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The objective of this study was to investigate the possibility of developing a topical cream that allows maximum release rate of the active compound while having suitable consistency, i.e., sufficient apparent plasticity. A submicron (o/w) emulsion containing a model compound was investigated in the presence and absence of different polymers: sodium carboxymethylcellulose (CMC), Carbopol 934P (C934), polyethylene glycol 400 (PEG400) and polyethylene glycol 4000 (PEG4000). Various concentrations of the polymers were used in order to produce different rheological behaviours. The amount of drug passing through the membrane was measured as a function of time, using static diffusion cells with either Silastic sheeting 500-1 or guinea pig skin as membrane. The emulsion without polymer was used as reference. Rheological measurements were performed, giving the viscosity and the apparent yield stress of the formulations. Furthermore, theoretical values for diffusion coefficients and diffusion pathways were estimated and compared with the experimental data to discuss different diffusion models. Gelling polymers have been shown to produce an increase in the macroviscosity, thus inhibiting the diffusion of the oil droplets in the formulation without affecting the molecular diffusion. However, we suggest that when a compound of limited solubility is emulsified, the intact oil droplets contribute to the transport of the compound through the formulation. Thus, both release and permeation rates are decreased as the apparent yield stress, i.e., the macroviscosity of the formulation, is increased sufficiently by addition of gelling polymers.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89451 (URN)10.1016/S0928-0987(01)00118-X (DOI)11384854 (PubMedID)
    Tilgjengelig fra: 2001-10-03 Laget: 2001-10-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    3. In vitro permeation profile of a local anaesthetic compound from topical formulations with different rheological behaviour - verified by in vivo efficacy data
    Åpne denne publikasjonen i ny fane eller vindu >>In vitro permeation profile of a local anaesthetic compound from topical formulations with different rheological behaviour - verified by in vivo efficacy data
    2001 (engelsk)Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, nr 3, s. 229-236Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The object of this study was to develop a topical cream of suitable consistency, i.e. with a high apparent yield stress, without affecting the in vitro permeation profile and the subsequent in vivo efficacy of the formulation. Different formulations of a model compound were manufactured, an oil-in-water (o/w) emulsion, a cream consisting of the o/w emulsion thickened with various concentrations of neutralised Carbopol934P gel, and a semisolid water-in-oil (w/o) emulsion. Rheological measurements were performed giving the apparent yield stress of the formulations. The in vitro permeation rate of the compound was measured, using static diffusion cells with both guinea pig and human skin as membrane. The o/w emulsion without polymer was used as reference. The in vivo efficacy of the formulations was investigated on guinea pigs by the pinprick method. The apparent yield stress of the w/o emulsion was in the same range as that of the most viscous o/w cream while the o/w emulsion behaved as a Newtonian liquid. Furthermore, the yielding property of the w/o emulsion was not as temperature-sensitive as that of the o/w cream. The permeation rate of the compound from the two emulsions, o/w and w/o, was similar at 6% (w/w), while the o/w cream resulted in a significantly lower permeation rate at the same concentration. The two emulsions produced sufficient and comparable in vivo efficacy, while the o/w cream was less efficient. In conclusion, a reversed-phase emulsion may be used to produce the appropriate apparent yield stress, without affecting the in vivo efficacy of the formulation. The viscosity of a w/o emulsion depends on the amount of the aqueous phase and the degree of dispersity. Thus, the transport of the active compound is not prevented by the excipients present in the formulation, as is the case for the o/w cream.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89452 (URN)10.1016/S0928-0987(01)00181-6 (DOI)11576828 (PubMedID)
    Tilgjengelig fra: 2001-10-03 Laget: 2001-10-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    4. In vitro-in vivo correlation in man of a topically applied local anesthetic agent using numerical convolution and deconvolution
    Åpne denne publikasjonen i ny fane eller vindu >>In vitro-in vivo correlation in man of a topically applied local anesthetic agent using numerical convolution and deconvolution
    Vise andre…
    2003 (engelsk)Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 92, nr 2, s. 398-406Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The aim of this study was to evaluate the relevance of the in vitro permeation method used at our laboratory in predicting in vivo dermal and transdermal absorption. Two different emulsions, a submicron oil-in-water (o/w) emulsion and a semisolid water-in-oil (w/o) emulsion, containing a model compound were investigated. The in vitro permeation rate of the compound from these emulsions was measured using static diffusion cells with human skin as membrane. The emulsions were allowed to remain in contact with the skin in the donor chamber for 15, 60, and 240 min. The study was monitored for 240 min and the steady state flux was calculated. The systemic concentration of the compound was measured in vivo as a function of time after dermal application to healthy volunteers with 15 and 60 min of application. A short-lasting i.v. infusion study in healthy volunteers was used to simulate the i.v. bolus dose. Numerical convolution was used to predict the in vivo plasma concentration of the compound while the in vivo absorption rate of the compound was estimated using numerical deconvolution. To establish correlation, the predicted in vivo flux was compared with the corresponding observed in vitro parameter after adjusting for the lag time. No major differences were seen in the systemic plasma levels between the two emulsions, which is in close agreement with the steady state flux measured in vitro. A linear correlation representing a point-to-point relationship was established for each of the investigated formulations and application times. The longer application time was predicted more accurately for both emulsions.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89453 (URN)10.1002/jps.10203 (DOI)12532389 (PubMedID)
    Tilgjengelig fra: 2001-10-03 Laget: 2001-10-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
    5. Physicochemical interaction of local anesthetics with lipid model systems: Correlation with in vitro permeation and in vivo efficacy
    Åpne denne publikasjonen i ny fane eller vindu >>Physicochemical interaction of local anesthetics with lipid model systems: Correlation with in vitro permeation and in vivo efficacy
    2002 (engelsk)Inngår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 81, nr 1-2, s. 33-43Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In dermal/transdermal drug administration stratum corneum (SC) is often the rate-limiting step. Furthermore, the intercellular lipid domain of SC is nowadays widely accepted as the major contributor to the skin barrier. The current work investigates whether the difference in the level of topical efficacy of local anesthetic compounds correlates with the type of interaction between the drug and the intercellular lipids of SC. Therefore, local anesthetics of varying topical efficacy were evaluated with respect to their effect on the morphology of various model lipid systems using small and wide angle X-ray diffraction (SWAXD) and differential scanning calorimetry (DSC). The model lipids used were glyceryl monooleate, sphingomyelin and lipids isolated from human SC. Furthermore, partitioning into isolated human SC as well as permeation through isolated human SC and human tape-stripped skin were investigated in vitro. The results indicate that local anesthetics may act as their own permeation enhancers by increasing the degree of hydrocarbon chain fluidity of the intercellular lipids. Eventually these interactions may induce non-lamellar reversed types of liquid crystalline structures locally in SC, which further facilitate the drug mobility. The large difference in topical efficacy of the investigated local anesthetics could not be explained simply by looking at their effect on the phase behavior of lipid model systems. Despite the similarities in physicochemical properties of these substances, the in vitro skin permeability differed markedly (AD>EMLA>lidocaine>prilocaine>sameridine). Thus, it was concluded that sufficient drug permeability over SC is essential to obtain local anesthesia by blocking the superficial nociceptors.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-89454 (URN)10.1016/S0168-3659(02)00035-4 (DOI)11992676 (PubMedID)
    Tilgjengelig fra: 2001-10-03 Laget: 2001-10-03 Sist oppdatert: 2017-12-14bibliografisk kontrollert
  • 1660.
    Welin-Berger, Katayoun
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Neelissen, J.A.M.
    Bergenståhl, B.
    In vitro permeation profile of a local anaesthetic compound from topical formulations with different rheological behaviour - verified by in vivo efficacy data2001Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 14, nr 3, s. 229-236Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The object of this study was to develop a topical cream of suitable consistency, i.e. with a high apparent yield stress, without affecting the in vitro permeation profile and the subsequent in vivo efficacy of the formulation. Different formulations of a model compound were manufactured, an oil-in-water (o/w) emulsion, a cream consisting of the o/w emulsion thickened with various concentrations of neutralised Carbopol934P gel, and a semisolid water-in-oil (w/o) emulsion. Rheological measurements were performed giving the apparent yield stress of the formulations. The in vitro permeation rate of the compound was measured, using static diffusion cells with both guinea pig and human skin as membrane. The o/w emulsion without polymer was used as reference. The in vivo efficacy of the formulations was investigated on guinea pigs by the pinprick method. The apparent yield stress of the w/o emulsion was in the same range as that of the most viscous o/w cream while the o/w emulsion behaved as a Newtonian liquid. Furthermore, the yielding property of the w/o emulsion was not as temperature-sensitive as that of the o/w cream. The permeation rate of the compound from the two emulsions, o/w and w/o, was similar at 6% (w/w), while the o/w cream resulted in a significantly lower permeation rate at the same concentration. The two emulsions produced sufficient and comparable in vivo efficacy, while the o/w cream was less efficient. In conclusion, a reversed-phase emulsion may be used to produce the appropriate apparent yield stress, without affecting the in vivo efficacy of the formulation. The viscosity of a w/o emulsion depends on the amount of the aqueous phase and the degree of dispersity. Thus, the transport of the active compound is not prevented by the excipients present in the formulation, as is the case for the o/w cream.

  • 1661.
    Wessman, Per
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Structural effects caused by spray- and freeze-drying of liposomes and bilayer disks2010Inngår i: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 99, nr 4, s. 2032-2048Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cryo-TEM and dynamic light scattering was used to investigate morphological changes induced by spray- and freeze-drying of liposomes and nanosized bilayer disks composed of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-5000] (DSPE-PEG) from lactose solution. Particular focus was put on the identification of structural alterations that risk influencing the performance of liposomes and bilayer disks as carriers for protein and peptide drugs. Significant changes in the lipid aggregate structure and/or size was noted upon dehydration. Uni-lamellar liposomes tended to shrink in size and become bi-lamellar as a consequence of the drying process. The same transformation was observed upon deliberate establishment of a lactose gradient over the membranes of liposomes in solution. A mechanism based on an osmotically driven invagination of the liposomes is proposed to explain the change from uni- to bi-lamellar structures. PEGylation promoted formation of larger liposomes during spray-drying, and had a similar, but less pronounced, effect also during freeze-drying. The observed structural changes may have important consequences for the bioavailability of protein/peptide drugs bound to, or embedded in, the liposome membranes. The radius of bilayer disks increased upon both spray- and freeze-drying, but the drying procedure did not change the open single-bilayer structure of the disks.

  • 1662.
    Wessman, Per
    et al.
    Department of Mircobiology, SLU, Swedish University of Agricultural Sciences.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Akhtar, Sultan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Rubino, Stefano
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Leifer, Klaus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Kessler, Vadim
    Department of Chemistry, SLU, Swedish University of Agricultural Sciences.
    Håkansson, Sebastian
    Department of Microbiology, SLU, Swedish University of Agricultural Sciences.
    Impact of matrix properties on survival of freeze-dried bacteria2011Inngår i: Journal of the Science of Food and Agriculture, ISSN 0022-5142, E-ISSN 1097-0010, Vol. 91, nr 14, s. 2518-2528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Disaccharides are in general first choice as formulation compounds when freezedrying microorganisms. Although polysaccharides and other biopolymers are considered too large to stabilize and interact with cell components in the same beneficial way as disaccharides, polymers have been reported to support cell survival. In the present study we compare the efficiency of sucrose, the polymers Ficoll, hydroxyethylcellulose, hydroxypropylmethylcellulose and polyvinylalcohol to support survival of three bacterial strains during freeze-drying. The initial osmotic conditions were adjusted to be similar for all formulations. Formulation characterization was used to interpret the impact that different compound properties had on cell survival.

    Results:

    Despite differences in molecular size, both sucrose and the sucrose based polymer Ficoll supported cell survival after freeze-drying equally well. All formulations became amorphous upon dehydration. Scanning electron microscopy and X-ray diffraction data showed that the discerned differences in structure of the dry formulations had little impact on the survival rates. The capability of the polymers to support cell survival correlated with the surface activity of the polymers in a similar way for all investigated bacterial strains.

    Conclusion:

    Polymer-based formulations can support cell survival as effectively as disaccharides if formulation properties of importance for maintaining cell viability are identified and controlled.

  • 1663.
    Wessman, Per
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Strömstedt, Adam A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Edwards, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Fysikalisk kemi.
    Melittin-lipid bilayer interactions and the role of cholesterol2008Inngår i: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 95, nr 9, s. 4324-4336Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The membrane-destabilizing effect of the peptide melittin on phosphatidylcholine membranes is modulated by the presence of cholesterol. This investigation shows that inclusion of 40 mol % cholesterol in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine or 1,2-dioleoyl-sn-glycero-3-phosphocholine liposomes reduces melittin's affinity for the membrane. It is significant that the presence of cholesterol does not increase the amount of membrane-associated melittin needed to cause maximum leakage from, or major structural rearrangements of, the liposomes. Furthermore, comparison of microscopy and leakage data suggests that melittin-induced leakage occurs via different mechanisms in the cholesterol-free and cholesterol-supplemented systems. In the absence of cholesterol, leakage of carboxyfluorescein takes place from intact liposomes in a manner compatible with the presence of small melittin-induced pores. In the presence of cholesterol, on the other hand, adsorption of the peptide causes complete membrane disruption and the formation of long-lived open-bilayer structures. Moreover, in the case of cholesterol-supplemented systems, melittin induces pronounced liposome aggregation. Cryotransmission electron microscopy was used, together with ellipsometry, circular dichroism, turbidity, and leakage measurements, to investigate the effects of melittin on phosphatidylcholine membranes in the absence and presence of cholesterol. The melittin partitioning behavior in the membrane systems was estimated by means of steady-state fluorescence spectroscopy measurements.

  • 1664.
    Westin, Ulrika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Piras, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Jansson, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Ekotoxikologi.
    Dahlin, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Björk, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents2005Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 24, nr 5, s. 565-573Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study was to investigate whether morphine can be transferred along the olfactory pathway to the CNS, thereby circumventingthe blood–brain barrier, after nasal administration to rodents. Radiolabelled and unlabelled morphine were administered via the right nostrilto mice and rats. Olfactory bulbs, brain tissue and blood samples were collected. Morphine-derived radioactivity was measured using liquidscintillation (LS) and the concentrations of morphine and its metabolite morphine-3-glucuronide (M3G) were also assessed with highperformanceliquid chromatography. The location of morphine-derived radioactivity in the rat brain was visualised by autoradiography.Overall, the levels of morphine in the right olfactory bulbs (ROBs) significantly exceeded those in the left olfactory bulbs (LOBs) and braintissue samples 15, 60 and 240 min after right-sided nasal administration. Fifteen minutes after intravenous administration, there were nosignificant differences between olfactory bulbs and the other brain areas. Five minutes after nasal administration, autoradiography revealedradioactivity surrounding the ROB and reaching one of the ventricles in the brain. After 60 min, radioactivity had reached the peripheral partsof the ROB. All the techniques used in this study demonstrate that morphine was transferred along the olfactory pathway to the CNS afternasal administration to rodents.

  • 1665. Wettergren, L
    et al.
    Kettis, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sprangers, M
    Ring, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The use, feasibility and psychometric properties of an individualised quality-of-life instrument: a systematic review of the SEIQoL-DW2009Inngår i: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 18, nr 6, s. 737-746Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To review published studies regarding the use, feasibility and psychometric performance of the schedule for the evaluation of individual quality of life-direct weighting (SEIQoL-DW) in clinical research. METHODS: Systematic literature review. Studies using the SEIQoL-DW were included if they were published in English and employed a quantitative design. A pre-defined checklist was used to analyse the reported results. RESULTS: Thirty-nine relevant articles were identified. The SEIQoL-DW has been included in studies relating to a variety of populations, including those who are severely ill. The results of convergent and discriminant validity support our hypotheses in which SEIQoL-DW was expected to correlate moderately to high with measures of global QoL, life satisfaction and mental health and weakly with measures of functional status and health. CONCLUSION: The SEIQoL-DW appears to be a feasible and valid instrument. The lack of association between the Index score and health, functional status, demographic and clinical parameters may be explained by the instrument's focus on global QoL and by that of the idiographic measurement approach reflecting the capacity of a patient to value domains other than health in life, despite having health problems. Nevertheless, continued psychometric evaluation in large populations with a longitudinal design is recommended.

  • 1666. Wettergren, Lena
    et al.
    Kettis, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Ring, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Comparing two versions of the Schedule for Evaluation of Individual Quality of Life in patients with advanced cancer2011Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, nr 5, s. 648-652Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. The aim was to compare two individualized patient reported outcomes or the Schedule for the Evaluation of Individual Quality of Life - Direct Weighting (SEIQoL-DW) measuring quality of life in general, and the disease-related version (SEIQoL-DR) measuring quality of life related to disease. Both instruments have been used in clinical practice settings within oncology. The instruments were compared with regard to feasibility, the areas nominated by patients as important and patients' ratings of how they were doing in these areas (Index scores). Material and methods. The study included 40 patients with gastrointestinal cancer. All patients completed both versions of the instrument on a touch screen computer in relation to a medical consultation. Firstly, the participants were invited to nominate the five domains she/he currently considered to be most important in life. Secondly, they were asked to rate how they were doing in each of these domains. Finally, they were asked to quantify the relative importance of each area. Cohen's effect sizes were calculated to illuminate the clinical importance of mean value differences. Results. Both instruments took less than ten minutes to complete and the procedure was considered feasible by both patients and interviewers. The proportion of patients nominating the same areas in the two versions did not differ, however, the SEIQoL-DW Index score was significantly higher than the corresponding score for the SEIQoL-DR. The detected difference in the mean score measured by effect size was medium. Conclusion. The magnitude of the effect size of the difference in Index score imply that the two versions tap into different constructs, i.e. quality of life (QoL) versus health-related QoL (HRQL), supporting the construct validity of the two versions of the instrument. The SEIQoL-DW and the SEIQoL-DR should be considered as complementary rather than interchangeable when used in patients with cancer.

  • 1667. Whiddon, C
    et al.
    Söderman, O
    Hansson, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Physicochemical properties of a mixed alkylglucoside surfactant/water system: Phase behavior, salt effects and microstructure surrounding a closed-loop liquid/liquid miscibility gap2002Inngår i: Langmuir, Vol. 18, s. 4610-Artikkel i tidsskrift (Fagfellevurdert)
  • 1668.
    Widenbring, Ronja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Microgel Interactions with Peptides and Proteins: Consequence of Peptide and Microgel Properties2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Microgels are lightly cross-linked hydrogel particles in the sub-micrometer to micrometer size range with a capacity to drastically change their volume in response to changes in the external environment. Microgels have an ability to bind and store substances such as biomacromolecular drugs, notably proteins and peptides, and release them upon stimuli, making them potential candidates as drug delivery vehicles and functional biomaterials. This thesis aims at clarifying important factors affecting peptide-microgel interactions. These interactions were studied by micromanipulator-assisted light and fluorescence microscopy focusing on microgel deswelling in response to peptide binding, as well as re-swelling in response to peptide release or enzymatic degradation. To evaluate peptide uptake in microgels, solution depletion measurements were used whereas the peptide secondary structure was investigated by circular dichroism. In addition, the peptide and enzyme distribution within microgels was analyzed with confocal microscopy.

    Results presented in this thesis demonstrate that peptide incorporation into microgels, as well as peptide-induced microgel deswelling, increases with peptide length and charge density. In addition, results demonstrate that the peptide charge (length) rather than peptide charge density determines microgels deswelling. End-to-end cyclization is shown to not noticeably influence peptide-microgel interactions, suggesting that peptide cyclization can be used in combination with oppositely charged microgel carriers to improve the proteolytic and chemical stability of the peptide compared to the corresponding linear variant. Peptide secondary structure is found to drastically affect peptide incorporation into, and release from, oppositely charged microgels. Furthermore, it is shown that microgel charge density, peptide molecular weight, and enzyme concentration all greatly influence microgel bound peptide degradation. Of importance for applications, protective effects of microgels against proteolytic peptide degradation are observed only at sufficiently high microgel charge densities. Enzyme-mediated microgel degradation is shown to increase with increasing enzyme concentration, while an increased peptide loading in microgels causes a concentration-dependent decrease in microgel degradation.

    Taken together, results obtained in this work have provided some insight into factors of importance for rational use of microgels as delivery systems for protein or peptide drugs, but also in a host of other biomedical applications using weakly cross-linked polymer systems.

    Delarbeid
    1. Effects of Peptide Secondary Structure on the Interaction with Oppositely Charged Microgels
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of Peptide Secondary Structure on the Interaction with Oppositely Charged Microgels
    Vise andre…
    2011 (engelsk)Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 12, nr 2, s. 419-424Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The importance of peptide secondary structure on the interaction between antimicrobial peptides and oppositely charged poly(acrylic acid-co-acrylamide) microgels of various charge density was investigated for EFKRIVQRIKDFLRNLV (EFK17). Through D-enantiomer (EFK17-d/a; E(dF)KR(dI)VQR(dI)KD(dF)LRNLV) or tryptophan (EFK17-W/a; EWKRWVQRWKDFLRNLV) substitutions, both conformation-dependent and -independent amphiphilicity of this peptide could be precisely controlled. Peptide secondary structure was investigated by circular dichroism, whereas microgel deswelling and reswelling in response to peptide binding and release were studied by micromanipulator-assisted light and fluorescence microscopy, and peptide uptake in the microgels was determined from solution depletion measurements. Results show that peptide binding to the microgel is highly influenced by peptide secondary structure. EFK17-a, characterized by an idealized helix with all polar/charged amino acids located at one side of the helix, and all nonpolar/hydrophobic residues on the other, displays pronounced alpha-helix induction on peptide binding to the microgels. EFK17-d/a, on the other hand, displays no such amphiphilic helix induction. Mirroring this, EFK17-a displays substantially higher binding to the microgels than EFK17-d/a as well as much larger peptide-induced microgel deswelling. For EFK17-W/a, both conformation-dependent and -independent amphiphilicity effects were demonstrated. Overall, the results show that peptide conformational aspects need to be considered in peptide/microgel interactions, for example, in the design of microgel carrier systems for peptide drugs.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-149054 (URN)10.1021/bm101165e (DOI)000287175700017 ()21182237 (PubMedID)
    Tilgjengelig fra: 2011-03-15 Laget: 2011-03-15 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    2. Effects of peptide cyclization on the interaction with oppositely charged microgels
    Åpne denne publikasjonen i ny fane eller vindu >>Effects of peptide cyclization on the interaction with oppositely charged microgels
    2011 (engelsk)Inngår i: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 391, nr 1-3, s. 62-68Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The effect of peptide cyclization on the interaction between antimicrobial peptides and oppositely charged poly(acrylic acid-co-acrylamide) microgels of various charge density was investigated for linear and cyclic variants of peptide oligomers (C(ARKKAAKA)nC) (n = 1, 1.5, 2, 3). Through this, peptide length could be varied without substantially affecting peptide charge density and mean hydrophobicity. Furthermore, the peptides were demonstrated to display random coil conformation both in aqueous solution and when bound to oppositely charged microgels, allowing effects of cyclization to be monitored without interference from conformational transitions. With increasing peptide length, both cyclic and linear peptide variants displayed increased binding affinity to oppositely charged microgels. For all peptide lengths, however, the difference between cyclic and linear peptide variants was marginal at most, hence cyclization had little or no influence in peptide incorporation to oppositely charged microgels. In parallel, microgel deswelling increased with peptide length for both linear and cyclic peptide variants, while linear and cyclic peptide variants of the same length displayed very similar peptide-induced deswelling. Also electrolyte-induced peptide desorption from the microgels was similar for linear and cyclic peptide variants. Taken together, these findings demonstrate that end-to-end cyclization does not markedly affect peptide incorporation into, and release from, oppositely charged microgels. This opens up opportunities for the use of microgels as carriers for peptides which have been cyclized in order to improve their proteolytic and chemical stability, or in order to achieve other therapeutic advantages compared to the corresponding linear peptide variant.

    Emneord
    Cyclization, Microgel, Peptide
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-168831 (URN)10.1016/j.colsurfa.2011.01.029 (DOI)000299068100009 ()
    Merknad
    18th International Symposium on Surfactants in Solution (SIS), Melbourne Australia, 14-19 November 2010Tilgjengelig fra: 2012-02-16 Laget: 2012-02-16 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    3. Peptide-Microgel Interactions in the Strong Coupling Regime
    Åpne denne publikasjonen i ny fane eller vindu >>Peptide-Microgel Interactions in the Strong Coupling Regime
    2012 (engelsk)Inngår i: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, nr 35, s. 10964-10975Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    The interaction between lightly cross-linked poly(acrylic acid) microgels and oppositely charged peptides was investigated as a function of peptide length, charge density, pH, and salt concentration, with emphasis on the strong coupling regime at high charge contrast. By micromanipulator-assisted light microscopy, the equilibrium volume response of single microgel particles upon oligolysine and oligo(lysine/alanine) absorption could be monitored in a controlled fashion. Results show that microgel deswelling, caused by peptide binding and network neutralization, increases with peptide length (3 < 5 < 10) and charge density (30% < 50% < 100%). Furthermore, oligomer-induced microgel deswelling was more pronounced at pH 5 than at pH 8, reflecting the lower network charge density in the former case (pK(a) for the isolated acrylic acid approximate to 4.7). In order to describe these highly coupled systems, a model was developed, in which counterion/peptide-mediated electrostatic attraction between the network chains is described using an exponential force law, and the network elasticity by the inverse Langevin theory. The model was used to calculate the composition of microgels in contact with reservoir solutions of peptides and simple electrolytes. At high electrostatic coupling, the calculated swelling curves were found to display first-order phase transition behavior. The model was demonstrated to capture pH- and electrolyte-dependent microgel swelling, as well as effects of peptide length and charge density on microgel deswelling. The analysis demonstrated that the peptide charge (length), rather than the peptide charge density, determines microgel deswelling. Furthermore, a transition between continuous and discrete network collapse was identified, consistent with experimental results in the present investigations, as well as with results from the literature on microgel deswelling caused by multivalent cations.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-182754 (URN)10.1021/jp306121h (DOI)000308339400060 ()
    Tilgjengelig fra: 2012-10-18 Laget: 2012-10-15 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    4. Factors Affecting Enzymatic Degradation of Microgel-Bound Peptides
    Åpne denne publikasjonen i ny fane eller vindu >>Factors Affecting Enzymatic Degradation of Microgel-Bound Peptides
    2013 (engelsk)Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 14, nr 7, s. 2317-2325Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Proteolytic degradation and release of microgel-bound peptides was investigated for trypsin, poly(acrylic acid-co-acrylamide) microgels (70-90 mu m in diameter), and oppositely charged polylysine, using a method combination of confocal microscopy and micromanipulator-assisted light microscopy. Results show that trypsin-induced release of polylysine increased with increasing trypsin concentration, decreasing microgel charge density and decreasing peptide molecular weight. While the microgel offered good protection against enzymatic degradation at high microgel charge density, it was also observed that the cationic peptide enabled trypsin to bind throughout the peptide-loaded microgels, even when it did not bind to the peptide-void ones. With the exception of highly charged microgels, proteolytic degradation throughout the peptide-loaded microgel resulted in the generation of short and non-adsorbing peptide stretches, giving rise to the concentration and peptide length dependence observed. A simple random scission model was able to qualitatively capture these experimental findings. collectively, the results demonstrate that microgel charge density, peptide molecular weight, and enzyme concentration greatly influence degradation/release of microgel-bound peptides and need to be considered in the use of microgels, e.g., as carriers for protein and peptide drugs.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-204977 (URN)10.1021/bm400431f (DOI)000321793700021 ()
    Tilgjengelig fra: 2013-08-16 Laget: 2013-08-13 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    5. Chain and Pore-Blocking Effects on Matrix Degradation in Protein-Loaded Microgels
    Åpne denne publikasjonen i ny fane eller vindu >>Chain and Pore-Blocking Effects on Matrix Degradation in Protein-Loaded Microgels
    2014 (engelsk)Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, nr 10, s. 3671-3678Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Factors affecting matrix degradation in protein-loaded microgels were investigated for dextran-based microgels, the sugar-binding protein Concanavalin A (ConA), and the dextran-degrading enzyme Dextranase. For this system, effects of enzyme, protein, and glucose concentrations, as well as pH, were considered. Microgel network degradation was monitored by micromanipulator-assisted light microscopy, whereas enzyme and protein distributions were monitored by confocal microscopy. Results show that Dextranase-mediated microgel degradation increased with increasing enzyme concentration, whereas an increased ConA loading in the dextran microgels caused a concentration-dependent decrease in microgel degradation. In the presence of glucose, competitive release of microgel-bound ConA restored the microgel degradation observed in the absence of ConA. To clarify effects of mass transport limitations, microgel degradation was compared to that of non-cross-linked dextran, demonstrating that ConA limits enzyme substrate access in dextran microgels primarily through pore blocking and induction of pore shrinkage. The experimentally observed effects were qualitatively captured by a modified Michaelis-Menten approach for spherical symmetry, in which network blocking by ConA was included. Taken together, the results demonstrate that matrix degradation of protein-loaded microgels depends sensitively on a number of factors, which need to be considered in the use of microgels in biomedical applications.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-236549 (URN)10.1021/bm5009525 (DOI)000343026600022 ()25144139 (PubMedID)
    Tilgjengelig fra: 2014-11-26 Laget: 2014-11-19 Sist oppdatert: 2017-12-05bibliografisk kontrollert
  • 1669.
    Widenbring, Ronja
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Frenning, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Chain and Pore-Blocking Effects on Matrix Degradation in Protein-Loaded Microgels2014Inngår i: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, nr 10, s. 3671-3678Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Factors affecting matrix degradation in protein-loaded microgels were investigated for dextran-based microgels, the sugar-binding protein Concanavalin A (ConA), and the dextran-degrading enzyme Dextranase. For this system, effects of enzyme, protein, and glucose concentrations, as well as pH, were considered. Microgel network degradation was monitored by micromanipulator-assisted light microscopy, whereas enzyme and protein distributions were monitored by confocal microscopy. Results show that Dextranase-mediated microgel degradation increased with increasing enzyme concentration, whereas an increased ConA loading in the dextran microgels caused a concentration-dependent decrease in microgel degradation. In the presence of glucose, competitive release of microgel-bound ConA restored the microgel degradation observed in the absence of ConA. To clarify effects of mass transport limitations, microgel degradation was compared to that of non-cross-linked dextran, demonstrating that ConA limits enzyme substrate access in dextran microgels primarily through pore blocking and induction of pore shrinkage. The experimentally observed effects were qualitatively captured by a modified Michaelis-Menten approach for spherical symmetry, in which network blocking by ConA was included. Taken together, the results demonstrate that matrix degradation of protein-loaded microgels depends sensitively on a number of factors, which need to be considered in the use of microgels in biomedical applications.

  • 1670. Widhe, Mona
    et al.
    Bysell, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Nystedt, Sara
    Schenning, Ingrid
    Malmsten, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Johansson, Jan
    Rising, Anna
    Hedhammar, My
    Recombinant spider silk as matrices for cell culture2010Inngår i: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, nr 36, s. 9575-9585Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The recombinant miniature spider silk protein, 4RepCT, was used to fabricate film, foam, fiber and mesh matrices of different dimensionality, microstructure and nanotopography. These matrices were evaluated regarding their suitability for cell culturing. Human primary fibroblasts attached to and grew well on all matrix types, also in the absence of serum proteins or other animal-derived additives. The highest cell counts were obtained on matrices combining film and fiber/mesh. The cells showed an elongated shape that followed the structure of the matrices and exhibited prominent actin filaments. Moreover, the fibroblasts produced, secreted and deposited collagen type I onto the matrices. These results, together with findings of the matrices being mechanically robust, hold promise not only for in vitro cell culturing, but also for tissue engineering applications.

  • 1671. Wikingsson, L
    et al.
    Sjoholm, I
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Polyacryl starch microparticles as adjuvant in oral immunisation, inducingmucosal and systemic immune responses in mice.2002Inngår i: Vaccine, Vol. 20, s. 3355-3363Artikkel i tidsskrift (Fagfellevurdert)
  • 1672.
    WIKMAN LARHED, A
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    ARTURSSON, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    COCULTURES OF HUMAN INTESTINAL GOBLET (HT29-H) AND ABSORPTIVE (CACO-2) CELLS FOR STUDIES OF DRUG AND PEPTIDE ABSORPTION1995Inngår i: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 3, s. 171-Artikkel i tidsskrift (Fagfellevurdert)
  • 1673.
    Wikman Larhed, Agneta
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The mucus layer and other barriers to intestinal drug absorption1997Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The extraepithelial mucus layer acts as a barrier to the absorption and diffusion of drugs. Three in vitro models have been used for studies of this and other intestinal barriers to drug transport. A drug absorption model based on monolayers of the mucus-producing human intestinal goblet HT29-H cell line was developed. The goblet cells produced mucin molecules and a mucus layer that covered the surface of the cells. The permeability of the gobletcell monolayers to the lipophilic molecule testosterone increased after removal of the mucus layer while the permeability to the small hydrophilic molecule mannitol was not altered.

    The mucus layer contributed 78% of the total resistance to absorption of testosterone in the HT29-H model, while the corresponding values for the unstirred water layer, the cell monolayer and the filter were 16%, 5% and 1%, respectively.

    A co-culture model containing absorptive Caco-2 cells and goblet HT29-H cells (the two most abundant epithelial cell types) was developed. A seeding density of 1% HT29-H cells resulted in co-cultures comprising 30% goblet cells in small clusters after 4 weeks in culture. Tight junctions were formed between the two cell types as revealed by electron microscopy and transepithelial electrical resistance measurements. The permeability of the monolayers tohydrophilic drugs increased with increasing numbers of goblet cells. The specific tight junction permeability, adjusted for junctional path length, was higher in HT29-H cells than Caco-2 cells.

    A relationship between the octanol/water distribution ratio and the self-diffusion coefficient of drugs was found in a native pig intestinal mucus model (PIM) but not in a purified pig gastric mucin model (PPGM), indicating that mucus components other than mucin molecules interact with drugs. PIM was thus found to be a more complete model of the barrier properties of gastrointestinal mucus than PPGM.

    The major components of PIM, other than water, were lipids and proteins; concentrations of mucin and DNA were lower. Of the individual components of native intestinal mucus, lipids were found to have the greatest influence on the diffusion of drugs.

  • 1674. Wilson, Timothy R
    et al.
    Alexander, David J
    Kind, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Measurement of health-related quality of life in the early follow-up of colon and rectal cancer.2006Inngår i: Dis Colon Rectum, ISSN 0012-3706, Vol. 49, nr 11, s. 1692-702Artikkel i tidsskrift (Fagfellevurdert)
  • 1675.
    Winiwarter, S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Ax, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lennernas, H
    Institutionen för farmaci.
    Hallberg, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Pettersson, C
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Karlen, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hydrogen bonding descriptors in the prediction of human in vivo intestinal permeability.2003Inngår i: J Mol Graph Model, Vol. 21, s. 273-Artikkel i tidsskrift (Fagfellevurdert)
  • 1676.
    Winiwarter, S
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Bonham, NM
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Ax, F
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Hallberg, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Lennernas, H
    Institutionen för farmaci.
    Karlen, A
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach1998Inngår i: J MEDI CHEM , Vol. 41, s. 4939-Artikkel i tidsskrift (Fagfellevurdert)
  • 1677. Wiren, K
    et al.
    Frithiof, H
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sjöqvist, C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Loden, M
    Enhancement of bioavailability by lowering of fat content in topical formulations2009Inngår i: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 160, nr 3, s. 552-556Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The cosmetic properties of topical formulations are important parameters for the adherence to treatment, where modern oil-in-water emulsions are considered more acceptable compared with ointments. After application of an emulsion to the skin, the concentration of active ingredients in the formulation residue on the skin will increase, due to evaporation of volatile ingredients. The aim of the present study was to investigate the effect of changes in vehicle fatty content on the skin penetration of two active ingredients: benzyl nicotinate (BN) and betamethasone valerate (BV). Formulations containing 0.5% BN and 0.3% BV in vehicles with different lipid content (10-80%) were applied in a randomized and double-blind manner to the forearm of healthy volunteers. The changes in skin colour (erythema and blanching) were then monitored visually and with a new noninvasive instrument. The BN formulation containing 10% fat induced erythema more rapidly and with higher intensity than the formulations with higher fat content. Increased efficacy was also observed from the low-fat content formulation of BV, which gave more blanching than the formulations with high fat content. The rate of penetration of the active ingredients was inversely related to the lipid content, i.e. simple changes of the cosmetic properties by modifications of the lipid content may affect the efficacy of a formulation.

  • 1678.
    Wisell, Kristin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    The Liberalization Experiment: Understanding the political rationales leading to change in pharmacy policy2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In 2009, a pharmacy policy reform was introduced in Sweden whereby the state owned community pharmacy monopoly was abolished. As a result two thirds of the pharmacies were sold. As there were no longer restrictions on ownership and establishment, new pharmacies and new owners appeared. The overall aim of this thesis is to contribute to a more nuanced understanding of the stated and the underlying rationales for the reform, specifically, to understand how key stakeholders view the reform, and the future role of the community pharmacy. Document analysis was the method used to study the preparatory work, plenary debates, and interviews with stakeholders from political, professional and patient organizations.

    The government directive stated that the reform would lead to improvement of availability and efficiency, a pressure on prices and a better use of medicines.  However, the results show that during the reforms’ preparatory phase, the rationales changed and only availability remained throughout the process. Diversity on the market was added later as a rationale. The effects of the reform were perceived in similar ways by the different stakeholder groups. The views on the reform was more negative after the reform.

    Interviewees who were previously in favor of the reform were surprised that diversity had not been achieved; that the counseling in the pharmacies had deteriorated and that the availability of medicines decreased after the reform. Interviewees from political organizations had a more business-oriented view of pharmacies/ists, while participants from professional organizations had a more healthcare-oriented perspective.

    Finally, this thesis studied the diversity rationale behind the pharmacy reform and compared it to the primary care reform. The results show that, in both cases, policy makers definitions of diversity were vague and unclear, which appear to have complicated their implementation.

    Since the pharmacy reform neglected to investigate alternative means of achieving the goals/rationales, it can be argued that the reform was ideologically based and had a preconceived understanding as to how the community pharmacy sector should be regulated. There are several reasons for drawing this conclusion: the reform was launched despite the original rationales being considered as impossible to fulfill, and, except for abolishing the monopoly on state-owned pharmacies, the stakeholders did not seem to know what the reform would lead to, except increasing the number of pharmacies. The latter could have been achieved without the reform as the government had control over the state-owned pharmacy monopoly.

    Delarbeid
    1. Reregulation of the Swedish pharmacy sector: A qualitative content analysis of the political rationale
    Åpne denne publikasjonen i ny fane eller vindu >>Reregulation of the Swedish pharmacy sector: A qualitative content analysis of the political rationale
    2015 (engelsk)Inngår i: Health Policy, ISSN 0168-8510, E-ISSN 1872-6054, Vol. 119, nr 5, s. 648-653Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    In 2009, a reregulation of the Swedish pharmacy sector took place, and a fundamental change in ownership and structure followed. The reregulation provides an opportunity to reveal the politicians' views on pharmacies. The aim of thiS study was to explore and analyze the political arguments for the reregulation of the Swedish pharmacy sector in 2009. The method used was a qualitative content analysis of written political documents regarding the reregulation. The primary rationales for the reregulation were better availability, efficiency, price pressure, and safe usage of medicines. During the preparatory work, the rationales of diversity on the market and entrepreneurship were added, while the original rationales of efficiency, price pressure, and better usage of medicines were abandoned. The reform can be seen as a typical New Public Management reform influenced by the notion that private actors are better equipped to perform public activities. The results point to that the reform was done almost solely in order to introduce private ownership in the pharmacy sector, and was not initiated in order to solve any general problems, or to enhance patient outcomes of medicine use.

    Emneord
    Pharmacy policy, Regulation, Community pharmacy, Sweden
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-256851 (URN)10.1016/j.healthpol.2015.03.009 (DOI)000355031900011 ()25841749 (PubMedID)
    Tilgjengelig fra: 2015-06-26 Laget: 2015-06-26 Sist oppdatert: 2019-03-24bibliografisk kontrollert
    2. The Raison D’être for the Community Pharmacy and the Community Pharmacist in Sweden:: A Qualitative Interview Study
    Åpne denne publikasjonen i ny fane eller vindu >>The Raison D’être for the Community Pharmacy and the Community Pharmacist in Sweden:: A Qualitative Interview Study
    2016 (engelsk)Inngår i: Pharmacy, ISSN 2226-4787, Vol. 4, nr 1Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Community pharmacies are balancing between business (selling medicines and other products) and healthcare (using the pharmacists’ knowledge in order to improve drug utilization). This balance could be affected by regulations decided upon by politicians, but also influenced by others. The aim of this study was to explore important stakeholders’ views on community pharmacy and community pharmacists in Sweden. The method used was that of semi-structured qualitative interviews. Political, professional, and patient organization representatives were interviewed.

    The results show that informants who are pharmacists or representatives of a professional pharmacist organization generally have a healthcare-centered view on community pharmacy/pharmacists. However, different views on how this orientation should be performed were revealed, ranging from being specialists to dealing with uncomplicated tasks. Political organization representatives generally had a more business-oriented view, where competition in the market was believed to be the main driving force for development. A third dimension in which competition was not stressed also emerged; that community pharmacies should primarily distribute medicines. This dimension was most prevalent among the political and patient organization representatives. One conclusion to be drawn is that no stakeholder seemed to have a clear vision or was willing to take the lead for the development of the community pharmacy sector.

    Emneord
    community pharmacy; regulation; pharmacy policy; pharmacy reform; legislation; Sweden
    HSV kategori
    Forskningsprogram
    Samhällsfarmaci
    Identifikatorer
    urn:nbn:se:uu:diva-380060 (URN)10.3390/pharmacy4010003 (DOI)
    Tilgjengelig fra: 2019-03-23 Laget: 2019-03-23 Sist oppdatert: 2019-09-05bibliografisk kontrollert
    3. Stakeholders’ expectations and perceived effects of the pharmacy ownership liberalization reform in Sweden: a qualitative interview study
    Åpne denne publikasjonen i ny fane eller vindu >>Stakeholders’ expectations and perceived effects of the pharmacy ownership liberalization reform in Sweden: a qualitative interview study
    2016 (engelsk)Inngår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 16, artikkel-id 379Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Background: Reforms in the health-care sector, including the pharmacy sector, can have different rationales. The Swedish pharmacies were prior to 2009 organized in a state-owned monopoly. In 2009, a liberalization of the ownership took place, in which a majority of the pharmacies were sold to private owners. The rationales for this liberalization changed profoundly during the preparatory work, making it probable that other rationales than the ones first expressed existed. The aim of this study was to explore the underlying rationales (not stated in official documents) for the liberalization in the Swedish pharmacy sector, and also to compare the expectations with the perceived outcomes.

    Methods: Semi-structured interviews were conducted with representatives from key stakeholder organizations; i.e., political, patient, and professional organizations. The analysis was performed in steps, and themes were developed in an inductive manner.

    Results: One expectation among the political organization participants was that the ownership liberalization would create opportunities for ideas. The competition introduced in the market was supposed to lead to a more diversified pharmacy sector. After the liberalization, the participants in favor of the liberalization were surprised that the pharmacies were so similar.

    Among the professional organization participants, one important rationale for the liberalization was to get better use of the pharmacists’ knowledge. However, all the professional, and some of the patient organization participants, thought that the counseling in the pharmacies had deteriorated after the liberalization.

    As expected in the interviews, the post-liberalization pharmacy sector consists of more pharmacies. However, an unexpected perceived effect of the liberalization was, among participants from all the stakeholder groups, less access to prescription medicines in the pharmacies.

    Conclusions: This study showed that the political organization participants had an ideological basis for their opinion. The political stakeholders did not have a clear view about what the liberalization should lead to, apart from abolishing the monopoly. The perceived effects are quite similar in the different stakeholder groups, and not as positive as were expected.

    Emneord
    community pharamcy, regulation, pharmacy policy, Sweden
    HSV kategori
    Forskningsprogram
    Samhällsfarmaci
    Identifikatorer
    urn:nbn:se:uu:diva-301433 (URN)10.1186/s12913-016-1637-6 (DOI)000381258500001 ()27519573 (PubMedID)
    Prosjekter
    The monopoly experiment
    Tilgjengelig fra: 2016-08-23 Laget: 2016-08-23 Sist oppdatert: 2019-03-24bibliografisk kontrollert
    4. Diversity as salvation?: A comparison of the diversity rationale in the Swedish pharmacy ownership liberalization reform and the primary care choice reform
    Åpne denne publikasjonen i ny fane eller vindu >>Diversity as salvation?: A comparison of the diversity rationale in the Swedish pharmacy ownership liberalization reform and the primary care choice reform
    2019 (engelsk)Inngår i: Health Policy, ISSN 0168-8510, E-ISSN 1872-6054, Vol. 123, nr 5, s. 457-461Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Widespread liberalizing reform of the Swedish community pharmacy and primary care sectors took place in 2009–2010, including opening the market to private providers. One important rationale for the reforms was to increase diversity in the health-care system by providing more choices for individuals. The aim of this study was to increase the understanding how policy makers understood and defined diversity as a concept, and as a rationale for the reforms. The method used was document analysis of preparatory work and plenary parliament debate protocols. The results show that policy makers held vague and unclear definitions of diversity, which complicated its implementation. Diversity was sometimes seen as an effect of competition–a goal–while in other cases it was seen as a condition to be met in order to achieve competition–a means. Thus, policy makers viewed diversity both as a goal and as a means, making the underlying mechanisms unclear. The findings also revealed that policy makers failed to consistently demonstrate how the introduction of competition would lead to diversity.

    Emneord
    Community pharmacy, Community health care, Regulations, Liberalization, Sweden, Diversity
    HSV kategori
    Forskningsprogram
    Samhällsfarmaci
    Identifikatorer
    urn:nbn:se:uu:diva-380072 (URN)10.1016/j.healthpol.2019.03.005 (DOI)000468719700003 ()30890380 (PubMedID)
    Tilgjengelig fra: 2019-03-23 Laget: 2019-03-23 Sist oppdatert: 2019-06-24bibliografisk kontrollert
  • 1679.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Kälvemark Sporrong, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Winblad, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    The public health rationale that disappeared: The reregulation of the Swedish pharmacies2013Konferansepaper (Fagfellevurdert)
    Abstract [en]

    Conclusion: When constructing pharmacy policy, be aware that the preferred goals are in line with what was wished for.

    Objective: The aim of this study was to explore and analyze

    the political arguments for the reregulation of the Swedish

    pharmacy sector.

    Introduction:  

    Pharmacies are balancing between the business-driven

    economic sphere, and the professional health-improving sphere.

    A reform driven by health policy considerations, should have

    rationales that would improve the health of the population.

    Methods: The method used was qualitative content analysis of

    written political documents regarding the reregulation of the pharmacy market in Sweden.

    Results: During the preparatory work, the rationales of effectiveness, price pressure, and better usage of medicines were abandoned. Diversity on the market, entrepreneurship, and gender issues were added. The rationale availability, defined as an increased number of pharmacies, were consistent throughout the documents.

    Discussion: In this reform preferred health goals were replaced by other goals. The reform could be seen as influenced by the theory that private actors are better equipped to perform public activities, namely New Public Management. It could be argued that this reform was done almost solely on an ideological basis, from a business policy point-of-view. If a pharmacy market reform does not take the health perspective into consideration, the importance of pharmacists and pharmacies is in danger of disappearing.

  • 1680.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Kälvemark-Sporrong, Sofia
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen O, Denmark.
    The Raison D’être for the Community Pharmacy and the Community Pharmacist in Sweden: A Qualitative Interview Study2016Inngår i: Pharmacy, ISSN 2226-4787, Vol. 4, nr 1, artikkel-id 3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Community pharmacies are balancing between business (selling medicines and other products) and healthcare (using the pharmacists’ knowledge in order to improve drug utilization). This balance could be affected by regulations decided upon by politicians, but also influenced by others. The aim of this study was to explore important stakeholders’ views on community pharmacy and community pharmacists in Sweden. The method used was that of semi-structured qualitative interviews. Political, professional, and patient organization representatives were interviewed. The results show that informants who are pharmacists or representatives of a professional pharmacist organization generally have a healthcare-centered view on community pharmacy/pharmacists. However, different views on how this orientation should be performed were revealed, ranging from being specialists to dealing with uncomplicated tasks. Political organization representatives generally had a more business-oriented view, where competition in the market was believed to be the main driving force for development. A third dimension in which competition was not stressed also emerged; that community pharmacies should primarily distribute medicines. This dimension was most prevalent among the political and patient organization representatives. One conclusion to be drawn is that no stakeholder seemed to have a clear vision or was willing to take the lead for the development of the community pharmacy sector.

  • 1681.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sporrong, Sofia Kälvemark
    Köpenhamns universitet.
    The Raison D’être for the Community Pharmacy and the Community Pharmacist in Sweden:: A Qualitative Interview Study2016Inngår i: Pharmacy, ISSN 2226-4787, Vol. 4, nr 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Community pharmacies are balancing between business (selling medicines and other products) and healthcare (using the pharmacists’ knowledge in order to improve drug utilization). This balance could be affected by regulations decided upon by politicians, but also influenced by others. The aim of this study was to explore important stakeholders’ views on community pharmacy and community pharmacists in Sweden. The method used was that of semi-structured qualitative interviews. Political, professional, and patient organization representatives were interviewed.

    The results show that informants who are pharmacists or representatives of a professional pharmacist organization generally have a healthcare-centered view on community pharmacy/pharmacists. However, different views on how this orientation should be performed were revealed, ranging from being specialists to dealing with uncomplicated tasks. Political organization representatives generally had a more business-oriented view, where competition in the market was believed to be the main driving force for development. A third dimension in which competition was not stressed also emerged; that community pharmacies should primarily distribute medicines. This dimension was most prevalent among the political and patient organization representatives. One conclusion to be drawn is that no stakeholder seemed to have a clear vision or was willing to take the lead for the development of the community pharmacy sector.

  • 1682.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Sporrong, Sofia Kälvemark
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark..
    Winblad Spångberg, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälso- och sjukvårdsforskning.
    The innovation that never came true: stakeholders views of the perceived effects of the reregulation of the Swedish pharmacies2015Inngår i: International Journal of Clinical Pharmacy, ISSN 2210-7703, E-ISSN 2210-7711, Vol. 37, s. 15-15Artikkel i tidsskrift (Annet vitenskapelig)
  • 1683.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Winblad, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälso- och sjukvårdsforskning.
    Kälvemark Sporrong, Sofia
    Köpenhamns universitet.
    Diversity as salvation?: A comparison of the diversity rationale in the Swedish pharmacy ownership liberalization reform and the primary care choice reform2019Inngår i: Health Policy, ISSN 0168-8510, E-ISSN 1872-6054, Vol. 123, nr 5, s. 457-461Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Widespread liberalizing reform of the Swedish community pharmacy and primary care sectors took place in 2009–2010, including opening the market to private providers. One important rationale for the reforms was to increase diversity in the health-care system by providing more choices for individuals. The aim of this study was to increase the understanding how policy makers understood and defined diversity as a concept, and as a rationale for the reforms. The method used was document analysis of preparatory work and plenary parliament debate protocols. The results show that policy makers held vague and unclear definitions of diversity, which complicated its implementation. Diversity was sometimes seen as an effect of competition–a goal–while in other cases it was seen as a condition to be met in order to achieve competition–a means. Thus, policy makers viewed diversity both as a goal and as a means, making the underlying mechanisms unclear. The findings also revealed that policy makers failed to consistently demonstrate how the introduction of competition would lead to diversity.

  • 1684.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Winblad, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälso- och sjukvårdsforskning.
    Kälvemark Sporrong, Sofia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Centrum för forsknings- och bioetik.
    Reregulation of the Swedish pharmacy sector: Changed rationales over time2015Inngår i: Health Policy, ISSN 0168-8510, E-ISSN 1872-6054, Vol. 3, nr 9, s. 70-76Artikkel i tidsskrift (Fagfellevurdert)
    Abstract
  • 1685.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Winblad, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Hälso- och sjukvårdsforskning.
    Sporrong, Sofia Kalvemark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Reregulation of the Swedish pharmacy sector: A qualitative content analysis of the political rationale2015Inngår i: Health Policy, ISSN 0168-8510, E-ISSN 1872-6054, Vol. 119, nr 5, s. 648-653Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In 2009, a reregulation of the Swedish pharmacy sector took place, and a fundamental change in ownership and structure followed. The reregulation provides an opportunity to reveal the politicians' views on pharmacies. The aim of thiS study was to explore and analyze the political arguments for the reregulation of the Swedish pharmacy sector in 2009. The method used was a qualitative content analysis of written political documents regarding the reregulation. The primary rationales for the reregulation were better availability, efficiency, price pressure, and safe usage of medicines. During the preparatory work, the rationales of diversity on the market and entrepreneurship were added, while the original rationales of efficiency, price pressure, and better usage of medicines were abandoned. The reform can be seen as a typical New Public Management reform influenced by the notion that private actors are better equipped to perform public activities. The results point to that the reform was done almost solely in order to introduce private ownership in the pharmacy sector, and was not initiated in order to solve any general problems, or to enhance patient outcomes of medicine use.

  • 1686.
    Wisell, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Winblad, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sporrong, Sofia Kälvemark
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen O, Denmark.
    Stakeholders’ expectations and perceived effects of the pharmacy ownership liberalization reform in Sweden: a qualitative interview study2016Inngår i: BMC Health Services Research, ISSN 1472-6963, E-ISSN 1472-6963, Vol. 16, artikkel-id 379Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Reforms in the health-care sector, including the pharmacy sector, can have different rationales. The Swedish pharmacies were prior to 2009 organized in a state-owned monopoly. In 2009, a liberalization of the ownership took place, in which a majority of the pharmacies were sold to private owners. The rationales for this liberalization changed profoundly during the preparatory work, making it probable that other rationales than the ones first expressed existed. The aim of this study was to explore the underlying rationales (not stated in official documents) for the liberalization in the Swedish pharmacy sector, and also to compare the expectations with the perceived outcomes.

    Methods: Semi-structured interviews were conducted with representatives from key stakeholder organizations; i.e., political, patient, and professional organizations. The analysis was performed in steps, and themes were developed in an inductive manner.

    Results: One expectation among the political organization participants was that the ownership liberalization would create opportunities for ideas. The competition introduced in the market was supposed to lead to a more diversified pharmacy sector. After the liberalization, the participants in favor of the liberalization were surprised that the pharmacies were so similar.

    Among the professional organization participants, one important rationale for the liberalization was to get better use of the pharmacists’ knowledge. However, all the professional, and some of the patient organization participants, thought that the counseling in the pharmacies had deteriorated after the liberalization.

    As expected in the interviews, the post-liberalization pharmacy sector consists of more pharmacies. However, an unexpected perceived effect of the liberalization was, among participants from all the stakeholder groups, less access to prescription medicines in the pharmacies.

    Conclusions: This study showed that the political organization participants had an ideological basis for their opinion. The political stakeholders did not have a clear view about what the liberalization should lead to, apart from abolishing the monopoly. The perceived effects are quite similar in the different stakeholder groups, and not as positive as were expected.

  • 1687. Wisniewski, Jacek R.
    et al.
    Gaugaz, Fabienne Z.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fast and Sensitive Total Protein and Peptide Assays for Proteomic Analysis2015Inngår i: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 87, nr 8, s. 4110-4116Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The determination of total protein content is one of the most frequent analytical tasks in biochemistry and molecular biology. Here we evaluate measurements of tryptophan fluorescence (WF) for total protein determination in whole tissue lysates and for peptide quantification in protein digests. We demonstrate that the fluorescence spectrometry of tryptophan offers a simple, sensitive, and direct method for protein and peptide assays. The WF assay is fully compatible with SDS and other solutes that are commonly used for lysis of tissue and cells. We found that the content of tryptophan varies only a little between mouse tissues (1.16 +/- 0.08% of total amino acids) and is similar in human cells (1.19 +/- 0.06%). Therefore, free tryptophan can be used as a universal standard. We show that the assay can be carried out on a standard fluorescence spectrometer with cuvettes as well as in a 96-well format using a plate reader. The method is particularly suitable for determination of peptide content in diluted samples. Notably, the whole sample can be recovered after the measurement.

  • 1688.
    Wisniewski, Jacek R.
    et al.
    Max Planck Inst Biochem, Biochem Prote Grp, Dept Prote & Signal Transduct, Klopferspitz 18, D-82152 Martinsried, Germany..
    Vildhede, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Norén, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    In-depth quantitative analysis and comparison of the human hepatocyte and hepatoma cell line HepG2 proteomes2016Inngår i: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 136, s. 234-247Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hepatocytes play a pivotal role in human homeostasis. They are essential in regulation of glucose and lipid levels in blood and play a central role in metabolism of amino acids, lipids, drugs and xenobiotic-compounds. In addition, hepatocytes produce a major portion of proteins circulating in the blood. Hepatocytes were isolated from liver tissue obtained from surgical resections. Proteins were extracted and processed using filter aided sample preparation protocol and were analyzed by LC-MS/MS using high accuracy mass spectrometry. Proteins were quantified by the 'Total Protein Approach' and 'Proteomic Ruler'. We report a comprehensive proteomic analysis of purified human hepatocytes and the human hepatoma cell line HepG2. The complete dataset comprises 9400 proteins and provides a comprehensive and quantitative depiction of the proteomes of hepatocytes and HepG2 cells at the protein titer and copy number dimensions. We describe basic cell organization and in detail energy metabolism pathways and metabolite transport. We provide quantitative insights into protein synthesis and drug and xenobiotics catabolism. Our data delineate differences between the native human hepatocytes and HepG2 cells by providing for the first time quantitative data at protein concentrations and copy numbers. 

  • 1689.
    Wisniewski, Jacek R.
    et al.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, Klopferspitz 18, D-82152 Martinsried, Germany.
    Wegler, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. AstraZeneca, Cardiovasc Renal & Metab, Innovat Med & Early Dev Biotech Unit, Gothenburg, Sweden.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Multiple-Enzyme-Digestion Strategy Improves Accuracy and Sensitivity of Label- and Standard-Free Absolute Quantification to a Level That Is Achievable by Analysis with Stable Isotope-Labeled Standard Spiking2019Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 18, nr 1, s. 217-224Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Quantification of individual proteins is an essential task in understanding biological processes. For example, determination of concentrations of proteins transporting and metabolizing xenobiotics is a prerequisite for drug disposition predictions in humans based on in vitro data. So far, this task has frequently been accomplished by targeted proteomics. This type of analyses requires preparation of stable isotope labeled standards for each protein of interest. The selection of appropriate standard peptides is usually tedious and the number of proteins that can be studied in a single experiment by these approaches is limited. In addition, incomplete digestion of proteins often affects the accuracy of the quantification. To circumvent these constrains in proteomic protein quantification, label- and standard-free approaches, such as "total protein approach" (TPA) have been proposed. Here we directly compare an approach using stable isotope labeled (SIL) standards and TPA for quantification of transporters and enzymes in human liver samples within the same LC-MS/MS runs. We show that TPA is a convenient alternative to SIL-based methods. Optimization of the sample preparation beyond commonly used single tryptic digestion, by adding consecutive cleavage steps, improves accuracy and reproducibility of the TPA method to a level, which is achievable by analysis using stable isotope-labeled standard spiking.

  • 1690.
    Wisniewski, Jacek R.
    et al.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
    Wegler, Christine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. AstraZeneca, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Subcellular fractionation of human liver reveals limits in global proteomic quantification from isolated fractions2016Inngår i: Analytical Biochemistry, ISSN 0003-2697, E-ISSN 1096-0309, Vol. 509, s. 82-88Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The liver plays an important role in metabolism and elimination of xenobiotics, including drugs. Determination of concentrations of proteins involved in uptake, distribution, metabolism, and excretion of xenobiotics is required to understand and predict elimination mechanisms in this tissue. In this work, we have fractionated homogenates of snap -frozen human liver by differential centrifugation and performed quantitative mass spectrometry -based proteomic analysis of each fraction. Concentrations of proteins were calculated by the "total protein approach". A total of 4586 proteins were identified by at least five peptides and were quantified in all fractions. We found that the xenobiotics transporters of the canalicular and basolateral membranes were differentially enriched in the subcellular fractions and that phase I and II metabolizing enzymes, the cytochrome P450s and the UDP glucuronyl transferases, have complex subcellular distributions. These findings show that there is no simple way to scale the data from measurements in arbitrarily selected membrane fractions using a single scaling factor for all the proteins of interest. This study also provides the first absolute quantitative subcellular catalog of human liver proteins obtained from frozen tissue specimens. Our data provide quantitative insights into the sub cellular distribution of proteins and can be used as a guide for development of fractionation procedures.

  • 1691. Witthöft, Cornelia M
    et al.
    Arkbåge, Karin
    Johansson, Madelene
    Lundin, Eva
    Berglund, Gerd
    Zhang, Jie-Xian
    Lennernäs, Hans
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Dainty, Jack R
    Folate absorption from folate-fortified and processed foods using a human ileostomy model.2006Inngår i: Br J Nutr, ISSN 0007-1145, Vol. 95, nr 1, s. 181-7Artikkel i tidsskrift (Annet vitenskapelig)
  • 1692. Wong, AK
    et al.
    Ross, BP
    Chan, YN
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lazorova, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Jones, A
    Toth, I
    Determination of transport in the Caco-2 cell assay of compounds varying in lipophilicity using LC-MS: enhanced transport of Leu-enkephalin analogues2002Inngår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 16, nr 3, s. 113-118Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    To synthesize a number of analogues of Leu-enkephalin with different lipophilicities and to develop an LC-MS method for determining the Caco-2 cell permeability values of these compounds.

    METHODS:

    A number of sugar and sugar plus lipoamino acid analogues of Leu-enkephalin were synthesized by solid-phase and solution methods. An LC-MS method was developed for analyzing the Caco-2 cell assay samples and validated against the traditional method using radiolabelled compounds.

    RESULTS:

    A sensitive and specific LC-MS assay was developed. Standard curves were linear in the range of 0.025-5 microM. Apparent permeability values determined by LC-MS and liquid scintillation counter were identical, for both a hydrophilic drug, cephalexin and a lipophilic Leu-enkaphalin analogue. Caco-2 permeability values for the analogues of Leu-enkephalin were determined and it was found that attachment of sugar or sugar and lipoamino acid to the Leu-enkephalin peptide resulted in an increase in the apparent permeability values compared to the native peptide, which was not transported across the Caco-2 cell monolayers.

    CONCLUSIONS:

    A rapid, generic LC-MS method for analyzing a range of compounds was developed. Attachment of a sugar or sugar and lipoamino acid to Leu-enkephalin improves the apparent permeability across Caco-2 cell monolayers.

  • 1693.
    Wreje, U.
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Isacson, D.
    Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Aberg, H.
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Oral contraceptives and back pain in women in a Swedish community1997Inngår i: Int J Epidemiol, Vol. 26, s. 71-Artikkel i tidsskrift (Fagfellevurdert)
  • 1694.
    Wulff, M
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi, Strukturkemi.
    Aldén, M
    Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi, Strukturkemi.
    Tegenfeldt, Jörgen
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för materialkemi, Strukturkemi. strukturkemi.
    Solid-state NMR investigation of indomethacin-cyclodextrin complexes in PEG 6000 carrier2002Inngår i: Bioconjugate Chem., Vol. 13, s. 240-Artikkel i tidsskrift (Fagfellevurdert)
  • 1695.
    Xie, Rujia
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pharmacokinetic aspects of the blood-brain barrier transport and equilibration of opioids studied with microdialysis in rats and mice2000Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The blood-brain barrier (BBB) transport and equilibration of opioids with different physico-chemical properties and similar structures - codeine, morphine, morphine3-glucuronide (M3G) and morphine-6-glucuronide (M6G) - were investigated in rats and mice using microdialysis. The influences of active efflux pumps, P-glycoprotein (Pgp) and multidrug resistance protein (MRP1), on the BBB transport of morphine and M3G were studied. Modeling of the BBB transport was performed in NONMEM to estimate the intlux and efflux clearances (CLin and CLout). Simulations were performed on the different possible transport processes at the BBB: passive diffusion, influx hindrance, active efflux, or a combination of influx hindrance and active efflux.

    Codeine was rapidly transported into the brain and quickly reached BBB equilibration with an unbound area under the concentration-time curve (AUC) ratio of brain extracellular fluid (ECF) to blood of 1.0 ± 0.2. The unbound morphine concentration ratio of brain ECF to blood at the end of infusion was 0.5 ± 0.4 in mdrla (+/+) mice and 0.9 ± 0.4 in mdrla (-/-) mice lacking Pgp. The brain ECF-to-blood unbound steady-state concentration ratio of M6G was 0.22± 0.09, while it was 0.10 ± 0.04 for M3G. The ratio for M3G was increased to 0.16 ± 0.05 during co-administration of probenecid, an inhibitor of MRP1. From the modeling analysis, it was shown that CLout of M3G and M6G (1.15 and 2.17 μl/min*g-brain, respectively) were significantly higher than the CLin (0.11 and 0.35 μl/min*g-brain, respectively). These results indicate that the BBB transport of codeine is dominated by passive diffusion, that Pgp contributes to lower the brain concentration of morphine, that MRP1 is involved in the BBB transport of M3G. and that one or both active efflux pumps are active on M6G.

    All studied opioids had similar half-lives in blood (20-24 min). Longer half-lives were found in brain ECF for M6G (58 ± 17 min) and M3G (81 ± 25 min). Codeine's half-life was similar to that in blood (brain 24 ± 5 min VS. blood 26 ± 3 min. Together with the need for two compartments in the modeling to describe the concentration-time profiles in the brain for M3G and M6G, this indicates that the redistribution within the brain is the rate-limiting step for the elimination of M3G and M6G from the. brain, not the BBB transport itself.

    Simulations showed that influx hindrance is mom efficient in restraining the drug transport into the brain than active efflux, and it does not affect the half-life in brain. The most powerful mechanism to lower brain concentration is a combination of influx hindrance and active efflux processes, which is the most physiologically plausible process.

  • 1696.
    Yang, Jiaojiao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Alvebratt, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Lu, Xi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Welch, Ken
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Amorphous Magnesium Carbonate Nanoparticles with Strong Stabilizing Capability for Amorphous Ibuprofen2018Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 548, nr 1, s. 515-521Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Formulating active pharmaceutical ingredients (APIs) in the amorphous state can increase their apparent aqueous solubility and dissolution rate and consequently improve their bioavailability. This study demonstrates, for the first time, the ability to stabilize an API in the amorphous state using a solid dispersion of magnesium carbonate nanoparticles within the API. Specifically, high proportions of ibuprofen were able to be stabilized in the amorphous state using as little as 17% wt/wt amorphous magnesium carbonate nanoparticles, and drug release rates 83 times faster than from the crystalline state were achieved. Biocompatibility of the nanoparticles was demonstrated in vitro using human dermal fibroblasts and stability of the nanocomposite formulation was verified with a storage time of six months. The success of this novel formulation provides a promising approach for achieving improved apparent solubility and enhanced bioavailability of drugs.

  • 1697.
    Yang, Jiaojiao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Alvebratt, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Luo, Jun
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Welch, Ken
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Synthesis of amorphous magnesium carbonate nanoparticles for biomedical applications2017Inngår i: Bioceramics 29 ISCM 2017, 2017Konferansepaper (Fagfellevurdert)
  • 1698.
    Yang, Jiaojiao
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Alvebratt, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Zhang, Peng
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Zardán Gómez de la Torre, Teresa
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Strömme, Maria
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Welch, Ken
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Nanoteknologi och funktionella material.
    Enhanced release of poorly water-soluble drugs from synergy between mesoporous magnesium carbonate and polymers2017Inngår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 525, nr 1, s. 183-190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The need to combat poor water solubility has increased interest in supersaturating drug delivery systems. In this study, amorphous mesoporous magnesium carbonate (MMC) was used as a drug carrier to achieve supersaturation of tolfenamic acid and rimonabant, two drug compounds with low aqueous solubility. The potential synergy between MMC and hydroxypropyl methylcellulose (HPMC), a polymer commonly included as a precipitation inhibitor in drug delivery systems, was explored with the aim of extending the time that high supersaturation levels were maintained. Release was studied under physiological conditions using USP-2 dissolution baths. A new small-scale method was developed to enable measurement of the initial drug release occurring when the MMC is immersed in the water phase. It was shown that MMC and HPMC together resulted in significant supersaturation and that the polymer enabled both the achievement of a higher API concentration and extension of the supersaturation period. The new small-scale release method showed that the release was linearly increasing with the dose and that similar release rates were observed for the two model compounds. It was hence concluded that the MMC release was diffusion limited for the compounds explored.

  • 1699.
    Yang, Jing
    et al.
    Southern Univ Sci & Technol SUSTech, Dept Chem, Shenzhen 518055, Peoples R China;Southern Univ Sci & Technol SUSTech, Shenzhen Grubbs Inst, Shenzhen 518055, Peoples R China.
    An, Junxue
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Tong, Lianpeng
    Guangzhou Univ, Dept Chem & Chem Engn, Guangzhou 510006, Guangdong, Peoples R China.
    Long, Baihua
    Southern Univ Sci & Technol SUSTech, Dept Chem, Shenzhen 518055, Peoples R China;Southern Univ Sci & Technol SUSTech, Shenzhen Grubbs Inst, Shenzhen 518055, Peoples R China.
    Fan, Ting
    South China Univ Technol, Sch Chem & Chem Engn, Guangzhou 510641, Guangdong, Peoples R China.
    Duan, Lele
    Southern Univ Sci & Technol SUSTech, Dept Chem, Shenzhen 518055, Peoples R China;Southern Univ Sci & Technol SUSTech, Shenzhen Grubbs Inst, Shenzhen 518055, Peoples R China.
    Sulfur Coordination Effects on the Stability and Activity of a Ruthenium-Based Water Oxidation Catalyst2019Inngår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 58, nr 5, s. 3137-3144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Water oxidation is regarded as the bottleneck of the water splitting and the development of water oxidation catalysts is of importance in the view of reducing reaction barriers and promoting water oxidation efficiency. Recently, the Sun group has disclosed a family of highly active water oxidation catalysts, [Ru(bda)(L)(2)] (bda(2) = 2,2'-bipyridine-6,6'-dicarboxylate; L = N-containing ligands). Herein, we replaced the bda(2) ligand with a 2,2'-bipyridine-6,6'-dicarbothioate (bct(2)) ligand and prepared a mononuclear ruthenium complex [Ru(bct)(pic)(2)] (Ru-bct, pic = 4-picoline). Less equatorial ligand distortion is observed for Ru-II-bct which displays improved stability than Ru-II-bda. The Ru-bct complex undergoes chemicalstructural evolution during electrochemical and chemical oxidation, generating Ru-bda as the intrinsic active species to afford water oxidation. This study provides an example to understand structurestabilityreactivity relationship of molecular water oxidation catalysts.

  • 1700. Yasar, U
    et al.
    Annas, A
    Svensson, J-O
    Lazorova, L
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Artursson, P
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Al-Shurbaji, A
    Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein.2005Inngår i: Xenobiotica, ISSN 0049-8254, Vol. 35, nr 8, s. 785-96Artikkel i tidsskrift (Fagfellevurdert)
3132333435 1651 - 1700 of 1718
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