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  • 1.
    Aasa, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Abramsson-Zetterberg, Lilianne
    Carlsson, Henrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Törnqvist, Margareta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    The genotoxic potency of glycidol established from micronucleus frequency and hemoglobin adduct levels in mice2017Inngår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 100, 168-174 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycidol is a genotoxic animal carcinogen that has raised concern due to its presence in food, as glycidyl fatty acid esters. Here we investigated the genotoxicity of glycidol in BalbC mice (0-120 mg/kg) by monitoring the induction of micronuclei in peripheral blood as a marker of chromosomal damage. The scoring of the micronuclei was assessed by flow cytometry. In the treated mice, the internal dose of glycidol, expressed as area under the concentration-time curve, AUC (mol x L-1 x h; Mh), was measured by dihydroxypropyl adducts to hemoglobin (Hb). The study showed that glycidol induced linear dose dependent increases of Hb adducts (20 pmol/g Hb per mg/kg) and of micronuclei frequencies (12 parts per thousand per mMh). Compared to calculations based on administered dose, an improved dose-response relationship was observed when considering internal dose, achieved through the applied combination of sensitive techniques used for the scoring of micronuclei and AUC estimation of glycidol in the same mice. By comparing with earlier studies on micronuclei induction in mice exposed to ionizing radiation we estimated the radiation dose equivalent (rad-eq.) of glycidol to be ca 15 rad-eq./mMh.

  • 2.
    Aasa, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Vare, Daniel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Motwani, Hitesh V.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Jenssen, Dag
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Törnqvist, Margareta
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions2016Inngår i: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 805, 38-45 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glycidol (Gly) is an electrophilic low-molecular weight epoxide that is classified by IARC as probably carcinogenic to humans. Humans might be exposed to Gly from food, e.g. refined vegetable oils, where Gly has been found as a food process contaminant. It is therefore important to investigate and quantify the genotoxicity of Gly as a primary step towards cancer risk assessment of the human exposure. Here, quantification of the mutagenic potency expressed per dose (AUC: area under the concentration time curve) of Gly has been performed in Chinese hamster ovary (CHO) cells, using the HPRT assay. The dose of Gly was estimated in the cell exposure medium by trapping Gly with a strong nucleophile, cob(I)alamin, to form stable cobalamin adducts for analysis by LC-MS/MS. Gly was stable in the exposure medium during the time for cell treatment, and thus the dose in vitro is the initial concentration x cell treatment time. Gly induced mutations in the hprt-gene at ante of 0.08 +/- 0:01 mutations/10(5) cells/mMh. Through comparison with the effect of ionizing radiation in the same system a relative mutagenic potency of 9.5 rad-eq./mMh was obtained, which could be used for comparison of genotoxicity of chemicals and between test systems and also in procedures for quantitative cancer risk assessment. Gly was shown to induce strand breaks, that were repaired by base excision repair. Furthermore, Gly-induced lesions, present during replication, were found to delay the replication fork elongation. From experiments with repair deficient cells, homologous recombination repair and the ERCC1-XPF complex were indicated to be recruited to support in the repair of the damage related to the stalled replication elongation. The type of DNA damage responsible for the mutagenic effect of Gly could not be concluded from the present study.

  • 3. Abbasi, Arshad Mehmood
    et al.
    Khan, Mir Ajab
    Khan, Nadeem
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för fysiologisk botanik. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå Plant Science Centre (UPSC).
    Shah, Munir H
    Ethnobotanical survey of medicinally important wild edible fruits species used by tribal communities of Lesser Himalayas-Pakistan2013Inngår i: Journal of Ethnopharmacology, ISSN 0378-8741, E-ISSN 1872-7573, Vol. 148, nr 2, 528-536 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ethnopharmacological relevance: Present survey was conducted to explore ethnomedicinal uses and cultural importance of wild edible fruits species by the inhabitants of Lesser Himalayas-Pakistan. Materials and methods: Information was obtained through informed consent semi-structured interviews, questionnaires, market survey, focus group conversation, unceremonious dialogue and village walks with key informants. Cultural significance of each species was calculated based on use report by participants at each study site. Results: A total of 35 wild edible fruits belonging to 21 genera and 17 families were used for the treatment of various ailments and consumed. Rosaceae was found dominating family with (8 spp.), followed by Moraceae (6 spp.), Rhamnaceae (5 spp.), Palmae and Vitaceae (2 spp. each) and remaining families were represented by one species each. Fruits (48%) were found highly utilized plant parts, followed by leaves (34%), bark, flowers and seeds (4% each), branches, latex and roots (2% each). Water was used as a medium for preparation while milk, ghee, oil, egg and butter are used for application. Modes of preparation were fall into seven categories like fresh parts eaten raw (38%), powder (24%), decoction (20%), extract (12 %), paste (4%), juice and latex (2% each). Based on cultural important index (CI) Morus nigra was found most significant species within top ten fruit plants followed by Morus alba, Olea ferruginea, Berberis lycium, Pyrus pashia, Ficus carica, Ficus palmata, Ziziphus mauritiana, Diospyros lotus and Ziziphus nummularia. Conclusions: Traditional uses of wild edible plant depend mainly on socio-economic factors rather than climatic conditions or wealth of flora. Use reports and citation demonstrated that there is a common cultural heritage regarding the gathered food plants. Further investigation is required for Antioxidant study, essential and toxic components, pharmacological applications; dietary requirements and biotechnological techniques to improve yields.

    (C) 2013 Elsevier Ireland Ltd. All rights reserved.

  • 4.
    Abdal Hadi, Jehan
    Högskolan i Kalmar, Naturvetenskapliga institutionen.
    Hur skiljer sig traditionella från nyare generationer antipsykotika åt vad gäller biverkningen viktökning?2008Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Antipsykotiska läkemedel är basen för behandling av schizofreni, en psykisk sjukdom som uppträder redan hos unga människor. Symtomen vid schizofreni brukar delas in i positiva symtom (hallucinationer, vanföreställningar, paranoida tankar), negativa symtom (koncentrationssvårigheter, nedsatt språk- och tankeförmåga, minskat intresse för omgivningen, och initiativlöshet), samt kognitiva symtom (minnesproblem, problem med uppmärksamhet och koncentration).

    Antipsykotiska läkemedel delas in i typiska (den äldre generationen) och atypiska (den nyare generationen) antipsykotika. För båda grupperna antipsykotiska läkemedel finns det risk för biverkningar. De vanligaste biverkningarna vid behandling med den äldre generationen antipsykotika är extrapyramidala biverkningar. En biverkning som förefaller mer specifik för de nya atypiska preparaten är viktökning, vilken även kan orsaka utveckling av många allvarliga sjukdomstillstånd.

    Syftet med detta arbete var att jämföra typiska och atypiska antipsykotiska läkemedel med avseende på utveckling av viktökning.

    För att få svar på min frågeställning har en litteraturstudie av fem vetenskapliga artiklar genomförts. De vetenskapliga artiklarna har hittats genom databassökningar i PubMed, medan övriga fakta har hämtats från andra källor.

    Resultatet av de vetenskapliga artiklarna visar att det finns skillnader mellan traditionella och nyare generationer antipsykotika vad gäller tendens att orsaka viktökning. Med några undantag, är flera antipsykotiska läkemedel, som tillhör den nyare generationen, associerade med högre risk för utveckling av viktökning jämfört med den äldre generationen antipsykotika. Viktökning orsakas mest av klozapin, följt av olanzapin och risperidon. Quetiapin orsakar, i likhet med haloperidol, mindre viktökning.

    På grund av detta faktum, forskar man numera kring orsakerna till denna skillnad för att förbättra biverkningsprofilen hos framtida antipsykotika.

    2008:F2

  • 5. Abdallah, Qasem M. A.
    et al.
    Phillips, Roger M.
    Johansson, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Helleday, Thomas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
    Cosentino, Laura
    Abdel-Rahman, Hamdy
    Etzad, Jasarat
    Wheelhouse, Richard T.
    Kiakos, Konstantinos
    Bingham, John P.
    Hartley, John A.
    Patterson, Laurence H.
    Pors, Klaus
    Minor structural modifications to alchemix influence mechanism of action and pharmacological activity2012Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1873-2968, Vol. 83, nr 11, 1514-1522 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.

  • 6.
    Abdel Rehim, Abbi
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Abdel Rehim, Mohamed
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för analytisk kemi.
    Screening and determination of drugs in human saliva utilizing microextraction by packed sorbent and liquid chromatography-tandem mass spectrometry2013Inngår i: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 27, nr 9, 1188-1191 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This study presents a new method for collecting and handling saliva samples using an automated analytical microsyringe and microextraction by packed syringe (MEPS). The screening and determination of lidocaine in human saliva samples utilizing MEPS and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were carried out. An exact volume of saliva could be collected. The MEPS C-8-cartridge could be used for 50 extractions before it was discarded. The extraction recovery was about 60%. The pharmacokinetic curve of lidocaine in saliva using MEPS-LC-MS/MS is reported.

  • 7.
    Abdi, Hafsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Finns det någon koppling mellan Alzheimers sjukdom och Diabetes Mellitus?2014Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Alzheimers sjukdom är en neurodegenerativ sjukdom vars orsak är okänd, kännetecknas av en gradvis försämring av kognitiva funktioner. Alzheimers sjukdom och Diabetes Mellitus har flera gemensamma patofysiologiska samband, bland annat insulinresistens. Försämrad insulinsignalering kan leda till kognitiv funktionsförsämring, som i sin tur kan leda till Alzheimers sjukdom. Båda insulin och amyloid-β metaboliseras av insulinnedbrytande enzym (IDE), defekt i IDE kan delvis orsaka amyloid-β ansamlingar. Syftet med detta arbete är att undersöka om försämrad insulinsignalering kan leda till kognitiv försämring och påskynda utvecklingen av Alzheimers sjukdom.

    Jag har gjort en systematisk litteraturöversikt för att undersöka detta. Det är större risk att drabbas av Alzheimers sjukdom om man har Diabetes Mellitus. Man såg ett samband mellan försämrad insulinsignalering och försämrad kognitiv funktion. Förhöjda glukosnivåer var förenade med kognitiv försämring, medan nedsatt glukosnivå inte hade någon betydelse vid kognitiv försämring. Dessutom påskyndar en hög glukosnivå omvandlingen från MCI (mild kognitivs vikt) till Alzheimers sjukdom. Trots detta resultat krävs det mer forskning inom området eftersom olika metoder användes på de olika studierna vilket kan ge ett falskt samband.

  • 8.
    Abdulla Karim, Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Ersättning av två aminosyror i 9S-dioxygenas-allenoxidsyntas av Colletotrichum graminicola samt förkortning av dioxygenasdomänen för 3D-strukturanalys2015Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [sv]

    Oxylipiner är oxiderade metaboliter av fleromättade fettsyror. Hos svampar är dessa inblandade i kommunikation, reproduktion, reglering av mykotoxinproduktion och modulering av växtförsvarssystemet vid infektion. Colletotrichum graminicola tillhör de mest kända och viktigaste svampar som orsakar skador på grödor. Genen EFQ_27323 från C. graminicola kodar för 9S-dioxygenas-allenoxidsyntas (9S-DOX-AOS) och vid inkubation med linolsyra bildar hydroperoxyoctadekadiensyra (9-HPODE).

     

    Syftet med projektet är dels att ändra kiraliteten av 9S-DOX-AOS i genen EFQ_27323 genom att ersätta aminosyrorna Ile590 och Leu601 mot Gly590 och Phe601, respektive, och dels att förkorta DOX-domänen av enzymet för vidare 3D-strukturanalyser.

     

    Site directed mutagenesis används för mutationer av gener genom PCR-tekniken. Mutanten både transformeras och uttrycks i E.coli (BL21) med hjälp av expressionsvektorn pET101D-TOPO. De uttryckta enzymerna inkuberas med linolsyra (18:2n-6) och aktiviteten och dess kiralitet analyseras med hjälp av LC-MS/MS.

     

    Ersättningen av Ile590 med Gly590 ändrade kiraliteten av 9S-HPODE till 9R-HPODE med 20 % medan dubbelmutanten, d.v.s. Gly590 och Phe601 ändrade kiraliteten med 58 %. Enzymet förlorar sin 9-HPODE aktivitet när en förkortning av DOX-domän utan CYP-domän genomförs.

     

    Specifika aminosyrasubstitutioner i aktivt centrum påverkar regio- och stereoselektiviteten. Aminosyrorna i genen EFQ_27323, Gly590 och Phe601 istället för Ile590 med Leu601 ändrar kiraliteten från 9S-DOX-AOS till 9R-DOX-AOS

  • 9.
    Abdulrasul, Ali
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Neurosteroids and Alzheimer’s disease: Mechanistic studies of neuroprotection and neurogenesis2015Independent thesis Advanced level (professional degree), 20 poäng / 30 hpOppgave
    Abstract [en]

    Alzheimer’s disease (AD) and its consequent memory and cognitive impairments continue to be unhaltable and incurable to this day. Yet, recent studies demonstrating neuroprotective effects of some neurosteroids have shown a potential of these steroids to modulate AD progression in vitro and in vivo. In the present study, the effects of neurosteroids were studied on hydrogen peroxide (H2O2), as well as staurosporine-induced toxicity in SH-SY5Y neuroblastoma cells. Moreover, underlying mechanisms were investigated. Cell viability was measured with MTT-assay. The results demonstrated that the neurosteroids investigated reduced hydrogen peroxide-induced toxicity. One of the neurosteroid even reduced staurosporine-induced toxicity. Moreover, the present study also showed neurogenic properties for one of the neurosteroid studied.  In conclusion, this report demonstrates that neurosteroids act neuroprotective against hydrogen peroxide-induced toxicity and that one of the neurosteroids studied even acts neuroprotective against staurosporine-induced toxicity and possesses neurogenic effects. 

  • 10.
    Abdurahman, Samir
    et al.
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Végvári, Akos
    Clinical Protein Science, Department of Electrical Measurements, Lund University, Lund, Sweden.
    Youssefi, Masoud
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Levi, Michael
    Tripep AB, Huddinge, Sweden .
    Höglund, Stefan
    Department of Biochemistry, Uppsala University, Uppsala, Sweden .
    Andersson, Elin
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Horal, Peter
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Svennerholm, Bo
    Department of Clinical Virology, University of Göteborg, Göteborg, Sweden.
    Balzarini, Jan
    Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.
    Vahlne, Anders
    Division of Clinical Microbiology, Karolinska Institutet, F68 Karolinska University Hospital Huddinge, Stockholm, Sweden .
    Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity2008Inngår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, nr 10, 3737-3744 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.

  • 11.
    Abramsson-Zetterberg, Lilianne
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Ilback, Nils-Gunnar
    The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo2013Inngår i: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 59, 86-89 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b.w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic.

  • 12. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne M.
    Wikman, Anna S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Rahnasto, Minna
    Juvonen, Risto O.
    Vepsalainen, Jouko
    Raunio, Hannu
    Ng, Jack C.
    Lang, Matti A.
    Metabolism of bilirubin by human cytochrome P450 2A62012Inngår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, nr 1, 50-58 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The mouse cytochrome P450 (CYP) 2A5 has recently been shown to function as hepatic "Bilirubin Oxidase" (Abu-Bakar, A., et al., 2011. Toxicol. Appl. Pharmacol. 257, 14-22). To date, no information is available on human CYP isoforms involvement in bilirubin metabolism. In this paper we provide novel evidence for human CYP2A6 metabolising the tetrapyrrole bilirubin. Incubation of bilirubin with recombinant yeast microsomes expressing the CYP2A6 showed that bilirubin inhibited CYP2A6-dependent coumarin 7-hydroxylase activity to almost 100% with an estimated K-i of 2.231 mu M. Metabolite screening by a high-performance liquid chromatography/electrospray ionisation mass spectrometry indicated that CYP2A6 oxidised bilirubin to biliverdin and to three other smaller products with m/z values of 301,315 and 333. Molecular docking analyses indicated that bilirubin and its positively charged intermediate interacted with key amino acid residues at the enzyme's active site. They were stabilised at the site in a conformation favouring biliverdin formation. By contrast, the end product, biliverdin was less fitting to the active site with the critical central methylene bridge distanced from the CYP2A6 haem iron facilitating its release. Furthermore, bilirubin treatment of HepG2 cells increased the CYP2A6 protein and activity levels with no effect on the corresponding mRNA. Co-treatment with cycloheximide (CHX), a protein synthesis inhibitor, resulted in increased half-life of the CYP2A6 compared to cells treated only with CHX. Collectively, the observations indicate that the CYP2A6 may function as human "Bilirubin Oxidase" where bilirubin is potentially a substrate and a regulator of the enzyme.

  • 13.
    Adjan, V. V.
    et al.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA.
    Hauser, K. F.
    Department of Anatomy and Neurobiology, University of Kentucky, Lexington, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, USA.
    Bakalkin, Georgy
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Yakovleva, T.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Gharibyan, A.
    Experimental Alcohol and Drug Addiction Research Section, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.
    Scheff, S. W.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA; Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Knapp, P. E.
    Department of Anatomy and Neurobiology, 800 Rose Street, MS209, University of Kentucky, Lexington, KY 40536-0298, USA and Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 40536-0298, USA.
    Caspase-3 activity is reduced after spinal cord injury in mice lacking dynorphin: differential effects on glia and neurons2007Inngår i: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, nr 3, 724-36 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Dynorphins are endogenous opioid peptide products of the prodynorphin gene. An extensive literature suggests that dynorphins have deleterious effects on CNS injury outcome. We thus examined whether a deficiency of dynorphin would protect against tissue damage after spinal cord injury (SCI), and if individual cell types would be specifically affected. Wild-type and prodynorphin(-/-) mice received a moderate contusion injury at 10th thoracic vertebrae (T10). Caspase-3 activity at the injury site was significantly decreased in tissue homogenates from prodynorphin(-/-) mice after 4 h. We examined frozen sections at 4 h post-injury by immunostaining for active caspase-3. At 3-4 mm rostral or caudal to the injury, >90% of all neurons, astrocytes and oligodendrocytes expressed active caspase-3 in both wild-type and knockout mice. At 6-7 mm, there were fewer caspase-3(+) oligodendrocytes and astrocytes than at 3-4 mm. Importantly, caspase-3 activation was significantly lower in prodynorphin(-/-) oligodendrocytes and astrocytes, as compared with wild-type mice. In contrast, while caspase-3 expression in neurons also declined with further distance from the injury, there was no effect of genotype. Radioimmunoassay showed that dynorphin A(1-17) was regionally increased in wild-type injured versus sham-injured tissues, although levels of the prodynorphin processing product Arg(6)-Leu-enkephalin were unchanged. Our results indicate that dynorphin peptides affect the extent of post-injury caspase-3 activation, and that glia are especially sensitive to these effects. By promoting caspase-3 activation, dynorphin peptides likely increase the probability of glial apoptosis after SCI. While normally beneficial, our findings suggest that prodynorphin or its peptide products become maladaptive following SCI and contribute to secondary injury.

  • 14. af Klinteberg, Britt
    et al.
    Alm, Per-Olof
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Serotonin, personality and smoking2000Konferansepaper (Fagfellevurdert)
  • 15. Agerstrand, Marlene
    et al.
    Berg, Cecilia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Bjorlenius, Berndt
    Breitholtz, Magnus
    Brunström, Björn
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Miljötoxikologi.
    Fick, Jerker
    Gunnarsson, Lina
    Larsson, D. G. Joakim
    Sumpter, John P.
    Tysklind, Mats
    Ruden, Christina
    Improving Environmental Risk Assessment of Human Pharmaceuticals2015Inngår i: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 49, nr 9, 5336-5345 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

  • 16.
    Ahlenius, Sven
    et al.
    Göteborgs universitet.
    Heimann, Mikael
    Göteborgs universitet.
    Larsson, Knut
    Göteborgs universitet.
    Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine.1979Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 65, nr 2, 137-140 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.

  • 17.
    Aithal, Guruprasad P.
    et al.
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Nicoletti, Paola
    Columbia Univ, New York, NY USA..
    Bjornsson, Einar
    Landspitali Univ Hosp, Reykjavik, Iceland..
    Lucena, M. I.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Andrade, Raul J.
    CIBERehd, Madrid, Spain.;Univ Malaga, E-29071 Malaga, Spain..
    Grove, Jane
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Digest Dis Biomed Res Unit, Nottingham, England..
    Stephens, C.
    Univ Malaga, E-29071 Malaga, Spain..
    Hallberg, Pär
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Maitland-van der Zee, Anke H.
    Univ Utrecht, Utrecht, Netherlands..
    Martin, Jennifer H.
    Univ Queensland, Brisbane, Qld, Australia.;Princess Alexandra Hosp, Brisbane, Qld, Australia..
    Cascorbi, Ingolf
    Univ Hosp Schleswig Holstein, Kiel, Germany..
    Dillon, John F.
    Ninewells Hosp & Med Sch, Dundee, Scotland..
    Laitinen, Tarja
    Univ Helsinki, Cent Hosp, Helsinki, Finland..
    Larrey, Dominique G.
    Hop St Eloi, Montpellier, France..
    Molokhia, Mariam
    Univ London, Kings Coll London, London SW3 6LX, England..
    Kullak-Ublick, Gerd A.
    Univ Zurich, Zurich, Switzerland..
    Ibanez, Luisa
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Pirmohamed, Munir
    Univ Liverpool, Liverpool L69 3BX, Merseyside, England..
    Qin, Shengying
    Shanghai Jiao Tong Univ, Shanghai 200030, Peoples R China..
    Sawle, Ashley
    Columbia Univ, New York, NY USA..
    Bessone, Fernando
    Univ Nacl Rosario, Fac Ciencias Med, RA-2000 Rosario, Argentina..
    Hernandez, Nelia
    Univ Republ, Mentevideo, Uruguay..
    Stolz, Andrew
    Univ So Calif, Los Angeles, CA USA..
    Chalasani, Naga P.
    Indiana Univ, Indianapolis, IN 46204 USA..
    Serrano, Jose
    Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD USA..
    Barnhart, Huiman X.
    Duke Clin Res Inst, Durham, NC USA..
    Fontana, Robert J.
    Univ Michigan, Ann Arbor, MI 48109 USA..
    Watkins, Paul
    Hamner UNC Inst Drug Safety Sci, Durham, NC USA..
    Urban, Thomas J.
    UNC Eshelman Sch Pharm, Chapel Hill, NC USA..
    Daly, Ann K.
    Newcastle Univ, Newcastle, NSW, Australia..
    HLA-A*33:01 is strongly associated with drug-induced liver injury (DILI) due to terbinafine and several other unrelated compounds2015Inngår i: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, 325A-326A s.Artikkel i tidsskrift (Annet vitenskapelig)
  • 18. Aitio, Antero
    et al.
    Bernard, Alfred
    Fowler, Bruce A.
    Nordberg, Gunnar F.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Miljömedicin.
    Biological Monitoring and Biomarkers2007Inngår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, 65-78 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
    Abstract [en]

    Biomonitoring was developed for the assessment of the health risks from exposure to metals at work, and the approaches and concepts of biomonitoring are derived from such exposures. At present, biomonitoring is increasingly used to assess exposure from the environment. Biomonitoring and assessment of external exposure are complementing activities, where the exposure assessments are much more widely applied, especially when the number of chemicals concerned is considered; environmental analysis also offers the distinct advantage of speciation analysis, which is very poorly developed for biomonitoring. Biomonitoring, on the other hand, provides information on exposure from all sources, and via all absorption routes, and also considers accumulation of the chemical in the body. Biomonitoring using exposure biomarkers thus considers interindividual differences in the absorption, whereas use of effect biomarkers also considers interindividual differences in sensitivity. Few effect biomarkers, however, have been validated. Biomarkers of susceptibility have so far not been adapted for use in metal toxicology. The major challenges of biomonitoring are the development of monitoring methods, which are inexpensive enough to be applied at a frequency that makes possible meaningful biomonitoring of metals with a short half-time; development of exposure biomarker guidance values specific to individual species of different metals; expansion of the repertoire of validated effect biomarkers; and validation and application to effect monitoring of the "omic" technologies.

  • 19. Akkermann, Kirsti
    et al.
    Nordquist, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Harro, Jaanus
    Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population2010Inngår i: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, nr 1, 111-114 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Objective: The s-allele of the 5-HTTLPR has been suggested to lead to the development of less efficient and less flexible 5-HT system and has been associated to different forms of psychopathology. It has also been shown that alterations in serotonergic activity contribute to the pathophysiology of binge eating but it is not clear which changes in 5-HT function observed in eating disorder patients represent trait vs state effect. We investigated the association between the 5-HTTLPR and binge eating in a population-representative sample of women, and tested whether the 5-HTTLPR genotype influences the severity of binge eating. Methods: The sample was based on women participating in the third wave of the Estonian Children Personality, Behaviour and Health Study. EDI-2 subscales - drive for thinness and bulimia - were used to assess eating behaviour and attitudes. Barratt Impulsiveness Scale (BIS-11) and State and Trait Anxiety Inventory (STAI) were used to measure impulsivity and anxiety. Participants were genotyped for the 5-HTTLPR. Results: There was no 5-HTTLPR genotype effect on binge eating even after the covarying effect of impulsivity and anxiety was controlled for. However, women prone to binge eating and carrying the s-allele showed significantly higher levels of bulimia scores, and among them, women with s/s genotype had also higher levels of state anxiety and tendency for higher impulsivity. Conclusions: While the 5-HTTLPR genotype does not predict symptoms of eating disorder in general population, the s-allele, and especially the s/s genotype increases the risk for affective instability and symptom severity.

  • 20.
    Al Shemaili, Jasem
    et al.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Parekh, Khatija A.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Newman, Robert A.
    Phoenix Biotechnol Inc, San Antonio, TX 78217 USA..
    Hellman, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Woodward, Carl
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adem, Abdu
    United Arab Emirates Univ, Dept Pharmacol, Fac Med, POB 17666, Al Ain, U Arab Emirates..
    Collin, Peter
    Coastside Bio Resources, Deer Isle, ME 04627 USA..
    Adrian, Thomas E.
    United Arab Emirates Univ, Fac Med, Dept Physiol, POB 17666, Al Ain, U Arab Emirates..
    Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer2016Inngår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, nr 6, 115Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.

  • 21. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Bergman, Åke
    Andersson, Patrik L
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, 164-173 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 22. Al-Anati, Lauy
    et al.
    Viluksela, Matti
    Strid, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi.
    Bergman, Åke
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för miljövetenskap och analytisk kemi. Swedish Toxicology Sciences Research Center (Swetox), Sweden.
    Andersson, Patrik L.
    Stenius, Ulla
    Högberg, Johan
    Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene2015Inngår i: Chemico-Biological Interactions, ISSN 0009-2797, E-ISSN 1872-7786, Vol. 239, 164-173 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and gamma H2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3'-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 mu M of PCB180 and 3'-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 mu M). 3'-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and gamma H2AX. CYP1A1 mRNA induction was seen at 1 h, and gamma H2AX at 3 h. The anti-oxidant N-Acetyl-L-Cysteine (NAC) completely prevented, and 17 beta-estradiol amplified the gamma H2AX induction by 3'-OH-PCB180. As 3'-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3'-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.

  • 23. Alfirevic, A.
    et al.
    Neely, D.
    Armitage, J.
    Chinoy, H.
    Cooper, R. G.
    Laaksonen, R.
    Carr, D. F.
    Bloch, K. M.
    Fahy, J.
    Hanson, A.
    Yue, Q-Y
    Wadelius, Mia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014Inngår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6519, Vol. 96, nr 4, 470-476 s.Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

  • 24.
    Alfredsson, Antonia
    Karlstads universitet.
    Läkemedelsorsakade förgiftningar i Sveringe: Trender, riskgrupp och tillgång2013Independent thesis Advanced level (professional degree), 10 poäng / 15 hpOppgave
  • 25.
    Alfredsson, Joakim
    et al.
    Region Östergötland, Hjärt- och Medicincentrum, Kardiologiska kliniken US. Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Duke University, NC 27710 USA.
    Alexander, Karen P.
    Duke University, NC 27710 USA.
    Multiple Chronic Conditions in Older Adults with Acute Coronary Syndromes2016Inngår i: Clinics in Geriatric Medicine, ISSN 0749-0690, E-ISSN 1879-8853, Vol. 32, nr 2, 291-+ s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Older adults presenting with acute coronary syndromes (ACSs) often have multiple chronic conditions (MCCs). In addition to traditional cardiovascular (CV) risk factors (ie, hypertension, hyperlipidemia, and diabetes), common CV comorbidities include heart failure, stroke, and atrial fibrillation, whereas prevalent non-CV comorbidities include chronic kidney disease, anemia, depression, and chronic obstructive pulmonary disease. The presence of MCCs affects the presentation (eg, increased frequency of type 2 myocardial infarctions [MIs]), clinical course, and prognosis of ACS in older adults. In general, higher comorbidity burden increases mortality following MI, reduces utilization of ACS treatments, and increases the importance of developing individualized treatment plans.

  • 26.
    Ali, Ehood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Harvard Medical school / Boston Children's Hospital.
    The Role of the Glycine Receptor’s Alpha 2Subunit in the Behavior of Mice2014Independent thesis Advanced level (degree of Master (Two Years)), 20 poäng / 30 hpOppgave
  • 27. Allgardsson, Anders
    et al.
    Andersson, C. David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Akfur, Christine
    Worek, Franz
    Linusson, Anna
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Ekström, Fredrik
    An unusual dimeric inhibitor of acetylcholinesterase: cooperative binding of crystal violet2017Inngår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, nr 9, 1433Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Acetylcholinesterase (AChE) is an essential enzyme that terminates cholinergic transmission by a rapid hydrolysis of the neurotransmitter acetylcholine. AChE is an important target for treatment of various cholinergic deficiencies, including Alzheimer's disease and myasthenia gravis. In a previous high throughput screening campaign, we identified the dye crystal violet (CV) as an inhibitor of AChE. Herein, we show that CV displays a significant cooperativity for binding to AChE, and the molecular basis for this observation has been investigated by X-ray crystallography. Two monomers of CV bind to residues at the entrance of the active site gorge of the enzyme. Notably, the two CV molecules have extensive intermolecular contacts with each other and with AChE. Computational analyses show that the observed CV dimer is not stable in solution, suggesting the sequential binding of two monomers. Guided by the structural analysis, we designed a set of single site substitutions, and investigated their effect on the binding of CV. Only moderate effects on the binding and the cooperativity were observed, suggesting a robustness in the interaction between CV and AChE. Taken together, we propose that the dimeric cooperative binding is due to a rare combination of chemical and structural properties of both CV and the AChE molecule itself.

  • 28.
    Alm, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Proteomic Characterization of Induced Developmental Neurotoxicity2009Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The developing brain goes through a number of developmental periods during which it displays an increased sensitivity to exogenous disturbances. On such period is the so called “Brain growth spurt” (BGS) which in humans takes place starting from the third trimester of pregnancy and throughout the first few years of life. The corresponding period in rats and mice is the first postnatal weeks. Exposure to relatively modest concentrations of the brominated flame retardant PBDE-99 during the second week of life in mice causes a more or less permanent impairment in the ability of the animals to adjust properly to environmental changes at adulthood. This “late response on early exposure” reflects the long-term consequences of disrupting the developing brain during a sensitive time period.

    The cellular mechanisms underlying the behavioral effects are far from clear. To address the initial damage occurring around the time of exposure, the approach used in this thesis is to use proteomics to analyze the effects of PBDE-99 on protein expression soon (24 hours) after exposure of the neonatal mouse on postnatal day (PND) 10.The thesis comprises the effects on the proteome in three distinct brain parts: cerebral cortex, striatum and the hippocampus. In addition, an in vitro model was developed and used to evaluate the PBDE-99 effects on cultured cerebral cortex cells from embryonic rat brains.

    Gel-based proteomics (2D-DIGE) coupled to MALDI- or ESI-MS has been used throughout for the proteomics experiments, but other techniques aimed at analyzing both proteins and mRNA have also been used to better characterize the effects.

    Even if the protein complements expressed by the different brain parts and separated with 2D-DIGE are seemingly similar, the effects are apparently specific for the different brain regions. In hippocampus, PBDE induces effects on proteins involved in metabolism and energy production, while the effects in striatum point towards effects on neuroplasticity.

    PBDE-99 changes the expression of cytoskeletal proteins in the cerebral cortex 24 hours after exposure. Interestingly, in vitro exposure of cerebral cortex cells to a PBDE-99 concentration in the same order of magnitude as in the in vivo neonatal brain also induces cytoskeletal effects, in the absence of cytotoxicity. This may suggest effects on regulatory aspects of cytoskeletal dynamics such as those involved in neurite sprouting.

    This thesis also addresses the problems involved in presenting proteomics data. Many of the available methods and approaches for presenting transcriptomics data are not suitable for isoform rich protein data. Modifications of existing methods and the development of a new approach (DEPPS) is also presented. Most importantly, the thesis presents the application and usefulness of proteomics as hypothesis generating techniques in neurotoxicology.

  • 29.
    Almqvist, Helena
    et al.
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Axelsson, Hanna
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Jafari, Rozbeh
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Dan, Chen
    School of Biological Sciences, Nanyang Technological University.
    Mateus, André
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Haraldsson, Martin
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Larsson, Andreas
    School of Biological Sciences, Nanyang Technological University.
    Martinez-Molina, Daniel
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    Artursson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lundbäck, Thomas
    Laboratories for Chemical Biology Karolinska Institutet Science for Life Laboratory Stockholm, Division of Translational Medicine & Chemical Biology.
    Nordlund, Pär
    Department of Medical Biochemistry & Biophysics, Division of Biophysics, Karolinska Institutet.
    CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 11040Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 30.
    Alnuaimy, Ranin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Granskning av läkemedelsinformation i FASS gällande risk under graviditet och amning2014Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
    Abstract [sv]

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

  • 31.
    Al-Obaidi, Omar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för farmaceutisk farmakologi.
    Endocannabinoider som mål för nya läkemedel vid Alzheimer sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

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

  • 32.
    Al-Shammari, Rotana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Nya behandlingsmål för att minska levodopainducerade dyskinesier vid Parkinsons sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 poäng / 15 hpOppgave
    Abstract [sv]

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

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

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

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

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

  • 33.
    Alsiö, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms2010Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

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

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

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

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

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

     

  • 34.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015Inngår i: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, nr 21-22, 4017-4031 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 35.
    Alsiö, Johan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Roman, Erika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Olszewski, Pawel K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Jonsson, Petra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Fredriksson, Robert
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009Inngår i: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, nr 2, 193-202 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 36.
    Alvarsson, Jonathan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Andersson, Claes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Spjuth, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Wikberg, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Brunn: an open source laboratory information system for microplates with a graphical plate layout design process2011Inngår i: BMC Bioinformatics, ISSN 1471-2105, Vol. 12, nr 1, 179Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Compound profiling and drug screening generates large amounts of data and is generally based on microplate assays. Current information systems used for handling this are mainly commercial, closed source, expensive, and heavyweight and there is a need for a flexible lightweight open system for handling plate design, and validation and preparation of data.

    Results:

    A Bioclipse plugin consisting of a client part and a relational database was constructed. A multiple-step plate layout point-and-click interface was implemented inside Bioclipse. The system contains a data validation step, where outliers can be removed, and finally a plate report with all relevant calculated data, including dose-response curves.

    Conclusions:

    Brunn is capable of handling the data from microplate assays. It can create dose-response curves and calculate IC50 values. Using a system of this sort facilitates work in the laboratory. Being able to reuse already constructed plates and plate layouts by starting out from an earlier step in the plate layout design process saves time and cuts down on error sources.

  • 37.
    Alzghoul, Ahmad
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Datalogi.
    Alhalaweh, Amjad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Mahlin, Denny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel A. S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Experimental and Computational Prediction of Glass Transition Temperature of Drugs2014Inngår i: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, nr 12, 3396-3403 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glass transition temperature (T-g) is an important inherent property of an amorphous solid material which is usually determined experimentally. In this study, the relation between T-g and melting temperature (T-m) was evaluated using a data set of 71 structurally diverse druglike compounds. Further, in silico models for prediction of T-g were developed based on calculated molecular descriptors and linear (multilinear regression, partial least-squares, principal component regression) and nonlinear (neural network, support vector regression) modeling techniques. The models based on T-m predicted T-g with an RMSE of 19.5 K for the test set. Among the five computational models developed herein the support vector regression gave the best result with RMSE of 18.7 K for the test set using only four chemical descriptors. Hence, two different models that predict T-g of drug-like molecules with high accuracy were developed. If T-m is available, a simple linear regression can be used to predict T-g. However, the results also suggest that support vector regression and calculated molecular descriptors can predict T-g with equal accuracy, already before compound synthesis.

  • 38. Anand, Praveen
    et al.
    Whiteside, Garth
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hohmann, Andrea G
    Targeting CB2 receptors and the endocannabinoid system for the treatment of pain2009Inngår i: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 60, nr 1, 255-266 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The endocannabinoid system consists of the cannabinoid (CB) receptors, CB(1) and CB(2), the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB(1) receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB(2) receptor agonists. Selective CB(2) agonists and peripherally restricted CB(1) or CB(1)/CB(2) dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB(2) receptors were originally described as being restricted to cells of immune origin, but there is evidence for their expression in human primary sensory neurons, and increased levels of CB(2) receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB(2) receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of mu-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment strategy, while minimizing the potential for NSAID-induced gastrointestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include alpha(2)-adrenoceptor modulators, peroxisome proliferator-activated receptor alpha agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.

  • 39. Andersen, Toril
    et al.
    Bleher, Stefan
    Flaten, Goril Eide
    Tho, Ingunn
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Skalko-Basnet, Natasa
    Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy2015Inngår i: Marine Drugs, ISSN 1660-3397, Vol. 13, nr 1, 222-236 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mucoadhesive drug therapy destined for localized drug treatment is gaining increasing importance in today's drug development. Chitosan, due to its known biodegradability, bioadhesiveness and excellent safety profile offers means to improve mucosal drug therapy. We have used chitosan as mucoadhesive polymer to develop liposomes able to ensure prolonged residence time at vaginal site. Two types of mucoadhesive liposomes, namely the chitosan-coated liposomes and chitosan-containing liposomes, where chitosan is both embedded and surface-available, were made of soy phosphatidylcholine with entrapped fluorescence markers of two molecular weights, FITC-dextran 4000 and 20,000, respectively. Both liposomal types were characterized for their size distribution, zeta potential, entrapment efficiency and the in vitro release profile, and compared to plain liposomes. The proof of chitosan being both surface-available as well as embedded into the liposomes in the chitosan-containing liposomes was found. The capability of the surface-available chitosan to interact with the model porcine mucin was confirmed for both chitosan-containing and chitosan-coated liposomes implying potential mucoadhesive behavior. Chitosan-containing liposomes were shown to be superior in respect to the simplicity of preparation, FITC-dextran load, mucoadhesiveness and in vitro release and are expected to ensure prolonged residence time on the vaginal mucosa providing localized sustained release of entrapped model substances.

  • 40. Andersen, Toril
    et al.
    Mishchenko, Ekaterina
    Flaten, Gøril Eide
    Ericson Sollid, Johanna U.
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap.
    Tho, Ingunn
    Škalko-Basnet, Nataša
    Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes2017Inngår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 15, nr 3, 64Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vaginal infections are associated with high recurrence, which is often due to a lack of efficient treatment of complex vaginal infections comprised of several types of pathogens, especially fungi and bacteria. Chitosan, a mucoadhesive polymer with known antifungal effect, could offer a great improvement in vaginal therapy; the chitosan-based nanosystem could both provide antifungal effects and simultaneously deliver antibacterial drugs. We prepared chitosan-containing liposomes, chitosomes, where chitosan is both embedded in liposomes and surface-available as a coating layer. For antimicrobial activity, we entrapped metronidazole as a model drug. To prove that mucoadhesivness alone is not sufficient for successful delivery, we used Carbopol-containing liposomes as a control. All vesicles were characterized for their size, zeta potential, entrapment efficiency, and in vitro drug release. Chitosan-containing liposomes were able to assure the prolonged release of metronidazole. Their antifungal activity was evaluated in a C. albicans model; chitosan-containing liposomes exhibited a potent ability to inhibit the growth of C. albicans. The presence of chitosan was crucial for the system's antifungal activity. The antifungal efficacy of chitosomes combined with antibacterial potential of the entrapped metronidazole could offer improved efficacy in the treatment of mixed/complex vaginal infections.

  • 41. Andersen, Toril
    et al.
    Vanić, Zeljka
    Flaten, Gøril Eide
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Tho, Ingunn
    Skalko-Basnet, Nataša
    Pectosomes and chitosomes as delivery systems for metronidazole: the one-pot preparation method2013Inngår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 5, nr 3, 445-456 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mucoadhesive liposomes offer a potential for improved residence time of liposomal systems targeting contact with mucosal tissues, such as in buccal, oral, colon, and vaginal drug delivery. Most of the currently available methods rely on the coating of preformed liposomes by various mucoadhesive polymers. The aim of this study was to develop novel mucoadhesive system by the one-pot preparation method. The pectin- and chitosan-containing liposomes, namely pectosomes and chitosomes, were prepared by the modified solvent injection method. In order to optimize this novel delivery system, we used pectins and chitosans of both high and low degree of esterification/deacetylation (DE/DD), respectively. Sonication was applied to reduce the original vesicle size. All vesicles were characterized for their size, zeta potential, metronidazole entrapment, and stability. Both pectosomes and chitosomes were found to entrap more metronidazole than conventional plain liposomes. Preliminary data indicate that the polymer is present on the liposomal surface, embedded within inner liposomal bilayers, and entrapped inside the aqueous compartment. The next step in the evaluation of this system is the testing of its mucoadhesiveness.

  • 42.
    Andersson, Annsofie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Pharmaceutical knowledge retrieval through reasoning of ChEMBL RDF2011Independent thesis Advanced level (degree of Master (Two Years)), 30 poäng / 45 hpOppgave
  • 43.
    Andersson, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap, Avdelningen för toxikologi.
    Leaching of Pharmaceuticals in Soil Columns amended with Sludge2015Independent thesis Advanced level (degree of Master (One Year)), 20 poäng / 30 hpOppgave
    Abstract [en]

    Occurrence of pharmaceutical residues in surface and ground waters, used as a source for drinking water supply has been studied over the years. Wastewater treatment plants are generally not efficient enough to remove pharmaceuticals from wastewater and sewage sludge. As a result, they are released into the environment mainly via effluent discharges to surface water bodies, the reuse of biosolids in agriculture as soil amendment, and the disposal of biosolids to landfill areas.

    The aim of this study was to investigate the leaching behavior of pharmaceuticals from several therapeutic groups (i.e. atorvastatin, bicalutamide, carbamazepine, furosemide, hydrochlorothiazide, losartan, oxazepam, valsartan, and venlafaxine) using undisturbed soil columns (loamy sand, loam, and clay) and disturbed soil columns (till mixed with peat) amended with sewage sludge at laboratory-scale. The experiment was performed under controlled conditions to gain a better understanding of the leaching behavior of pharmaceuticals in the natural environment. Another objective was to single out the pharmaceuticals with the highest leaching potential (i.e. carbamazepine, hydrochlorothiazide, oxazepam, and valsartan) in order to analyze their effects on the environment based on earlier studies on the subject. Oxazepam, for example, has shown to have effects on fish such as increased feeding rate and activity.

    Leachate analysis show that, in general, pharmaceuticals leach slower in loamy sand compared to loam and clay which might be due to macro pores and funnel flow in the loamy and clayish soil which enhance the leaching rate. The accumulated mass (µg) in the leachate from clay (13) were also higher than in loam (5.7), loamy sand (2.6), and the till and peat (0) soil.  This indicates that the slow leaching of pharmaceuticals in loamy sand, and till and peat might enhance the sorption or degradation of pharmaceuticals compared to clay and loam.

  • 44.
    Andersson, Helén
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Helmestam, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Zebrowska, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Brittebo, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands2010Inngår i: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 38, nr 1, 200-207 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The beneficial effects of tamoxifen in the prevention and treatment of breast cancer are compromised by an increased risk of endometrial polyps, hyperplasia, and cancer. Tamoxifen is metabolized to an array of metabolites with estrogenic effects but also to reactive intermediates that may form protein and DNA adducts. The aim of this study was to investigate cellular [(3)H]tamoxifen adduct formation by light microscopic autoradiography and cell stress by immunohistochemical analysis of glucose-regulating protein 78 (GRP78), nuclear factor kappaB (NF-kappaB), and caspase 3 in human endometrial explants after short-term incubation with tamoxifen. The cellular expression of tamoxifen-metabolizing enzymes in human endometrial biopsy samples was also determined by immunohistochemistry. The results showed selective [(3)H]tamoxifen adduct formation in glandular and surface epithelia after incubation with a nontoxic concentration of [(3)H]tamoxifen (6 nM). There was also a selective expression of the endoplasmic reticulum stress chaperone GRP78 and activated caspase 3 at these sites after incubation with cytotoxic concentrations of tamoxifen (10-100 microM). The cell stress was preferentially observed in samples from women in the proliferative menstrual phase. No treatment-related expression of NF-kappaB was observed. Constitutive expression of the tamoxifen-metabolizing enzymes CYP1B1, CYP2A6, CYP2B6, CYP2C8/9/19, CYP2D6, and SULT2A1 in glandular and surface epithelia was shown, but there was a large interindividual variation. The colocalization of [(3)H]tamoxifen adducts, expression of GRP78, caspase 3, and tamoxifen-metabolizing enzymes in human glandular and surface epithelia suggest a local bioactivation of tamoxifen at these sites and that epithelial cells are early target sites for tamoxifen-induced cell stress.

  • 45.
    Andersson, Ingemar
    Högskolan Kristianstad, Sektionen för Hälsa och Samhälle.
    Rehabilitering vid långvarig smärta2010Inngår i: Smärta och smärtbehandling / [ed] Mads Werner, Ido Leden, Stockholm: Liber , 2010, 2, 401-409 s.Kapittel i bok, del av antologi (Annet vitenskapelig)
  • 46.
    Andersson, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Läkemedelspotentialen hos Melanotan II och andra melanokortinreceptoragonister2013Independent thesis Basic level (professional degree), 10 poäng / 15 hpOppgave
    Abstract [sv]

    Melancortin II, eller Melanotan II, är en melanokortinreceptoragonist som säljs på internet mot impotens, för att gå ned i vikt och för att inducera solbränna. Melanotan II är inte ett godkänt läkemedel men flera kliniska studier har undersökt dess effekt samt effekten hos andra melanokortinreceptoragonister, främst Melanotan I och bremelanotid. Syftet var att utröna huruvida melanokortinreceptoragonister har potential som läkemedel. Metoden var främst sökningar på databasen PubMed.  Rapporten visar att både Melanotan I och II ger ökad pigmentering. Melanotan I verkar även minska UV-inducerade DNA-skador. Subkutana implantat med Melanotan I har också visats ge effekt hos patienter med erytropoetisk protofyri, acne vulgaris, urtikaria utlöst av solljus och vitiligo.

    Melanotan II och bremelanotid ger båda erektil effekt hos studiedeltagare. En effekt av bremelanotid på kvinnlig sexuell dysfunktion har också setts. Bremelanotid har gett förhöjt systoliskt blodtryck som biverkan och denna biverkan verkar inte kunna elimineras genom receptorselektivitet. Ett ställningstagande kring huruvida biverkan är rimlig i behandlingen av kvinnlig sexuell dysfunktion, där andra behandlingsalternativ inte finns, behövs.

    Melanotan II har hos råttor minskat födointag, reducerat kroppsvikten, ökat energiåtgången, påverkat fettmetabolismen och insulinkänsligheten. MC4R verkar ha den viktigaste funktionen. Problem finns dock med desensitisering och en selektiv MC4R-agonist gav inte en permanent, långsiktig reducering av kroppsvikt hos människa. På grund av det förefaller melanokortinreceptoragonister inte ha en potential i läkemedelsbehandlingen av fetma.

    Sammanfattningsvis tyder rapporten på en potential hos melanokortinreceptoragonister i behandlingen av kvinnlig sexuell dysfunktion och ett flertal hudsjukdomar.

  • 47.
    Andersson, Patrik
    et al.
    AstraZeneca R&D, Mölndal, Sweden.
    Kenne, Kerstin
    AstraZeneca R&D, Södertälje, Sweden.
    Glinghammar, Björn
    AstraZeneca R&D, Södertälje, Sweden.
    Pointon, Amy V.
    Global Safety Assessment AstraZeneca, Macclesfield, United Kingdom.
    Åkerblad, Peter
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Lutz, Mareike
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Hovdal, Daniel
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Maxvall, Ingela
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Lindstedt, Eva-Lotte
    CVGI iMed AstraZeneca, Mölndal, Sweden.
    Toxicity with LXR agonists – Problem solving activities for mechanistic understanding2012Inngår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 211, nr Suppl. (S), S39-S39 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several lines of evidence points toward the potential positive effects of LXR (Liver X Receptor) modulators for effective and safe therapy of cardiovascular diseases (CVDs). LXR is a dimeric nuclear hormone receptor that exists as a combination of RXR and one of two subtypes LXR alpha or beta, which act as cholesterol sensors. LXR alpha is highly expressed in the liver, intestine and adipose tissue while LXR beta is ubiquitously expressed. Activation of LXR up-regulates several genes involved in reverse cholesterol transport (RCT), including ABC transporters. This results in increased efflux of cholesterol from macrophages in atherosclerotic vascular lesions to the circulation and further on to other tissues to ultimately be excreted into the faeces. These effects together with systemic and local anti-inflammatory properties of LXR modulation are likely to contribute to decreased atherosclerosis. The positive effects of LXR activation on RCT and cholesterol balance must be obtained without negative lipid effects, since LXR also activates lipogenic genes. Other types of toxicity and approaches to better understand the mechanism(s) behind these will be presented. Copyright © 2012 Published by Elsevier Ireland Ltd.

  • 48.
    Andersson, Patrik
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    van der Burght, Aafje S.A.M.
    van den Berg, Martin
    Tysklind, Mats
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Multivariate modeling of polychlorinated biphenyl-induced CYP1A activity in hepatocytes from three different species: ranking scales and species differences2000Inngår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 19, nr 5, 1454-1463 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cytochrome P4501A–induced activity of 20 selected polychlorinated biphenyls (PCBs) was evaluated by measuring ethoxyresorufin-O-deethylase and methoxyresorufin-O-demethylase activities induced in the hepatocytes of cynomolgus monkeys, male castrated pigs, and chicken embryos. Quantitative structure-activity relationships have been established, including 52 physi-cochemical parameters and different measures of the dose-response curves. Relative effect potencies are predicted for the 154 tetra-to hepta-PCBs and reported for the most potent congeners according to both EC50 and maximal response values. Important physicochemical parameters of the PCBs as related to the modeled activity are parts of their ultraviolet absorption spectra, the Henry's law constant, the ionization potential, and the octanol-water partition coefficient. Interspecies differences were found in terms of varied sensitivity to different structural subgroups of the compounds. The chicken hepatocyte assay showed the most specific structure-activity relationship, with high activity for the non-ortho PCBs, whereas the pig hepatocytes responded even for some di- to tetra-ortho PCBs. An interspecies response, the principal induction potency, is presented for the 41 most potent PCBs. These responses showed strong correlation with the toxic equivalency factors and are likely to be useful in risk assessment of the compounds.

  • 49.
    Andersson, Rolf G
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Bartonek, M
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindström, Eva
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Lindström, I M
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Toll, Johan B
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och vård, Farmakologi.
    Studies of the mechanism of desensitization of anti-IgE-mediated histamine release from human basophils1989Inngår i: Agents and actions, ISSN 0065-4299, Vol. 27, nr 1-2, 25-28 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human basophils became hyporesponsive to anti-IgE when exposed to this agent in the absence of Ca2+ for more than 10 min. The desensitization process proceeded in parallel to the releasing-process. The mechanism of desensitization seems to involve a very early step in the release-reaction, since the response to phospholipase A2 and diolein, agents involved in the release-reaction, was not affected by the desensitization.

  • 50.
    Andersson, Sara B. E.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Alvebratt, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Bergström, Christel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaci.
    Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds2017Inngår i: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, nr 9, 1805-1816 s.Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.

    Methods: The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.

    Results: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.

    Conclusions: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.

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