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  • 201.
    Almgren, Birgitta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Endotracheal Suction a Reopened Problem2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    During mechanical ventilation, patients are connected to the ventilator by an endotracheal tube. The tube needs to be cleaned from mucus by suction, which can cause negative effects such as lung collapse, hypoxemia and desaturation. These can be avoided by preoxygenation, change of ventilator settings, use of closed suction systems and recruitment manoeuvres. The aim of the study was to investigate the effects of endotracheal suction during different ventilator settings and by different suction methods. A method to reverse side effects was investigated.

    In anaesthetized pigs, the effect of suction during volume and pressure-controlled ventilation was investigated, and the effect of different suction systems and catheter sizes were compared. Suction efficacy was investigated in a bench study. The effect of recruitment manoeuvre added after suction, i.e. post-suction recruitment manoeuvre was evaluated.

    Endotracheal suction causes lung volume loss leading to impaired gas exchange, an effect that is more severe in pressure-controlled ventilation than in volume-controlled ventilation. When 14 French suction catheters were used more side effects were found compared to 12 French catheters, but no difference was found between open and closed suction system in pressure-controlled ventilation. Open suction system was more effective to remove mucus compared to closed system. Post-suction recruitment manoeuvre restored the side effects after the first recruitment when it was applied directly after suction.

    In conclusion, open endotracheal suction causes impairment in gas exchange and lung mechanics, and more so in pressure-controlled than in volume-controlled mode. These changes can be minimized if smaller suction catheters are used. A post-suction recruitment manoeuvre applied directly after suction restores lung function. It is obvious that the recruitment manoeuvre should be added directly after suction, because if the manoeuvre is delayed and the lung is collapsed and left collapsed, it will be more difficult to recruit the lung.

    Delarbeten
    1. Side effects of endotracheal suction in pressure and volume controlled ventilation
    Öppna denna publikation i ny flik eller fönster >>Side effects of endotracheal suction in pressure and volume controlled ventilation
    2004 (Engelska)Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, nr 3, s. 1077-1080Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate the effects of endotracheal suction in volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) with an open suction system (OSS) or a closed suction system (CSS).

    DESIGN:

    Randomized comparison.

    SETTING:

    Animal research laboratory.

    PATIENTS:

    Twelve healthy anesthetized pigs.

    INTERVENTIONS:

    The effects of endotracheal suction during VCV and PCV with tidal volume (VT) of 14 mL/kg were compared. A 60-mm inner-diameter endotracheal tube was used. Ten-second suction was performed using OSS and CSS with 12F and 14F catheters connected to - 14 kPa vacuum.

    MEASUREMENTS AND RESULTS:

    Thirty minutes after suction in PCV, VT was still decreased by 27% (p < 0.001), compliance (Crs) by 28% (p < 0.001), and PaO(2) by 26% (p < 0.001); PaCO(2) was increased by 42% (p < 0.0001) and venous admixture by 158% (p = 0.003). Suction in VCV affected only Crs (decreased by 23%, p < 0.001) and plateau pressure (increased by 24%, p < 0.001). The initial impairment of gas exchange following suction in VCV was no longer statistically significant after 30 min.

    CONCLUSIONS:

    In conclusion, endotracheal suction causes lung collapse leading to impaired gas exchange, an effect that is more severe and persistent in PCV than in VCV.

    Nyckelord
    Animals, Intubation; Intratracheal/*adverse effects, Lung Compliance, Pulmonary Gas Exchange, Respiration; Artificial/*methods, Suction/*adverse effects, Support; Non-U.S. Gov't, Swine, Tidal Volume
    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-92641 (URN)10.1378/chest.125.3.1077 (DOI)15006972 (PubMedID)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    2. Negative tracheal pressure during suction differs between suction systems and catheter sizes
    Öppna denna publikation i ny flik eller fönster >>Negative tracheal pressure during suction differs between suction systems and catheter sizes
    2005 (Engelska)Artikel i tidskrift (Refereegranskat) Published
    Ort, förlag, år, upplaga, sidor
    Uppsala: Institutionen för medicinsk cellbiologi, 2005
    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-7236 (URN)
    Tillgänglig från: 2007-10-24 Skapad: 2007-10-24 Senast uppdaterad: 2018-01-13
    3. Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Öppna denna publikation i ny flik eller fönster >>Effectiveness and side effects of closed and open suctioning: an experimental evaluation
    Visa övriga...
    2004 Ingår i: Intensive Care Medicine, Vol. 30, nr 8, s. 1630-7Artikel i tidskrift (Refereegranskat) Published
    Identifikatorer
    urn:nbn:se:uu:diva-92643 (URN)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25Bibliografiskt granskad
    4. Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    Öppna denna publikation i ny flik eller fönster >>Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs
    2004 (Engelska)Ingår i: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, nr 3, s. 339-345Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Endotracheal suction can cause partial lung collapse and hypoxia and alter lung mechanics. We investigated the effects of adding a recruitment manoeuvre directly after endotracheal suction to restore lung volume in volume-controlled ventilation and pressure-controlled ventilation modes. Five anaesthetized pigs were investigated. The effects of endotracheal suction with or without a recruitment manoeuvre were compared in random order. In volume-controlled ventilation, compliance decreased after suction from 33 +/- 5 to 26 +/- 6 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 6 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 8 +/- 4% (P<0.05), but had recovered at 30 minutes. In pressure-controlled ventilation, compliance decreased after suction from 34 +/- 3 to 25 +/- 7 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 7 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 13 +/- 7% (P<0.05), and had not recovered after 30 minutes, 10 +/- 4%. When a recruitment manoeuvre was applied directly after suction, no negative side-effects were registered in volume-controlled ventilation or pressure-controlled ventilation. We conclude that the impairment of lung mechanics and gas exchange induced by endotracheal suction can be prevented by a simple post-suction recruitment manoeuvre. Further studies are needed to identify a suitable suction recruitment manoeuvre in patients with diseased lungs.

    Nationell ämneskategori
    Fysiologi
    Identifikatorer
    urn:nbn:se:uu:diva-92644 (URN)15264727 (PubMedID)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2018-01-13Bibliografiskt granskad
    5. The time frame for post-suction recruitment manoeuvre
    Öppna denna publikation i ny flik eller fönster >>The time frame for post-suction recruitment manoeuvre
    Manuskript (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-92645 (URN)
    Tillgänglig från: 2005-02-25 Skapad: 2005-02-25 Senast uppdaterad: 2010-01-13Bibliografiskt granskad
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 202.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Strid, Niklas
    Wickerts, Carl-Johan
    Högman, Marieann
    Negative tracheal pressure during suction differs between suction systems and catheter sizes2005Artikel i tidskrift (Refereegranskat)
  • 203.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wickerts, Carl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Heinonen, Erkki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Högman, Marieann
    Side effects of endotracheal suction in pressure and volume controlled ventilation2004Ingår i: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 125, nr 3, s. 1077-1080Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    STUDY OBJECTIVES:

    To investigate the effects of endotracheal suction in volume-controlled ventilation (VCV) and pressure-controlled ventilation (PCV) with an open suction system (OSS) or a closed suction system (CSS).

    DESIGN:

    Randomized comparison.

    SETTING:

    Animal research laboratory.

    PATIENTS:

    Twelve healthy anesthetized pigs.

    INTERVENTIONS:

    The effects of endotracheal suction during VCV and PCV with tidal volume (VT) of 14 mL/kg were compared. A 60-mm inner-diameter endotracheal tube was used. Ten-second suction was performed using OSS and CSS with 12F and 14F catheters connected to - 14 kPa vacuum.

    MEASUREMENTS AND RESULTS:

    Thirty minutes after suction in PCV, VT was still decreased by 27% (p < 0.001), compliance (Crs) by 28% (p < 0.001), and PaO(2) by 26% (p < 0.001); PaCO(2) was increased by 42% (p < 0.0001) and venous admixture by 158% (p = 0.003). Suction in VCV affected only Crs (decreased by 23%, p < 0.001) and plateau pressure (increased by 24%, p < 0.001). The initial impairment of gas exchange following suction in VCV was no longer statistically significant after 30 min.

    CONCLUSIONS:

    In conclusion, endotracheal suction causes lung collapse leading to impaired gas exchange, an effect that is more severe and persistent in PCV than in VCV.

  • 204.
    Almgren, Birgitta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Wickerts, Carl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Högman, Marieann
    Post-suction recruitment manoeuvre restores lung function in healthy, anaesthetized pigs2004Ingår i: Anaesthesia and Intensive Care, ISSN 0310-057X, E-ISSN 1448-0271, Vol. 32, nr 3, s. 339-345Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Endotracheal suction can cause partial lung collapse and hypoxia and alter lung mechanics. We investigated the effects of adding a recruitment manoeuvre directly after endotracheal suction to restore lung volume in volume-controlled ventilation and pressure-controlled ventilation modes. Five anaesthetized pigs were investigated. The effects of endotracheal suction with or without a recruitment manoeuvre were compared in random order. In volume-controlled ventilation, compliance decreased after suction from 33 +/- 5 to 26 +/- 6 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 6 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 8 +/- 4% (P<0.05), but had recovered at 30 minutes. In pressure-controlled ventilation, compliance decreased after suction from 34 +/- 3 to 25 +/- 7 ml x cmH2O(-1) (P<0.05), and 30 minutes later it remained decreased at 25 +/- 7 ml x cmH2O(-1). Venous admixture increased after suction from 5 +/- 2 to 13 +/- 7% (P<0.05), and had not recovered after 30 minutes, 10 +/- 4%. When a recruitment manoeuvre was applied directly after suction, no negative side-effects were registered in volume-controlled ventilation or pressure-controlled ventilation. We conclude that the impairment of lung mechanics and gas exchange induced by endotracheal suction can be prevented by a simple post-suction recruitment manoeuvre. Further studies are needed to identify a suitable suction recruitment manoeuvre in patients with diseased lungs.

  • 205.
    Almgren, Mats
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Garamus, Vasil M
    Nordstierna, Lars
    Luc-Blin, Jean
    Stébé, Marie-José
    Nonideal mixed micelles of fluorinated and hydrogenous surfactants in aqueous solution: NMR and SANS studies of anionic and nonionic systems.2010Ingår i: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 26, nr 8, s. 5355-5363Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Contrast variation SANS and (19)F chemical shifts were measured for three mixed equimolar micelle systems: sodium perfluorooctanoate (SPFO) and sodiumdecylsulfate (SDeS) in 200 mM NaCl, lithium perfluorononanate (LiPFN) and lithium dodecylsulfate (LiDS) in 200 mM LiCl, and a nonionic system C(8)F(17)C(2)H(4)(OC(2)H(4))(9) and C(12)H(25)(OC(2)H(4))(8) in water, all at 25 degrees C. The chemical shift measurements allow the calculation of the average fraction of nearest neighbors of each kind around the reporter group (the trifluoromethyl group). A preference for like neighbors were found in all systems, smallest in the SDeS/SPFO system and largest in the nonionic system, but in all cases substantially smaller than expected at critical conditions. From the SANS measurements the width of the micelle composition distribution was obtained. For the ionic systems similar values were obtained, showing a broadening compared to ideal mixtures, but not broad enough for demixing or clearly bimodal distributions. In the nonionic system the width was estimated as sigma = 0.18 and 0.22 using two different evaluation methods. These values suggest that the system is close to critical conditions. The lower value refers to a direct modeling of the system, assuming an ellipsoidal shape and a Gaussian composition distribution. The modeling showed the nonionic mixed micelles to be prolate ellipsoids with axial ratio 2.2 and an aggregation number larger than 100, whereas the two ionic systems fitted best to oblate shapes (axial ratios 0.8 and 0.65 for SDeS/SPFO and LiDS/LiPFN, respectively) and aggregation numbers of 60 for both.

  • 206.
    Almkvist, Ove
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Rodriguez-Vieitez, Elena
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Thordardottir, Steinunn
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.
    Nordberg, Agneta
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Viitanen, Matti
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, SE-14157 Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Graff, Caroline
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.
    Longitudinal cognitive decline in autosomal-dominant Alzheimer's disease varies with mutations in APP and PSEN1 genes2019Ingår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 82, s. 40-47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose was to compare longitudinal cognitive changes in APP and PSEN1 gene mutation carriers and noncarriers from four autosomal-dominant Alzheimer's disease (ADAD) families across preclinical and early clinical stages of disease. Carriers (n = 34) with four different mutations (PSEN1(M146V), PSEN1(H163Y), APP(SWE), and APP(ARC)) and noncarriers (n = 41) were followed up longitudinally with repeated cognitive assessments starting many years before the expected clinical onset. The relationship between cognition and years to expected clinical onset, education, age, and type of mutation was analyzed using mixed-effects models. Results showed an education-dependent and time-related cognitive decline with linear and quadratic predictors in mutation carriers. Cognitive decline began close to the expected clinical onset and was relatively rapid afterward in PSEN1 mutation carriers, whereas decline was slower and started earlier than 10 years before expected clinical onset in APP mutation carriers. In noncarriers, the decline was minimal across time in accordance with normal aging. These results suggest that phenotypes for onset and rate of cognitive decline vary with PSEN1 and APP genes, suggesting a behavioral heterogeneity in ADAD. (C) 2019 Elsevier Inc. All rights reserved.

  • 207.
    Almqvist, Helena
    et al.
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Axelsson, Hanna
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Jafari, Rozbeh
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Dan, Chen
    School of Biological Sciences, Nanyang Technological University.
    Mateus, André
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Haraldsson, Martin
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Larsson, Andreas
    School of Biological Sciences, Nanyang Technological University.
    Martinez-Molina, Daniel
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Nordlund, Pär
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil2016Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikel-id 11040Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.

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    fulltext
  • 208.
    Almstedt, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    New targeted therapies for malignant neural tumors: From systematic discovery to zebrafish models2020Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cancers in the neural system presents a major health challenge. The most aggressive brain tumor in adults, glioblastoma, has a median survival of 15 months and few therapeutic options. High-risk neuroblastoma, a childhood tumor originating in the sympathetic nervous system, has a 5-year survival under 50%, despite extensive therapy. Molecular characterization of these tumors has had some, but so far limited, clinical impact. In neuroblastoma, patients with ALK mutated tumors can benefit from treatment with ALK inhibitors. In glioblastoma, molecular subgroups have not yet revealed any subgroup-specific gene dependencies due to tumor heterogeneity and plasticity. In this thesis, we identify novel treatment candidates for neuroblastoma and glioblastoma. 

    In paper I, we discover novel drug targets for high-risk neuroblastoma by integrating patient data, large-scale pharmacogenomic profiles, and drug-protein interaction maps. Using a novel algorithm, TargetTranslator, we identify more than 80 targets for this patient group. Activation of cannabinoid receptor 2 (CNR2) or inhibition of mitogen-activated protein kinase 8 (MAPK8) reduces tumor growth in zebrafish and mice models of neuroblastoma, establishing TargetTranslator as a useful tool for target discovery in cancer. 

    In paper II, we screen approximately 1500 compounds across 100 molecularly characterized cell lines from patients to uncover heterogeneous responses to drugs in glioblastoma. We identify several connections between pathway activities and drug response. Sensitivity to proteasome inhibition is linked to oxidative stress response and p53 activity in cells, and can be predicted using a gene signature. We also discover sigma receptors as novel drug targets for glioblastoma and find a synergistic vulnerability in targeting cholesterol homeostasis.

    In paper III, we systematically explore novel targets for glioblastoma using an siRNA screen. Downregulation of ZBTB16 decreases cell cycle-related proteins and transcripts in patient-derived glioblastoma cells. Using a zebrafish assay, we find that ZBTB16 promotes glioblastoma invasion in vivo

    In paper IV, we characterized the growth of seven patient-derived glioblastoma cell lines in orthotopic zebrafish xenografts. Using automated longitudinal imaging, we find that tumor engraftment strongly correlates with tumor initiation capacity in mice xenografts and that the heterogeneous response to proteasome inhibitors is maintained in vivo

    In summary, this thesis identifies novel targets for glioblastoma and neuroblastoma using systematic approaches. Treatment candidates are evaluated in novel zebrafish xenograft models that are developed for high-throughput glioblastoma and neuroblastoma drug evaluation. Together, this thesis provides promising evidence of new therapeutic options for malignant neural tumors.

    Delarbeten
    1. Integrative discovery of treatments for high-risk neuroblastoma.
    Öppna denna publikation i ny flik eller fönster >>Integrative discovery of treatments for high-risk neuroblastoma.
    Visa övriga...
    2020 (Engelska)Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 71Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi Bioinformatik (beräkningsbiologi)
    Identifikatorer
    urn:nbn:se:uu:diva-402363 (URN)10.1038/s41467-019-13817-8 (DOI)31900415 (PubMedID)
    Tillgänglig från: 2020-01-16 Skapad: 2020-01-16 Senast uppdaterad: 2020-02-04Bibliografiskt granskad
    2. A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
    Öppna denna publikation i ny flik eller fönster >>A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic states
    Visa övriga...
    (Engelska)Ingår i: Artikel i tidskrift (Övrigt vetenskapligt) Submitted
    Nationell ämneskategori
    Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) Cancer och onkologi Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-402456 (URN)
    Tillgänglig från: 2020-01-16 Skapad: 2020-01-16 Senast uppdaterad: 2020-02-04Bibliografiskt granskad
    3. ZBTB16 orchestrates growth and invasion in glioblastoma
    Öppna denna publikation i ny flik eller fönster >>ZBTB16 orchestrates growth and invasion in glioblastoma
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    ZBTB16/PLZF, glioblastoma, siRNA, targeted therapy
    Nationell ämneskategori
    Cancer och onkologi Cell- och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-402522 (URN)
    Tillgänglig från: 2020-01-16 Skapad: 2020-01-16 Senast uppdaterad: 2020-01-18
    4. Real-time evaluation of glioblastoma treatments in patient-specific zebrafish xenografts
    Öppna denna publikation i ny flik eller fönster >>Real-time evaluation of glioblastoma treatments in patient-specific zebrafish xenografts
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Cancer och onkologi Annan medicinsk bioteknologi
    Identifikatorer
    urn:nbn:se:uu:diva-402416 (URN)
    Tillgänglig från: 2020-01-16 Skapad: 2020-01-16 Senast uppdaterad: 2020-01-27
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    presentationsbild
  • 209.
    Almstedt, Elin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hekmati, Neda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Rosén, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Wärn, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Olsen, Thale Kristin
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Dyberg, Cecilia
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Doroszko, Milena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Larsson, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Arsenian Henriksson, Marie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Påhlman, Sven
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Bexell, Daniel
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Vanlandewijck, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Department of Medicine, Integrated Cardio-Metabolic Centre Single Cell Facility, Karolinska Institutet, Stockholm, Sweden..
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden..
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Integrative discovery of treatments for high-risk neuroblastoma.2020Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, nr 1, artikel-id 71Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

  • 210.
    Almén, Markus Sällman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Nilsson, Emil K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jacobsson, Josefin A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Kalnina, Ineta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Klovins, Janis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Genome-wide analysis reveals DNA methylation markers that vary with both age and obesity2014Ingår i: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 548, nr 1, s. 61-67Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The combination of the obesity epidemic and an aging population presents growing challenges for the healthcare system. Obesity and aging are major risk factors for a diverse number of diseases and it is of importance to understand their interaction and the underlying molecular mechanisms. Herein the authors examined the methylation levels of 27578 CpG sites in 46 samples from adult peripheral blood. The effect of obesity and aging was ascertained with general linear models. More than one hundred probes were correlated to aging, nine of which belonged to the KEGG group map04080. Additionally, 10 CpG sites had diverse methylation profiles in obese and lean individuals, one of which was the telomerase catalytic subunit (TERT). In eight of ten cases the methylation change was reverted between obese and lean individuals. One region proved to be differentially methylated with obesity (LINC00304) independent of age. This study provides evidence that obesity influences age driven epigenetic changes, which provides a molecular link between aging and obesity. This link and the identified markers may prove to be valuable biomarkers for the understanding of the molecular basis of aging, obesity and associated diseases.

    Ladda ner fulltext (pdf)
    fulltext
  • 211.
    Alniss, Hasan Y.
    et al.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Witzel, Ini-Isabee
    New York Univ Abu Dhabi, Core Technol Platform, POB 129188, Abu Dhabi, U Arab Emirates.
    Semreen, Mohammad H.
    Univ Sharjah, Coll Pharm, POB 27272, Sharjah, U Arab Emirates;Univ Sharjah, Sharjah Inst Med Res, POB 27272, Sharjah, U Arab Emirates.
    Panda, Pritam Kumar
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori.
    Mishra, Yogendra Kumar
    Univ Kiel, Inst Mat Sci, Funct Nanomat, Kaiserstr 2, D-24143 Kiel, Germany;Univ Southern Denmark, NanoSYD, Mads Clausen Inst, Alsion 2, DK-6400 Sonderborg, Denmark.
    Ahuja, Rajeev
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Fysiska sektionen, Institutionen för fysik och astronomi, Materialteori. Royal Inst Technol KTH, Dept Mat & Engn, SE-10044 Stockholm, Sweden.
    Parkinson, John A.
    Univ Strathclyde, Dept Pure & Appl Chem, WestCHEM, 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland.
    Investigation of the Factors That Dictate the Preferred Orientation of Lexitropsins in the Minor Groove of DNA2019Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 62, nr 22, s. 10423-10440Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lexitropsins are small molecules that bind to the minor groove of DNA as antiparallel dimers in a specific orientation. These molecules have shown therapeutic potential in the treatment of several diseases; however, the development of these molecules to target particular genes requires revealing the factors that dictate their preferred orientation in the minor grooves, which to date have not been investigated. In this study, a distinct structure (thzC) was carefully designed as an analog of a well-characterized lexitropsin (thzA) to reveal the factors that dictate the preferred binding orientation. Comparative evaluations of the biophysical and molecular modeling results of both compounds showed that the position of the dimethylaminopropyl group and the orientation of the amide links of the ligand with respect to the 5'-3'-ends; dictate the preferred orientation of lexitropsins in the minor grooves. These findings could be useful in the design of novel lexitropsins to selectively target specific genes.

  • 212.
    Alnuaimy, Ranin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Granskning av läkemedelsinformation i FASS gällande risk under graviditet och amning2014Självständigt arbete på grundnivå (yrkesexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund: År 1978 introduceras ett klassificeringssystem i FASS (Farmaceutiska specialiteter i Sverige) för att underlätta bedömningen vid förskrivning av läkemedel till gravida och ammande kvinnor. Detta gäller bedömningen av ett läkemedels risk för bieffekter under graviditet och amning utifrån vilken kategori det placeras i. När Sverige 1995 går med i EU beslutar den medicinska expertgruppen att inte längre granska FASS- texter utan lämna över uppgiften till själva läkemedelsföretagen. Syfte: I detta projektarbete jämförs FASS-texter under rubrikerna Graviditet och Amning med läkemedelskategorin som de är placerade i. Metod och Material: Läkemedelsprodukter som granskas i arbetet är totalt 422 produkter med indikationsområden för andningsorgan (ATC- grupp R) samt ögon och öron (ATC-grupp S). Läkemedelsgrupperna är intressanta eftersom de innehåller läkemedel som rekommenderas under graviditet samt amning som till exempel inhalationspreparat mot astma eller ögondroppar mot glaukom. De texter som granskas har hämtats från FASS hemsida www.fass.se. Ytterligare information såsom namn, form, styrka, beredningsform och tillverkare för läkemedlen har hämtats från NPL (Nationellt Produktregister för Läkemedel). Resultat: Studien visar att ca 5 % respektive 13 % av läkemedel inom indikationsområden Andningsorgan (ATC-grupp R) samt Ögon och Öron (ATC-grupp S) är felklassificerade i förhållande till kriterierna för en FASS-text. Procenten inkluderar även läkemedel med saknad klassificering. Diskussion: Eftersom granskning av FASS-texter inte sköts av någon myndighet längre är läkemedelsföretagen själva ansvariga för informationen som står i FASS idag. Detta har lett till problem i form av saknad klassificering eller fel klassificering av läkemedel i FASS-texter något som är viktigt ur graviditets- och amningsperspektiv. Problemet bör uppmärksammas av ansvariga läkemedelsföretag och kontrollmyndigheter.

  • 213.
    Al-Obaidi, Omar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Endocannabinoider som mål för nya läkemedel vid Alzheimer sjukdom2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Alzheimers sjukdom (AD) är en neurodegenerativ sjukdom, där hjärnatrofi och minnesförlust ses på grund av en irreversibel celldöd. Sjukdomen drabbar framför allt människor i åldern 65 år eller äldre. Mikroskopiskt ses ansamlingar av β-amyloida plack och neurofibriller. Vid sjukdomen ses en långvarig inflammatorisk process i hjärnan som troligen uppkommer på grund av ökade halter av reaktiva syreradikaler (ROS) intracellulärt. Forskare har observerat att mängden ROS ökar i de neuron som omges av β-amyloida plack (ökad ansamling av β-amyloid leder till neurodegeneration). Tidigare studier har visat att det endocannabinoida systemet spelar en viktig roll vid inflammatoriska nervsjukdomar. Mekanismerna för hur endocannabinoider påverkar hjärnans aktivitet är långt ifrån kända. Endocannabioider som anandamid och arachidonoylglycerol (2-AG) kan modulera cellulära processer och därmed utöva både anti-inflammatoriska och anti-excitotoxiska effekter. Syftet med detta arbete var att undersöka den neuroprotektiva benägenhet hos 2-AG. För att kunna utföra arbetet användes humana neuroblastoma SH-SY5Y celler, som behandlades med det toxiska ämnet t-butylväteperoxid (t-BHP). t-BHP inducerar oxidativ stress i cellerna. Cellerna behandlades sedan med t-BHP i närvaro av endocannabinoiden 2-AG. Cellöverlevaden bestämdes med MTT-metoden. Resultaten uppvisade en dos-beroende celldöd med tBHP. 2-AG kunde motverka t-BHP inducerad toxicitet och ökade signifikant cellöverlevnaden. Utifrån resultaten observerades att cellöverlevnad hade signifikant ökat i närvaro 2-AG. Resultaten från denna studie visar på att 2-AG uppvisar en neuroprotektiv egenskap. Vidare studier behövs för att utreda mekanismerna bakom dess neuroprotektiva egenskaper.

  • 214. Alogheli, Hiba
    A study of conformational energy penalties of protein-bound macrocyclesIngår i: Artikel i tidskrift (Refereegranskat)
  • 215.
    Alogheli, Hiba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Computational Studies of Macrocycles and Molecular Modeling of Hepatitis C Virus NS3 Protease Inhibitors2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Computational tools are utilized in the drug discovery process to discover, design, and optimize new therapeutics. One important approach is structure-based drug design which relies on knowledge about the 3D structure of the biological target. The first part of this work focuses on applying structure-based drug design for binding mode prediction of HCV NS3 protease inhibitors. The NS3 protease is a challenging target from a computational perspective as it contains an extended binding site. Binding mode predictions were performed for various classes of new acyclic and macrocyclic HCV NS3 protease inhibitors and was used in the design of new inhibitors. None of the synthetized inhibitors have been co-crystallized yet, which has made the evaluation of the suggested binding mode predictions challenging.

    Macrocycles are an interesting compound class in drug discovery due to their unique structural architecture, which can enable access to new chemical space. Macrocycles can successfully modulate difficult therapeutic targets, as exemplified in the development of protease inhibitors. Furthermore they can improve drug-like properties, such as cell permeability and bioavailability. The second part of this thesis focuses on macrocycles from a computational point of view. A data set of 47 clinically relevant macrocycles was compiled and used in these studies. First, two different docking protocols rigid docking of pre-generated conformers and flexible docking in Glide were evaluated and compared. The results showed that flexible docking in Glide was sufficient for docking of macrocycles with respect to accuracy and speed.

    The aim of the second study was to evaluate and compare the performance of the more general conformational analysis tools, MCMM and MTLMOD, with the recently developed macrocycle-specialized conformational sampling tools, Prime-MCS and MMBS. In most cases, the general conformational analysis tools (with enhanced parameter settings) performed equally well as compared to the macrocycle-specialized conformational sampling techniques. However, MMBS was superior at locating the global energy minimum conformation.

    Finally, calculation of the conformational energy penalty of protein-bound macrocycles was performed. The macrocycle data set was complemented with linear analogues that are similar either with respect to physicochemical properties or 2D fingerprints. The conformational energy penalties of these linear analogues were calculated and compared to the conformational energy penalties of the macrocycles. The complete data set of macrocycles and non-macrocycles in this study differ from previously published work addressing conformational energy penalties, since it covers a more extended area of chemical space. Furthermore, there was a weak correlation between the calculated conformational energy penalties and the flexibility of the structures.

    Delarbeten
    1. Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
    Öppna denna publikation i ny flik eller fönster >>Pan-NS3 protease inhibitors of hepatitis C virus based on an R3-elongated pyrazinone scaffold
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    2018 (Engelska)Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 148, s. 453-464Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Herein, we present the design and synthesis of 2(1H)-pyrazinone based HCV NS3 protease inhibitors and show that elongated R-3 urea substituents were associated with increased inhibitory potencies over several NS3 protein variants. The inhibitors are believed to rely on beta-sheet mimicking hydrogen bonds which are similar over different genotypes and current drug resistant variants and correspond to the beta-sheet interactions of the natural peptide substrate. Inhibitor 36, for example, with a urea substituent including a cyclic imide showed balanced nanomolar inhibitory potencies against genotype la, both wild-type (K-i=30 nM) and R155K (K-i=2 nM), and genotype 3a (K-i=5 nM).

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2018
    Nyckelord
    Hepatitis C, NS3, Genotype 3, Resistance, Pyrazinone
    Nationell ämneskategori
    Läkemedelskemi
    Forskningsämne
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-340862 (URN)10.1016/j.ejmech.2018.02.032 (DOI)000428824700036 ()
    Forskningsfinansiär
    Vetenskapsrådet, D0571301
    Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2018-05-31Bibliografiskt granskad
    2. A study of conformational energy penalties of protein-bound macrocycles
    Öppna denna publikation i ny flik eller fönster >>A study of conformational energy penalties of protein-bound macrocycles
    (Engelska)Ingår i: Artikel i tidskrift (Refereegranskat) Submitted
    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-340863 (URN)
    Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2018-02-04
    3. Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    Öppna denna publikation i ny flik eller fönster >>Conformational Analysis of Macrocycles: Comparing General and Specialized Methods
    2020 (Engelska)Ingår i: Journal of Computer-Aided Molecular Design, ISSN 0920-654X, E-ISSN 1573-4951, Vol. 34, s. 231-252Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Macrocycles represent an important class of medicinally relevant small molecules due to their interesting biological properties. Therefore, a firm understanding of their conformational preferences is important for drug design. Given the importance of macrocycle-protein modelling in drug discovery, we envisaged that a systematic study of both classical and recent specialized methods would provide guidance for other practitioners within the field. In this study we compare the performance of the general, well established conformational analysis methods Monte Carlo Multiple Minimum (MCMM) and Mixed Torsional/Low-Mode sampling (MTLMOD) with two more recent and specialized macrocycle sampling techniques: MacroModel macrocycle Baseline Search (MD/LLMOD) and Prime macrocycle conformational sampling (PRIME-MCS). Using macrocycles extracted from 44 macrocycle-protein X-ray crystallography complexes, we evaluated each method based on their ability to (i) generate unique conformers, (ii) generate unique macrocycle ring conformations, (iii) identify the global energy minimum, (iv) identify conformers similar to the X-ray ligand conformation after Protein Preparation Wizard treatment (X-ray(ppw)), and (v) to the X-ray(ppw) ring conformation. Computational speed was also considered. In addition, conformational coverage, as defined by the number of conformations identified, was studied. In order to study the relative energies of the bioactive conformations, the energy differences between the global energy minima and the energy minimized X-ray(ppw) structures and, the global energy minima and the MCMM-Exhaustive (1,000,000 search steps) generated conformers closest to the X-ray(ppw) structure, were calculated and analysed. All searches were performed using relatively short run times (10,000 steps for MCMM, MTLMOD and MD/LLMOD). To assess the performance of the methods, they were compared to an exhaustive MCMM search using 1,000,000 search steps for each of the 44 macrocycles (requiring ca 200 times more CPU time). Prior to our analysis, we also investigated if the general search methods MCMM and MTLMOD could also be optimized for macrocycle conformational sampling. Taken together, our work concludes that the more general methods can be optimized for macrocycle modelling by slightly adjusting the settings around the ring closure bond. In most cases, MCMM and MTLMOD with either standard or enhanced settings performed well in comparison to the more specialized macrocycle sampling methods MD/LLMOD and PRIME-MCS. When using enhanced settings for MCMM and MTLMOD, the X-ray(ppw) conformation was regenerated with the greatest accuracy. The, MD/LLMOD emerged as the most efficient method for generating the global energy minima. Graphic abstract

    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-340864 (URN)10.1007/s10822-020-00277-2 (DOI)000515183900002 ()31965404 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 521-2014-6711
    Tillgänglig från: 2018-02-04 Skapad: 2018-02-04 Senast uppdaterad: 2020-03-26Bibliografiskt granskad
    4. Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
    Öppna denna publikation i ny flik eller fönster >>Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide
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    2017 (Engelska)Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 2, s. 190-202Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

    Nationell ämneskategori
    Läkemedelskemi
    Identifikatorer
    urn:nbn:se:uu:diva-318050 (URN)10.1021/acs.jcim.6b00443 (DOI)000395226100010 ()28079375 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 521-2014-6711
    Tillgänglig från: 2017-03-23 Skapad: 2017-03-23 Senast uppdaterad: 2018-03-05Bibliografiskt granskad
    5. Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
    Öppna denna publikation i ny flik eller fönster >>Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
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    2014 (Engelska)Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 22, nr 23, s. 6595-6615Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.

    Nyckelord
    HCV, NS3, Protease inhibitors, Macrocyclization, Phenylglycine, Metathesis
    Nationell ämneskategori
    Biokemi och molekylärbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-239738 (URN)10.1016/j.bmc.2014.10.010 (DOI)000345287300007 ()
    Tillgänglig från: 2014-12-31 Skapad: 2014-12-30 Senast uppdaterad: 2018-02-04Bibliografiskt granskad
    6. Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
    Öppna denna publikation i ny flik eller fönster >>Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
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    2014 (Engelska)Ingår i: ACS Medicinal Chemistry Letters, ISSN 1948-5875, E-ISSN 1948-5875, Vol. 5, nr 3, s. 249-254Artikel i tidskrift, Letter (Refereegranskat) Published
    Abstract [en]

    Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-221229 (URN)10.1021/ml400217r (DOI)000333006200005 ()
    Tillgänglig från: 2014-03-26 Skapad: 2014-03-26 Senast uppdaterad: 2018-02-04Bibliografiskt granskad
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  • 216.
    Alogheli, Hiba
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Olanders, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Schaal, Wesley
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Brandt, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Anders, Karlén
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Docking of Macrocycles: Comparing Rigid and Flexible Docking in Glide2017Ingår i: Journal of Chemical Information and Modeling, ISSN 1549-9596, E-ISSN 1549-960X, Vol. 57, nr 2, s. 190-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle-containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pregenerated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide flexible docking after performing ring-templating. The two protocols were compared to rigid docking of pregenerated conformational ensembles produced by an exhaustive Monte Carlo multiple minimum (MCMM) conformational search and a shorter MCMM conformational search (MCMM-short). The docking accuracy was evaluated and expressed as the RMSD between the heavy atoms of the ligand as found in the X-ray structure after refinement and the poses obtained by the docking protocols. The median RMSD values for top-scored poses of the screening set were 0.83, 0.80, 0.88, and 0.58 Å for MCMM, MCMM-short, MCS, and Glide flexible docking, respectively. There was no statistically significant difference in the performance between rigid docking of pregenerated conformations produced by the MCS and direct docking using Glide flexible docking. However, the flexible docking protocol was 2-times faster in docking the screening set compared to that of the MCS protocol. In a final study, the new Prime-MCS method was evaluated in Schrödinger Release 2016-3. This method is faster compared that of to MCS; however, the conformations generated were found to be suboptimal for rigid docking. Therefore, on the basis of timing, accuracy, and ease of set up, standard Glide flexible docking with prior ring-templating is recommended over current gold standard protocols using rigid docking of pregenerated conformational ensembles.

  • 217.
    Al-Sabti, Samar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Följsamhet till Kloka Listan i Stockholms läns landsting– en jämförelse mellan år 2010 och 20132014Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Följsamhet till Kloka Listan i Stockholms läns landsting– en jämförelse mellan år 2010 och 2013

    Samar Al-Sabti

    Handledare: Maria Juhasz Haverinen och Björn Wettermark. Stockholms läns landsting. Institution farmaceutisk biovetenskap/ avdelningen för farmakokinetik och läkemedelsterapi, 15hp, V14. Examinator: Margareta Hammarlund-Udenaes.

    Introduktion: År 2000 fick hela Stockholms läns landsting en gemensam lista som innehöll ett urval av rekommenderade läkemedel med syfte att ge läkare och annan vårdpersonal stöd vid läkemedelsförskrivning för vanliga sjukdomar. Under 2001 kallades denna lista för Kloka Listan. Urvalet av dessa läkemedel beslutas av Stockholms läns läkemedelskommitté. Kloka Listan finns både som tryckt bok och webbaserad i olika versioner för patienter och för vårdpersonal.

    Syfte: Att analysera hur följsamheten till Kloka Listan förändrats mellan år 2010 och 2013 på två olika terapiområden samt alla rekommenderade läkemedel.

    Material och metoder: Studien var en deskriptiv studie baserad på data över uthämtade recept hämtat från Stockholms läns landstings vårddatabaser. Följsamheten till Kloka Listan mättes med hjälp av Drug Utilization 90 % metoden (DU90 %). DU90 % anger det antal läkemedel som står för 90% av förskrivningsvolymen mätt i antalet definierade dygndoser. Analyser gjordes på alla rekommenderade läkemedel i Kloka Listan och på två terapiområden vilka var NSAID och hjärt-kärlläkemedel 2010 och 2013.

    Resultat: År 2010 var följsamheten till Kloka Listan på alla rekommenderade läkemedel 79% och den ökade till 82% under 2013. Följsamheten för NSAID och hjärt-kärlläkemedel var också hög båda åren och det skedde stora förändringar i rekommendationerna mellan substanserna inom varje grupp.

    Konklusion: En liten ökning på 3 % på följsamheten till Kloka Listan har skett i 2013 jämfört med 2010. Det skedde stora förändringar i rekommendationerna mellan substanserna inom grupperna NSAID och hjärt-kärlläkemedel.

     

     

  • 218.
    AL-Saeigh, Farah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Utvärdering och förbättring av enteral läkemedelsadministrering vid Astrid Lindgrens Barnsjukhus2014Självständigt arbete på avancerad nivå (yrkesexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 219.
    Alserr, Amal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Upplever KOL-patienter sig följsamma till sina inhalationsläkemedel och anser sig apotekspersonalen ha tillräckligt med kompetens för att demonstrera inhalationstekniken?2019Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund: Kroniskt obstruktiv lungsjukdom (KOL) är en progressiv sjukdom som orsakas främst av en nedbrytning av alveolsäckarna så att dessa sammanfaller till större hålrum i lungan (emfysem) och av inflammation i de små luftrören (bronkiolit).

    Följsamheten till läkarens ordination och korrekt inhalationsteknik är två viktiga områden som bör kontrolleras vid behandling och uppföljning av KOL- och astmapatienter. Dålig följsamhet till dessa kan bland annat leda till en sämre prognos av sjukdomen. Flera studier har visat att apoteksinterventioner där patientutbildning ingår förbättrar följsamheten till läkemedelsordinationen och den korrekta användningen av inhalationspreparatet hos KOL- och astmapatienter.

    Syfte: Syftet var att undersöka om KOL-patienter upplevde sig följsamma till sin läkemedelsbehandling med inhalatorer, vilken kunskap de hade om dessa inhalatorer och hur de hade inhämtat denna. Vidare undersöktes om apotekspersonal demonstrerade inhalatorerna vid expedition och om de upplevde sig ha tillräcklig med kompetens vid utförandet.

    Material och metod: Två enkäter, en patientenkät och personalenkät utformades. De innehöll frågor baserade på studiens syfte och frågeställningar. Patientenkäten delades ut till patienter i samband med expediering på sex apotek i Uppsala och Stockholm under en sex-veckorsperiod. Inklusionskriterierna för patientundersökningen var vuxna patienter med diagnosen KOL, som under studieperioden hämtade ut ett preparat innehållandes långverkande antikolinergika (LAMA) ensamt eller i kombination med långverkande beta-2-agonist (LABA) eller en kortikosteroid (ICS). Exklusionskriterierna var  patienter med diagnosen astma, astma-KOL överlapp eller kronisk bronkit. Personalenkäten delades ut till apotekspersonal på 13 apotek i Stockholm och Uppsala under en fem-veckorsperiod. Inklusionskriterierna för personalundersökningen var legitimerade apotekare, receptarier eller apotekstekniker. Exklusionskriterierna var kassapersonal som saknade farmaceutisk utbildning. Innan utdelning av personalenkäten gjordes en pilotstudie, något som inte gjordes för patientenkäten på grund av tidsbrist. Erhållna resultat från enkätundersökningarna sammanställdes manuellt och redovisades i form av diagram och tabeller i Excel och Word.

    Resultat:

    Patientenkät: Totalt deltog nio personer. Enbart en person uppgav att hen hoppade över att använda sitt/sina läkemedel och orsaken till detta var glömska. De flesta upplevde inte några svårigheter med handhavandet av inhalatorn. Endast en upplevde detta och angav ”att göra en djup inandning” som en svårighet. Över hälften, 56 % hade tidigare fått en demonstration av inhalationspreparatet utförd av läkare. Vidare uppgav de flesta 78 % att de inte önskade att apotekspersonal skulle demonstrera inhalatorn i samband med expedition. Orsaken till detta var att de ansåg att de redan hade denna kunskap.

    Personalenkät: Totalt deltog 48 personer, 27% uppgav att de frågade patienterna om de behövde en demonstration av inhalatorn varje gång vid expediering. Ca 42% angav att de endast gjorde det om det var första gången patienten hämtade ut preparatet. Vid demonstration använde majoriteten (73%) en placeboinhalator. Vidare indikerade resultaten att apotekspersonal upplevde sig säkra i att demonstrera inhalatorer. Trots detta uppgav 60 % att det fanns ett behov av extra utbildning. Endast hälften hade fått en utbildning i hur olika inhalationspreparat används och då främst av en företagsrepresentant. Majoriteten uppgav också att de hade inhämtat kunskap om inhalatorn via bipacksedeln.                        

    Slutsats: Resultaten från denna undersökningen tyder på att KOL-patienter var följsamma till läkemedelsordinationen, hade fått en demonstration av inhalatorn och upplevde inte några svårigheter med handhavandet av denna. Undersökningen tydde även på att apotekspersonal demonstrerade inhalatorn för patienter och upplevde sig ha tillräckligt med kompetens till att utföra detta, trots detta önskade de mer utbildning. För att bekräfta resultaten krävs en längre undersökning med ett högre antal deltagare och på flera apotek.

  • 220.
    Al-shakagri, Bilall
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fetma - en fortsatt växande global epedemi2012Självständigt arbete på grundnivå (kandidatexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
  • 221.
    Al-Shamkhi, Nasrin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Alving, Kjell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Dahlen, S. E.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Hedlin, G.
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden..
    Middelveld, R.
    Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res Unit, Stockholm, Sweden..
    Bjerg, A.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Ekerljung, L.
    Univ Gothenburg, Krefting Res Ctr, Dept Internal Med & Clin Nutr, Gothenburg, Sweden..
    Olin, A. C.
    Univ Gothenburg, Sect Occupat & Environm Med, Dept Publ Hlth & Community Med, Inst Med,Sahlgrenska Acad, Gothenburg, Sweden..
    Sommar, J.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Forsberg, B.
    Umea Univ, Dept Publ Hlth & Clin Med Occupat & Environm Med, Umea, Sweden..
    Janson, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Lungmedicin och allergologi.
    Malinovschi, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Important non-disease-related determinants of exhaled nitric oxide levels in mild asthma - results from the Swedish GA(2)LEN study2016Ingår i: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 46, nr 9, s. 1185-1193Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Fractional exhaled nitric oxide (FeNO) has a potential clinical role in asthma management. Constitutive factors such as age, height and gender, as well as individual characteristics, such as IgE sensitization and smoking, affect the levels of FeNO in population-based studies. However, their effect on FeNO in subjects with asthma has been scarcely studied. Objective To study the effects on FeNO of these commonly regarded determinants, as demonstrated in healthy subjects, as well as menarche age and parental smoking, in a population of asthmatics. Material and Methods Fractional exhaled nitric oxide was measured in 557 subjects with asthma from the Swedish GA(2)LEN study. Allergic sensitization was assessed by skin prick tests to most common aeroallergens. Upper airway comorbidities, smoking habits, smoking exposure during childhood and hormonal status (for women) were questionnaire-assessed. Results Male gender (P < 0.001), greater height (P < 0.001) and sensitization to both perennial allergens and pollen (P < 0.001) are related to higher FeNO levels. Current smoking (P < 0.001) and having both parents smoking during childhood, vs. having neither (P < 0.001) or only one parent smoking (P = 0.002), are related to lower FeNO. Women with menarche between 9 and 11 years of age had lower FeNO than those with menarche between 12 and 14 years of age (P = 0.03) or 15 and 17 years of age (P = 0.003). Conclusions and Clinical relevance Interpreting FeNO levels in clinical practice is complex, and constitutional determinants, as well as smoking and IgE sensitisation, are of importance in asthmatic subjects and should be accounted for when interpreting FeNO levels. Furthermore, menarche age and parental smoking during childhood and their effects on lowering FeNO deserve further studies.

  • 222.
    Al-Shammari, Rotana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nya behandlingsmål för att minska levodopainducerade dyskinesier vid Parkinsons sjukdom2016Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
    Abstract [sv]

    Bakgrund: Parkinsons sjukdom (PD) är en åldersrelaterad sjukdom och bland de vanligaste neurodegenerativa sjukdomarna. Till neurodegenerativa sjukdomar hör de sjukdomarna som leder till förtvining av centrala nervsystemet i hjärnan i form av förlust av nervceller eller aggregering av proteiner. Vid PD är det förlust av dopaminerga nervceller som förefaller i ett visst område i hjärnan, så kallad substantia nigra (SN). PD kännetecknas av motoriska symtom i form av stelhet, skakningar och rörelsehämning. PD behandlas idag i första hand med levodopa. Levodopa omvandlas till dopamin i hjärnan vilket ger den önskade effekten av att höja dopaminhalten i hjärnan. Nackdelen med levodopa är utveckling av ofrivillig överrörlighet, s.k. levodopainducerade dyskinesier (LID), efter ca 7-10 år av behandlingen. Studier har visat att rökare har mindre risk för PD vilket väckte intresse för att forska på nikotinets roll. Andra studier har bevisat ökad aktivitet av glutamat vid PD vilket ledde till att vidare undersöka vad hämning av glutamatreceptorer kan ge för effekt.

    Syfte: Syftet med detta arbete var att undersöka nya behandlingsstrategier för att minska risken för LID.

    Metod: Arbete är en litteraturstudie baserad på sekundärdata från vetenskapliga artiklar och relevant litteratur. Litteratursökningen gjordes på olika databaser, framförallt PubMed.

    Resultat: Administrering av vissa typer av nikotinreceptor agonister innan intag av levodopa kan minska LID med ca 50%. En hämning av LID har även setts vid intag av olika antagonister till glutamatreceptorer.

    Slutsats: Flera substanser som verkar på olika nikotin- och glutamatreceptorer visar en bra effekt mot LID. En kombination av dessa substanser kan leda den framtida forskningen till den efterlängtade optimala behandlingen i att förebygga LID samtidigt som den ökar dopaminhalten i SN. 

  • 223.
    Alsiö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Preference for palatable and energy-dense foods may be a risk factor for body weight gain and has both genetic and environmental components. Once obesity develops in an individual, weight loss is difficult to achieve. Indeed, obesity is often characterized by repeated attempts to reduce the overconsumption of energy-dense foods, followed by food craving and relapse to overconsumption. Relapse and loss of control over intake are observed also in drug addicts, and it has been shown that obesity and drug addiction not only share behavioural features but also neural circuitry, e.g. the mesolimbic dopamine pathway. In this thesis, we sought to investigate the mechanisms related to food preferences and craving using animal models previously used in addiction research.

    The risk of gaining weight may implicate behavioural traits and emotional states. We showed in rats that a risk-taking behavioural profile was associated both with increased preference for a high-fat (HF) diet and with increased motivational response to a palatable high-sucrose (HS) diet. Hypothalamic urocortin 2 expression was associated with the preference for the HF diet. We also tested the hypothesis that consumption of HS and HF diets separately or provided simultaneously (HFHS) affect anxiety-like behaviour and locomotion.

    Furthermore, we showed that withdrawal from HFHS food affects diet-induced obesity-prone (OP) and obesity-resistant (OR) animals differently. OP animals had increased motivation (craving) for HS food pellets as measured by the operant self-administration technique during withdrawal. Dopamine receptor expression in the striatum differed between OP and OR animals both at access to HFHS and during withdrawal. This strongly implicates dopaminergic signaling in the OP phenotype.

    In humans, food preferences may be monitored using questionnaires. We analyzed food preference data from parents of preschool children, and identified an inverse association of parental preference for high-fat high-protein food and overweight in children.

    In conclusion, we have employed animal models previously used in the addiction field to identify molecular mechanisms related both to food preference and vulnerability to obesity, and to food craving associated with withdrawal from palatable food. These findings add to our current understanding of obesity.

     

    Delarbeten
    1. Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
    Öppna denna publikation i ny flik eller fönster >>Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
    Visa övriga...
    2009 (Engelska)Ingår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, nr 2, s. 193-202Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

    Nyckelord
    Anxiety, corticotropin-releasing factor receptor, dietary fat, elevated plus maze, exploratory behavior, food preferences, multivariate concentric square field, novelty seeking, palatable, urocortin 2, Wistar
    Nationell ämneskategori
    Farmakologi och toxikologi Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-117598 (URN)10.1111/j.1601-183X.2008.00464.x (DOI)000263756100007 ()19077174 (PubMedID)
    Tillgänglig från: 2010-03-01 Skapad: 2010-02-21 Senast uppdaterad: 2018-01-12Bibliografiskt granskad
    2. Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
    Öppna denna publikation i ny flik eller fönster >>Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Obesity may be induced in rodents by long-term access to dietary fat. Such treatment has been reported to have behavioural effects including reduced anxiety-like behaviour and diminished operant responding for psychostimulants. It is unclear whether such effects are secondary to metabolic changes due to excess body weight, or to the extended access to palatable food reward. The aim of this study was to investigate the effects of a short palatable diet exposure (10 days) on performance in the open field test of novelty-induced locomotion and anxiety-like behaviour in rats. We subjected rats to a free-choice high-fat or high-sugar diet, or both, for a period of 10 days. Increased caloric intake was observed in all groups but body weight at Day 10 did not differ from chow-fed controls. We report that consumption of the free-choice high-fat diets was associated with higher novelty-induced activity and reduced anxiety-like behaviour in the open field test. In addition, we used RT-PCR to show that the high-fat group had 39% higher expression of mu opioid receptor in the lateral hypothalamus, and that tyrosine hydroxylase expression was elevated more than two-fold in the ventral tegmental area of rats with access to both high-fat and high-sugar. In conclusion, these results show that subchronic exposure to a free-choice high-fat diet induces behavioural adaptations such as elevated locomotor activity and attenuated experimental anxiety. The changes observed in gene expression related to reward after high-fat diet exposure indicate that these behavioural adaptations are related to reward function.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-119489 (URN)
    Tillgänglig från: 2010-03-01 Skapad: 2010-02-25 Senast uppdaterad: 2013-01-08
    3. Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
    Öppna denna publikation i ny flik eller fönster >>Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
    Visa övriga...
    2009 (Engelska)Ingår i: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, nr 3, s. 193-197Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Anxiety has been implicated in obesity and in the overconsumption of highly palatable foods such as those high in fat, sugar, or both. Also, the novelty-seeking trait has been associated with failure in weight-loss programs. The aim of this study was to investigate the associations of experimental anxiety and the self-administration of sucrose and high fat pellets in non-food deprived rats across different operant schedules. Male Wistar rats were subjected to the elevated plus-maze test (EPM) of anxiety-like behavior. The rats were tested for fixed ratio 5 (FR5) and progressive ratio (PR) operant responding for 50% sucrose, 95% sucrose, and high-fat pellets. PR active lever press response for 95% sucrose, but not the other pellet types, was correlated to % time spent on open arms (P=0.019) in the EPM. On the FR5 schedule, activity (closed arm entries) was correlated to the self-administration of 50% sucrose (P=0.027) and high-fat (P=0.002). This indicates an association of novelty-induced activity and self-administration of palatable food in sated rats, as well as a specific association of PR lever press response for 95% sucrose and low anxiety-like behavior. It has been argued that such active lever press response on PR may be interpreted as craving for the reinforcer; thus, our findings indicate an inverse relationship of experimental anxiety and craving for sucrose. This connection may have implications for human situations, since anxiety and novelty-seeking have been associated with obesity and failure in weight-loss programs.

    Ort, förlag, år, upplaga, sidor
    Elsevier, 2009
    Nyckelord
    Craving; Sucrose, Dietary fat, Progressive ratio, Anxiety, Novelty-seeking
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-117599 (URN)10.1016/j.neulet.2009.03.045 (DOI)000265275500005 ()19429082 (PubMedID)
    Tillgänglig från: 2010-03-01 Skapad: 2010-02-21 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    4. Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    Öppna denna publikation i ny flik eller fönster >>Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    2009 (Engelska)Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, nr 3, s. 431-443Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

    Nyckelord
    Diet-induced obesity, Operant self-administration, Progressive ratio, Fixed ratio, Whole-animal physiology
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-117600 (URN)10.1007/s00213-009-1474-y (DOI)000266085700006 ()19205668 (PubMedID)
    Tillgänglig från: 2010-03-01 Skapad: 2010-02-21 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    5. Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
    Öppna denna publikation i ny flik eller fönster >>Downregulation of nucleus accumbens D1 and D2 receptor expression occurs upon exposure to and persists long-term after withdrawal from palatable food: conclusions from diet-induced obesity models
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-119449 (URN)
    Anmärkning
    The nucleus accumbens (NAcc) mediates feeding reward; its activity reflects tastants’ hedonic value. The NAcc dopamine guides immediate responses to reward, however, its involvement in establishing long-term responses after a period of exposure to palatable foods has not been defined. Furthermore, reward-driven overeating propels weight increase, but the scale of weight gain depends on animals’ obesity-prone (OP) or -resistant (OR) phenotype. It is unclear whether responses of NAcc dopamine to palatable foods depend on susceptibility to obesity. We investigated the effect of restricted and unrestricted extended access to high-fat high-sugar (HFHS) diet on expression of genes encoding dopamine receptors in the NAcc of OP and OR rats. We examined persistence of HFHS diet-induced changes in D1 and D2 gene expression in OP and OR rats subjected to HFHS withdrawal by receiving bland chow for 18 days after HFHS. Effects of restricted access to HFHS by pair-feeding to bland chow-fed controls were also studied. Using RT-PCR, we found that NAcc D1 mRNA was downregulated after long-term HFHS access in OP vs. OR animals. The effect persisted after 18 days of HFHS withdrawal. Noteworthy, even restricted HFHS led to downregulation of D1 as well as of D2 mRNA levels compared to chow-fed controls. Detection of concurrent expression changes of mu and kappa opioid receptors in the NAcc and caudate putamen confirmed their link to the effects of feeding reward withdrawal. We conclude that exposure to palatability has lasting consequences for the NAcc dopamine system, perhaps underlying the persistent search for feeding reward. The fact that the NAcc D1 expression changes long-term in OP animals after both un- and restricted exposure to palatability and extends well into the reward discontinuation phase, implicates the D1 receptor with the propensity to overeat and, in effect, gain weight in obesity prone individuals.Tillgänglig från: 2010-03-01 Skapad: 2010-02-25 Senast uppdaterad: 2010-03-01
    6. Parental food preferences are associated with body weight disturbance in preschool children
    Öppna denna publikation i ny flik eller fönster >>Parental food preferences are associated with body weight disturbance in preschool children
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Parental factors such as stress induced by parenting and certain food preferences are suspected to promote obesity in preschool children. In this context, especially the intake of dietary fat is assumed to play a key role for the children’s risk to become obese. Here we analyzed eating behaviors in parents of 3-year-olds in order to identify parental traits that are associated with body weight in these children. We also tested for possible interactions between psychosocial factors such as stress induced by parenting and parental food cravings. Questionnaires were sent out to 1300 parents whose children’s body weight was measured during ambulatory medical care visits (parental response rate 70.4%). Using the Food Craving Inventory scale allowed examining parental preferences for the following food categories:  high-fat/high-protein, sweets, carbohydrates, and fast food. Psychosocial stress caused by parenting was assessed with the Swedish Parenthood Stress Questionnaire (SPSQ). Our main finding was that the parental preference for foods rich in high-fat/high-protein nutrients displayed an inverse U-shaped function to the children’s body weight such that low preference for this category was associated with both overweight and underweight in offspring. Parental preference for sweet-foods were associated with higher odds for developing overweight in early childhood. The level of parental food preferences was significantly modulated by stress induced by parenting. In conclusion, we show that parental food preference is affected by stress and is associated with the body weight status of their children. The results suggest that parental intake of high-fat/high-protein foods protects against weight disturbances in preschool children.

    Identifikatorer
    urn:nbn:se:uu:diva-119472 (URN)
    Tillgänglig från: 2010-03-01 Skapad: 2010-02-25 Senast uppdaterad: 2010-03-01
    Ladda ner fulltext (pdf)
    FULLTEXT01
  • 224.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Birgner, Carolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Björkblom, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Isaksson, Pernilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Bergström, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Impact of nandrolone decanoate on gene expression in endocrine systems related to the adverse effects of anabolic androgenic steroids2009Ingår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 105, nr 5, s. 307-314Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Elite athletes, body builders and adolescents misuse anabolic-androgenic steroids (AAS) in order to increase muscle mass or to enhance physical endurance and braveness. The high doses misused are associated with numerous adverse effects. The purpose of this study was to evaluate the impact of chronic supratherapeutic AAS treatment on circulating hormones and gene expression in peripheral tissues related to such adverse effects. Quantitative real-time PCR was used to measure expression levels of in total 37 genes (including peptide hormones, cell membrane receptors, nuclear receptors, steroid synthesising enzymes and other enzymes) in the pituitary, testes, adrenals, adipose tissue, kidneys and liver of male Sprague-Dawley rats after 14-day administration of the AAS nandrolone decanoate, 3 or 15 mg/kg. Plasma glucose and levels of adrenocorticotropic hormone (ACTH), adiponectin, corticosterone, ghrelin, insulin and leptin were also measured. We found several expected effects on the hypothalamic-pituitary-gonadal axis, while the treatment also caused a number of other not previously identified changes in circulating factors and gene transcription levels such as the dose-dependent reduction of the beta(3)-adrenergic receptor in adipose tissue, reduction of both circulating and mRNA levels of adiponectin, up-regulation of both hydroxymethylglutaryl-CoA-reductase, the rate-limiting enzyme in de novo synthesis of cholesterol, and the receptor for ACTH in the adrenals. The results provide evidence for wide ranging effects of AAS on the hypothalamic-pituitary-adrenal axis, adipose tissue and substrates of the renal control of blood pressure.

  • 225.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015Ingår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, nr 21-22, s. 4017-4031Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 mu g/side) on performance in this task. In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

  • 226.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Nordenankar, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Arvidsson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Birgner, Carolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Mahmoudi, Souha
    Halbout, Briac
    Smith, Casey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Fortin, Guillaume M.
    Olson, Lars
    Descarries, Laurent
    Trudeau, Louis-Eric
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Levesque, Daniel
    Wallén-Mackenzie, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Enhanced Sucrose and Cocaine Self-Administration and Cue-Induced Drug Seeking after Loss of VGLUT2 in Midbrain Dopamine Neurons in Mice2011Ingår i: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 31, nr 35, s. 12593-12603Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The mesostriatal dopamine (DA) system contributes to several aspects of responses to rewarding substances and is implicated in conditions such as drug addiction and eating disorders. A subset of DA neurons has been shown to express the type 2 Vesicular glutamate transporter (Vglut2) and may therefore corelease glutamate. In the present study, we analyzed mice with a conditional deletion of Vglut2 in DA neurons (Vglut2(f/f;DAT-Cre)) to address the functional significance of the glutamate-DA cophenotype for responses to cocaine and food reinforcement. Biochemical parameters of striatal DA function were also examined by using DA receptor autoradiography, immediate-early gene quantitative in situ hybridization after cocaine challenge, and DA-selective in vivo chronoamperometry. Mice in which Vglut2 expression had been abrogated in DA neurons displayed enhanced operant self-administration of both high-sucrose food and intravenous cocaine. Furthermore, cocaine seeking maintained by drug-paired cues was increased by 76%, showing that reward-dependent plasticity is perturbed in these mice. In addition, several lines of evidence suggest that adaptive changes occurred in both the ventral and dorsal striatum in the absence of VGLUT2: DA receptor binding was increased, and basal mRNA levels of the DA-induced early genes Nur77 and c-fos were elevated as after cocaine induction. Furthermore, in vivo challenge of the DA system by potassium-evoked depolarization revealed less DA release in both striatal areas. This study demonstrates that absence of VGLUT2 in DA neurons leads to perturbations of reward consumption as well as reward-associated memory, features of particular relevance for addictive-like behavior.

  • 227.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Pickering, Christopher
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Anxiolytic response after palatable diet consumption but not food restriction in rats2009Ingår i: Appetite, ISSN 0195-6663, E-ISSN 1095-8304, Vol. 52, nr 3, s. 816-816Artikel i tidskrift (Övrigt vetenskapligt)
  • 228.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hulting, Anna-Lena
    Meyerson, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Anxiety-like behaviour predicts the preference for a high-carbohydrate diet in outbred rats2007Ingår i: Behavioural Pharmacology, ISSN 0955-8810, E-ISSN 1473-5849, Vol. 18, s. S41-S41Artikel i tidskrift (Övrigt vetenskapligt)
  • 229.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Olszewski, Pawel K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jonsson, Petra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009Ingår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, nr 2, s. 193-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate whether the preference for a palatable high-fat diet (HFD) is associated with response to novelty and with anxiety-like behavior in rats and whether such fat preference correlates with gene expression of hypothalamic neuropeptides related to feeding. We subjected male rats to two tests of exploration of novel environments: the multivariate concentric square field (MCSF) and the elevated plus maze (EPM). The rats were then exposed to a 5-day test of preference for a palatable HFD versus reference diets. Messenger RNA (mRNA) levels of 21 neuropeptides were investigated by quantitative polymerase chain reaction. We found a strong positive correlation of HFD preference and open-arm activity in the EPM (% open-arm time, r(s) = 0.629, df = 26, P < 0.001). Thus, HFD preference was inversely associated with anxiety-like behavior. The same association was found for HFD preference and behavior in the MCSF (bridge entries, r(s) = 0.399, df = 23, P = 0.048). In addition, the HFD preference was positively correlated (r(s) = 0.433, df = 25, P = 0.021) with hypothalamic mRNA levels of urocortin 2 (Ucn 2). Moreover, behavior in the EPM was significantly correlated with expression levels of the receptor for Ucn 2, the corticotropin-releasing factor receptor 2, in the hypothalamus (r(s) = 0.382, df = 33, P = 0.022, pituitary (r(s) = 0.494, df = 31, P = 0.004) and amygdala (r(s) = 0.381, df = 30, P = 0.032). We conclude that preference for palatable HFD is inversely associated with anxiety and propose that Ucn 2 signaling may play a role in this association.

  • 230.
    Alskär, Linda C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Improved Molecular Understanding of Lipid-Based Formulations: for Enabling Oral Delivery of Poorly Water-Soluble Drugs2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The majority of emerging drug candidates are not suited for conventional oral dosage forms, as they do not dissolve in the aqueous environment of the gastrointestinal (GI) tract. Consequently, a large number of enabling formulation strategies have emerged. One such strategy is to deliver the drug pre-dissolved in a lipid-based formulation (LBF), thereby bypassing the rate-limiting dissolution step. To date, only about 4% of the marketed oral drugs are delivered as LBFs. The limited use of this strategy is a result of the incomplete understanding of drug solubility in lipid vehicles, the reduced chemical stability of pre-dissolved drug, and the complex interplay between drug and formulation undergoing intestinal lipid processing. Hence, this thesis targeted an improved molecular understanding of lipid-based drug delivery to make an informed formulation development. In the first part of the thesis, drug solubility in LBF excipients and composed formulations was assessed. Through experimental studies of nearly forty compounds in nine excipients drug physicochemical properties related to solubility in these excipients were identified. The obtained data was used to develop in silico tools for prediction of drug solubility in excipients and formulations. The second part of the thesis focused on LBF performance in vitro and in vivo. Factors associated with the type of solid form that is precipitating during digestions was revealed, which provides an initial framework for understanding drug precipitation behaviour under physiological conditions. It was also shown that clinically relevant doses of LBF significantly increases intestinal drug solubilization as a result of GI lipid processing and bile secretion. Moreover, simultaneous assessment of digestion and absorption in vitro provided the same rank order of absorbed drug as the in vivo studies. Coadministration of LBF and drug was shown to be a promising alternative to pre-dissolved drug in the LBF. In summary, this thesis has improved the molecular understanding of factors that govern drug solubility in lipid vehicles and solid form of precipitated drug under digestive conditions. It was also proved that clinically relevant doses of LBFs significantly increase the intestinal drug solubilization, and proof-of-concept was shown for coadministration of LBF with solid drug as an alternative to drug-loaded LBF.  

    Delarbeten
    1. Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients
    Öppna denna publikation i ny flik eller fönster >>Computational Prediction of Drug Solubility in Lipid Based Formulation Excipients
    2013 (Engelska)Ingår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 30, nr 12, s. 3225-3237Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties. Solubility was measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TG(LC)), Captex355 (medium-chain triglyceride; TG(MC)), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests. Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (R (2) = 0.98). A strong correlation was also found between PS80 and PEG400 (R (2) = 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80. In silico models based on calculated descriptors were successfully developed for drug solubility in SBO (R (2) = 0.81, Q (2) = 0.76) and Captex355 (R (2) = 0.84, Q (2) = 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure. Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TG(MC) versus TG(LC), and PS80 versus PEG400. We also show, for the first time, that solubility in TG(MC) and TG(LC) can be predicted from rapidly calculated molecular descriptors.

    Nyckelord
    computational prediction, lipid based formulation, loading capacity, molecular properties, solubility
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-213917 (URN)10.1007/s11095-013-1083-7 (DOI)000327878300019 ()
    Tillgänglig från: 2014-01-06 Skapad: 2014-01-05 Senast uppdaterad: 2018-11-21Bibliografiskt granskad
    2. Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
    Öppna denna publikation i ny flik eller fönster >>Tools for Early Prediction of Drug Loading in Lipid-Based Formulations
    2016 (Engelska)Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, nr 1, s. 251-261Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R-2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R-2 0.85; Polysorbate 80, R-2 0.90; Cremophor EL, R-2 0.93). A melting point below 150 degrees C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R-2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R-2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

    Nyckelord
    lipid-based formulations, solubility prediction, loading capacity, molecular properties, in silico prediction
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-275856 (URN)10.1021/acs.molpharmaceut.5b00704 (DOI)000367866200026 ()26568134 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 621-2011-2445 621-2014-3309EU, Europeiska forskningsrådet, 638965
    Tillgänglig från: 2016-02-16 Skapad: 2016-02-08 Senast uppdaterad: 2018-11-21Bibliografiskt granskad
    3. Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
    Öppna denna publikation i ny flik eller fönster >>Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations
    Visa övriga...
    2018 (Engelska)Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, nr 10, s. 4733-4744Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.

    Ort, förlag, år, upplaga, sidor
    American Chemical Society (ACS), 2018
    Nyckelord
    Poorly water-soluble drugs, lipid digestion, physicochemical properties, precipitation, solid state, supersaturation
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-366563 (URN)10.1021/acs.molpharmaceut.8b00699 (DOI)000446413400041 ()30142268 (PubMedID)
    Forskningsfinansiär
    EU, Europeiska forskningsrådet, 638965Vetenskapsrådet, 621-2011-2445, 621-2014-3309
    Tillgänglig från: 2018-11-21 Skapad: 2018-11-21 Senast uppdaterad: 2018-12-03Bibliografiskt granskad
    4. Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?
    Öppna denna publikation i ny flik eller fönster >>Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?
    Visa övriga...
    2019 (Engelska)Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 304, s. 90-100Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs.

    Nyckelord
    Intestinal digestion, in vivo dog study, lipid-based formulation, coadministration, absorption, in vitro in vivo correlation (IVIVC)
    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Identifikatorer
    urn:nbn:se:uu:diva-366566 (URN)10.1016/j.jconrel.2019.04.038 (DOI)000473719700009 ()31047962 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 621-2011-2445Vetenskapsrådet, 621-2014-3309EU, Europeiska forskningsrådet, 638965
    Tillgänglig från: 2018-11-21 Skapad: 2018-11-21 Senast uppdaterad: 2019-08-16Bibliografiskt granskad
    Ladda ner fulltext (pdf)
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    presentationsbild
  • 231.
    Alskär, Linda C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Models for Predicting Drug Absorption From Oral Lipid-Based Formulations2015Ingår i: Current molecular biology reports, ISSN 2198-6428, Vol. 1, nr 4, s. 141-147Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this review, we describe the in vitro tools currently used to identify when a lipid-based formulation has the potential to deliver a poorly water-soluble drug via the oral route. We describe the extent to which these tools reflect the in vivo performance of the formulation and, more importantly, we present strategies that we foresee will improve the in vitro-in vivo correlations. We also present emerging computational methods that are likely to allow large parts of the formulation development to be carried out in the computer rather than in the test tube. We suggest that these computational tools will also improve the mechanistic understanding of in vivo formulation performance in the complex and dynamic environment of the gut.

  • 232.
    Alskär, Linda C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Keemink, Janneke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Johannesson, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Porter, Christopher J H
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
    Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations2018Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, nr 10, s. 4733-4744Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.

  • 233.
    Alskär, Linda C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Parrow, Albin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Keemink, Janneke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Pernilla, Johansson
    AstraZeneca R&D, Gothenburg, Sweden .
    Abrahamsson, Bertil
    AstraZeneca R&D, Gothenburg, Sweden .
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Effect of lipids on absorption of carvedilol in dogs: Is coadministration of lipids as efficient as a lipid-based formulation?2019Ingår i: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 304, s. 90-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipidbased drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acids) and bile salts. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acids and bile salts in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in the solid form, e.g. due to chemical instability in the lipid vehicle. LBFs.

  • 234.
    Alskär, Linda C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Porter, Christopher J. H.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. UMonash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
    Tools for Early Prediction of Drug Loading in Lipid-Based Formulations2016Ingår i: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, nr 1, s. 251-261Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R-2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R-2 0.85; Polysorbate 80, R-2 0.90; Cremophor EL, R-2 0.93). A melting point below 150 degrees C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R-2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R-2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

  • 235.
    Alskär, Oskar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Glucose is an important nutrient and energy source in the body. However, too high concentration in the blood is harmful and may lead to several complications developing over time. It was estimated that 5 million people in the world died from complications related to diabetes during 2015. Several hormones and physiological factors are involved in the regulation of glucose homeostasis. To evaluate different aspects of glucose homeostasis and the effect of interventions, such as pharmacological treatment, glucose tolerance tests can be performed. In a glucose tolerance test glucose is administered either orally or intravenously, blood is sampled frequently and analyzed for different biomarkers. Mechanism-based pharmacometric models is a valuable tool in drug development, which can be applied to increase the knowledge about complex systems such as glucose homeostasis, quantify the effects of drugs, generate more information from clinical trials and contribute to more efficient study design. In this thesis, a new comprehensive mechanism-based pharmacometric model was developed. The model is capable of describing the most important aspects of glucose homeostasis during glucose tolerance test in healthy individuals and patients with type 2 diabetes, over a wide range of oral and intravenous glucose doses. Moreover, it can simultaneously describe regulation of gastric emptying and glucose absorption, regulation of the incretin hormones GLP-1 and GIP, hepatic extraction of insulin and the incretin effect, regulation of glucagon synthesis and regulation of endogenous glucose production. In addition, an interspecies scaling approach was developed by scaling a previously developed clinical glucose insulin model to describe intravenous glucose tolerance tests performed in mice, rats, dogs, pigs and monkeys. In conclusion, the developed mechanism-based models in this thesis increases the knowledge about short term regulation of glucose homeostasis and can be used to investigate combination treatments, drugs with multiple effects, and translation of drug effects between species, leading to improved drug development of new antidiabetic compounds.

    Delarbeten
    1. Model-Based Interspecies Scaling of Glucose Homeostasis
    Öppna denna publikation i ny flik eller fönster >>Model-Based Interspecies Scaling of Glucose Homeostasis
    2017 (Engelska)Ingår i: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, nr 11, s. 778-786Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species-specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

    Ort, förlag, år, upplaga, sidor
    John Wiley & Sons, 2017
    Nationell ämneskategori
    Farmakologi och toxikologi
    Identifikatorer
    urn:nbn:se:uu:diva-339699 (URN)10.1002/psp4.12247 (DOI)000418823400009 ()28960826 (PubMedID)
    Tillgänglig från: 2018-01-29 Skapad: 2018-01-29 Senast uppdaterad: 2018-02-26Bibliografiskt granskad
    2. Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Öppna denna publikation i ny flik eller fönster >>Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, nr 3, s. 340-348Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

    Nationell ämneskategori
    Farmaceutiska vetenskaper
    Forskningsämne
    Farmakokinetik och läkemedelsterapi
    Identifikatorer
    urn:nbn:se:uu:diva-259411 (URN)10.1002/jcph.602 (DOI)000370162700011 ()26224050 (PubMedID)
    Tillgänglig från: 2015-08-03 Skapad: 2015-08-03 Senast uppdaterad: 2018-02-26
    3. Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Öppna denna publikation i ny flik eller fönster >>Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Visa övriga...
    2017 (Engelska)Ingår i: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, nr 4, s. 290-297Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.

    Nationell ämneskategori
    Endokrinologi och diabetes
    Identifikatorer
    urn:nbn:se:uu:diva-279065 (URN)10.1111/bcpt.12792 (DOI)000409507900013 ()28374974 (PubMedID)
    Forskningsfinansiär
    EU, FP7, Sjunde ramprogrammet, 115156
    Tillgänglig från: 2016-02-29 Skapad: 2016-02-29 Senast uppdaterad: 2018-02-26Bibliografiskt granskad
    4. Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Öppna denna publikation i ny flik eller fönster >>Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Farmakologi och toxikologi
    Forskningsämne
    Farmakokinetik och läkemedelsterapi
    Identifikatorer
    urn:nbn:se:uu:diva-343114 (URN)
    Tillgänglig från: 2018-02-26 Skapad: 2018-02-26 Senast uppdaterad: 2018-02-26
    5. An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Öppna denna publikation i ny flik eller fönster >>An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nationell ämneskategori
    Farmakologi och toxikologi
    Forskningsämne
    Farmakokinetik och läkemedelsterapi
    Identifikatorer
    urn:nbn:se:uu:diva-343115 (URN)
    Tillgänglig från: 2018-02-26 Skapad: 2018-02-26 Senast uppdaterad: 2018-02-26
    Ladda ner fulltext (pdf)
    fulltext
    Ladda ner (jpg)
    presentationsbild
  • 236.
    Alskär, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bagger, Jonatan I
    Eriksson, Sara
    Holst, Jens J
    Knop, Filip K
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 DiabetesManuskript (preprint) (Övrigt vetenskapligt)
  • 237.
    Alskär, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bagger, Jonatan I
    Røge, Rikke M
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Knop, Filip K
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes2016Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, nr 3, s. 340-348Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

  • 238.
    Alskär, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bagger, Jonatan I
    Røge, Rikke M
    Komatsu, Kanji
    Kristensen, Niels
    Klim, Søren
    Holst, Jens J
    Ingwersen, Steen H
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Knop, Filip K
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucoseManuskript (preprint) (Övrigt vetenskapligt)
  • 239. Alskär, Oskar
    et al.
    Bagger, Jonatan
    Røge, Rikke Meldgaard
    Knop, Filip
    Karlsson, Mats
    Vilsbøll, Tina
    Kjellsson, Maria
    Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes2015Ingår i: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604Artikel i tidskrift (Refereegranskat)
  • 240.
    Alskär, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kjellsson, Maria C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Model-Based Interspecies Scaling of Glucose Homeostasis2017Ingår i: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, nr 11, s. 778-786Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species-specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

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  • 241.
    Alskär, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Korell, Julia
    Duffull, Stephen B.
    A pharmacokinetic model for the glycation of albumin2012Ingår i: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 39, nr 3, s. 273-282Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glycated haemoglobin (HbA1c) concentrations can be falsely lowered in circumstances when red blood cell (RBC) survival is reduced, e.g. in patients with chronic kidney disease (CKD). Glycated albumin (GA) has been suggested as an alternative marker of glycaemic control in these patients since it is independent of the RBC life span. The primary aim of this work was to develop a pharmacokinetic model that describes the time course of GA. The secondary aim was to assess the performance of GA as marker for glycaemic control in comparison to HbA1c based on simulations. For the second aim, three different scenarios were considered in the simulations: 1) assessment of the effect of large intra-day fluctuations in mean blood glucose on GA concentrations, 2) initiation of antidiabetic treatment on the GA profile, and 3) a hypothetical phase II study for a new antidiabetic compound. The GA model, as well as a previously developed HbA1c model described literature data well. GA concentrations appear to be stable even in the presence of high intra-day fluctuations in mean blood glucose concentrations. Simulation of a decrease in mean blood glucose concentrations resulted in a faster change in GA compared to HbA1c. GA also provided a time to 90 % power of the effect of a hypothetical antidiabetic drug that was 16 days shorter than when using HbA1c. These results indicate that GA could be used as alternative marker to assess blood glucose control in diabetic patients with CKD and also to follow an individual patient over time.

  • 242.
    Alsmark, U. Cecilia
    et al.
    Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, UK.
    Sicheritz-Ponten, Thomas
    Foster, Peter G.
    Hirt, Robert P.
    Embley, T. Martin
    Horizontal gene transfer in eukaryotic parasites: a case study of Entamoeba histolytica and Trichomonas vaginalis2009Ingår i: Horizontal Gene Transfer: Methods in Flux / [ed] Maria Boekels Gogarten, Johann Peter Gogarten and Lorraine Olendzenski, Humana Press , 2009, Vol. 532, s. 489-500Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Over the past few years it has become apparent that horizontal gene transfer (HGT) has played an important role in the evolution of pathogenic prokaryotes. What is less clear is the exact role that HGT has played in shaping the metabolism of eukaryotic organisms. The main problems are the reliable inference of HGT on a genomic scale as well as the functional assignment of genes in these poorly studied organisms. We have screened the completed genomes of the protists Entamoeba histolytica and Trichomonas vaginalis for cases of HGT from prokaryotes. Using a fast primary screen followed by a conservative phylogenetic approach, we found 68 and 153 recent cases of HGT in the respective organisms. The majority of transferred genes that fall into functional categories code for enzymes involved in metabolism. We found a broad range of prokaryotic lineages represented among the donors, but organisms that share similar environmental niches with E. histolytica and T. vaginalis, such as the gut and the vaginal mucosa, dominate.

  • 243.
    Altai, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 49, nr 3, s. 1185-1194Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 244.
    Altai, Mohamed
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Strand, Joanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Rosik, Daniel
    Selvaraju, Ram Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Eriksson Karlström, Amelie
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Plattformen för preklinisk PET.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap.
    Influence of Nuclides and Chelators on Imaging Using Affibody Molecules: Comparative Evaluation of Recombinant Affibody Molecules Site-Specifically Labeled with 68Ga and 111In via Maleimido Derivatives of DOTA and NODAGA2013Ingår i: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 24, nr 6, s. 1102-1109Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Accurate detection of cancer-associated molecular abnormalities in tumors could make cancer treatment more personalized. Affibody molecules enable high contrast imaging of tumor-associated protein expression shortly after injection. The use of the generator-produced positron-emitting radionuclide 68Ga should increase sensitivity of HER2 imaging. The chemical nature of radionuclides and chelators influences the biodistribution of Affibody molecules, providing an opportunity to further increase the imaging contrast. The aim of the study was to compare maleimido derivatives of DOTA and NODAGA for site-specific labeling of a recombinant ZHER2:2395 HER2-binding Affibody molecule with 68Ga. DOTA and NODAGA were site-specifically conjugated to the ZHER2:2395 Affibody molecule having a C-terminal cysteine and labeled with 68Ga and 111In. All labeled conjugates retained specificity to HER2 in vitro. Most of the cell-associated activity was membrane-bound with a minor difference in internalization rate. All variants demonstrated specific targeting of xenografts and a high tumor uptake. The xenografts were clearly visualized using all conjugates. The influence of chelator on the biodistribution and targeting properties was much less pronounced for 68Ga than for 111In. The tumor uptake of 68Ga-NODAGA-ZHER2:2395 and 68Ga-DOTA-ZHER2:2395 and tumor-to-blood ratios at 2 h p.i. did not differ significantly. However, the tumor-to-liver ratio was significantly higher for 68Ga-NODAGA- ZHER2:2395 (8 ± 2 vs 5.0 ± 0.3) offering the advantage of better liver metastases visualization. In conclusion, influence of chelators on biodistribution of Affibody molecules depends on the radionuclides and reoptimization of labeling chemistry is required when a radionuclide label is changed.

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  • 245.
    Alterman, Mathias
    Uppsala universitet, Medicinska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk kemi.
    Design and synthesis of HIV-1 protease inhibitors2001Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). The C2-symmetric HIV-1 protease is one of the prime targets for chemotherapy in the treatment of the HIV infection. Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. Design and synthesis of a number of C2-symmetrical C-terminal duplicated HIV-1 protease inhibitors and subsequent biological evaluation is presented in this thesis.

    A versatile three step synthetic route has been developed using a carbohydrate as an inexpensive chiral starting material thus allowing inhibitors with the desired stereochemistry to be obtained. By this efficient method a series of tailor-made P2/P2' modified inhibitors were synthesized, and these were evaluated on purified HIV-1 protease and in HIV-1 infected cell assays. Highly active HIV-1 protease inhibitors were identified among the tested compounds. Analyses of the X-ray crystal structures of two of the most active compounds, as complexes with the protease, guided the further design of P1/P1' elongated inhibitors. Substitutions in the para-position of the P1/P1' benzyl groups were promoted efficiently by microwave-irradiated of palladium-catalyzed reactions. Particular modifications in the P1/P1' region of the inhibitors resulted in a 40-fold increase of the anti-viral activity on HIV-1 infected cells. Furthermore, a fast, efficient, and general one-pot microwave enhanced synthesis protocol for transformations of organo-bromides to tetrazoles was developed and applied on the inhibitor scaffold. Attachment of linker molecules to the P1/P1' benzyl groups of one inhibitor was used to develop of sensitivity enhancer tools in surface plasmon resonance biosensor assays. These new assays enable the evaluation of low-molecular weight compounds as HIV-1 protease inhibitors.

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  • 246.
    Alterman, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Development of selective non-peptide angiotensin II type 2 receptor agonsists2010Ingår i: jraas. Journal of the renin-angiotensin-aldosterone system, ISSN 1470-3203, E-ISSN 1752-8976, Vol. 11, nr 1, s. 57-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The development of the first drug-like selective angiotensin II type 2 (AT(2)) receptor agonist (22) derived from the non-selective angiotensin II type 1 (AT(1)) receptor/AT(2) receptor agonist L-162,313 is presented. Compound 22 with a K-i value of 0.4 nM for the AT(2) receptor and a K-i > 10 mu M for the AT(1) receptor induces outgrowth of neurite cells, stimulates p42/p44(mapk), enhancesin vivo duodenal alkaline secretion in Sprague-Dawley rats and lowers the mean arterial blood pressure in anaesthetised spontaneously hypertensive rats. Thus, the peptidomimetic 22 exerts a similar biological response as the endogenous peptide angiotensin II after selective activation of the AT(2) receptor. In addition, Compound 22 has a bioavailability of 20-30% after oral administration and a half-life estimated to four hours in the rat. Compound 22 will therefore serve as a valuable research tool enabling studies of the function of the AT(2) receptor in more detail.

  • 247.
    Alterman, Mathias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Andersson, Hans O.
    Garg, Neeraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Ahlsén, Göran
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Lövgren, Seved
    Classon, Björn
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Kvarnström, Ingemar
    Vrang, Lotta
    Unge, Torsten
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Design and fast synthesis of C-terminal duplicated potent C2-symmetric P1/P1'-modified HIV-1 protease inhibitors1999Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 42, nr 19, s. 3835-3844Artikel i tidskrift (Refereegranskat)
  • 248.
    Alterman, Mathias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Björsne, Magnus
    Mühlman, Anna
    Classon, Björn
    Kvarnstrom, Ingemar
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Markgren, Per-Olof
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Nillroth, Ulrika
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Unge, Torsten
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Samuelsson, Bertil
    Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors: Use of L-mannaric acid as a peptidomimetic scaffold1998Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 41, nr 20, s. 3782-3792Artikel i tidskrift (Refereegranskat)
  • 249.
    Alterman, Mathias
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Sjöbom, Hans
    Säfsten, Pär
    Markgren, Per-Olof
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Danielson, U. Helena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för naturvetenskaplig biokemi.
    Hämäläinen, Markku
    Löfås, Stefan
    Hultén, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Classon, Björn
    Samuelsson, Bertil
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    P1/P1' modified HIV protease inhibitors as tools in two new sensitive surface plasmon resonance biosensor screening assays2001Ingår i: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 13, nr 2, s. 203-212Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The commonly used HIV-1 protease assays rely on measurements of the effect of inhibitions on the hydrolysis rate of synthetic peptides. Recently an assay based on surface plasmon resonance (SPR) was introduced. We have taken advantage of the fact that the SPR signal is proportional to the mass of the analyte interacting with the immobilised molecule and developed two new improved efficient competition assay methods. Thus, high molecular weight binders were used as amplifiers of the surface plasmon resonance signal. Linkers were attached by a Heck reaction to the para-positions of the P1/P1′ benzyloxy groups of a linear C2-symmetric C-terminal duplicated inhibitor to enable (a) biotin labelling or (b) direct immobilisation of the inhibitor to the biosensor surface matrix. The interaction properties of a series of 17 structurally diverse inhibitors was assessed and compared to previously reported data. The most sensitive assay was obtained by immobilising the enzyme and amplifying the signal with an antibody, giving a detection range between 0.1 nM and 10 μM. Immobilisation of the inhibitor resulted in a stable and durable surface but a narrower detection range (1–100 nM). The two competition assays are anticipated to be very suitable for fast screening of potential HIV inhibitors.

  • 250.
    Altman, S., Kirsebom, L.A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Teknisk-naturvetenskapliga fakulteten, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. MIKROBIOLOGI.
    Ribonuclease P1999Ingår i: RNA World (second edition), Cold Spring Harbor Press, NY , 1999, s. 351-Kapitel i bok, del av antologi (Övrigt vetenskapligt)
2345678 201 - 250 av 8367
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