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  • 151.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yazdanian, Mehran
    Teva Branded Pharmaceut R&D Inc, Dept Pharmaceut, W Chester, PA USA..
    Lipophilicity in Drug Development: Too Much or Not Enough?2016In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 18, no 5, p. 1095-1100Article in journal (Refereed)
    Abstract [en]

    A round table discussion was held during the AAPS Annual Meeting on October 27, 2015, with the somewhat provocative topic of whether we need more or less lipophilic compounds in drug development. The session was attended by more than 250 participants, and the feedback was very positive as this round table became a forum for the exchange of ideas from scientists within the academia and industry. Most importantly, the discussion highlighted the difference in approaches to compound selection and development strategies in various companies and organizations. As moderators of this session, we are writing this report to highlight the points and counterpoints made at the session and to bring the importance of the dialogue and debate to the forefront of discussions on how to select the best drug development candidates to enable efficient delivery and, hence, treatment of diseases.

  • 152.
    Bergström, Christel A.S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Avdeef, Alex
    In ADME Res, 1732 First Ave,102, New York, NY 10128 USA.
    Perspectives in solubility measurement and interpretation2019In: ADMET AND DMPK, ISSN 1848-7718, Vol. 7, no 2, p. 88-105Article, review/survey (Refereed)
    Abstract [en]

    Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equation and possible interpretations for these distortions are provided. The scope is not exhaustive; rather it is focused on detailed descriptions of a few cases. Topics discussed are limitations of kinetic solubility, 'brick-dust and grease-balls,' applications of simulated and human intestinal fluids, supersaturation and the relevance of pre-nucleation clusters and sub-micellar aggregates in the formation of solids, drug-buffer/excipient complexation, hydrotropic solubilization, acid-base 'supersolubilization,' cocrystal route to supersaturation, as well as data quality assessment and solubility prediction. The goal is to highlight principles of solution equilibria - graphically more than mathematically - that could invite better assay design, to result in improved quality of measurements, and to impart a deeper understanding of the underlying solution chemistry in suspensions of drug solids. The value of solid state characterizations is stressed but not covered explicitly in this mini-review.

  • 153. Bergström, Christel A.S.
    et al.
    Wassvik, Carola M.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Luthman, Kristina
    Artursson, Per
    Global and Local Computational Models for Aqueous Solubility Prediction of Drug-Like Molecules2004In: Journal of Chemical Information and Computer Sciences, Vol. 44, no 4, p. 1477-1488Article in journal (Refereed)
  • 154.
    Bergström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Box, Karl
    PION Inc, Forest Row Business Pk, Forest Row RH18 5DW, E Sussex, England.
    Holm, Rene
    Johnson & Johnson, Janssen R&D, Drug Prod Dev, Turnhoutseweg 30, B-2340 Beerse, Belgium.
    Matthews, Wayne
    GlaxoSmith Kline Med Res Ctr, Dept Prod Dev, 2G118,Gunnels Wood Rd, Stevenage, Herts, England.
    McAllister, Mark
    Pfizer Ltd, Pharmaceut Sci, Drug Prod Design, Sandwich CT13 9NJ, Kent, England.
    Mullertz, Anette
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Rades, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Schäfer, Kerstin J.
    Boehringer Ingelheim Pharma GmBH & Co KG, Pharmaceut Dev, Birkendorfer Str 65, D-88397 Biberach, Germany.
    Teleki, Alexandra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Biorelevant intrinsic dissolution profiling in early drug development: Fundamental, methodological, and industrial aspects2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 139, p. 101-114Article, review/survey (Refereed)
    Abstract [en]

    Intrinsic dissolution rate (IDR) is the surface specific dissolution rate of a drug. In early drug development, this property (among other parameters) is measured in order to compare different polymorphs and salt forms, guide formulation decisions, and to provide a quality marker of the active pharmaceutical ingredient (API) during production. In this review, an update on different methods and small-scale techniques that have recently evolved for determination of IDR is provided. The importance of biorelevant media and the hydrodynamic conditions of dissolution are also discussed. Different preparation techniques for samples are presented with a focus on disc, particle- and crystal-based methods. A number of small-scale techniques are then described in detail, and their applicability domains are identified. Finally, an updated industrial perspective is provided about IDR's place in the early drug development process.

  • 155.
    Bergström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haeberlein, Markus
    AstraZeneca R&D Södertälje.
    Norinder, Ulf
    AstraZeneca R&D Södertälje.
    Computational absorption prediction2008In: Drug bioavailability: Estimation of solubility, permeability, absorption and bioavailability / [ed] Han van de Waterbeemd, Bernard Testa, Wernheim: Wiley-VCH , 2008, 2., completely revised edition, p. 409-432Chapter in book (Other academic)
  • 156.
    Bergström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wassvik, Carola M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, Kajsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hubatsch, Ina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Poorly soluble marketed drugs display solvation limited solubility2007In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 23, p. 5858-5862Article in journal (Refereed)
    Abstract [en]

    We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 μM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.

  • 157.
    Bergström, L. Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bending elasticity of charged surfactant layers: the effect of mixing2006In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 22, no 16, p. 6796-6813Article in journal (Refereed)
    Abstract [en]

    Expressions have been derived from which the spontaneous curvature (H-0), bending rigidity (k(c)), and saddle-splay constant ((k) over bar (c)) of mixed monolayers and bilayers may be calculated from molecular and solution properties as well as experimentally available quantities such as the macroscopic hydrophobic-hydrophilic interfacial tension. Three different cases of binary surfactant mixtures have been treated in detail: (i) mixtures of an ionic and a nonionic surfactant, (ii) mixtures of two oppositely charged surfactants, and (iii) mixtures of two ionic surfactants with identical headgroups but different tail volumes. It is demonstrated that k(c)H(0), k(c), and (k) over bar (c) for mixtures of surfactants with flexible tails may be subdivided into one contribution that is due to bending properties of an infinitely thin surface as calculated from the Poisson-Boltzmann mean field theory and one contribution appearing as a result of the surfactant film having a finite thickness with the surface of charge located somewhat outside the hydrophobic-hydrophilic interface. As a matter of fact, the picture becomes completely different as finite layer thickness effects are taken into account, and as a result, the spontaneous curvature is extensively lowered whereas the bending rigidity is raised. Furthermore, an additional contribution to k(c) is present for surfactant mixtures but is absent for k(c)H(0) and (k) over bar (c). This contribution appears as a consequence of the minimization of the free energy with respect to the composition of a surfactant layer that is open in the thermodynamic sense and must always be negative (i.e., k(c) is generally found to be brought down by the process of mixing two or more surfactants). The magnitude of the reduction of kc increases with increasing asymmetry between two surfactants with respect to headgroup charge number and tail volume. As a consequence, the bending rigidity assumes the lowest values for layers formed in mixtures of two oppositely charged surfactants, and k(c) is further reduced in anionic/cationic surfactant mixtures where the surfactant in excess has the smaller tail volume. Likewise, the reduction of kc is enhanced in mixtures of an ionic and a nonionic surfactant where the ionic surfactant has the smaller tail. The effective bilayer bending constant (k(bi)) is also found to be reduced by mixing, and as a result, k(bi) is seen to go through a minimum at some intermediate composition. The reduction of k(bi) is expected to be most pronounced in mixtures of two oppositely charged surfactants where the surfactant in excess has the smaller tail in agreement with experimental observations.

  • 158.
    Bergström, L. Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bending energetics of tablet-shaped micelles: A novel approach to rationalize micellar systems2007In: ChemPhysChem, ISSN 1439-4235, E-ISSN 1439-7641, Vol. 8, no 3, p. 462-472Article in journal (Refereed)
    Abstract [en]

    A novel approach to rationalize micellar systems is expounded in which the structural behaviour of tablet-shaped micelles is theoretically investigated as a function of the three bending elasticity constants: spontaneous curvature (H-0), bending rigidity (k(c)), and saddle-splay constant (k(c)). As a result, experimentally accessible micellar properties, such as aggregation number, length-to-width ratio, and polydispersity, may be relation to the different bending elasticity constants. Is it demonstrated that discrete micelles or connected cylinders form when H-0 > 1/4 xi where xi is the thickness of a surfacant monolayer, whereas various bilayer structures are expected to predominate when H-0 > 1/4 xi. Our theory predicts, in agreement with experiments, a transition from discrete globular (tablet-shaped) micelles to a phase of ordered, or disordered, connected cylinders above a critital surfactant concentration. Moreover, a novel explanation for the mechanism of growth, from small globular to long rodlike or wormlike micelles, follows as a consequence from the theory. In accordance, polydiperse elongated micelles (large length-to-width ratio) for as the bending rigidity is lowered, approaching the critical point at k(c) - 0, whereas monodisperse globular micelles (small length-to-width ratio) are expected to be present at larg k(c) values. The spontaneous curvature mainly determines the width of tablet-shaped or ribbonlike micelles, or the radius of dislike micelles, whereas the saddle-splay constant primarily influences the size but not the shape of the micelles.

  • 159.
    Bergström, L. Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Influence of bending energetics on the size, shape and polydispersity of droplet microemulsions2008In: Colloids and Surfaces A: Physicochemical and Engineering Aspects, ISSN 0927-7757, E-ISSN 1873-4359, Vol. 316, no 1-3, p. 15-26Article in journal (Refereed)
    Abstract [en]

    A theory for ellipsoidal shape fluctuating droplet microemulsions in the presence of excess discrete phase (Winsor I and II) is expounded that combines bending energetics of the amphiphilic monolayer at the droplet interface with thermodynamics of self-assembling solute and amphiphilic molecules. The theory relates the three bending elasticity constants spontaneous curvature (H-0), bending rigidity (k(c)) and saddle-splay constant (k(c)) with interfacial tension, average size and shape and polydispersity of microemulsion droplets. It is demonstrated that the well-known conventional relations become modified as the entropy of self-assembling amphiphilic as well as solute molecules are taken into account, in particular at low values of the effective bending constant 2k(c) + (k) over bar (c). As a result, the average droplet radius (R) as well as the droplet polydispersity sigma(R)/< R > behave consistently in the limit 2k(c) + (k) over bar (c) -> 0 whereas the conventional expressions are recovered in the limit 2k(c) + (k) over bar (c) -> infinity. It is demonstrated that association entropy effects may be quantified by a parameter k(s) with same dimension and order of magnitude as k(c) and (k) over bar (c). k(s) is found to be always negative and tends to decrease (R) and to increase sigma(R)/< R. Moreover, the average axial ratio of an oblate/prolate fluctuating droplet is found to be a strong function of the bending rigidity (the droplets become increasingly non-spherical with decreasing k(c)) but is independent of (k) over bar (c), in contrast to previous investigations where association entropy effects were neglected.

  • 160.
    Bergström, L. Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Second CMC in surfactant micellar systems2016In: Current Opinion in Colloid & Interface Science, ISSN 1359-0294, E-ISSN 1879-0399, Vol. 22, p. 46-50Article, review/survey (Refereed)
    Abstract [en]

    Experimental reports of surfactant systems displaying a second critical micelle concentration (second CMC) have been surveyed. It turns out that surfactant micelles usually show a growth behavior with some typical features. (i) Micelles grow weakly at low surfactant concentrations but may switch to a much stronger growth behavior at higher concentrations. The second CMC is defined as the point of transition from wealdy to strongly growing micelles. (ii) Micelles are found to be non-spherically shaped below the second CMC. (iii) At the second CMC micelles are found to be much smaller, with aggregation numbers typically 100-200, than expected for flexible micelles. (iv) Micelles of intermediate size are present in a narrow concentration regime close to the second CMC. (v) Micelles grow much stronger above the second CMC than expected from a sphere-to-rod transition. The conventional spherocylindrical micelle model predicts a smooth growth behavior that contradicts the appearance of a second CMC. Modifying the model by means of including swollen end caps neither account for the presence of micelles with intermediate size, nor the strong growth behavior above the second CMC. Taking into account micelle flexibility is not consistent with the rather low micelle aggregation numbers observed at the second CMC. On the other hand, a recently proposed alternative theoretical approach, the general micelle model, have been demonstrated to take into account basically all features that are typical of experimentally observed micellar growth behaviors.

  • 161. Bergström, L Magnus
    et al.
    Bramer, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Synergistic effects in mixtures of oppositely charged surfactants as calculated from the Poisson-Boltzmann theory: A comparison between theoretical predictions and experiments2008In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 322, no 2, p. 589-595Article in journal (Refereed)
    Abstract [en]

    Critical micelle concentrations in mixtures of an anionic surfactant and a cationic amphiphilic drug have been investigated using a model-independent procedure to quantify observed synergistic effects. Experimental results were compared with a theory based on the Poisson-Boltzmann mean field approximation of a charged interface with a diffuse layer of counterions. Explicit expressions for the activity coefficients from which the critical micelle concentration can be calculated and quantitatively predicted have been derived and excellent agreement between experimental data and theory was obtained. As a result, we demonstrate that it is possible to rationalize and predict the magnitude of synergism in mixtures of oppositely charged surfactants in the presence of added salt.

  • 162.
    Bergström, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Bastardo, LA
    Garamus, VM
    A small-angle neutron scattering study of micelles formed in aqueous mixtures of a nonionic alkylglucoside and an anionic surfactant.2005In: J Phys Chem B, Vol. 109, p. 12387-Article in journal (Refereed)
  • 163.
    Bergström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A theoretical investigation of the influence of the second critical micelle concentration on the solubilization capacity of surfactant micelles2018In: AIP Advances, ISSN 2158-3226, E-ISSN 2158-3226, Vol. 8, no 5, article id 055136Article in journal (Refereed)
    Abstract [en]

    The solubilization of hydrophobic components by surfactants that form microemulsion droplets has been investigated from a theoretical point of view. By means of combining thermodynamics of self-assembly to form small systems with bending elasticity theory, we have been able to demonstrate a strong correlation between the second critical micelle concentration (CMC2) of surfactant micelles and their solubilization capacity (sigma). The correlation may be rationalized as a consequence of all three bending elasticity constants spontaneous curvature (H-0), bending rigidity (k(c)) and saddle-splay constant ((k) over bar (c)) showing similar trends with respect to the two quantities, i.e. sigma increases and CMC2 decreases with decreasing values of k(c)H(0) and increasing values of k(c) and (k) over bar (c), respectively. As a result, we demonstrate that the solubilization capacity is predicted to always be higher for a gemini surfactant with CMC2 = 11 mM as compared with a gemini surfactant with CMC2 = 18 mM. The predicted correlation between solubilization capacity and CMC2 agrees with experimental observations showing that surfactants forming larger micelles in general have better solubilization capacity than surfactants forming smaller micelles. The theory also demonstrates, in agreement with experiments, that sigma is raised in the entire range of surfactant concentrations, below as well as aboveCMC(2), regardless of micelle size. Consequently, our theory predicts that small micelles formed below CMC2 increase in size, whereas large rodlike or wormlike micelles formed above CMC2 decrease in size, as a hydrophobic solubilizate is added to a micellar solution.

  • 164.
    Bergström, Magnus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Bending elasticity of charged surfactant layers: the effect of layer thickness.2006In: Langmuir, ISSN 0743-7463, Vol. 22, no 8, p. 3678-91Article in journal (Refereed)
  • 165.
    Bergström, Magnus
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Model calculations of the spontaneous curvature, mean and Gaussian bending constants for a thermodynamically open surfactant film.2006In: J Colloid Interface Sci, ISSN 0021-9797, Vol. 293, no 1, p. 181-93Article in journal (Refereed)
  • 166.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, PET Ctr, Uppsala, Sweden..
    The Use of Microdosing in the Development of Small Organic and Protein Therapeutics2017In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 58, no 8, p. 1188-1195Article in journal (Refereed)
    Abstract [en]

    Microdosing as a regulatory concept was introduced to facilitate exploratory studies in humans. The concept involves the use of very low doses of a radionuclide-labeled compound for imaging studies or for assessing plasma pharmacokinetics using equipment that has a highly sensitive readout. The supporting principle is that use of these low doses for a limited time in well-controlled, small populations will limit exposure and have a low risk of adverse effects. Microdosing regulations specify a reduced preclinical toxicology-assessment package in order to shorten the route to human studies and reduce its cost. However, for extrapolation to therapeutically relevant doses and plasma concentrations, there are specific aspects of the use of these low doses and low plasma concentrations that require special attention. These specific aspects are reviewed in this article, with separate attention being paid to small organic molecules and protein therapeutics. The indications for microdosing in drug development are discussed in terms of the 3 pillars of survival in drug development, the first of which is characterization of tissue distribution and access to the site of action; the second, engagement of the target; and the third, induction of tissue responses relevant to a therapeutic response.

  • 167. Berthelsen, Ragna
    et al.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jacobsen, Jette
    Kristensen, Jakob
    Holm, Rene
    Abrahamsson, Bertil
    Mullertz, Anette
    Combining in vitro and in silico methods for better prediction of surfactant effects on the absorption of poorly water soluble drugs-a fenofibrate case example2014In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 473, no 1-2, p. 356-365Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to develop a sensitive and discriminative in vitro-in silico model able to simulate the in vivo performance of three fenofibrate immediate release formulations containing different surfactants. In addition, the study was designed to investigate the effect of dissolution volume when predicting the oral bioavailability of the formulations. In vitro dissolution studies were carried out using the USP apparatus 2 or a mini paddle assembly, containing 1000 mL or 100 mL fasted state biorelevant medium, respectively. In silico simulations of small intestinal absorption were performed using the GI-Sim absorption model. All simulation runs were performed twice adopting either a total small intestinal volume of 533 mL or 105 mL, in order to examine the implication of free luminal water volumes for the in silico predictions. For the tested formulations, the use of a small biorelevant dissolution volume was critical for in vitro-in silico prediction of drug absorption. Good predictions, demonstrating rank order in vivo-in vitro-in silico correlations for C-max, were obtained with in silico predictions utilizing a 105 mL estimate for the human intestinal water content combined with solubility and dissolution data performed in a mini paddle apparatus with 100 mL fasted state simulated media.

  • 168.
    Bingefors, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Compliance vid schizofrenibehandling. 2003In: Rapport 2:a 3P-mötet, Pfizer Psychiatrica Praevernalis.Other (Other scientific)
  • 169.
    Bingefors, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Depression och hög konsumtion av läkemedel går hand i hand2001In: Läkartidningen, Vol. 98, p. 4329-Article in journal (Other scientific)
  • 170.
    Bingefors, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Patient treatment concordance in schizophrenia.2002In: Eur Psychiatry, Vol. 17Article, book review (Other scientific)
  • 171.
    Bingefors, K
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Smärtan är ojämlik2004In: Primärvårdens nyheter, no 9Article in journal (Other scientific)
  • 172.
    Bingefors, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lindstrom, E
    Faculty of Medicine, Department of Neuroscience.
    Dosage patterns of antipsychotic drugs for the treatment of schizophrenia in Swedish ambulatory clinical practice - a highly individualized therapy.2003In: Nord J Psychiatry, Vol. 57, p. 263-Article in journal (Refereed)
  • 173.
    Bingefors, K
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lindberg, M
    Isacson, D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Self-reported dermatological problems and use of prescribed topical drugs correlate with decreased quality of life: an epidemiological survey2002In: Br J Dermatology, Vol. 147, p. 285-Article in journal (Refereed)
  • 174.
    Bingefors, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Comparing countries in population studies - is it possible?2008In: International research in healthcare / [ed] Felicity Smith, Sally-Anne Francis and Ellen Schafheutle, London: Pharmaceutical Press , 2008, 1Chapter in book (Other academic)
  • 175.
    Bingefors, Kerstin
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Den sköra människan. Depression och långtidssjuklighet2000In: Den sköra människan - socialtjänsten och vuxenpsykiatrin, Socialvetenskapliga forskningsrådet , 2000Chapter in book (Other scientific)
  • 176.
    Bingefors, Kerstin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Ekselius, L
    Faculty of Medicine, Department of Neuroscience.
    von Knorring, L
    Faculty of Medicine, Department of Neuroscience.
    Long-term course, comorbidity and long-term outcome in depressive disorders.2001In: In: Leonard BE (Ed) Antidepressants., Birkhäuser, Basel , 2001Chapter in book (Other scientific)
  • 177.
    Bingefors, Kerstin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Concomitant prescribing of tranquillizers and hypnotics among patients receiving antidepressant prescriptions.1998In: Ann Pharmacotheraphy, Vol. 32, p. 531-Article in journal (Refereed)
  • 178.
    Bingefors, Kerstin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Continued use of antidepressants among patients in ambulatory care1996In: Nordic Journal of Psychiatry, Vol. 50, p. 217-Article in journal (Refereed)
  • 179.
    Bingefors, Kerstin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Epidemiology, co-morbidity, and impact on health-related quality of life of self-reported headache and musculoskeletal pain - a gender perspective.2004In: Eur J Pain, ISSN 1090-3801, Vol. 8, no 5, p. 435-50Article in journal (Other scientific)
  • 180.
    Bingefors, Kerstin
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    von Knorring, L
    Faculty of Medicine, Department of Neuroscience.
    Antidepressant dose patterns in Swedish clinical practice.1997In: International Clinical Psychopharmacology, Vol. 12, p. 283-Article in journal (Refereed)
  • 181.
    Bingefors, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Smedby, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Ekselius, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Kupper, Lawrence L.
    Antidepressant-treated patients in ambulatory care long-term use of non-psychotropic and psychotropic drugs1996In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 168, no 3, p. 292-98Article in journal (Refereed)
    Abstract [en]

    Abstract

    Background. Despite the problems involved in treating depression and concomitant medical disease, there are virtually no longitudinal studies on drug utilisation among depressed patients.

    Method

    Use of prescription drugs among all first-time users of antidepressants in a defined population five years before and six years after the index (first) treatment was compared to a referent group without antidepressant treatment. The generalised estimating equations (GEE) method was used for analysis.

    Results

    The antidepressant-treated group used considerably more non-psychotropic drugs during the whole study period than the referent group. They also used more psychotropic drugs, a use which increased in connection with the initiation of antidepressant treatment, and stayed high for a further five years.

    Conclusions

    The high use of prescription drugs indicated widespread somatic and psychiatric health problems during the whole study period. Antidepressant-treated patients are at risk for drug interactions and adverse effects, and would benefit from a closer collaboration between psychiatry and medicine.

  • 182.
    Bingefors, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Isacson, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Smedby, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Wicknertz, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Antidepressant-treated patients in ambulatory care: Mortality during a nine-year period after first treatment1996In: British Journal of Psychiatry, ISSN 0007-1250, E-ISSN 1472-1465, Vol. 169, no 5, p. 647-54Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Non-institutionalised patients treated with antidepressants have been shown to have indicators of a generalised vulnerability, such as high rates of health service use and excessive prescription drug use. Therefore, mortality in this patient group is of interest.

    METHOD

    All first-incidence antidepressant users in a defined population during a five-year period were identified. Their total mortality during a nine-year follow-up was analysed. Cox proportional hazards regression was used to analyse total mortality, and mortality in cardiovascular disease, controlling for baseline chronic medical disease.

    RESULTS

    Antidepressant treatment at the index date was a statistically significant predictor for increased long-term mortality in the over-65s, even when controlling for pre-existing chronic medical disease. Baseline ischaemic heart disease and concurrent antidepressant treatment significantly predicted mortality from cardiovascular causes.

    CONCLUSION

    Prescribed antidepressant treatment identifies patients who are at risk of increased mortality. For the physician in ambulatory care, knowledge of a patient's antidepressant treatment history may be a valuable tool in managing patient care.

  • 183.
    Bingefors, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lindberg, Magnus
    Isacson, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quality of Life, Use of Topical Medications and Socio-economic Data in Hand Eczema: A Swedish Nationwide Survey2011In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 91, no 4, p. 452-458Article in journal (Refereed)
    Abstract [en]

    Hand eczema is common and has an adverse impact on the lives of patients. There is a need for population-based surveys on the pharmacoepidemiological aspects, quality of life and impact of socioeconomic factors in hand eczema. The aim of this cross-sectional study was to investigate these factors. A questionnaire-based nationwide survey of health was performed, including questions on hand eczema, use of pharmaceuticals and socioeconomic factors. Quality of life was estimated with the generic instrument Short Form 36 (SF-36). The questionnaire was sent to 7,985 persons (age range 18-84 years), response rate 61.1% (n=4,875). The 1-year prevalence of hand eczema in the study population was 7.5%. In this group, quality of life was lower. All dimensions of SF-36 were affected, most markedly general health and those dimensions reporting on mental health. In the group with self-reported hand eczema, 51% reported using topical pharmaceuticals. Hand eczema was more common among women (9.1%, n=2,630) than among men (5.6%, n=2,245) and in the age group below 65 years (8.5%, n=3,274) compared with those aged 65 years and over (4.3%, n=1,151). This survey clearly demonstrates the impact of hand eczema on several dimensions of life and also highlights age, gender and socioeconomic differences.

  • 184.
    Bingefors, Kerstin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Åke
    Isacson, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lindberg, Magnus
    Self-reported Lifetime Prevalence of Atopic Dermatitis and Co-morbidity with Asthma and Eczema in Adulthood: A Population-based Cross-sectional Survey2013In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 93, no 4, p. 438-441Article in journal (Refereed)
    Abstract [en]

    Atopic dermatitis and its co-morbidity with asthma and allergy is well described in younger age groups. However, population-based studies on adults with atopic dermatitis in childhood are sparse. The aims of this study were to determine: (i) the prevalence of self-reported childhood atopic dermatitis in the population; and (ii) its association with present self-reported hand eczema, eczema, allergy, urticaria and asthma. A questionnaire was sent to a cross-sectional random sample of the Swedish population (n = 7,985), age range 18-84 years (response rate 61.1%). The questionnaire included the question "Have you had childhood eczema?" and questions on 5 other medical problems (hand eczema, other eczema, asthma, urticaria and allergy). Persons reporting eczema in childhood reported increased odds ratios (OR) for hand eczema (4.01), other eczema (3.88), urticaria (2.50), allergy (2.98), and asthma (2.06) as adults. The combination of eczema, allergy and asthma had an OR of 14.10 (95% confidence interval 8.44-23.54). Adults in the age range 18-84 years reporting childhood atopic dermatitis still have high co-morbidity with eczema, asthma, urticaria and allergy.

  • 185.
    Bjerre, C
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Bjork, E
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Camber, O
    Bioavailability of the sedative propiomazine after nasal administration in rats1996In: INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol. 144, p. 217-Article in journal (Refereed)
  • 186.
    BJORK, E
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    ISAKSSON, U
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    EDMAN, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    ARTURSSON, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    STARCH MICROSPHERES INDUCE PULSATILE DELIVERY OF DRUGS AND PEPTIDES ACROSS THE EPITHELIAL BARRIER BY REVERSIBLE SEPARATION OF THE TIGHT JUNCTIONS1995In: JOURNAL OF DRUG TARGETING, Vol. 2, p. 501-Article in journal (Refereed)
  • 187.
    Boge, Lukas
    et al.
    RISE Res Inst Sweden, S-50115 Boras, Sweden;Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Browning, Kathryn L.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Campana, Mario
    Rutherford Appleton Lab, Didcot OX11 0DE, Oxon, England.
    Darngaard, Liv S. E.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Caous, Josefin Seth
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Hellsing, Maja
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Ringstad, Lovisa
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Andersson, Martin
    Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coil2019In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, no 24, p. 21314-21322Article in journal (Refereed)
    Abstract [en]

    Dispersions of cubic liquid crystalline phases, also known as cubosomes, have shown great promise as delivery vehicles for a wide range of medicines. Due to their ordered structure, comprising alternating hydrophilic and hydrophobic domains, cubosomes possess unique delivery properties and compatibility with both water-soluble and-insoluble drugs. However, the drug delivery mechanism and cubosome interaction with human cells and bacteria are still poorly understood. Herein, we reveal how cubosomes loaded with the human cathelicidin antimicrobial peptide LL-37, a system with high bacteria-killing effect, interact with the bacterial membrane and provide new insights into the eradication mechanism. Combining the advanced experimental techniques neutron reflectivity and quartz crystal microbalance with dissipation monitoring, a mechanistic drug delivery model for LL-37-loaded cubosomes on bacterial mimicking bilayers was constructed. Moreover, the cubosome interaction with Escherichia coli was directly visualized using super-resolution laser scanning microscopy and cryogenic electron tomography. We could conclude that cubosomes loaded with LL-37 adsorbed and distorted bacterial membranes, providing evidence that the peptide-loaded cubosomes function as an antimicrobial unit.

  • 188. Bonlokke, L
    et al.
    Christensen, FN
    Knutson, L
    Kristensen, HG
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    A new approach for direct in vivo dissolution studies of poorly soluble drugs1997In: PHARMACEUTICAL RESEARCH, Vol. 14, p. 1490-Article in journal (Refereed)
  • 189. Bonlokke, L
    et al.
    Hovgaard, L
    Kristensen, HG
    Knutson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Lennernas, H
    Faculty of Pharmacy, Department of Pharmacy.
    Direct estimation of the in vivo dissolution of spironolactone, in twoparticle size ranges, using the single-pass perfusion technique(Loc-I-Gut) in humans.2001In: Eur J Pharm Sci, Vol. 12, p. 239-Article in journal (Refereed)
  • 190. Bonlokke, L
    et al.
    Hovgaard, L
    Kristensen, HG
    Knutson, L
    Lindahl, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lennernas, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    A comparison between direct determination of in vivo dissolution and the deconvolution technique in humans1999In: Eur J Pharm Sci, Vol. 8, p. 19-Article in journal (Refereed)
  • 191. Borde, A. S.
    et al.
    Karlsson, E. M.
    Andersson, K.
    Bjorhall, K.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, B.
    Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids2012In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 80, no 3, p. 630-637Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine the stability of three ester prodrugs, chloramphenicol succinate, enalapril and candesartan cilexetil, in human proximal small intestinal fluid (HIF), dog proximal small intestinal fluids (DIF) and simulated intestinal fluid (FaSSIF), with the addition of pancreatin. The total protein content in the proximal jejuna] fluids was determined in HIF and DIF, respectively. Candesartan cilexetil was significantly degraded in HIF (initial t(1/2(0-5min)) 5.4 +/- 0.5 min) and in DIF (initial t(1/2(0-5min))) = 5.7 +/- 0.1 min), while chloramphenicol succinate and enalapril were stable in both media. The degradation of candesartan cilexetil was shown to be mediated by enzymes following Michaelis-Menten enzyme kinetics and was inhibited by addition of esterase inhibitors. The enzymatic capacity reflected by V-max was 4-fold higher in DIF than in HIF and correlated to its 2-fold higher protein concentration. The degradation of candesartan cilexetil in the FaSSIF-pancreatin solution was slower (t(1/2) = 207 +/- 34 min) than the degradation in both HIF and DIF. Changing the pH to the enzyme optima or increasing the amount of pancreatin, increased the degradation rate of candesartan cilexetil, but not in the magnitude as in HIF. As a result, two in vitro models, based on in vivo intestinal fluids, were developed using candesartan cilexetil as a model drug. The DIF seems to be a reasonably good model for HIF, although the degradation capacity seems to be somewhat higher, possibly due to the higher enzyme concentration in DIF. Future investigations will develop novel enzymatic based in vitro models for rapid assessment and biopharmaceutical screening tools for prodrugs.

  • 192.
    Borhade, Sanjay R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Arvidsson, Per I.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties2015In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 10, no 3, p. 455-460Article in journal (Refereed)
    Abstract [en]

    Herein we present the preclinical characterization of novel compounds containing the linear acyl sulfonimidamide functionality. Specifically, we studied the pK(a), lipophilicity, in vitro metabolic stability, plasma protein binding, Caco-2 permeability, and aqueous solubility for nine aryl acyl sulfonimidamides. In comparison with widely used carboxylic acid bioisosteres, the acyl sulfonimidamides were found to be less acidic and more lipophilic depending on the substitution pattern in the studied compounds. Importantly, the pKa values (5.9-7.6) were significantly influenced by substituents on the nitrogen atom and the aryl substituents. Moreover, the acyl sulfonimidamides displayed membrane permeabilities ranging from moderate to very high, which correlated with decreased pKa and low to negligible efflux ratios. We foresee that the chiral sulfur center and the two handles for structural diversity of linear acyl sulfonimidamides will offer new opportunities for drug design and for improving the oral bioavailability of acidic drug candidates.

  • 193. Borissova, R
    et al.
    Lammek, B
    Stjarnkvist, P
    Sjoholm, I
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Biodegradable microspheres. 16. Synthesis of primaquine-peptide spacers for lysosomal release from starch microparticles.1995In: J Pharm Sci, Vol. 84, p. 249-Article in journal (Refereed)
  • 194. Borissova, R
    et al.
    Stjarnkvist, P
    Karlsson, MO
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sjoholm, I
    Department of Pharmacy.
    Biodegradable microspheres. 17. Lysosomal degradation of primaquine-peptide spacer arms.1995In: J Pharm Sci, Vol. 84, p. 256-Article in journal (Refereed)
  • 195.
    Borro, Bruno C.
    et al.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Bohr, Adam
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Bucciarelli, Saskia
    Univ Copenhagen, Dept Drug Design & Pharmacol, Jagtvej 162, DK-2100 Copenhagen, Denmark.
    Boetker, Johan P.
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Foged, Camilla
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Rantanen, Jukka
    Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Univ Copenhagen, Dept Pharm, Univ Pk 2, DK-2100 Copenhagen, Denmark.
    Microfluidics-based self-assembly of peptide-loaded microgels: Effect of three dimensional (3D) printed micromixer design2019In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 538, p. 559-568Article in journal (Refereed)
    Abstract [en]

    In an effort to contribute to research in scalable production systems for polymeric delivery systems loaded with antimicrobial peptides (AMPS), we here investigate effects of hydrodynamic flow conditions on microfluidic particle generation. For this purpose, rapid prototyping using 3D printing was applied to prepare micromixers with three different geometric designs, which were used to prepare Ca2+-crosslinked alginate microgels loaded with the AMP polymyxin B in a continuous process. Based on fluid dynamic simulations, the hydrodynamic flow patterns in the micromixers were designed to be either (i) turbulent with chaotic disruption, (ii) laminar with convective mixing, or (iii) convective with microvortex formation. The physicochemical properties of the microgels prepared with these micromixers were characterized by photon correlation spectroscopy, laser-Doppler micro-electrophoresis, smallangle x-ray scattering, and ellipsometry. The particle size and compactness were found to depend on the micromixer geometry: From such studies, particle size and compactness were found to depend on micromixer geometry, the smallest and most compact particles were obtained by preparation involving microvortex flows, while larger and more diffuse microgels were formed upon laminar mixing. Polymyxin B was found to be localized in the particle interior and to cause particle growth with increasing peptide loading. Ca2+-induced cross-linking of alginate, in turn, results in particle contraction. The peptide encapsulation efficiency was found to be higher than 80% for all investigated micromixer designs; the highest encapsulation efficiency observed for the smallest particles generated by microvortexmediated self-assembly. Ellipsometry results for surface-immobilized microgels, as well as results on peptide encapsulation, demonstrated electrolyte-induced peptide release. Taken together, these findings demonstrate that rapid prototyping of microfluidics using 3D-printed micromixers offers promises for continuous manufacturing of AMP-loaded microgels. Although the micromixer combining turbulent flow and microvortexes was demonstrated to be the most efficient, all three micromixer designs were found to mediate self-assembly of small microgels displaying efficient peptide encapsulation. This demonstrates the robustness of employing 3D-printed micromixers for microfluidic assembly of AMP-loaded microgels during continuous production. 

  • 196.
    Bose, Partha Pratim
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Chatterjee, Urmimala
    Hubatsch, Ina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Govender, Thavendran
    Kruger, Hendrik G.
    Bergh, Margareta
    Johansson, Jan
    Arvidsson, Per I.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    In vitro ADMET and physicochemical investigations of poly-N-methylated peptides designed to inhibit Aβ aggregation2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 16, p. 5896-5902Article in journal (Refereed)
    Abstract [en]

    N-Methylation is a common strategy for improving oral bioavailability of peptide-based lead structures. Herein, we present a detailed study on how the degree of N-methylation affects the absorption-distribution-metabolism-excretion-toxicity (ADMET) properties such as solubility, membrane transport, proteolytic stability, and general cell toxicity of the investigated peptides. As representative structures we chose hexapeptides 1-8. These peptides, corresponding to N-methylated analogues of residues 16-21 and 32-37 of the Abeta-peptide, pathological hallmark of Alzheimer's disease (AD), have previously been shown to inhibit aggregation of Abeta fibrils in vitro. This study suggests that poly-N-methylated peptides are non-toxic and have enhanced proteolytic stability over their non-methylated analogues. Furthermore, solubility in aqueous solution is seen to increase with increased degree of N-methylation, while membrane transport was found to be low for all investigated hexapeptides. The present results, together with those reported in the literature, suggest that poly-N-methylated peptides, especially shorter or equal to six residues, can be suitable candidates for drug design.

  • 197. Bouvier d'Yvoire, Michel
    et al.
    Prieto, Pilar
    Blaauboer, Bas
    Bois, Frederic
    Boobis, Alan
    Brochot, Céline
    Coecke, Sandra
    Freidig, Andreas
    Gundert-Remy, Ursula
    Hartung, Thomas
    Jacobs, Miriam
    Lavé, Thierry
    Leahy, David
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Loizou, George
    Meek, Bette
    Pease, Camilla
    Rowland, Malcolm
    Spendiff, Martin
    Yang, Jiansong
    Zeilmaker, Marco
    Physiologically-based Kinetic Modelling (PBK Modelling): Meeting the 3Rs agenda. The report and recommendations of ECVAM Workshop 632007In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 35, no 6, p. 661-671Article in journal (Refereed)
  • 198.
    Bouw, Marcel René
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Microdialysis as a tool in pharmacokinetic-pharmacodynamic studies investigating the brain distribution and effect delay of morphine and morphine-6-glucuronide2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The microdialysis technique was developed as a tool for studying the pharmacokinetic and pharmacodynamicrelationships of morphine and morphine-6-glucronide (M6G). Concentrations of unbound drug in blood andbrain were monitored in order to elucidate the origin of the observed delay in antinociceptive effect in rats.The antinociceptive effect was measured as the response to electrical stimulation of the tail and respiratoryeffects were monitored by measuring the blood gas status. The data analysis was performed in NONMEM andPCNONLIN.

    It was shown that in vitro testing is an essential step in the selection of a candidate drug for in vivomicrodialysis. A comparative study of in vivo calibration methods showed no significant difference betweenthe unbound concentration-time profiles obtained with retrodialysis by drug or by calibrator (nalorphine).The delay in antinociceptive effect of morphine in relation to the blood concentration was estimated to havean equilibration half-life of 32 min, which was considerably shorter than the equilibration half-life of 103 minfor M6G. Remaining effect delays of 5 or 53 mitt, respectively, were observed when the effect was related tothe brain extracellular fluid (ECF) concentrations of morphine and M6G. Unexpectedly, the brain ECF:bloodratio for unbound morphine (0.25 ± 0.13) was comparable with the value for M6G (0,22 ± O.O9), indicating theinvolvement of active mechanisms of transport across the blood-brain barrier (BBB) for both compounds.Significantly longer half-lives for morphine and M6G were observed in brain (43 ± 9 and 58 ± 17 min,respectively) than in blood (31 ± 8 and 23 ± 5 min, respectively), Thus, redistribution in the brain is the ratelimiting step for the elimination of both morphine and M6G out of the brain.

    Clinical microdialysis of morphine showed a similar pattern to that observed in the animal studies, with asignificantly longer half-life in uninjured (73 min) or injured (77 min) brain tissue, than in blood (28 min) andadipose tissue (27 min).

  • 199.
    Boyd, Ben J.
    et al.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic, Australia.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Vinarov, Zahari
    Univ Sofia, Fac Chem & Pharm, Sofia, Bulgaria.
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharma Technol, Basel, Switzerland.
    Brouwers, Joachim
    Univ Leuven, Drug Delivery & Disposit, Leuven, Belgium.
    Augustijns, Patrick
    Univ Leuven, Drug Delivery & Disposit, Leuven, Belgium.
    Brandl, Martin
    Univ Southern Denmark, Dept Phys Chem & Pharm, Odense, Denmark.
    Bernkop-Schnürch, Andreas
    Univ Innsbruck, Inst Pharm, Dept Pharmaceut Technol, Innsbruck, Austria.
    Shrestha, Neha
    Catholic Univ Louvain, Louvain Drug Res Inst, Adv Drug Delivery & Biomat, Brussels, Belgium.
    Preat, Veronique
    Catholic Univ Louvain, Louvain Drug Res Inst, Adv Drug Delivery & Biomat, Brussels, Belgium.
    Müllertz, Anette
    Univ Copenhagen, Physiol Pharmaceut, Copenhagen, Denmark.
    Bauer-Brandl, Annette
    Univ Southern Denmark, Dept Phys Chem & Pharm, Odense, Denmark.
    Jannin, Vincent
    Gattefosse SAS, St Priest, France.
    Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems2019In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 137, article id 104967Article in journal (Refereed)
    Abstract [en]

    Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.

  • 200. Brabant, Georg
    et al.
    Krogh Rasmussen, Ase
    Biller, Beverly M K
    Buchfelder, Michael
    Feldt-Rasmussen, Ulla
    Forssmann, Kristin
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Maiter, Dominique
    Saller, Bernhard
    Toogood, Andy
    Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 7, p. 2604-2609Article in journal (Refereed)
    Abstract [en]

    Context: The diagnosis of GH deficiency (GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication.

    Objectives: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 µg/liter after an insulin tolerance test (ITT) and evaluated its potential physiological role.

    Design, Settings, and Patients: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 µg/liter during ITT as well as documented IGF-I levels.

    Outcomes: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed.

    Results: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides.

    Conclusions: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.

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