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  • 101.
    Bjarnadóttir, Þóra Kristín
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    The Gene Repertoire of G protein-coupled Receptors: New Genes, Phylogeny, and Evolution2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The superfamily of G protein-coupled receptors (GPCRs) is one of the largest protein families of mammalian genomes and can be divided into five main families; Glutamate, Rhodopsin, Adhesion, Frizzled, and Secretin. GPCRs participate in most major physiological functions, contributing to the fact that they are important targets in drug discovery. In paper I we mined the human and mouse genomes for new Adhesion GPCR genes. We found two new human genes (GPR133 and GPR144) and 17 mouse Adhesion genes, bringing the number up to 33 human and 31 mouse genes. In paper II we describe 53 new splice variants for human Adhesion receptors supported by expressed sequence tags (EST) data. 29 of these variants seem to code for functional proteins, several of which lack one or more functional domains in the N-termini. Lack of certain domains is likely to affect ligand binding or interaction with other proteins. Paper III describes the Glutamate GPCR in human, mouse, Fugu, and zebrafish. We gathered a total of 22 human, 79 mouse, 30 Fugu, and 32 zebrafish sequences and grouped these into eight clans using phylogenetic methods. The report provides an overview of the expansion or deletions among the different branches of the Glutamate receptor family. Paper IV focuses on the trace amine (TA) clan of Rhodopsin GPCRs. We identified 18 new rodent genes, 57 zebrafish genes, and eight Fugu genes belonging to the clan. Chromosomal mapping together with phylogenetic relationships suggests that the family arose through several mechanisms involving tetraploidisation, block duplications, and local duplication events. Paper V provides a comprehensive dataset of the GPCR superfamily of human and mouse containing 495 mouse and 400 human non-olfactory GPCRs. Phylogenetic analyses showed that 329 of the receptors are found in one-to-one orthologous pairs, whereas other receptors may have originated from species-specific expansions.

    List of papers
    1. The human and mouse repertoire of the adhesion family of G-protein-coupled receptors
    Open this publication in new window or tab >>The human and mouse repertoire of the adhesion family of G-protein-coupled receptors
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    2004 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 84, no 1, p. 23-33Article in journal (Refereed) Published
    Abstract [en]

    The adhesion G-protein-coupled receptors (GPCRs) (also termed LN-7TM or EGF-7TM receptors) are membrane-bound proteins with long N-termini containing multiple domains. Here, 2 new human adhesion-GPCRs, termed GPR133 and GPR144, have been found by searches done in the human genome databases. Both GPR133 and GPR144 have a GPS domain in their N-termini, while GPR144 also has a pentraxin domain. The phylogenetic analyses of the 2 new human receptors show that they group together without close relationship to the other adhesion-GPCRs. In addition to the human genes, mouse orthologues to those 2 and 15 other mouse orthologues to human were identified (GPR110, GPR111, GPR112, GPR113, GPR114, GPR115, GPR116, GPR123, GPR124, GPR125, GPR126, GPR128, LEC1, LEC2, and LEC3). Currently the total number of human adhesion-GPCRs is 33. The mouse and human sequences show a clear one-to-one relationship, with the exception of EMR2 and EMR3, which do not seem to have orthologues in mouse. EST expression charts for the entire repertoire of adhesion-GPCRs in human and mouse were established. Over 1600 ESTs were found for these receptors, showing widespread distribution in both central and peripheral tissues. The expression patterns are highly variable between different receptors, indicating that they participate in a number of physiological processes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-97652 (URN)10.1016/j.ygeno.2003.12.004 (DOI)
    Available from: 2008-10-23 Created: 2008-10-23 Last updated: 2017-12-14Bibliographically approved
    2. Identification of novel splice variants of Adhesion G protein-coupled receptors
    Open this publication in new window or tab >>Identification of novel splice variants of Adhesion G protein-coupled receptors
    Show others...
    2007 (English)In: Gene, ISSN 0378-1119, E-ISSN 1879-0038, Vol. 387, no 1-2, p. 38-48Article in journal (Refereed) Published
    Abstract [en]

    Alternative splicing is an important mechanism to generate proteome diversity in higher eukaryotic organisms. We searched for splice variants of the human Adhesion family of G protein-coupled receptors (GPCRs) using mRNA sequences and expressed sequence tags. The results presented here describe 53 human splice variants among the 33 Adhesion GPCRs. Many of these variants appear to be coding for “functional” proteins (29) while the others are seemingly “non-functional” (24). Novel functional splice variants were found for: CD97, CELR3, EMR2, EMR3, GPR56, GPR110, GPR112–GPR114, GPR116, GPR123–GPR126, GPR133, HE6, and LEC1–LEC3. Splice variants for GPR116, GPR125, GPR126, and HE6 were found conserved in other species. Several of the functional splice variants lack one or more of the functional domains that are found in the N-termini of these receptors. These functional domains are likely to affect ligand binding or interaction with other proteins and these novel splice variants may have important roles for the specificity of interactions between these receptors and extracellular molecules. Another type of splice variants found here lacks a GPCR proteolytic site (GPS). The GPS domain has been shown to be essential for the proteolytic cleavage of the receptors N-termini and for cellular surface expression. We suggest that these alternative splice variants may be crucial for the function of the receptors while the seemingly non-functional splice variants may be a part of a regulative mechanism.

    Keywords
    GPCR; Clan B2, EGF-7TM, Splice variants, N-termini, Functional domains
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94121 (URN)10.1016/j.gene.2006.07.039 (DOI)000243761300006 ()
    Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2017-12-14Bibliographically approved
    3. The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste (1) and other related G protein-coupled receptors
    Open this publication in new window or tab >>The gene repertoire and the common evolutionary history of glutamate, pheromone (V2R), taste (1) and other related G protein-coupled receptors
    2005 In: Gene, ISSN 0378-1119, Vol. 362, p. 70-84Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94122 (URN)
    Available from: 2006-03-22 Created: 2006-03-22Bibliographically approved
    4. The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish
    Open this publication in new window or tab >>The repertoire of trace amine G-protein-coupled receptors: large expansion in zebrafish
    Show others...
    2005 In: Molecular Phylogenetics and Evolution, ISSN 1055-7903, Vol. 35, no 2, p. 470-482Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-94123 (URN)
    Available from: 2006-03-22 Created: 2006-03-22Bibliographically approved
    5. Comprehensive repertoire and phylogenetic analysis of the G-protein-coupled receptors in human and mouse
    Open this publication in new window or tab >>Comprehensive repertoire and phylogenetic analysis of the G-protein-coupled receptors in human and mouse
    Show others...
    2006 (English)In: Genomics, ISSN 0888-7543, E-ISSN 1089-8646, Vol. 88, no 3, p. 263-273Article in journal (Refereed) Published
    Abstract [en]

    Understanding differences in the repertoire of orthologous gene pairs is vital for interpretation of pharmacological and physiological experiments if conclusions are conveyed between species. Here we present a comprehensive dataset for G protein-coupled receptors (GPCRs) in both human and mouse with a phylogenetic road map. We performed systematic searches applying several search tools such as BLAST, BLAT, and Hidden Markov models and searches in literature data. We aimed to gather a full-length version of each human or mouse GPCR in only one copy referring to a single chromosomal position. Moreover, we performed detailed phylogenetic analysis of the transmembrane regions of the receptors to establish accurate orthologous pairs. The results show the identity of 495 mouse and 400 human functional nonolfactory GPCRs. Overall, 329 of the receptors are found in one-to-one orthologous pairs, while 119 mouse and 31 human receptors originate from species-specific expansions or deletions. The average percentage similarity of the orthologue pairs is 85%, while it varies between the main GRAFS families from an average of 59 to 94%. The orthologous pairs for the lipid-binding GPCRs had the lowest levels of conservation, while the biogenic amines had highest levels of conservation. Moreover, we searched for expressed sequence tags (ESTs) and identified more than 17,000 ESTs matching GPCRs in mouse and human, providing information about their expression patterns. On the whole, this is the most comprehensive study of the gene repertoire that codes for human and mouse GPCRs. The datasets are available for downloading.

    Keywords
    GPCR, glutamate, rhodopsin, adhesion, frizzled, taste2, secretin
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-94124 (URN)10.1016/j.ygeno.2006.04.001 (DOI)000240371500002 ()16753280 (PubMedID)
    Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2017-12-14Bibliographically approved
  • 102.
    Bjermo, Helena
    et al.
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Aune, Marie
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Cantillana, Tatiana
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Glynn, Anders
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Darnerud, Per Ola
    Swedish Natl Food Agcy, Uppsala, Sweden..
    Serum levels of brominated flame retardants (BFRs: PBDE, HBCD) and influence of dietary factors in a population-based study on Swedish adults2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 167, p. 485-491Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate associations between serum concentrations of brominated flame retardants and personal characteristics, including diet, in adults participating in a population-based study in Sweden 2010-11. Moreover, observed concentrations were used in a health risk assessment, using published health-based reference values. Serum samples of 170 adult individuals of both sexes were analyzed for 10 PBDE congeners and HBCD by GC-MS. When including concentrations between LOD and LOQ, highest median serum concentration was observed for BDE-153 (1.2 ng/g serum lipid), followed by BDE-209 (0.95 ng/g lipid), BDE-47 (0.49 ng/g lipid) and BDE-100 (0.21 ng/g lipid). Median concentration of HBCD was 0.10 ng/g lipid. A few markedly elevated concentrations of BDE-209, HBCD (77-78 ng/g lipid) and BDE-47 (44 ng/g lipid) were observed. The only statistical significant findings were higher BDE-153 concentrations in men than in women, and positive associations between serum BDE-153 concentrations and consumption of fish (total), beef, mutton and poultry. PBDE concentrations were in accordance with concentrations reported in other European countries but generally lower than those found in North America. Median PBDE serum concentrations observed in adults from Sweden suggest sufficient health protection, when compared with published health-based reference values, although some outliers with high serum concentrations had lower safety margins.

  • 103.
    Bjerre, Lise M.
    et al.
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada.
    Ramsay, Timothy
    Univ Ottawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Cahir, Catriona
    Trinity Coll Dublin, Dublin, Ireland.
    Ryan, Cristin
    Royal Coll Surgeons Ireland, Dublin, Ireland.
    Halil, Roland
    Univ Ottawa, Ottawa, ON, Canada.
    Farrell, Barbara
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;Univ Waterloo, Waterloo, ON, Canada.
    Thavorn, Kednapa
    Univ Ottawa, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Catley, Christina
    ICES UOttawa, Ottawa, ON, Canada.
    Hawken, Steven
    Univ Ottawa, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Ducharme, Robin
    ICES UOttawa, Ottawa, ON, Canada.
    Smith, Glenys
    ICES UOttawa, Ottawa, ON, Canada.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Manuel, Douglas G.
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Identifying Potentially Inappropriate Prescriptions in Whole Populations: Coding the Beers Criteria for Use with Large, Routinely Collected Population Datasets2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, p. 203-203Article in journal (Other academic)
  • 104.
    Bjerre, Lise M.
    et al.
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada.
    Ramsay, Timothy
    Univ Ottawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Cahir, Catriona
    Trinity Coll Dublin, Dublin, Ireland.
    Ryan, Cristin
    Royal Coll Surgeons Ireland, Dublin, Ireland.
    Halil, Roland
    Univ Ottawa, Ottawa, ON, Canada.
    Farrell, Barbara
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;Univ Waterloo, Waterloo, ON, Canada.
    Thavorn, Kednapa
    Univ Ottawa, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Catley, Christina
    ICES UOttawa, Ottawa, ON, Canada.
    Hawken, Steven
    Univ Ottawa, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Ducharme, Robin
    ICES UOttawa, Ottawa, ON, Canada.
    Smith, Glenys
    ICES UOttawa, Ottawa, ON, Canada.
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Manuel, Douglas G.
    Univ Ottawa, Ottawa, ON, Canada;Bruyere Res Inst, Ottawa, ON, Canada;ICES UOttawa, Ottawa, ON, Canada;Ottawa Hosp, Res Inst, Ottawa, ON, Canada.
    Identifying Potentially Inappropriate Prescriptions in Whole Populations: Coding the STOPP-START Criteria for Use with Large, Routinely Collected Population Datasets2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, p. 203-204Article in journal (Other academic)
  • 105.
    Bjerre, Lise M.
    et al.
    Univ Ottawa, Dept Family Med, Ottawa, ON, Canada.;Bruyere Res Inst, Ottawa, ON, Canada.;ICES uOttawa, Ottawa, ON, Canada.;Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada..
    Ramsay, Timothy
    Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada.;Ottawa Hosp, Res Inst, Ottawa, ON, Canada..
    Cahir, Catriona
    Univ Dublin Trinity Coll, Econ & Social Res Inst, Dublin 2, Ireland..
    Ryan, Cristin
    Royal Coll Surgeons Ireland, Sch Pharm, Dublin 2, Ireland..
    Halil, Roland
    Univ Ottawa, Dept Family Med, Ottawa, ON, Canada..
    Farrell, Barbara
    Univ Ottawa, Dept Family Med, Ottawa, ON, Canada.;Bruyere Res Inst, Ottawa, ON, Canada.;Univ Waterloo, Sch Pharm, Waterloo, ON N2L 3G1, Canada..
    Thavorn, Kednapa
    ICES uOttawa, Ottawa, ON, Canada.;Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada.;Ottawa Hosp, Res Inst, Ottawa, ON, Canada..
    Catley, Christina
    ICES uOttawa, Ottawa, ON, Canada..
    Hawken, Steven
    ICES uOttawa, Ottawa, ON, Canada.;Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada.;Ottawa Hosp, Res Inst, Ottawa, ON, Canada..
    Gillespie, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy.
    Manuel, Douglas G.
    Univ Ottawa, Dept Family Med, Ottawa, ON, Canada.;Bruyere Res Inst, Ottawa, ON, Canada.;ICES uOttawa, Ottawa, ON, Canada.;Univ Ottawa, Sch Epidemiol Publ Hlth & Prevent Med, Ottawa, ON, Canada.;Ottawa Hosp, Res Inst, Ottawa, ON, Canada..
    Assessing potentially inappropriate prescribing (PIP) and predicting patient outcomes in Ontario's older population: a population-based cohort study applying subsets of the STOPP/START and Beers' criteria in large health administrative databases2015In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 5, no 11, article id e010146Article in journal (Refereed)
    Abstract [en]

    Introduction: Adverse drug events (ADEs) are common in older people and contribute significantly to emergency department (ED) visits, unplanned hospitalisations, healthcare costs, morbidity and mortality. Many ADEs are avoidable if attention is directed towards identifying and preventing inappropriate drug use and undesirable drug combinations. Tools exist to identify potentially inappropriate prescribing (PIP) in clinical settings, but they are underused. Applying PIP assessment tools to population-wide health administrative data could provide an opportunity to assess the impact of PIP on individual patients as well as on the healthcare system. This would open new possibilities for interventions to monitor and optimise medication management on a broader, population-level scale. Methods and analysis: The aim of this study is to describe the occurrence of PIP in Ontario's older population (aged 65 years and older), and to assess the health outcomes and health system costs associated with PIP-more specifically, the association between PIP and the occurrence of ED visits, hospitalisations and death, and their related costs. This will be done within the framework of a population-based retrospective cohort study using Ontario's large health administrative and population databases. Eligible patients aged 66 years and older who were issued at least 1 prescription between 1 April 2003 and 31 March 2014 (approximately 2 million patients) will be included. Ethics and dissemination: Ethical approval was obtained from the Ottawa Health Services Network Ethical Review Board and from the Bruyere Research Institute Ethics Review Board. Dissemination will occur via publication, presentation at national and international conferences, and ongoing exchanges with regional, provincial and national stakeholders, including the Ontario Drug Policy Research Network and the Ontario Ministry of Health and Long-Term Care.

  • 106.
    Bjorklund, Geir
    et al.
    Council Nutr & Environm Med CONEM, Toften 24, N-8610 Mo I Rana, Norway.
    Chirumbolo, Salvatore
    Univ Verona, Dept Neurosci Biomed & Movement Sci, Verona, Italy;CONEM Sci Secretary, Verona, Italy.
    Dadar, Maryam
    AREEO, Razi Vaccine & Serum Res Inst, Karaj, Iran.
    Pivina, Lyudmila
    Semey Med Univ, Semey, Kazakhstan;Semey Med Univ, CONEM Kazakhstan Environm Hlth & Safety Res Grp, Semey, Kazakhstan.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Butnariu, Monica
    Banats Univ Agr Sci & Vet Med King Michael I Roma, Timisoara, Romania;Banats Univ Agr Sci & Vet Med King Michael I Roma, CONEM Romania Biotechnol & Environm Sci Grp, Timisoara, Romania.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, Elverum, Norway.
    Mercury exposure and its effects on fertility and pregnancy outcome2019In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 125, no 4, p. 317-327Article, review/survey (Refereed)
    Abstract [en]

    Mercury (Hg), a highly toxic environmental pollutant, shows harmfulness which still represents a big concern for human health, including hazards to fertility and pregnancy outcome. Research has shown that Hg could induce impairments in the reproductive function, cellular deformation of the Leydig cells and the seminiferous tubules, and testicular degeneration as well as abnormal menstrual cycles. Some studies investigated spontaneous abortion and complicated fertility outcome due to occupational Hg exposure. Moreover, there is a relation between inhaled Hg vapour and reproductive outcome. This MiniReview evaluates the hypothesis that exposure to Hg may increase the risk of reduced fertility, spontaneous abortion and congenital deficits or abnormalities.

  • 107. Björkholm, Carl
    et al.
    Marcus, Monica M
    Konradsson-Geuken, Åsa
    Jardemark, Kent
    Svensson, Torgny H
    The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism.2017In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 27, p. 411-417, article id S0924-977X(17)30047-0Article in journal (Refereed)
    Abstract [en]

    Brexpiprazole (Rexulti(®)), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

  • 108.
    Björklund, Geir
    et al.
    Council Nutr & Environm Med, Toften 24, N-8610 Mo I Rana, Norway.
    Hilt, Björn
    St Olavs Univ Hosp, Dept Occupat Med, Trondheim, Norway;Norwegian Univ Sci & Technol, Dept Publ Hlth & Nursing, Trondheim, Norway.
    Dadar, Maryam
    AREEO, Razi Vaccine & Serum Res Inst, Karaj, Iran.
    Lindh, Ulf
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, Fac Hlth & Social Sci, Elverum, Norway.
    Neurotoxic effects of mercury exposure in dental personnel2019In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 124, no 5, p. 568-574Article, review/survey (Refereed)
    Abstract [en]

    Numerous studies have reported neurobehavioural effects in dental personnel occupationally exposed to chronic low levels of mercury (Hg). Hg exposure from dental work may also induce various chronic conditions such as elevation of amyloid protein expression, deterioration of microtubules and increase or inhibition of transmitter release at motor nerve terminal endings. Therefore, clinical studies of Hg toxicity in dentistry may provide new knowledge about disturbed metal homeostasis in neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis and mood disorders. The purpose of this MiniReview is to evaluate the evidence of possible relevance between Hg exposure in dentistry and idiopathic disturbances in motor functions, cognitive skills and affective reactions, as well as dose-response relationships.

  • 109.
    Bloch, K. M.
    et al.
    Univ Liverpool, Liverpool, Merseyside, England..
    Carr, D.
    Univ Liverpool, Liverpool, Merseyside, England..
    Pirmohamed, M.
    Univ Liverpool, Liverpool, Merseyside, England..
    Morris, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Maroteau, C.
    Dundee Univ, Dundee, Scotland..
    Eriksson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Palmer, C.
    Dundee Univ, Dundee, Scotland..
    Alfirevic, A.
    Univ Liverpool, Liverpool, Merseyside, England..
    Whole exome sequencing in individuals with statin-induced myopathy2017In: Drug Safety, ISSN 0114-5916, E-ISSN 1179-1942, Vol. 40, no 10, p. 1026-1026Article in journal (Other academic)
  • 110.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Senkowski, Wojciech
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Jarvius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Berglund, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Lenhammar, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Parrow, Vendela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Loskog, Angelica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation2017In: Immunopharmacology and immunotoxicology, ISSN 0892-3973, E-ISSN 1532-2513, Vol. 39, no 4, p. 199-210Article in journal (Refereed)
    Abstract [en]

    Mebendazole (MBZ), a drug commonly used for helminitic infections, has recently gained substantial attention as a repositioning candidate for cancer treatment. However, the mechanism of action behind its anticancer activity remains unclear. To address this problem, we took advantage of the curated MBZ-induced gene expression signatures in the LINCS Connectivity Map (CMap) database. The analysis revealed strong negative correlation with MEK/ERK1/2 inhibitors. Moreover, several of the most upregulated genes in response to MBZ exposure were related to monocyte/macrophage activation. The MBZ-induced gene expression signature in the promyeloblastic HL-60 cell line was strongly enriched in genes involved in monocyte/macrophage pro-inflammatory (M1) activation. This was subsequently validated using MBZ-treated THP-1 monocytoid cells that demonstrated gene expression, surface markers and cytokine release characteristic of the M1 phenotype. At high concentrations MBZ substantially induced the release of IL-1 beta and this was further potentiated by lipopolysaccharide (LPS). At low MBZ concentrations, cotreatment with LPS was required for MBZ-stimulated IL-1 beta secretion to occur. Furthermore, we show that the activation of protein kinase C, ERK1/2 and NF-kappaB were required for MBZ-induced IL-1 release. MBZ-induced IL-1 release was found to be dependent on NLRP3 inflammasome activation and to involve TLR8 stimulation. Finally, MBZ induced tumor-suppressive effects in a coculture model with differentiated THP-1 macrophages and HT29 colon cancer cells. In summary, we report that MBZ induced a pro-inflammatory (M1) phenotype of monocytoid cells, which may, at least partly, explain MBZ's anticancer activity observed in animal tumor models and in the clinic.

  • 111.
    Bodén, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Bexelius, Tomas S
    Mattsson, Fredrik
    Lagergren, Jesper
    Lindblad, Mats
    Ljung, Rickard
    Antidopaminergic drugs and acute pancreatitis: a population-based study2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 3, p. e000914-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate the suggested association between antidopaminergic drugs and acute pancreatitis.

    DESIGN: A large population-based nested case-control study.

    SETTING: Swedish nationwide study from 2006 to 2008.

    PARTICIPANTS: The Patient Register was used to identify 6161 cases of acute pancreatitis. The 61 637 control subjects were randomly selected from the Register of the Total Population by frequency-based density sampling, matched for age, sex and calendar year.

    EXPOSURE: Exposure data were extracted from the Prescribed Drug Register. Antidopaminergic drugs were grouped into antiemetic/anxiolytic and other antipsychotics. Current use of antidopaminergic drugs was defined as filling a prescription 1-114 days before index date, while previous use was 115 days to 3.5 years before index date.

    MAIN OUTCOME MEASURES: Cases were defined as being diagnosed as having acute pancreatitis. ORs and 95% CIs were calculated using unconditional logistic regression.

    RESULTS: The unadjusted OR indicated an increased risk of acute pancreatitis among current users of antiemetic/anxiolytics (OR 1.9, 95% CI 1.4 to 2.6), but not in the multivariable model adjusting for alcohol-related comorbidity, chronic obstructive lung disease, ischaemic heart disease, obesity, diabetes, opioid use, gallstone disease, educational level, marital status and number of concomitant medications (OR 0.9, 95% CI 0.6 to 1.2). Similarly, among current users of other antipsychotics, the unadjusted OR was 1.4 (95% CI 1.1 to 1.6), while the adjusted OR was 0.8 (95% CI 0.6 to 0.9). Results regarding previous use of antidopaminergic drugs followed a similar risk pattern as for current use.

    CONCLUSIONS: The lack of association between antidopaminergic drugs and acute pancreatitis after adjustment for confounding factors in this study suggests that the previously reported positive associations might be explained by confounding.

  • 112.
    Boer, Jeltje
    et al.
    Netherlands Pharmacovigilance Ctr Lareb, Shertogenbosch, Netherlands.
    Ederveen, Ellen
    Netherlands Pharmacovigilance Ctr Lareb, Shertogenbosch, Netherlands.
    Grundmark, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala Monitoring Ctr, Uppsala, Sweden.
    Desloratadine and depression, a drug safety signal based on worldwide spontaneous reporting of side effects2018In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 123, no 3, p. 174-178Article in journal (Refereed)
    Abstract [en]

    Objective: Desloratadine, a third-generation antihistamine, is claimed to cause fewer central nervous system (CNS) adverse drug reactions (ADRs) than antihistamines of the first- and second-generation. While literature is inconclusive regarding the possible CNS effects, symptoms like somnolence and hallucinations are acknowledged ADRs of desloratadine, indeed suggesting some passage of this drug across the blood-brain barrier. Depression is currently not described as an ADR in the approved desloratadine product labelling.

    Materials and methods: In a joint signal detection workshop with the Uppsala Monitoring Centre and the Netherlands Pharmacovigilance Centre Lareb, case reports of suspected drug-ADR associations were analysed.

    Results: Forty-nine unique case reports of desloratadine associated with depression or depressed mood were detected in the WHO global ADR database. In these reports, the median time to onset of depression was three days. Most patients recovered after withdrawal of desloratadine, and in five patients the symptoms of depression recurred after re-administration of desloratadine.

    Conclusion: We hypothesize that desloratadine may enter the CNS and that it hence in rare cases may cause a clinically relevant state of depression, a relation that patients and their treating physicians should be made aware of.

  • 113.
    Boge, Lukas
    et al.
    RISE Res Inst Sweden, S-50115 Boras, Sweden;Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Browning, Kathryn L.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Nordström, Randi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Campana, Mario
    Rutherford Appleton Lab, Didcot OX11 0DE, Oxon, England.
    Darngaard, Liv S. E.
    Univ Copenhagen, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Caous, Josefin Seth
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Hellsing, Maja
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Ringstad, Lovisa
    RISE Res Inst Sweden, S-50115 Boras, Sweden.
    Andersson, Martin
    Chalmers Univ Technol, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden.
    Peptide-Loaded Cubosomes Functioning as an Antimicrobial Unit against Escherichia coil2019In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, no 24, p. 21314-21322Article in journal (Refereed)
    Abstract [en]

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

  • 114.
    Boger, E.
    et al.
    AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden.;Univ Warwick, Sch Engn, Coventry, W Midlands, England..
    Evans, N.
    Univ Warwick, Sch Engn, Coventry, W Midlands, England..
    Chappell, M.
    Univ Warwick, Sch Engn, Coventry, W Midlands, England..
    Lundqvist, A.
    AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
    Ewing, P.
    AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
    Wigenborg, A.
    AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca R&D, Dept Resp Inflammat & Autoimmun Innovat Med, Molndal, Sweden..
    Systems Pharmacology Approach for Prediction of Pulmonary and Systemic Pharmacokinetics and Receptor Occupancy of Inhaled Drugs2016In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 5, no 4, p. 201-210Article in journal (Refereed)
    Abstract [en]

    Pulmonary drug disposition after inhalation is complex involving mechanisms, such as regional drug deposition, dissolution, and mucociliary clearance. This study aimed to develop a systems pharmacology approach to mechanistically describe lung disposition in rats and thereby provide an integrated understanding of the system. When drug-and formulation-specific properties for the poorly soluble drug fluticasone propionate were fed into the model, it proved predictive of the pharmacokinetics and receptor occupancy after intravenous administration and nose-only inhalation. As the model clearly distinguishes among drug-specific, formulation-specific, and system-specific properties, it was possible to identify key determinants of pulmonary selectivity of receptor occupancy of inhaled drugs: slow particle dissolution and slow drug-receptor dissociation. Hence, it enables assessment of factors for lung targeting, including molecular properties, formulation, as well as the physiology of the animal species, thereby providing a general framework for rational drug design and facilitated translation of lung targeting from animal to man.

  • 115. Boger, Elin
    et al.
    Ewing, Par
    Eriksson, Ulf G.
    Fihn, Britt-Marie
    Chappell, Michael
    Evans, Neil
    Friden, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Novel In Vivo Receptor Occupancy Methodology for the Glucocorticoid Receptor: Toward An Improved Understanding of Lung Pharmacokinetic/Pharmacodynamic Relationships2015In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 353, no 2, p. 279-287Article in journal (Refereed)
    Abstract [en]

    Investigation of pharmacokinetic/pharmacodynamic (PK/PD) relationships for inhaled drugs is challenging because of the limited possibilities of measuring tissue exposure and target engagement in the lung. The aim of this study was to develop a methodology for measuring receptor occupancy in vivo in the rat for the glucocorticoid receptor (GR) to allow more informative inhalation PK/PD studies. From AstraZeneca's chemical library of GR binders, compound 1 [N-(2-amino-2-oxo-ethyl)-3-[5-[(1R,2S)-2-(2,2-difluoropropanoylamino)-1-(2,3-dihydro-1,4-benzodioxin-6-yl) propoxy] indazol-1-yl]-N-methyl-benzamide] was identified to have properties that are useful as a tracer for GR in vitro. When given at an appropriate dose (30 nmol/kg) to rats, compound 1 functioned as a tracer in the lung and spleen in vivo using liquid chromatography-tandem mass spectrometry bioanalysis. The methodology was successfully used to show the dose-receptor occupancy relationship measured at 1.5 hours after intravenous administration of fluticasone propionate (20, 150, and 750 nmol/kg) as well as to characterize the time profile for receptor occupancy after a dose of 90 nmol/kg i.v. The dose giving 50% occupancy was estimated as 47 nmol/kg. The methodology is novel in terms of measuring occupancy strictly in vivo and by using an unlabeled tracer. This feature confers key advantages, including occupancy estimation not being influenced by drug particle dissolution or binding/dissociation taking place postmortem. In addition, the tracer may be labeled for use in positron emission tomography imaging, thus enabling occupancy estimation in humans as a translatable biomarker of target engagement.

  • 116.
    Bohlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Fluorinated Substances Cytotoxicity and Influence on Proliferation of Human Breast Basal Epithelial Cells (MCF-10A)2018Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Introduction: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are man-made compounds that are water-, fat- and dirt repellent. Long-chain PFAS have been dominant on the market, until studies showed evidence of increased risk of cancer, developmental toxicity and liver toxicity. Regulations forced industries into change, which resulted in a transition to short-chain PFAS. However, growing evidence points towards similar adverse effects for several short-chained PFAS. This study investigates the toxicity of three short-chain PFAS.

    Materials and methods: Human breast epithelial cells (MCF-10A) were exposed to three short-chain PFAS in a varying range of concentrations and time of exposure. Results of cytotoxicity and proliferation were obtained by performing the MTT assay and receptor antagonists were used to investigate the role of each receptor. Also, oxidative stress was evaluated by DCFDA assay.

    Results: The investigated compounds demonstrated cytotoxicity at high concentrations (1 mM). Two compounds also induced cytotoxicity at lower concentrations In addition, one of the compounds induced cell proliferation at 500 µM after 72 h exposure.

    Conclusion: This study gives a first indication of the investigated compounds induced toxicological effects on human breast epithelial cells. The results contribute to the ongoing research with the aim to investigate the toxicological profiles of new PFAS compounds. 

  • 117.
    Bohlin, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Felth, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Strömstedt, Adam A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Bioassays in natural product research - Strategies and methods in the search for bioactive natural products2014In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 80, no 10, p. 753-753Article in journal (Other academic)
  • 118.
    Boldbaatar, Delgerbat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    El-Seedi, Hesham R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Findakly, Meriana
    Jabri, Safa
    Javzan, Batkhuu
    Choidash, Battsetseg
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Hellman, Bjorn
    Antigenotoxic and antioxidant effects of the Mongolian medicinal plant Leptopyrum fumarioides (L): An in vitro study2014In: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 155, no 1, p. 599-606Article in journal (Refereed)
    Abstract [en]

    Ethnopharmacological relevance: Leptopyrum fumarioides has been used in the traditional medicine of Mongolia for the treatment of various diseases, including drug intoxications. However, since there is only sparse information about its chemistry, active components, and pharmacological and toxicological effects, the major aim of the present study employing mouse lymphoma cells was to evaluate the genotoxic and antigenotoxic/antioxidative effects of extracts and components isolated from this plant. Material and methods: A crude methanol extract was separated into three different sub-extracts: dichloromethane, n-butanol, and water. The major constituent of the n-butanol extract, i.e., the flavone luteolin-7-O-glucoside and a mixture of the most abundant compounds in the dichloromethane sub-extract were then isolated. DNA damage was evaluated using the comet assay; the antioxidant activity was evaluated using the DPPH radical scavenging assay. Results: The crude methanol extract, the dichloromethane sub-extract and the mixture of compounds isolated from the latter fraction, increased the level of DNA damage after three hours of exposure. In contrast, no increase in DNA damage was observed in the cells that had been exposed to the n-butanol and water sub-extracts, or to the pure flavone. When non-DNA damaging concentrations of extracts and compounds were tested together with the DNA damaging agent catechol, all sub-extracts were found to reduce the catechol-induced DNA damage (the flavone was then found to be the most effective protective agent). The n-butanol sub-extract and the flavone were also found to have the most prominent antioxidative effects. Conclusion: Based on the results from the present study, components in Leptopyrum fumarioides were found to protect the DNA damage induced by catechol, probably by acting as potent antioxidants.

  • 119.
    Bonate, Peter L.
    et al.
    Astellas, 1 Astellas Way, Northbrook, IL 60062 USA..
    Ahamadi, Malidi
    Merck & Co Inc, 351 N Sumneytown Pike, N Wales, PA 19454 USA..
    Budha, Nageshwar
    Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA..
    de la Pena, Amparo
    Eli Lilly & Co Chorus, Lilly Corp Ctr, Indianapolis, IN 46285 USA..
    Earp, Justin C.
    US FDA, 10903 New Hampshire Ave,Bldg 51,Room 3154, Silver Spring, MD 20993 USA..
    Hong, Ying
    Novartis Pharmaceut, One Hlth Plaza, E Hanover, NJ 07936 USA..
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ravva, Patanjali
    Boehringer Ingelheim Pharmaceut Inc, 900 Ridgebury Rd, Ridgefield, CT 06877 USA..
    Ruiz-Garcia, Ana
    Pfizer, 10646 Sci Ctr Dr CB10 Off 2448, San Diego, CA 92121 USA..
    Struemper, Herbert
    Parexel Int Inc, 2520 Meridian Pkwy, Durham, NC 27713 USA..
    Wade, Janet R.
    Occams Cooperatie UA, Malandolaan 10, NL-1187 HE Amstelveen, Netherlands..
    Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group2016In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 43, no 2, p. 123-135Article in journal (Other academic)
    Abstract [en]

    The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results.

  • 120. Bondarenko, Olesja
    et al.
    Torres, Neus Feliu
    Kupferschmidt, Natalia
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Garcia-Bennett, Alfonso
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Fadeel, Bengt
    Cellular uptake of mesoporous silica particles is governed by activation state of macrophages2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S188-S188Article in journal (Refereed)
  • 121. Borg, Daniel
    et al.
    Bogdanska, Jasna
    Sundström, Maria
    Nobel, Stefan
    Håkansson, Helen
    Bergman, Åke
    DePierre, Joseph
    Halldin, Krister
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.2009In: Abstracts of the 46th Congress of the European Societies of Toxicology, 2009, p. S147-Conference paper (Refereed)
    Abstract [en]

    Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.

  • 122.
    Borg, Daniel
    et al.
    Karolinska Institutet.
    Bogdanska, Jasna
    Stockholms Universitet.
    Sundström, Maria
    Stockholms Universitet.
    Nobel, Stefan
    Stockholms Universitet.
    Håkansson, Helen
    Karolinska Institutet.
    Bergman, Åke
    Stockholms Universitet.
    Depierre, Jospeh W
    Stockholms Universitet.
    Halldin, Krister
    Karolinska Institutet.
    Bergström, Ulrika
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental Toxicology.
    Tissue distribution of (35)S-labelled perfluorooctane sulfonate (PFOS) in C57Bl/6 mice following late gestational exposure2010In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 30, no 4, p. 558-565Article in journal (Refereed)
    Abstract [en]

    Exposure of rodents in utero to perfluorooctane sulfonate (PFOS) impairs perinatal development and survival. Following intravenous or gavage exposure of C57Bl/6 mouse dams on gestational day (GD) 16 to (35)S-PFOS (12.5mg/kg), we determined the distribution in dams, fetuses (GD18 and GD20) and pups (postnatal day 1, PND1) employing whole-body autoradiography and liquid scintillation counting. In dams, levels were highest in liver and lungs. After placental transfer, (35)S-PFOS was present on GD18 at 2-3 times higher levels in lungs, liver and kidneys than in maternal blood. In PND1 pups, levels in lungs were significantly higher than in GD18 fetuses. A heterogeneous distribution of (35)S-PFOS was observed in brains of fetuses and pups, with levels higher than in maternal brain. This first demonstration of substantial localization of PFOS to both perinatal and adult lungs is consistent with evidence describing the lung as a target for the toxicity of PFOS at these ages.

  • 123.
    Borhade, Sanjay R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Brandt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Arvidsson, Per I.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Preclinical Characterization of Acyl Sulfonimidamides: Potential Carboxylic Acid Bioisosteres with Tunable Properties2015In: ChemMedChem, ISSN 1860-7179, E-ISSN 1860-7187, Vol. 10, no 3, p. 455-460Article in journal (Refereed)
    Abstract [en]

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

  • 124.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Rodriguez, David
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Romero Fernandez, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kapla, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jaiteh, Mariama
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ranganathan, Anirudh
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Lazarova, Tzvetana
    Autonomous Univ Barcelona, Fac Med, Dept Biochem & Mol Biol, Inst Neurosci, Barcelona, Spain.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 829Article in journal (Refereed)
    Abstract [en]

    The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

  • 125.
    Botros, Milad
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Biological Research on Drug Dependence.
    Characterization of Substance P (SP) Aminoterminal SP (1-7) Binding in Brain Regions and Spinal Cord of the Male Rat: Studies on the Interaction with Opioid Related Pathways2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Binding sites for substance P(1-7), SP(1-7) have been identified and characterized for the first time in crude membrane fraction from rat CNS using tritiated ([3H]) SP(1-7) as tracer. These putative receptors were investigated in relation to their affinity for tachykinins, opioid peptides and sigma receptor ligands. [3H]-SP(1-7) specifically binds to high affinity binding sites identified as receptor targets for the heptapeptide SP (1-7). Two distinct binding sites were observed in the spinal cord. One site is recognized by high affinity for SP(1-7) with a Kd of 0.5 nM, whereas the other site showed low affinity for the heptapeptide (Kd=12 nM). In the brain, the binding of SP(1-7) fitted a single site binding model with a Kd of 4.4 nM and a Ki of 4.2 nM. Further, using the spinal cord membranes the binding of [3H]-SP (1-7) was weakly displaced by SP and other N-terminal fragments thereof and no or negligible affinity was observed for ligands of the NK-1, NK-2 and NK-3 tachykinin receptors, C-terminal SP(5-11), Tyr-w-MIF-1 or the mu-opioid receptor antagonists naloxone and naloxonazine. On the other hand it was significantly displaced by endomorphin-2, DAMGO, and Try-MIF-1 and exhibit some affinity for MIF-1, ß-casomorphin and endomorphin-1. However, only endomorphin-2, DAMGO and Tyr-MIF-1 showed affinity in the close range of the native peptide SP(1-7). The affinity of endomorphin-2 for the spinal cord site was 10 times lower than that of SP(1-7) but more than 100 times higher than the affinity recorded for endomorphin-1. Tyr-MIF-1 but not Tyr-w-MIF-1 showed similar affinity as endomorphin-2 for SP(1-7) site. All peptides exhibiting high affinity at the SP(1-7) site, have a phenylalanine or a leucine residue in their C-terminal structure.

    Further, synthetic analogues of SP(1-7) were tested for their affinity for the SP(1-7) receptor in the rat spinal cord. An important finding here was that the receptor-ligand-interaction was favoured by the C-terminal region of SP(1-7). Residues at positions 5-7 appeared crucial for binding to the specific SP(1-7) site. The presence of the amidated Phe7 residue was extremely critical for binding to the SP(1-7) site.The analogue Gln5-Gln6-Phe7-NH2 was almost equipotent with the parent peptide in the SP (1-7) receptor binding assay.

    Furthermore, the SP(1-7)-amide potently and dose dependently reduced several signs of the reaction to morphine withdrawal and was significantly attenuated by the addition of the sigma agonist SK-10047.

    In conclusion, the work presented in this thesis has contributed the characterization of the properties of highly selective binding sites for SP(1-7) in the rat spinal cord and VTA. These sites appear to be distinct from the µ-opioid receptor or any of the known neurokinin receptors. The study further indicates that the SP(1-7)-amide mimics the effect of the nativ heptapeptide and that the mechanisms for its action involve a sigma receptor site.

    List of papers
    1. Endomorphin-1 and endomorphin-2 differently interact with specific binding sites for substance P (SP) aminoterminal SP (1-7) in the rat spinal cord
    Open this publication in new window or tab >>Endomorphin-1 and endomorphin-2 differently interact with specific binding sites for substance P (SP) aminoterminal SP (1-7) in the rat spinal cord
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    2006 In: Peptides, Vol. 27, no 4, p. 753-759Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97821 (URN)
    Available from: 2008-11-21 Created: 2008-11-21Bibliographically approved
    2. Endomorphins interact with the substance P (SP) aminoterminal SP (1-7) binding in the ventral tegmental area of the rat brain
    Open this publication in new window or tab >>Endomorphins interact with the substance P (SP) aminoterminal SP (1-7) binding in the ventral tegmental area of the rat brain
    Show others...
    2008 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 29, no 10, p. 1820-1824Article in journal (Refereed) Published
    Abstract [en]

    We have recently identified a specific binding site for the tachykinin peptide substance P (SP) fragment SP1-7 in the rat spinal cord. This site appeared very specific for SP1-7 as the binding affinity of this compound highly exceeded those of other SP fragments. We also observed that endomorphin-2 (EM-2) exhibited high potency in displacing SP1-7 from this site. In the present work using a [H-3]-labeled derivative of the heptapeptide we have identified and characterized [H-3]-SP1-7 binding in the rat ventral tegmental area (VTA). Similarly to the [H-3]-SP1-7 binding in the spinal cord the affinity of unlabeled SP1-7 to the specific site in VTA was significantly higher than those of other SP fragments. Further, the tachykinin receptor NK-1, NK-2 and NK-3 ligands showed no or negligible binding to the identified site. However, the mu-opioid peptide (MOP) receptor agonists DAMGO, EM-1 and EM-2 did, and significant difference was observed in the binding affinity between the two endomorphins. As recorded from displacement curves the affinity of EM-2 for the SP1-7 site was 4-5 times weaker than that for SP1-7 but about 5 times higher than that of EM-1. The opioid receptor antagonists naloxone and naloxonazine showed weak or negligible binding. it was concluded that the specific site identified for SP1-7 binding in the rat VTA is distinct from the MOP receptor although it exhibits high affinity for EM-2.

    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97822 (URN)10.1016/j.peptides.2008.05.014 (DOI)000260284100024 ()
    Available from: 2008-11-21 Created: 2008-11-21 Last updated: 2018-01-13Bibliographically approved
    3. Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality
    Open this publication in new window or tab >>Small peptides mimicking substance P (1-7) and encompassing a C-terminal amide functionality
    Show others...
    2008 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 42, no 1, p. 31-37Article in journal (Refereed) Published
    Abstract [en]

    Some of the biological effects demonstrated after administration of substance P (SP) in vivo can indirectly be attributed to the fragmentation of the undecapeptide to its N-terminal bioactive fragment SP1–7. This heptapeptide (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) is a major bioactive metabolite from SP that frequently exerts similar biological effects as the parent peptide but also, in several cases, completely opposite actions. Specific binding sites for the heptapeptide SP1–7 that are separate from the SP preferred NK receptors have been identified. In this study we demonstrate that (a) the C-terminal part of the SP metabolite SP1–7 is most important for binding as deduced from an Ala scan and that a replacement of Phe7 for Ala is deleterious, (b) truncation of the N-terminal amino acid residues of SP1–7 delivers peptides with retained binding activity, although with somewhat lower binding affinities than SP1–7 and (c) a C-terminal amide group as a replacement for the terminal carboxy group of SP1–7 and for all of the truncated ligands synthesized affords approximately 5–10-fold improvements of the binding affinities.

    Keywords
    Substance P (1–7), SP (1–7), SP1–7, Substance P, Structure–activity relationships (SAR), Ala scan, Peptidomimetics
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97823 (URN)10.1016/j.npep.2007.11.002 (DOI)000254231100003 ()18093649 (PubMedID)
    Available from: 2008-11-21 Created: 2008-11-21 Last updated: 2018-01-13Bibliographically approved
    4. The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats
    Open this publication in new window or tab >>The C-terminal amidated analogue of the Substance P (SP) fragment SP (1-7) attenuates the expression of naloxone- precipitated withdrawal in morphine dependent rats
    Show others...
    2009 (English)In: Peptides, ISSN 0196-9781, E-ISSN 1873-5169, Vol. 30, no 12, p. 2418-2422Article in journal (Refereed) Published
    Abstract [en]

    We previously demonstrated that intracerebroventricular (i.c.v.) administration of the substance P (SP) aminoterminal fragment SP(1-7) attenuates the expression of morphine withdrawal in the male rat. In this study we have used a synthetic analogue of this peptide, i.e. the SP(1-7) amide showing higher binding potency than the native heptapeptide, in a similar experimental set-up. Thus, Wistar male rats were made tolerant to morphine by daily injections of the opiate during 8 days. Following peptide administration (i.c.v.) and a subsequent naloxone challenge a variety of physical syndromes of withdrawal were recorded. We observed that the SP(1-7) amide potently and dose-dependently reduced several signs of reaction to morphine withdrawal. Interestingly, the effect of the peptide amide was significantly attenuated by the addition of the sigma agonist (+)-SKF-10047. We conclude that the SP(1-7) amide mimics the effect of the native SP fragment and that the mechanisms for its action involve a sigma receptor site.

    Keywords
    Morphine, Opiate, Substance P (SP), SP1-7 amide, Rat, Withdrawal, Sigma receptor
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97824 (URN)10.1016/j.peptides.2009.08.009 (DOI)000272903900044 ()19686790 (PubMedID)
    Available from: 2008-11-21 Created: 2008-11-21 Last updated: 2018-01-13Bibliographically approved
  • 126.
    Bouchene, Salim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Marchand, Sandrine
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Couet, William
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Friberg, Lena E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Gobin, Patrice
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Lamarche, Isabelle
    INSERM, U 1070, Pole Biol Sante, Poitiers, France.
    Gregoire, Nicolas
    INSERM, U 1070, Pole Biol Sante, Poitiers, France;CHU Poitiers, Lab Toxicol & Pharmacocinet, Poitiers, France.
    Björkman, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    A Whole-Body Physiologically Based Pharmacokinetic Model for Colistin and Colistin Methanesulfonate in Rat2018In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 123, no 4, p. 407-422Article in journal (Refereed)
    Abstract [en]

    Colistin is a polymyxin antibiotic used to treat patients infected with multidrug-resistant Gram-negative bacteria (MDR-GNB). The objective of this work was to develop a whole-body physiologically based pharmacokinetic (WB-PBPK) model to predict tissue distribution of colistin in rat. The distribution of a drug in a tissue is commonly characterized by its tissue-to-plasma partition coefficient, K-p. Colistin and its prodrug, colistin methanesulfonate (CMS) K-p priors, were measured experimentally from rat tissue homogenates or predicted in silico. The PK parameters of both compounds were estimated fitting invivo their plasma concentration-time profiles from six rats receiving an i.v. bolus of CMS. The variability in the data was quantified by applying a nonlinear mixed effect (NLME) modelling approach. A WB-PBPK model was developed assuming a well-stirred and perfusion-limited distribution in tissue compartments. Prior information on tissue distribution of colistin and CMS was investigated following three scenarios: K-p was estimated using in silico K-p priors (I) or K-p was estimated using experimental K-p priors (II) or K-p was fixed to the experimental values (III). The WB-PBPK model best described colistin and CMS plasma concentration-time profiles in scenario II. Colistin-predicted concentrations in kidneys in scenario II were higher than in other tissues, which was consistent with its large experimental K-p prior. This might be explained by a high affinity of colistin for renal parenchyma and active reabsorption into the proximal tubular cells. In contrast, renal accumulation of colistin was not predicted in scenario I. Colistin and CMS clearance estimates were in agreement with published values. The developed model suggests using experimental priors over in silico K-p priors for kidneys to provide a better prediction of colistin renal distribution. Such models might serve in drug development for interspecies scaling and investigate the impact of disease state on colistin disposition.

  • 127.
    Bouquet, Emilie
    et al.
    CHRU Tours, Univ Hosp, Dept Clin Pharmacol, F-37044 Tours, France;CHRU Tours, Univ Hosp, Reg Pharmacovigilance Ctr, F-37044 Tours, France.
    Star, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala Monitoring Ctr, S-75140 Uppsala, Sweden.
    Jonville-Bera, Annie Pierre
    CHRU Tours, Univ Hosp, Dept Clin Pharmacol, F-37044 Tours, France;CHRU Tours, Univ Hosp, Reg Pharmacovigilance Ctr, F-37044 Tours, France.
    Durrieu, Genevieve
    Toulouse Univ Hosp, Fac Med, Dept Med & Clin Pharmacol, 37 Allees Jules Guesde, F-31000 Toulouse, France.
    Pharmacovigilance in pediatrics2018In: Therapie (Paris), ISSN 0040-5957, E-ISSN 1958-5578, Vol. 73, no 2, p. 171-180Article in journal (Refereed)
    Abstract [en]

    The characteristics of pharmacology and drug evaluation in the pediatric age group highlight the necessity for the pharmacovigilance community to adjust to the specific features of children. At the time of marketing a medicinal product intended for children, the product's safety profile is sometimes less well known than for adults due to fewer or small sample clinical trials. Furthermore, the frequent off-labeled drug use, the use of unsuitable dosage forms and the need for continuous dose adjustments increase the risk of medication errors and thus lead to avoidable adverse drug reactions (ADRs). The occurrence of child-specific ADRs (such as growth disorders) or ADRs more commonly occurring in children than in adults make it necessary to monitor the safety of child-specific drugs. Pediatric pharmacovigilance includes also the consequences of in utero exposure, whether manifestations are present from birth or occur in early childhood (such as neurodevelopmental disorders). The incidence of ADRs varies with age, setting of medical care (in- or out-patients, pediatric specialties) and by country in which the study was carried out. The drugs most frequently reported with ADRs are those most commonly used in the pediatric age group, i.e. antibiotics and vaccines. The ADRs most often reported are skin, neurological and general disorders. As in adults, spontaneous notification is essential to generate alerts and child-specific pharmacoepidemiological studies are necessary and should be developed. (C) 2018 Societe francaise de pharmacologie et de therapeutique. Published by Elsevier Masson SAS. All rights reserved.

  • 128.
    Boyd, Ben J.
    et al.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic, Australia.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Vinarov, Zahari
    Univ Sofia, Fac Chem & Pharm, Sofia, Bulgaria.
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharma Technol, Basel, Switzerland.
    Brouwers, Joachim
    Univ Leuven, Drug Delivery & Disposit, Leuven, Belgium.
    Augustijns, Patrick
    Univ Leuven, Drug Delivery & Disposit, Leuven, Belgium.
    Brandl, Martin
    Univ Southern Denmark, Dept Phys Chem & Pharm, Odense, Denmark.
    Bernkop-Schnürch, Andreas
    Univ Innsbruck, Inst Pharm, Dept Pharmaceut Technol, Innsbruck, Austria.
    Shrestha, Neha
    Catholic Univ Louvain, Louvain Drug Res Inst, Adv Drug Delivery & Biomat, Brussels, Belgium.
    Preat, Veronique
    Catholic Univ Louvain, Louvain Drug Res Inst, Adv Drug Delivery & Biomat, Brussels, Belgium.
    Müllertz, Anette
    Univ Copenhagen, Physiol Pharmaceut, Copenhagen, Denmark.
    Bauer-Brandl, Annette
    Univ Southern Denmark, Dept Phys Chem & Pharm, Odense, Denmark.
    Jannin, Vincent
    Gattefosse SAS, St Priest, France.
    Successful oral delivery of poorly water-soluble drugs both depends on the intraluminal behavior of drugs and of appropriate advanced drug delivery systems2019In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 137, article id 104967Article in journal (Refereed)
    Abstract [en]

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

  • 129.
    Brandis, Gerrit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pietsch, Franziska
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Alemayehu, Rahel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hughes, Diarmaid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Comprehensive phenotypic characterization of rifampicin resistance mutations in Salmonella provides insight into the evolution of resistance in Mycobacterium tuberculosis2015In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 70, no 3, p. 680-685Article in journal (Refereed)
    Abstract [en]

    Objectives: Mutations in the beta-subunit of RNA polymerase (RNAP), encoded by rpoB, are responsible for rifampicin resistance (Rif(R)). Although many mutations in rpoB can reduce susceptibility, only a few are frequent amongst Rif(R) clinical Mycobacterium tuberculosis (MTB) isolates. It has been suggested that there is a negative correlation between the fitness costs of Rif(R) mutations and their respective clinical frequency, but so far comparable fitness cost measurements have only been conducted for a very limited number of Rif(R) mutations. We tested this hypothesis using Salmonella and Mycobacterium smegmatis as model organisms. Methods: We constructed 122 different Rif(R) mutations in Salmonella. MICs and relative fitness costs in the presence and absence of rifampicin were determined for each mutant, including for a smaller number of Rif(R) M. smegmatis strains. Results were compared with available mutation frequency data from clinical MTB isolates. Results: (i) Rif(R) mutations frequently found in MTB isolates have a fitness cost in Salmonella Typhimurium and M. smegmatis. (ii) Clinically frequent Rif(R) mutations have a high rifampicin MIC. (iii) There is a strong correlation between the magnitude of the fitness cost of a Rif(R) mutation in Salmonella Typhimurium or M. smegmatis and the frequency with which that mutation is associated with secondary (putative compensatory) mutations in RNAP of clinical MTB isolates. Conclusions: This suggests that the success of Rif(R) mutations in clinical MTB isolates may be dependent not only on a low initial fitness cost, but rather the results of three factors: (i) a high rifampicin MIC; (ii) a relatively low initial fitness cost; and (iii) the ability to additionally acquire compensatory mutations selected to further reduce fitness cost.

  • 130.
    Brekkan, Ari
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden.
    Lopez-Lazaro, Luis
    Dr Reddys Labs, Basel, Switzerland.
    Yngman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden;Uppsala Univ, Dept Pharmaceut Biosci, Pharmacometr Res Grp, Uppsala, Sweden.
    Plan, Elodie L.
    Pharmetheus, Uppsala, Sweden.
    Acharya, Chayan
    Pharmetheus, Uppsala, Sweden.
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden.
    Kankanwadi, Suresh
    Dr Reddys Labs, Basel, Switzerland.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Pharmetheus, Uppsala, Sweden.
    A Population Pharmacokinetic-Pharmacodynamic Model of Pegfilgrastim2018In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 5, article id 91Article in journal (Refereed)
    Abstract [en]

    Neutropenia and febrile neutropenia (FN) are serious side effects of cytotoxic chemotherapy which may be alleviated with the administration of recombinant granulocyte colony-stimulating factor (GCSF) derivatives, such as pegfilgrastim (PG) which increases absolute neutrophil count (ANC). In this work, a population pharmacokinetic-pharmacodynamic (PKPD) model was developed based on data obtained from healthy volunteers receiving multiple administrations of PG. The developed model was a bidirectional PKPD model, where PG stimulated the proliferation, maturation, and margination of neutrophils and where circulating neutrophils in turn increased the elimination of PG. Simulations from the developed model show disproportionate changes in response with changes in dose. A dose increase of 10% from the 6 mg therapeutic dose taken as a reference leads to area under the curve (AUC) increases of similar to 50 and similar to 5% for PK and PD, respectively. A full random effects covariate model showed that little of the parameter variability could be explained by sex, age, body size, and race. As a consequence, little of the secondary parameter variability (C-max and AUC of PG and ANC) could be explained by these covariates.

  • 131.
    Brekkan Viggosson, Ari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    PK/PD Modeling of Anti-Tumor Response in Xenograft Mice Receiving MetMAb, a One-Armed Monoclonal Antibody, in Combination With Tarceva®: 30 Point Master’s Project2012Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    PK/PD Modeling of Anti-Tumor Response in Xenograft Mice Receiving MetMAb, a One-Armed Monoclonal Antibody, in Combination With Tarceva®

    Ari Brekkan Viggosson

    Supervisors: Brendan Bender and Andrew Hooker

    Division of Pharmacometrics      30 Point Master’s Thesis           Examiner: Margareta Hammarlund-Udenaes                                             

     

    Introduction: Pharmacokinetic and pharmacodynamic (PK/PD) modeling can be used in the drug development process to make predictions of treatment success.  MetMAb and Tarceva are two anti-cancer agents shown to be effective against various tumors. In in-vivo and in-vitro experiments, a combination of the two agents indicated a potential synergistic drug effect.  This analysis uses PK/PD modeling to describe the tumor response and time-to-tumor-progression (TTP) in mice receiving MetMAb and Tarceva and to evaluate the apparent synergistic effect.  Aims: 1) Develop a PK/PD model to describe the tumor response in mice receiving single agent MetMAb.  2) Develop a PK/PD model to describe the effects of a drug combination comprised of MetMAb and Tarceva. 3) Using the models, simulate time-to-progression and evaluate synergy or additivity of the combination treatment.  Methods: Data was provided from 2 preclinical studies using tumor xenograft mice.  Tumor growth inhibition models describing the tumor response were developed and fit to data using NONMEM 7 software.  Visual predictive checks of tumor growth and TTP were done to assess model performance.  Combination effect was determined through comparisons of objective function values and goodness-of-fit plots obtained from different models.    Results:  Models well described the tumor response in mice and time-to-progression outcomes.  Models were able to indicate a synergistic effect of the combination treatment and predict TTP accurately.  Conclusion: Tumor response in mice to tyrosine kinase inhibitors can be modeled using PK/PD models of tumor growth inhibition. Additionally, these models can be used to support mechanistic hypotheses of additivity or synergism for combination treatments.

  • 132.
    Brenner, Philip
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Brandt, Lena
    Karolinska Inst, Stockholm, Sweden.
    Hägg, David
    Karolinska Inst, Stockholm, Sweden.
    Li, Gang
    Janssen, Global Serv, Titusville, NJ USA.
    DiBernardo, Allitia
    Janssen, Global Serv, Titusville, NJ USA.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Reutfors, Johan
    Karolinska Inst, Stockholm, Sweden.
    Substance use disorders are risk factors for treatment resistant depression2018In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 27, no Suppl. 2, p. 153-153, article id 331Article in journal (Other academic)
  • 133.
    Brenner, Philip
    et al.
    Karolinska Inst, Stockholm, Sweden.
    Hagg, David
    Karolinska Inst, Stockholm, Sweden.
    DiBernardo, Allitia
    Janssen, Global Serv, Titusville, NJ USA.
    Li, Gang
    Janssen, Global Serv, Titusville, NJ USA.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Brandt, Lena
    Karolinska Inst, Stockholm, Sweden.
    Reutfors, Johan
    Karolinska Inst, Stockholm, Sweden.
    Treatment resistant depression as a risk factor for substance use disorders-A national register-based cohort study2018In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 27, no Suppl. 2, p. 152-152, article id 329Article in journal (Other academic)
  • 134.
    Brill, Margreke JE
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Svensson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pandie, Mishal
    Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
    Maartens, Gary
    Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Confirming model-predicted pharmacokinetic interactions between bedaquiline and lopinavir/ritonavir or nevirapine in patients with HIV and drug resistant tuberculosis2017In: International Journal of Antimicrobial Agents, ISSN 0924-8579, E-ISSN 1872-7913, Vol. 49, p. 212-217Article in journal (Refereed)
    Abstract [en]

    Bedaquiline and its metabolite M2 are metabolised by CYP3A4. The antiretrovirals ritonavir-boosted lopinavir (LPV/r) and nevirapine inhibit and induce CYP3A4, respectively. Here we aimed to quantify nevirapine and LPV/r drug–drug interaction effects on bedaquiline and M2 in patients co-infected with HIV and multidrug-resistant tuberculosis (MDR-TB) using population pharmacokinetic (PK) analysis and compare these with model-based predictions from single-dose studies in subjects without TB. An observational PK study was performed in three groups of MDR-TB patients during bedaquiline maintenance dosing: HIV-seronegative patients (n = 17); and HIV-infected patients using antiretroviral therapy including nevirapine (n = 17) or LPV/r (n = 14). Bedaquiline and M2 samples were collected over 48 h post-dose. A previously developed PK model of MDR-TB patients was used as prior information to inform parameter estimation using NONMEM. The model was able to describe bedaquiline and M2 concentrations well, with estimates close to their priors and earlier model-based interaction effects from single-dose studies. Nevirapine changed bedaquiline clearance to 82% (95% CI 67–99%) and M2 clearance to 119% (92–156%) of their original values, indicating no clinically significant interaction. LPV/r substantially reduced bedaquiline clearance to 25% (17–35%) and M2 clearance to 59% (44–69%) of original values. This work confirms earlier model-based predictions of nevirapine and LPV/r interaction effects on bedaquiline and M2 clearance from subjects without TB in single-dose studies, in MDR-TB/HIV co-infected patients studied here. To normalise bedaquiline exposure in patients with concomitant LPV/r therapy, an adjusted bedaquiline dosing regimen is proposed for further study.

  • 135.
    Brittebo, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Toxicity in the respiratory system2006In: Pharmaceutical Toxicology, 2006Chapter in book (Other (popular scientific, debate etc.))
  • 136.
    Broberg, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Tissue-specific regulation of CYP19A1 – Implications for toxicological screening methods and breast cancer treatment strategies2013Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Abstract

    Background: Aromatase, encoded by CYP19A1, is an enzyme that converts androgens to estrogens. The enzyme is expressed in various tissues in the human body. The aim of this study is to investigate if there is a tissue-specific effect of 1α,25-dihydroxyvitamin D3 by analyzing the gene expression of CYP19A1 in cell lines representing the human adrenal cortex, the human ovarian, human osteoblastic cells and human breast glands. The results could be important for the evaluation of the NCI-H295R cell line as a toxicological screening method in which aromatase is an important enzyme and in the development of endocrine cancer therapy with CYP19A1 as a target.Methods: The change in gene expression followed exposure for 1α,25-dihydroxyvitamin D3 was measured  using qRT-PCR. Primers were specific for the total aromatase gene or promoter-specific regions of the gene.Results: The results show that 1α,25-dihydroxyvitamin D3 exerts a tissue specific effect on CYP19A1 expression. The gene expression was increased in the ovarian cells, the osteoblastic cells and the adrenocarcinoma cells, while it was decreased in the breast cancer cells. The results also showed an altered gene expression due to a promoter-specific regulation.Conclusion: It has become more clear that 1α,25-dihydroxyvitamin D3 could be a potential anti-breast cancer agent in the future. However, the difference in aromatase gene expression between the breast cancer cells and the adrenocarcinoma NCI-H295R cells indicates that the NCI-H295R cell line might not be reliable for toxicological screening on sex hormone production on its own, unless there is a way to take into account the tissue-specific regulation of CYP19A1.

  • 137.
    Brolin, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. University of Sydney.
    Does prenatal hypoxia lead to permanent cardiovascular change in the offspring?2015Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    Chronic prenatal hypoxia is associated with intrauterine growth retardation and there is now some evidence that it also induces programmed hypertension in offspring. However these studies are generally confounded as hypoxia is either induced by maternal hypoxia or placental insufficiency. The study described in this thesis is designed to overcome this problem. Pregnant rats were dosed daily with the drug dofetilide (2.5 mg/kg) or water on GD 11-14 and the cardiovascular parameters of the offspring at 8-12 weeks (>300g) were analysed using implanted telemetry blood pressure (BP) transmitters.Dofetilide is a class III antiarrhythmic drug that selectively blocks the Ikr channel which is expressed in the rat embryo but not in the adult rat. When administered to pregnant rats it induces bradycardia (and associated hypoxia) in the embryos without affecting maternal oxygenation or heart rate. Embryo culture studies showed that dofetilide induced a period of embryonic bradycardia for up to 9 hours following each dose. The dofetilide treated-rats had less completed pregnancies, smaller litters and lower weight pups compared to controls. At 8-12 weeks age the dofetilide offspring has increased BP (+10-12%) compared with controls. Postnatal stress in the form of air puffs did not reveal other cardiovascular differences between control and dofetilide offspring. The increased BP was not associated with an increased HR or changes in the autonomic nervous system. Remaining unexplored possibilities include impaired nephrogenesis, vascular dysfunction and microvascular

  • 138.
    Brolin, Erika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jonsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nyberg, Fred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat2018In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 167, p. 1-8Article in journal (Refereed)
    Abstract [en]

    The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.

  • 139.
    Bromée, Torun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Sjödin, Paula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Boswell, Tim
    Larsson, Tomas A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Salaneck, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Zoorob, Rima
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuropeptide Y-family receptors Y6 and Y7 in chicken: Cloning, pharmacological characterization, tissue distribution and conserved synteny with human chromosome region2006In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 273, no 9, p. 2048-2063Article in journal (Refereed)
    Abstract [en]

    The peptides of the neuropeptide Y (NPY) family exert their functions, including regulation of appetite and circadian rhythm, by binding to G-protein coupled receptors. Mammals have five subtypes, named Y1, Y2, Y4, Y5 and Y6, and recently Y7 has been discovered in fish and amphibians. In chicken we have previously characterized the first four subtypes and here we describe Y6 and Y7. The genes for Y6 and Y7 are located 1 megabase apart on chromosome 13, which displays conserved synteny with human chromosome 5 that harbours the Y6 gene. The porcine PYY radioligand bound the chicken Y6 receptor with a Kd of 0.80 ± 0.36 nm. No functional coupling was demonstrated. The Y6 mRNA is expressed in hypothalamus, gastrointestinal tract and adipose tissue. Porcine PYY bound chicken Y7 with a Kd of 0.14 ± 0.01 nm (mean ± SEM), whereas chicken PYY surprisingly had a much lower affinity, with a Ki of 41 nm, perhaps as a result of its additional amino acid at the N terminus. Truncated peptide fragments had greatly reduced affinity for Y7, in agreement with its closest relative, Y2, in chicken and fish, but in contrast to Y2 in mammals. This suggests that in mammals Y2 has only recently acquired the ability to bind truncated PYY. Chicken Y7 has a much more restricted tissue distribution than other subtypes and was only detected in adrenal gland. Y7 seems to have been lost in mammals. The physiological roles of Y6 and Y7 remain to be identified, but our phylogenetic and chromosomal analyses support the ancient origin of these Y receptor genes by chromosome duplications in an early (pregnathostome) vertebrate ancestor.

  • 140.
    Buratovic, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Viberg, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fredriksson, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Developmental exposure to the polybrominated diphenyl ether PBDE 209: Neurobehavioural and neuroprotein analysis in adult male and female mice2014In: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 38, no 2, p. 570-585Article in journal (Refereed)
    Abstract [en]

    Polybrominated diphenyl ethers (PBDEs), used as flame retardants in polymer products, are reported to cause developmental neurotoxic effects in mammals. The present study have investigated neurotoxic effects arising from neonatal exposure to PBDE 209, including alterations in sex differences, spontaneous behaviour, learning and memory, neuroproteins and altered susceptibility of the cholinergic system in adults. Three-day-old NMRI mice, of both sexes, were exposed to PBDE 209 (2,2',3,3',4,4',5,5',6,6'-decaBDE at 0, 1.4, 6.0 and 14.0 mu mol/kg b.w.). At adult age (2-7 months) a similar developmental neurotoxic effects in both male and female mice were seen, including lack of or reduced habituation to a novel home environment, learning and memory defects, modified response to the cholinergic agent's paraoxon (males) and nicotine (females) indicating increased susceptibility of the cholinergic system. The behavioural defects were dose-response related and persistent. In mice of both sexes and showing behavioural defects, neuroprotein tau was increased. (C) 2014 Elsevier B.V. All rights reserved.

  • 141.
    Burman, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Yeshak, Mariamawit Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Addis Ababa, Sch Pharm, Dept Pharmacognosy, Addis Ababa, Ethiopia..
    Larsson, Sonny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Craik, David J.
    Univ Queensland, Inst Mol Biosci, Chem & Struct Biol Div, Craik Lab, Brisbane, Qld, Australia..
    Rosengren, K. Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy. Univ Queensland, Sch Biomed Sci, Lab Peptide Struct Biol, Brisbane, Qld, Australia..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Distribution of circular proteins in plants: large-scale mapping of cyclotides in the Violaceae2015In: Frontiers in Plant Science, ISSN 1664-462X, E-ISSN 1664-462X, Vol. 6, article id 855Article in journal (Refereed)
    Abstract [en]

    During the last decade there has been increasing interest in small circular proteins found in plants of the violet family (Violaceae). These so-called cyclotides consist of a circular chain of approximately 30 amino acids, including six cysteines forming three disulfide bonds, arranged in a cyclic cystine knot (CCK) motif. In this study we map the occurrence and distribution of cyclotides throughout the Violaceae. Plant material was obtained from herbarium sheets containing samples up to 200 years of age. Even the oldest specimens contained cyclotides in the preserved leaves, with no degradation products observable, confirming their place as one of the most stable proteins in nature. Over 200 samples covering 17 of the 23-31 genera in Violaceae were analyzed, and cyclotides were positively identified in 150 species. Each species contained a unique set of between one and 25 cyclotides, with many exclusive to individual plant species. We estimate the number of different cyclotides in the Violaceae to be 5000-25,000, and propose that cyclotides are ubiquitous among all Violaceae species. Twelve new cyclotides from six phylogenetically dispersed genera were sequenced. Furthermore, the first glycosylated derivatives of cyclotides were identified and characterized, further increasing the diversity and complexity of this unique protein family.

  • 142.
    Bylund, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Annas, Anita
    Hellgren, Dennis
    Bjurström, Sivert
    Andersson, Håkan
    Svanhagen, Alexander
    Amide hydrolysis of a novel chemical series of microsomal prostaglandin e synthase-1 inhibitors induces kidney toxicity in the rat2013In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 41, no 3, p. 634-641Article in journal (Refereed)
    Abstract [en]

    A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.

  • 143.
    Bäckström, Erica
    et al.
    AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Hamm, Gregory
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fihn, Britt-Marie
    AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Strittmatter, Nicole
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Andrén, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Goodwin, Richard J. A.
    AstraZeneca, Pathol Sci Drug Safety & Metab IMED Biotech Unit, Cambridge, England.
    Fridén, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. AstraZeneca, Resp Inflammat & Autoimmun IMED Biotech Unit, Drug Metab & Pharmacokinet, Gothenburg, Sweden.
    Uncovering the regional localization of inhaled salmeterol retention in the lung2018In: Drug Delivery, ISSN 1071-7544, E-ISSN 1521-0464, Vol. 25, no 1, p. 838-845Article in journal (Refereed)
    Abstract [en]

    Treatment of respiratory disease with a drug delivered via inhalation is generally held as being beneficial as it provides direct access to the lung target site with a minimum systemic exposure. There is however only limited information of the regional localization of drug retention following inhalation. The aim of this study was to investigate the regional and histological localization of salmeterol retention in the lungs after inhalation and to compare it to systemic administration. Lung distribution of salmeterol delivered to rats via nebulization or intravenous (IV) injection was analyzed with high-resolution mass spectrometry imaging (MSI). Salmeterol was widely distributed in the entire section at 5 min after inhalation, by 15 min it was preferentially retained in bronchial tissue. Via a novel dual-isotope study, where salmeterol was delivered via inhalation and d(3)-salmeterol via IV to the same rat, could the effective gain in drug concentration associated with inhaled delivery relative to IV, expressed as a site-specific lung targeting factor, was 5-, 31-, and 45-fold for the alveolar region, bronchial sub-epithelium and epithelium, respectively. We anticipate that this MSI-based framework for quantifying regional and histological lung targeting by inhalation will accelerate discovery and development of local and more precise treatments of respiratory disease.

  • 144.
    Cao, Hao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Exposure to xenobiotic chemicals disrupts metabolism, rhythmicity and cell proliferation in Drosophila melanogaster2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Most species are constantly exposed to xenobiotic chemicals through multiple routes. Among all categories of xenobiotics, phthalates and bisphenols are two of the most widely used plasticizers and can be found in polyvinyl chloride (PVC) materials, medical devices and even drinking water. In paper I, we found that bis-(2-ethylhexyl) phthalate (DEHP) exposure caused a significant decrease in circulating carbohydrates and insulin-related genes. The Multidrug-Resistance like Protein 1 (MRP1, MRP in Drosophila) belongs to the ATP-binding cassette transporter family, and previous studies revealed the importance of MRP1 for transporting xenobiotics. However, the function of MRP1 in metabolism and other biological processes is still unclear. Therefore, in paper II, we showed that knocking down MRP expression in Malpighian tubules, the physiological equivalence of the vertebrate kidney, led to disrupted lipid homeostasis and oxidative resistance. In paper III and IV, we initially used whole transcriptome sequencing to assess the genetic interferences of exposure to Dibutyl Phthalate (DBP) and Bisphenol A Diglycidyl Ether (BADGE). The reproductive and developmental disruptions of DBP had been reported in many studies. However, the mechanism is still unclear. In paper III, we observed that DBP interfered with neuronal systems associated circadian genes, including in vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Furthermore, we demonstrated that the evolutionarily conserved gene, Hormone receptor-like in 38 (Hr38, human NR4A2) was involved in responding to DBP and regulated Pdf expression as a consequence. In paper IV, BADGE, a BPA-substitute, was tested for its disruptive effects on Drosophila. Based on the transcriptome sequencing, we found that several mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), had detectable overexpression by BADGE exposure. Developmental exposure to BADGE induced a large increase of hemocytes in fly 3rd instar larvae, while it did not damage the morphological structure of lymph gland and blood circulation. To summarize, our studies describe the potential disruptions of the industrial xenobiotics and provide the mechanistic hints for future investigations.

    List of papers
    1. Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
    Open this publication in new window or tab >>Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster
    Show others...
    2016 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, no 3, p. 309-316Article in journal (Refereed) Published
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.

    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-303019 (URN)10.1111/bcpt.12587 (DOI)000380889500011 ()27009472 (PubMedID)
    External cooperation:
    Funder
    Swedish Research Council
    Available from: 2016-09-14 Created: 2016-09-14 Last updated: 2018-07-31Bibliographically approved
    2. Multidrug-Resistance like Protein 1 activity in Malpighian tubules regulates lipid homeostasis in Drosophila
    Open this publication in new window or tab >>Multidrug-Resistance like Protein 1 activity in Malpighian tubules regulates lipid homeostasis in Drosophila
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Multidrug-Resistance like Proteins (MRPs) are ubiquitously expressed essential transporters required for many biological processes. Previous studies revealed that MRPs are pivotal for transporting endo- and xenobiotics, conferring resistance to anti-cancer agents and contributing to clearance of oxidative products. Nonetheless, their functions in other biological processes are still unclear. In our investigation, we suppress the expression of Drosophila Multidrug resistance like Protein 1 (MRP) in Malpighian tubules, the functional equivalent to the human kidney, and find this is sufficient to cause abnormal lipid accumulation, as well as disrupt normal feeding patterns. In addition, we suggest that the elevation of lipid contents may be a result of increasing Hr96 (homolog of human Pregnane X receptor) expression, which is known to play a role in detoxification and lipid metabolism processes. Finally, we validate that Malpighian tubules-specific MRP deficiency increases oxidative resistance in fruit flies. In summary, our results demonstrate that inadequate MRP expression in Malpighian tubules can lead to disrupted lipid homeostasis and feeding behavior. However, it may also elevate the oxidative resistance of the flies.

    National Category
    Biochemistry and Molecular Biology Genetics
    Identifiers
    urn:nbn:se:uu:diva-356540 (URN)
    Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31
    3. Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in Drosophila
    Open this publication in new window or tab >>Dibutyl phthalate exposure disrupts conserved circadian rhythm signaling systems in Drosophila
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Due to their common use as industrial plasticizers, agents in cosmetics and inclusion in skin care products, people are constantly exposed to phthalate xenobiotics. Although much research has focused on their ability to disrupt endocrine signaling, leading to developmental, reproductive and metabolic defects, how phthalates interfere with these biological functions is still unclear. Using whole transcriptome analysis, we demonstrate that exposing the genetically-tractable model system Drosophila melanogaster to the xenobiotic Dibutyl Pthalate (DBP) throughout development interferes with neuronal systems associated with vision and circadian rhythm. Of note, while DBP did not influence with eye development, it inhibited the expression of signaling systems regulating vision, including Rhodopsin 5 (Rh5) and Rhodopsin 6 (Rh6), two light-sensing G-protein coupled receptors involved in the daily resetting of circadian rhythm. Furthermore, DBP influenced the expression of genes central to circadian rhythm regulation, including vrille (vri, human NFIL3), timeless (tim, human TIMELESS), period (per, human PER3) and Pigment-dispersing factor (Pdf). Finally, we demonstrate that DBP disrupts circadian rhythm by interacting with the evolutionarily conserved nuclear receptor Hormone receptor-like in 38 (Hr38, human NR4A2), which in turn regulates Pdf expression. Our results are the first to provide comprehensive evidence that DBP interferes with the circadian rhythm system.

    National Category
    Neurosciences Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-356541 (URN)
    Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31
    4. Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in Drosophila
    Open this publication in new window or tab >>Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in Drosophila
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Since the estrogenic activity of bisphenol A had been reported, the industry started to find a proper replacement. Bisphenol A diglycidyl ether (BADGE) is one of the derivatives of BPA which is used widely in epoxy resin manufactory. Recently, some studies have demonstrated the adverse effects of BADGE on reproduction and development. However, the knowledge of BADGE is still scarce. Because of its hydrolytic property, BADGE is usually detected at a low level in commodities and the influences seem to be underestimated. In our study, we use the whole transcriptome sequencing to assess the effects of developmental BADGE exposure on Drosophila melanogaster. Notably, the genes related to cell proliferation are significantly affected by BADGE exposure. More detailed, a group of mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), are detectable overexpressed. Phenotypically, we observe that BADGE induces severe hemocytes over-proliferation in the 3rd instar larvae, but does not cause morphological damage of the larval lymph gland and blood circulation. In conclusion, we provide evidence to show the carcinogenic potential of BADGE and raise the concern of better understanding of xenobiotics. 

    National Category
    Biochemistry and Molecular Biology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-356544 (URN)
    Available from: 2018-07-31 Created: 2018-07-31 Last updated: 2018-07-31
  • 145.
    Cao, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Lindkvist, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Mothes, Tobias J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Developmental bisphenol A diglycidyl ether (BADGE) exposure causes cell over-proliferation in DrosophilaManuscript (preprint) (Other academic)
    Abstract [en]

    Since the estrogenic activity of bisphenol A had been reported, the industry started to find a proper replacement. Bisphenol A diglycidyl ether (BADGE) is one of the derivatives of BPA which is used widely in epoxy resin manufactory. Recently, some studies have demonstrated the adverse effects of BADGE on reproduction and development. However, the knowledge of BADGE is still scarce. Because of its hydrolytic property, BADGE is usually detected at a low level in commodities and the influences seem to be underestimated. In our study, we use the whole transcriptome sequencing to assess the effects of developmental BADGE exposure on Drosophila melanogaster. Notably, the genes related to cell proliferation are significantly affected by BADGE exposure. More detailed, a group of mitotic genes, including string (stg, human CDC25A), Cyclin B (CycB, human CCNB1), Cyclin E (CycE, human CCNE1), and pan gu (png, human NEK11), are detectable overexpressed. Phenotypically, we observe that BADGE induces severe hemocytes over-proliferation in the 3rd instar larvae, but does not cause morphological damage of the larval lymph gland and blood circulation. In conclusion, we provide evidence to show the carcinogenic potential of BADGE and raise the concern of better understanding of xenobiotics. 

  • 146.
    Cao, Hao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Wiemerslage, Lyle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Marttila, Petra S. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Williams, Michael J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Bis-(2-ethylhexyl) Phthalate Increases Insulin Expression and Lipid Levels in Drosophila melanogaster2016In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 119, no 3, p. 309-316Article in journal (Refereed)
    Abstract [en]

    Bis-(2-ethylhexyl) phthalate (DEHP) is one of the most widely used plasticizers, and human beings are exposed to DEHP via polyvinyl chloride (PVC) materials, medical equipment and even drinking water. While DEHP has been implicated to influence metabolism and endocrine functions, important questions remain about the molecular mechanisms of these effects. We employed the model organism Drosophila melanogaster and examined physiological, molecular and behavioural effects from DEHP-contaminated food. We found that DEHP, at levels comparable to human exposure, made male flies more resistant to starvation and increased lipid levels, while decreasing circulating carbohydrates. Moreover, DEHP-fed male flies had higher expression levels of an insulin-like peptide known to regulate metabolism, as well as the insulin receptor. Our results suggest that long-term DEHP feeding may induce diabetes-like dysfunctions. These findings provide a molecular background of how DEHP may have detrimental effects on metabolic functions.

  • 147. Carlsson, Gunnar
    et al.
    Patring, Johan
    Ullerås, Erik
    Oskarsson, Agneta
    Developmental toxicity of albendazole and its three main metabolites in zebrafish embryos.2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 32, no 1, p. 129-37Article in journal (Refereed)
    Abstract [en]

    Albendazole (ABZ) is used as an anthelmintic drug in humans and animals. ABZ has been shown to cause developmental toxicity in experimental animals, however it is not clear if this is caused by the parent compound or a metabolite. Zebrafish embryos were exposed from 1 to 144hpf (hours post fertilization) to investigate the developmental toxicity of ABZ, the first metabolite albendazole sulphoxide and the subsequent metabolites albendazole sulphone (ABZSO(2)) and albendazole-2-aminosulphone (ABZSO(2)NH(2)). The results showed that ABZ caused malformations of head and tail and embryonic lethality from 0.3μM. In contrast, the metabolites did not display developmental toxicity at any tested concentration. Dechorionation did not influence the developmental toxic potential of ABZ and ABZSO, indicating that bioavailability was not a limiting factor. Chemical analysis showed that at sublethal concentrations, most of ABZ was metabolized to ABZSO. The results demonstrate that in zebrafish embryos ABZ rather than ABZSO displays developmental toxicity.

  • 148.
    Carlsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Adenosin A2A-receptorer som mål för läkemedelsbehandling av motoriska symtom vid Parkinsons sjukdom2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Parkinsons sjukdom är en progressiv neurodegenerativ sjukdom. Orsaken till sjukdomen är degeneration av dopaminerga neuron i de basala ganglierna. Läkemedelsbehandlingen som finns tillgänglig idag är endast symtomlindrande och består framför allt av dopaminerga läkemedel, främst levodopa. Dessa läkemedel ger efter en tids användning upphov till oönskade bieffekter såsom dyskinesier och motoriska fluktuationer. Den icke-dopaminerga läkemedelsgruppen adenosin A2A-receptor (A2AR) antagonister har i djurstudier visats förbättra motorisk aktivitet utan att ge upphov till dyskinesier. I den här litteraturstudien baserad på sekundärdata sammanfattas ett flertal studier angående adenosin A2AR antagonister i tillägg till tidigare levodopabehandling eller som monoterapi hos parkinsonpatienter. Resultatet i studien visar att adenosin A2AR antagonister i tillägg till levodopa minskar daglig off-tid hos parkinsonpatienter med motoriska fluktuationer utan att förvärra besvärlig dyskinesi. De humana studierna i monoterapi kunde inte visa på förbättring i motorisk aktivitet medan djurstudierna gav goda resultatet. Det krävs mer storskaliga studier kring läkemedelsgruppen för att eventuellt påvisa effekt i monoterapi och säkerställa statistisk signifikans för studier genomförda i tillägg till levodopabehandling.

  • 149.
    Cars, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Malmstrom, Rickard E.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Div Clin Pharmacol, Stockholm, Sweden.
    Neovius, Martin
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    Schwieler, Jonas
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden.
    Wettermark, Bjorn
    Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Stockholm, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Dronedarone and Hepatic Toxicity?: A Model for Evaluation of Post-Marketing Safety of Drugs in Routine Care2017In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 26, p. 381-382Article in journal (Other academic)
  • 150.
    Cars, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Stockholm Cty Council, Publ Healthcare Serv Comm Adm, Stockholm, Sweden..
    Lindhagen, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Malmström, R. E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med Solna, Clin Pharmacol, Stockholm, Sweden..
    Neovius, M.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Schwieler, J.
    Karolinska Inst, Dept Cardiol, Stockholm, Sweden..
    Wettermark, B.
    Stockholm Cty Council, Publ Healthcare Serv Comm Adm, Stockholm, Sweden.;Karolinska Inst, Dept Med, Ctr Pharmacoepidemiol, Stockholm, Sweden..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effectiveness of Drugs in Routine Care: A Model for Sequential Monitoring of New Medicines Using Dronedarone as Example2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 103, no 3, p. 493-501Article in journal (Refereed)
    Abstract [en]

    Although there is no doubt about the scientific value of randomized controlled clinical trials, they are usually conducted in selected populations different fromthose treated in clinical practice. Therefore, it is important to optimize real-time post-marketing evaluation of the effectiveness, safety, and cost of new drugs. Using electronic health records and administrative health databases froma well-defined region with universal access to healthcare, we have built a framework for real-time sequential monitoring of the effectiveness of newly marketed drugs in routine care. We chose the antiarrhythmic agent dronedarone as the study drug and flecainide as the comparator drug for illustration of the model. We demonstrate that this model produces consistent results with increasing precision over time as data accumulates in the clinical systems. We believe that use of this model at the introduction of new drugs can provide complementary evidence, especially in settings of adaptive licensing of new drugs.

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