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  • 1.
    Abdi, Hafsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Finns det någon koppling mellan Alzheimers sjukdom och Diabetes Mellitus?2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    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.

  • 2.
    Abdulla Karim, Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    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 credits / 30 HE creditsStudent thesis
    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

  • 3.
    Abdulrasul, Ali
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Neurosteroids and Alzheimer’s disease: Mechanistic studies of neuroprotection and neurogenesis2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    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. 

  • 4.
    Abrantes, João A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nielsen, Elisabet I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Korth-Bradley, J.
    Pfizer Inc, Collegeville, PA USA..
    Harnisch, L.
    Pfizer Ltd, Global Clin Pharmacol, Sandwich, Kent, England..
    Jönsson, Siv
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Elucidation of Factor VIII Activity Pharmacokinetics: A Pooled Population Analysis in Patients With Hemophilia A Treated With Moroctocog Alfa2017In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 102, no 6, p. 977-988Article in journal (Refereed)
    Abstract [en]

    This study investigated the disposition of coagulation factor VIII activity in 754 patients with moderate to severe hemophilia A following the administration of moroctocog alfa, a B-domain deleted recombinant factor VIII. Data analyzed included patients aged 1 day to 73 years enrolled in 13 studies conducted over a period of 20 years in 25 countries. A two-compartment population pharmacokinetic model with a baseline model described the pooled data well. Body size, age, inhibitors, race, and analytical assay were identified as significant predictors of factor VIII disposition. In addition, simulations of prophylactic dosing schedules in several pediatric cohorts showed large variability and suggest that younger patients would require higher weight-adjusted doses than adolescents to achieve target factor VIII trough activity when receiving every other day or twice weekly dosing.

  • 5. Abu-Bakar, A'edah
    et al.
    Arthur, Dionne M.
    Wikman, Anna S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rahnasto, Minna
    Juvonen, Risto O.
    Vepsalainen, Jouko
    Raunio, Hannu
    Ng, Jack C.
    Lang, Matti A.
    Metabolism of bilirubin by human cytochrome P450 2A62012In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 261, no 1, p. 50-58Article in journal (Refereed)
    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.

  • 6.
    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 neurons2007In: Neuroscience, ISSN 0306-4522, E-ISSN 1873-7544, Vol. 148, no 3, p. 724-36Article in journal (Refereed)
    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.

  • 7. af Klinteberg, Britt
    et al.
    Alm, Per-Olof
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Serotonin, personality and smoking2000Conference paper (Refereed)
  • 8. Agerstrand, Marlene
    et al.
    Berg, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Bjorlenius, Berndt
    Breitholtz, Magnus
    Brunström, Björn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Fick, Jerker
    Gunnarsson, Lina
    Larsson, D. G. Joakim
    Sumpter, John P.
    Tysklind, Mats
    Ruden, Christina
    Improving Environmental Risk Assessment of Human Pharmaceuticals2015In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 49, no 9, p. 5336-5345Article in journal (Refereed)
    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.

  • 9.
    Agrawal, Mukta
    et al.
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai , Chhattisgarh, India..
    Ajazuddin, A
    Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud Road, Bhilai 490024, Chhattisgarh, India.
    Tripathi, Dulal K.
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai 490024, Chhattisgarh, India..
    Saraf, Swarnlata
    Pt Ravishankar Shukla Univ, Univ Inst Pharm, Raipur 492010, Chhattisgarh, India..
    Saraf, Shailendra
    Pt Ravishankar Shukla Univ, Univ Inst Pharm, Raipur 492010, Chhattisgarh, India..
    Antimisiaris, Sophia G.
    Univ Patras, Dept Pharm, Lab Pharmaceut Technol, Rion 26510, Greece.;Inst Chem Engn, FORTH ICE HT, Patras 25104, Greece..
    Mourtas, Spyridon
    Univ Patras, Dept Pharm, Lab Pharmaceut Technol, Rion 26510, Greece..
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alexander, Amit
    Rungta Coll Pharmaceut Sci & Res, Kohka Kurud Rd, Bhilai 490024, Chhattisgarh, India..
    Recent advancements in liposomes targeting strategies to cross blood-brain barrier (BBB) for the treatment of Alzheimer's disease2017In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 260, p. 61-77Article, review/survey (Refereed)
    Abstract [en]

    In this modern era, with the help of various advanced technologies, medical science has overcome most of the health-related issues successfully. Though, some diseases still remain unresolved due to various physiological barriers. One such condition is Alzheimer; a neurodegenerative disorder characterized by progressive memory impairment, behavioral abnormalities, mood swing and disturbed routine activities of the person suffering from. It is well known to all that the brain is entirely covered by a protective layer commonly known as blood brain barrier (BBB) which is responsible to maintain the homeostasis of brain by restricting the entry of toxic substances, drug molecules, various proteins and peptides, small hydrophilic molecules, large lipophilic substances and so many other peripheral components to protect the brain from any harmful stimuli. This functionally essential structure creates a major hurdle for delivery of any drug into the brain. Still, there are some provisions on BBB which facilitate the entry of useful substances in the brain via specific mechanisms like passive diffusion, receptor-mediated transcytosis, carrier-mediated transcytosis etc. Another important factor for drug transport is the selection of a suitable drug delivery systems like, liposome, which is a novel drug carrier system offering a potential approach to resolving this problem. Its unique phospholipid bilayer structure (similar to physiological membrane) had made it more compatible with the lipoidal layer of BBB and helps the drug to enter the brain. The present review work focused on various surface modifications with functional ligand (like lactoferrin, transferrin etc.) and carrier molecules (such as glutathione, glucose etc.) on the liposomal structure to enhance its brain targeting ability towards the successful treatment of Alzheimer disease.

  • 10.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    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 compounds2015In: Hepatology, ISSN 0270-9139, E-ISSN 1527-3350, Vol. 62, p. 325A-326AArticle in journal (Other academic)
  • 11. Akkermann, Kirsti
    et al.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Serotonin transporter gene promoter polymorphism affects the severity of binge eating in general population2010In: Progress in Neuro-psychopharmacology and Biological Psychiatry, ISSN 0278-5846, E-ISSN 1878-4216, Vol. 34, no 1, p. 111-114Article, review/survey (Refereed)
    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.

  • 12.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    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 Cancer2016In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 14, no 6, article id 115Article in journal (Refereed)
    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.

  • 13.
    Alajlani, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi. Karl Franzens Univ Graz, Inst Pharmaceut Sci, Dept Pharmacognosy, Univ Pl 4, A-8010 Graz, Austria..
    Backlund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Predicting the mechanism of action of antituberculosis agents using chemical global positioning system - natural product2016In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Article in journal (Other academic)
  • 14.
    Alavian-Ghavanini, Ali
    et al.
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Lin, Ping-I
    Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rimfors, Sabina Risen
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Tang, Mandy
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden.
    Lindh, Christian
    Lund Univ, Div Occupat & Environm Med, S-22185 Lund, Sweden.
    Bornehag, Carl-Gustaf
    Icahn Sch Med Mt Sinai, New York, NY 10029 USA;Karlstad Univ, Dept Hlth Sci, S-65188 Karlstad, Sweden.
    Rueegg, Joelle
    Karolinska Inst, Unit Toxicol Sci, Swetox, Forskargatan 20, S-15136 Sodertalje, Sweden;Karolinska Inst, Dept Clin Neurosci, CMM, S-17164 Solna, Sweden.
    Prenatal Bisphenol A Exposure is Linked to Epigenetic Changes in Glutamate Receptor Subunit Gene Grin2b in Female Rats and Humans2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 11315Article in journal (Refereed)
    Abstract [en]

    Bisphenol A (BPA) exposure has been linked to neurodevelopmental disorders and to effects on epigenetic regulation, such as DNA methylation, at genes involved in brain function. High doses of BPA have been shown to change expression and regulation of one such gene, Grin2b, in mice. Yet, if such changes occur at relevant doses in animals and humans has not been addressed. We investigated if low-dose developmental BPA exposure affects DNA methylation and expression of Grin2b in brains of adult rats. Furthermore, we assessed associations between prenatal BPA exposure and Grin2b methylation in 7-year old children. We found that Grin2b mRNA expression was increased and DNA methylation decreased in female, but not in male rats. In humans, prenatal BPA exposure was associated with increased methylation levels in girls. Additionally, Iow APGAR scores, a predictor for increased risk for neurodevelopmental diseases, were associated with higher Grin2b methylation levels in girls. Thus, we could link developmental BPA exposure and Iow APGAR scores to changes in the epigenetic regulation of Grin2b, a gene important for neuronal function, in a sexual dimorphic fashion. Discrepancies in exact locations and directions of the DNA methylation change might reflect differences between species, analysed tissues, exposure level and/or timing.

  • 15. 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 University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Maitland-van der Zee, A. H.
    Voora, D.
    Psaty, B. M.
    Palmer, C. N. A.
    Pirmohamed, M.
    Phenotype Standardization for Statin-Induced Myotoxicity2014In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 96, no 4, p. 470-476Article, review/survey (Refereed)
    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.

  • 16.
    Ali, Ehood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. 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 credits / 30 HE creditsStudent thesis
  • 17.
    Alimohammadi, Mohammed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Neurophysiological Measures of Efficacy and Safety for Botulinum Toxin Injection in Facial and Bulbar Muscles: Special Considerations2017In: Toxins, ISSN 2072-6651, E-ISSN 2072-6651, Vol. 9, no 11, article id 352Article, review/survey (Refereed)
    Abstract [en]

    Botulinum toxin (BoNT) injections into facial and bulbar muscles are widely and increasingly used as medical treatments for cervical and facial dystonia, facial hemispasm, correction of facial palsy, hyperhidrosis, as well as cosmetic treatment of glabellar lines associated with grief and anger. Although BoNT treatment is generally considered safe, the diffusion of the toxin to surrounding muscles may result in complications, including difficulties swallowing, in a dose-dependent manner. The sensitivity of clinical examination for detecting adverse events after BoNT treatment is limited. Few reports have highlighted the potential effects on other muscles in the facial area due to the spreading of the toxin. The possibilities of spreading and thus unknown pharmacological BoNT effects in non-targeted muscles emphasise the importance of correct administration of BoNT in terms of dose selection, injection points, and appropriate effect surveillance. In this review article, we will focus on novel objective measures of efficacy and safety regarding BoNT treatment of facial muscles and the reasons why this is important.

  • 18.
    Alm, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Proteomic Characterization of Induced Developmental Neurotoxicity2009Doctoral thesis, comprehensive summary (Other academic)
    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.

  • 19.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, 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-fluorouracil2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, article id 11040Article in journal (Refereed)
    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.

  • 20.
    Alnuaimy, Ranin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Granskning av läkemedelsinformation i FASS gällande risk under graviditet och amning2014Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    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.

  • 21.
    Al-Obaidi, Omar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Pharmaceutical Pharmacology.
    Endocannabinoider som mål för nya läkemedel vid Alzheimer sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    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.

  • 22.
    Al-Shammari, Rotana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nya behandlingsmål för att minska levodopainducerade dyskinesier vid Parkinsons sjukdom2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    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. 

  • 23.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    From Food Preference to Craving: Behavioural Traits and Molecular Mechanisms2010Doctoral thesis, comprehensive summary (Other academic)
    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.

     

    List of papers
    1. Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
    Open this publication in new window or tab >>Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 2
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    2009 (English)In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed) Published
    Abstract [en]

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

    Keywords
    Anxiety, corticotropin-releasing factor receptor, dietary fat, elevated plus maze, exploratory behavior, food preferences, multivariate concentric square field, novelty seeking, palatable, urocortin 2, Wistar
    National Category
    Pharmacology and Toxicology Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-117598 (URN)10.1111/j.1601-183X.2008.00464.x (DOI)000263756100007 ()19077174 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2018-01-12Bibliographically approved
    2. Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
    Open this publication in new window or tab >>Locomotor adaptation and elevated expression of reward-relevant genes following free-choice high-fat diet exposure
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

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

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-119489 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2013-01-08
    3. Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
    Open this publication in new window or tab >>Motivation for sucrose in sated rats is predicted by low anxiety-like behavior
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    2009 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 454, no 3, p. 193-197Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    Elsevier, 2009
    Keywords
    Craving; Sucrose, Dietary fat, Progressive ratio, Anxiety, Novelty-seeking
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-117599 (URN)10.1016/j.neulet.2009.03.045 (DOI)000265275500005 ()19429082 (PubMedID)
    Available from: 2010-03-01 Created: 2010-02-21 Last updated: 2017-12-12Bibliographically approved
    4. Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    Open this publication in new window or tab >>Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals
    2009 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed) Published
    Abstract [en]

    INTRODUCTION:

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

    MATERIALS AND METHODS:

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

    RESULTS AND DISCUSSION:

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

    CONCLUSION:

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

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

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

    Identifiers
    urn:nbn:se:uu:diva-119472 (URN)
    Available from: 2010-03-01 Created: 2010-02-25 Last updated: 2010-03-01
  • 24.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. 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 study2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 4017-4031Article in journal (Refereed)
    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.

  • 25.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olszewski, Pawel K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Jonsson, Petra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Fredriksson, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Levine, Allen S.
    Minnesota Obesity Center, VA Medical Center, Minneapolis, MN, USA.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Lindblom, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Inverse association of high-fat diet preference and anxiety-like behavior: a putative role for urocortin 22009In: Genes, Brain and Behavior, ISSN 1601-1848, E-ISSN 1601-183X, Vol. 8, no 2, p. 193-202Article in journal (Refereed)
    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.

  • 26.
    Alskär, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

    List of papers
    1. Model-Based Interspecies Scaling of Glucose Homeostasis
    Open this publication in new window or tab >>Model-Based Interspecies Scaling of Glucose Homeostasis
    2017 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 11, p. 778-786Article in journal (Refereed) Published
    Abstract [en]

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

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2017
    National Category
    Pharmacology and Toxicology
    Identifiers
    urn:nbn:se:uu:diva-339699 (URN)10.1002/psp4.12247 (DOI)000418823400009 ()28960826 (PubMedID)
    Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2018-02-26Bibliographically approved
    2. Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Open this publication in new window or tab >>Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
    Show others...
    2016 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, no 3, p. 340-348Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Pharmaceutical Sciences
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-259411 (URN)10.1002/jcph.602 (DOI)000370162700011 ()26224050 (PubMedID)
    Available from: 2015-08-03 Created: 2015-08-03 Last updated: 2018-02-26
    3. Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Open this publication in new window or tab >>Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
    Show others...
    2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, no 4, p. 290-297Article in journal (Refereed) Published
    Abstract [en]

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

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-279065 (URN)10.1111/bcpt.12792 (DOI)000409507900013 ()28374974 (PubMedID)
    Funder
    EU, FP7, Seventh Framework Programme, 115156
    Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-02-26Bibliographically approved
    4. Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Open this publication in new window or tab >>Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmacology and Toxicology
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-343114 (URN)
    Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
    5. An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Open this publication in new window or tab >>An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Pharmacology and Toxicology
    Research subject
    Pharmacokinetics and Drug Therapy
    Identifiers
    urn:nbn:se:uu:diva-343115 (URN)
    Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
  • 27.
    Alskär, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bagger, Jonatan I
    Eriksson, Sara
    Holst, Jens J
    Knop, Filip K
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 DiabetesManuscript (preprint) (Other academic)
  • 28.
    Alskär, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bagger, Jonatan I
    Røge, Rikke M
    Komatsu, Kanji
    Kristensen, Niels
    Klim, Søren
    Holst, Jens J
    Ingwersen, Steen H
    Karlsson, Mats O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knop, Filip K
    Vilsbøll, Tina
    Kjellsson, Maria C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucoseManuscript (preprint) (Other academic)
  • 29.
    Alskär, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model-Based Interspecies Scaling of Glucose Homeostasis2017In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 11, p. 778-786Article in journal (Refereed)
    Abstract [en]

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

  • 30.
    Alvarsson, Jonathan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Andersson, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wikberg, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brunn: an open source laboratory information system for microplates with a graphical plate layout design process2011In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 12, no 1, article id 179Article in journal (Refereed)
    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.

  • 31.
    Alzghoul, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Alhalaweh, Amjad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Experimental and Computational Prediction of Glass Transition Temperature of Drugs2014In: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, no 12, p. 3396-3403Article in journal (Refereed)
    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.

  • 32.
    Andersson, Annsofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Pharmaceutical knowledge retrieval through reasoning of ChEMBL RDF2011Independent thesis Advanced level (degree of Master (Two Years)), 30 credits / 45 HE creditsStudent thesis
  • 33.
    Andersson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Toxicology.
    Leaching of Pharmaceuticals in Soil Columns amended with Sludge2015Independent thesis Advanced level (degree of Master (One Year)), 20 credits / 30 HE creditsStudent thesis
    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.

  • 34.
    Andersson, H. S.
    et al.
    Linnaeus Univ, Ctr Biomat Chem, Dept Chem & Biomed Sci, Norra Vagen 49, S-39234 Kalmar, Sweden..
    Jacobsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Eriksson, Camilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Hedstrom, M.
    Lund Univ, Dept Biotechnol, Box 118, S-22100 Lund, Sweden..
    Seth, H.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Sundberg, P.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden..
    Rosengren, K. J.
    Univ Queensland, Sch Biomed Sci, Brisbane, Qld 4072, Australia..
    Strand, M.
    Univ Gothenburg, Dept Biol & Environm Sci, Box 463, S-40530 Gothenburg, Sweden.;Swedish Univ Agr Sci, Swedish Species Informat Ctr, Backlosavagen 10, S-75651 Uppsala, Sweden..
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    The toxicity of ribbon worms: Alpha-nemertides or tetrodotoxin, or both?2016In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Article in journal (Other academic)
  • 35.
    Andersson, Helén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Helmestam, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Zebrowska, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Brittebo, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands2010In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 38, no 1, p. 200-207Article in journal (Refereed)
    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.

  • 36.
    Andersson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Läkemedelspotentialen hos Melanotan II och andra melanokortinreceptoragonister2013Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    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.

  • 37.
    Andersson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Karlsson, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    The environmental neurotoxin β-N-methylamino-l-alanine (l-BMAA) is deposited into birds' eggs2018In: Ecotoxicology and Environmental Safety, ISSN 0147-6513, E-ISSN 1090-2414, Vol. 147, p. 720-724Article in journal (Refereed)
    Abstract [en]

    C-carboxyl-labeled BMAA were compared. The results revealed a pronounced incorporation of radioactivity in the eggs, predominantly in the yolk but also in the albumen. Imaging analysis showed that the concentrations of radioactivity in the liver decreased about seven times between the 24h and the 72h time points, while the concentrations in egg yolk remained largely unchanged. At 72h the egg yolk contained about five times the concentration of radioactivity in the liver. Both BMAA preparations gave rise to similar distribution pattern in the bird tissues and in the eggs, indicating metabolic stability of the labeled groups. The demonstrated deposition into eggs warrants studies of BMAAs effects on bird development. Moreover, birds' eggs may be a source of human BMAA exposure, provided that the laying birds are exposed to BMAA via their diet.

  • 38.
    Andersson, Sara B. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alvebratt, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 9, p. 1805-1816Article in journal (Refereed)
    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.

  • 39.
    Andrén, Per E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Shariatgorji, Mohammadreza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Goodwin, Richard
    AstraZeneca, Drug Safety & Metab, Cambridge, England..
    Investigating drug-induced toxicity in tissue samples using mass spectrometry imaging2016In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 258, no S, p. S42-S42Article in journal (Other academic)
  • 40.
    Angelison, L.
    et al.
    Helsingborg Hosp, Dept Med, Charlotte Yhlens Gata 10, S-25187 Helsingborg, Sweden..
    Almer, S.
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Eriksson, A.
    Sahlgrenska Univ Hospital Ostra, Dept Gastroenterol, Gothenburg, Sweden..
    Karling, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Div Med, Umea, Sweden..
    Fagerberg, U.
    Vastmanlands Hosp, Clin Res Ctr, Vasteras, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Halfvarson, J.
    Univ Orebro, Dept Gastroenterol, Fac Med & Hlth, Orebro, Sweden..
    Thörn, Mari
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Björk, J.
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Hindorf, U.
    Lund Univ, Div Gastroenterol, Dept Clin Sci, Lund, Sweden..
    Löfberg, R.
    Karolinska Inst, Dept Med, IBD Unit, Stockholm Gastro Ctr, Stockholm, Sweden. Sodra Alvsborgs Sjukhus, Dept Med, Boras, Sweden..
    Bajor, A.
    Hjortswang, H.
    Linkoping Univ, Dept Gastroenterol, Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Hammarlund, P.
    Angelholm Hosp, Dept Med, Angelholm, Sweden..
    Grip, O.
    Skane Univ Hosp, Dept Gastroenterol, Malmo, Sweden..
    Torp, J.
    Kristianstad Cent Hosp, Dept Med, Kristianstad, Sweden..
    Marsal, J.
    Hertervig, E.
    Skane Univ Hosp, Dept Gastroenterol, Lund, Sweden..
    Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients2017In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 45, no 4, p. 519-532Article in journal (Refereed)
    Abstract [en]

    Background Real-life long-term data on infliximab treatment in ulcerative colitis are limited. Aim To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. Methods A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age 18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant. Results Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. Conclusions Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.

  • 41.
    Anlind, Alice
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Improvments and evaluation of data processing in LC-MS metabolomics: for application in in vitro systems pharmacology2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The resistance of established medicines is rapidly increasing while the rate of

    discovery of new drugs and treatments have not increases during the last decades

    (Spiro et al. 2008). Systems pharmacology can be used to find new combinations or

    concentrations of established drugs to find new treatments faster (Borisy et al. 2003).

    A recent study aimed to use high resolution Liquid chromatography–mass

    spectrometry (LC-MS) for in vitro systems pharmacology, but encountered problems

    with unwanted variability and batch effects(Herman et al. 2017). This thesis builds on

    this work by improving the pipeline and comparing alternative methods and evaluating

    used methods. The evaluation of methods indicated that the data quality was often

    not improved substantially by complex methods and pipelines. Instead simpler

    methods such as binning for feature extraction performed best. In-fact many of the

    preprocessing method commonly used proved to have negative or neglect-able effects

    on resulting data quality. Finally the recently introduced Optimal Orthonormal System

    for Discriminant Analysis (OOS-DA) for batch removal was found to be a good

    alternative to the more complex Combat method.

  • 42.
    Anthony, Lowell
    et al.
    Univ Kentucky, Markey Canc Ctr, Lexington, KY USA..
    Ervin, Claire
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Lapuerta, Pablo
    Lexicon Pharmaceut Inc, 8800 Technol Forest Pl, The Woodlands, TX 77385 USA..
    Kulke, Matthew H.
    Dana Farber Canc Inst, Boston, MA 02115 USA..
    Kunz, Pamela
    Stanford Canc Ctr, Stanford, CA USA..
    Bergsland, Emily
    UCSF Helen Diller Family Comprehens Canc Ctr, San Francisco, CA USA..
    Hörsch, Dieter
    Zent Klin Bad Berka GmbH, Klin Innerre Med Gastroenterol & Endokrinol, Bad Berka, Germany..
    Metz, David C.
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA..
    Pasieka, Janice
    Tom Baker Canc Clin, Calgary, AB, Canada..
    Paylakis, Nick
    Royal North Shore Hosp, St Leonards, NSW, Australia..
    Pavel, Marianne
    Charite, Berlin, Germany..
    Caplin, Martyn
    Royal Free Hosp, London, England..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Ramage, John
    Hampshire Hosp NHS Trust, Basingstoke & North Hampshire Hosp, Basingstoke, Hants, England..
    Evans, Emily
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Yang, Qi Melissa
    Lexicon Pharmaceut Inc, 8800 Technol Forest Pl, The Woodlands, TX 77385 USA..
    Jackson, Shanna
    Lexicon Pharmaceut Inc, 8800 Technol Forest Pl, The Woodlands, TX 77385 USA..
    Arnold, Katie
    Lexicon Pharmaceut Inc, 8800 Technol Forest Pl, The Woodlands, TX 77385 USA..
    Law, Linda
    Lexicon Pharmaceut Inc, 8800 Technol Forest Pl, The Woodlands, TX 77385 USA.;BioHealthConsult, 2143 Riverside Dr, Cincinnati, OH 45202 USA..
    DiBenedetti, Dana B.
    RTI Hlth Solut, Res Triangle Pk, NC USA..
    Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl2017In: Clinical Therapeutics, ISSN 0149-2918, E-ISSN 1879-114X, Vol. 39, no 11, p. 2158-2168Article in journal (Refereed)
    Abstract [en]

    Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in FELESTAR, a Phase HI study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview sub study was conducted to provide insight into the patient experience in ILLESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful. Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment. Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving >= 30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoidsyndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo. Implications: Patient interviews revealed that I ELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl. (C) 2017 The Authors. Published by Elsevier HS Journals, Inc.

  • 43.
    Anwar, J.
    et al.
    Univ Agr, Dept Agr Chem, Peshawar 25100, Pakistan..
    Muhammad, Taj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Göransson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Farmakognosi.
    Iqbal, Z.
    Univ Agr, Dept Agr Chem, Peshawar 25100, Pakistan..
    Fungi as a source for antibacterial compounds2016In: Planta Medica, ISSN 0032-0943, E-ISSN 1439-0221, Vol. 82Article in journal (Other academic)
  • 44.
    Aoki, Yasunori
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Natl Inst Informat, Tokyo, Japan..
    Roshammar, Daniel
    AstraZeneca, IMED Biotech Unit, Quantitat Clin Pharmacol Innovat Med & Early Dev, Gothenburg, Sweden.;SGS Exprimo, Mechelen, Belgium..
    Hamren, Bengt
    AstraZeneca, IMED Biotech Unit, Quantitat Clin Pharmacol Innovat Med & Early Dev, Gothenburg, Sweden..
    Hooker, Andrew
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Model selection and averaging of nonlinear mixed-effect models for robust phase III dose selection2017In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 44, no 6, p. 581-597Article in journal (Refereed)
    Abstract [en]

    Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced. The key hypothesis is that by combining both model structure uncertainty and model parameter uncertainty using these methodologies, we can make a more robust model based dose selection decision at the end of a phase IIb clinical trial. These methods are investigated using realistic simulation studies based on the study protocol of an actual phase IIb trial for an oral asthma drug candidate (AZD1981). Based on the simulation study, it is demonstrated that a bootstrap model selection method properly avoids model selection bias and in most cases increases the accuracy of the end of phase IIb decision. Thus, we recommend using this bootstrap model selection method when conducting population model-based decision-making at the end of phase IIb clinical trials.

  • 45. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 46.
    Arif, Sivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Granskning av information för läkemedel i ATC-grupp G och H i FASS med avseende på risk vid graviditet och amning2015Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Sammanfattning

     

    Introduktion: Efter talidomidkatastrofen år 1960, började världen och Sverige reagera på dess innebörd. Sverige var det första landet i världen med ett klassificeringssystem, vilket infördes i FASS 1978. Ett klassificeringssystem var tänkt att underlätta förskrivning av läkemedel till gravida och ammande kvinnor. Syfte: Syftet med detta projekt var att undersöka de läkemedelsprodukter som har fel klassificering och föreslå en korrekt klassificering. Material och metod: Läkemedelsinformation på www.fass.se för 419 läkemedelsprodukter granskades.  Granskningen gick ut på hur läkemedlen klassificerade i ATC – grupperna G och H gällande risk med användning under graviditet och amning.  Av dem var 271 i ATC-grupp G (Urin och könsorgan samt könshormoner) och resten dvs. 148 i ATC gruppen H (Systemiska hormonpreparat exkl. könshormoner och insulin). Information om varje produkt som namn, form, styrka, ATC-kod, företag, godkännande datum, NPL-ID och länk till fass.se. försåg av LIF. Resultat: Av de 156 granskade produkterna i ATC-grupp G och av de 138 produkterna i ATC-grupp H var 20 % respektive 7%  felklassificerade eller saknade klassificering. I båda ATC grupperna G och H var det mest felaktigt i graviditet avsnittet. Slutsats: I nuläget ansvarar företagen för textinnehållet och klassificering för läkemedlen i FASS. Den gruppen som sköter klassificering av läkemedlen ska ha utbildning för det för att information kring klassificeringssystemet ska vara korrekta gällande graviditet och amning.

     

     

     

     

  • 47.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    New cell-based approaches for better predictions of drug transport and cellular drug exposure2016In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 48, p. 7-7Article in journal (Other academic)
  • 48.
    Arvidsson, Per I.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, no 10, p. 1690-1698Article, review/survey (Refereed)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

  • 49.
    Arvidsson, Per I.
    et al.
    Karolinska Inst, Sci Life Lab, Drug Discovery & Dev Platform, Stockholm, Sweden.;Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Stockholm, Sweden.;Univ KwaZulu Natal, Catalysis & Peptide Res Unit, Durban, South Africa..
    Sandberg, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Physiol & Pharmacol, Stockholm, Sweden..
    Sakariassen, Kjell S.
    KellSa Sas, Str Campo & Zampe 12, I-13900 Biella, BI, Italy..
    Institutional profile: the national Swedish academic drug discovery & development platform at SciLifeLab2017In: FUTURE SCIENCE OA, ISSN 2056-5623, Vol. 3, no 2, article id FSO176Article in journal (Other (popular science, discussion, etc.))
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development Platform (SciLifeLab DDD) was established in Stockholm and Uppsala, Sweden, in 2014. It is one of ten platforms of the Swedish national SciLifeLab which support projects run by Swedish academic researchers with large-scale technologies for molecular biosciences with a focus on health and environment. SciLifeLab was created by the coordinated effort of four universities in Stockholm and Uppsala: Stockholm University, Karolinska Institutet, KTH Royal Institute of Technology and Uppsala University, and has recently expanded to other Swedish university locations. The primary goal of the SciLifeLab DDD is to support selected academic discovery and development research projects with tools and resources to discover novel lead therapeutics, either molecules or human antibodies. Intellectual property developed with the help of SciLifeLab DDD is wholly owned by the academic research group. The bulk of SciLifeLab DDD's research and service activities are funded from the Swedish state, with only consumables paid by the academic research group through individual grants.

  • 50.
    Asp, Vendela
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Environmental Toxicology.
    In Vitro Studies of Adrenocorticolytic DDT Metabolites, with Special Focus on 3-methylsulfonyl-DDE2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO2-DDE) is bioactivated by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of mice and forms irreversibly bound protein adducts, reduces glucocorticoid secretion, and induces cell death selectively in cortisol-producing adrenocortical cells. 3-MeSO2-DDE has therefore been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) therapy.

    The aims of this thesis were to (1) develop in vitro test systems based on murine and human adrenocortical cell lines and to (2) investigate the mechanisms behind 3-MeSO2-DDE toxicity in adrenocortical cells.

    The cytotoxic and endocrine-modulating effects of 3-MeSO2-DDE were compared to those of o,p′-DDD (mitotane), the current ACC therapy, and to those of several structurally analogous compounds in both murine and human cell lines. 3-MeSO2-DDE bioactivation and cytotoxicity proceeded in a similar manner in the murine adrenocortical Y-1 cell line as in mice in vivo. The effects were highly structure-specific. Moreover, 3-MeSO2-DDE formed irreversibly bound protein adducts and caused cell death also in the human H295R cell line, and was slightly more cytotoxic than o,p′-DDD. However, 3-MeSO2-DDE toxicity in human cells was not affected by the CYP11B1 inhibitor etomidate, suggesting that bioactivation in human cells is performed by additional/other enzyme(s) than CYP11B1. 3-MeSO2-DDE generated biphasic responses in cortisol and aldosterone secretion and in expression levels of the steroidogenic genes CYP11B1, CYP11B2, and StAR. Such hormesis-like responses were not seen for o,p′-DDD or the precursor DDT metabolite p,p′-DDE.

    In addition, the two o,p′-DDD enantiomers (R)-(+)-o,p′-DDD and (S)-(-)-o,p′-DDD exhibited slight differences in cytotoxic and endocrine-modulating activity in H295R cells.

    In conclusion, this thesis  provides  extended  knowledge  on  the  mechanisms  of  action  of 3-MeSO2-DDE and points out important differences in effects between murine and human cells. Lead optimisation studies of 3-MeSO2-DDE using the herein presented in vitro test systems are ongoing.

     

    List of papers
    1. Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
    Open this publication in new window or tab >>Cytotoxicity and decreased corticosterone production in adrenocortical Y-1 cells by 3-methylsulfonyl-DDE and structurally related molecules
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    2009 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 83, no 4, p. 389-396Article in journal (Refereed) Published
    Abstract [en]

    The persistent environmental pollutant 3-methylsulfonyl-DDE (3-MeSO2-DDE) undergoes bioactivation by cytochrome P450 11B1 (CYP11B1) in the adrenal cortex of several animal species in vivo and causes decreased glucocorticoid production and cell death in the zona fasciculata. This study presents extended investigations of the cytotoxic and endocrine disrupting effects of 3-MeSO2-DDE and some structurally related molecules in the mouse adrenocortical cell line Y-1. Both 3-MeSO2-DDE and, to a lesser extent, 3,3'(bis)-MeSO2-DDE decreased corticosterone production and produced CYP11B1-dependent cytotoxicity in Y-1 cells. Neither 2-MeSO2-DDE nor p,p'-DDE had any significant effect on either cell viability or corticosterone production, indicating that the presence and position of the methylsulfonyl moiety of 3-MeSO2-DDE is crucial for its biological activity. The adrenocortical toxicant o,p'-DDD decreased corticosterone production but was not cytotoxic in this cell line. None of the compounds altered Cyp11b1 gene expression, indicating that 3-MeSO2-DDE inhibits CYP11B1 activity on the protein level.

    Keywords
    Adrenal cortex, Metabolic activation, Toxicity, Corticosterone, DDE, CYP11B1
    National Category
    Biological Sciences
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-100855 (URN)10.1007/s00204-008-0342-6 (DOI)000264883800012 ()18651133 (PubMedID)
    Available from: 2009-04-08 Created: 2009-04-08 Last updated: 2017-12-13Bibliographically approved
    2. Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
    Open this publication in new window or tab >>Comparative CYP-dependent binding of the adrenocortical toxicants 3-methylsulfonyl-DDE and o,p′-DDD in Y-1 adrenal cells
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    2007 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 81, no 11, p. 793-801Article in journal (Refereed) Published
    Abstract [en]

    The environmental pollutant 3-MeSO2–DDE [2-(3-methylsulfonyl-4-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethene] is an adrenocortical toxicant in mice, specifically in the glucocorticoid-producing zona fasciculata, due to a cytochrome P450 11B1 (CYP11B1)-catalysed bioactivation and formation of covalently bound protein adducts. o,p′-DDD [2-(2-chlorophenyl)-2-(4-chlorophenyl)-1,1-dichloroethane] is toxic and inhibits steroidogenesis in the human adrenal cortex after bioactivation by unidentified CYPs, but does not exert any toxic effects on the mouse adrenal. As a step towards determining in vitro/in vivo relationships for the CYP-catalysed binding and toxicity of 3-MeSO2–DDE and o,p′-DDD, we have investigated the irreversible protein binding of these two toxicants in the murine adrenocortical cell line Y-1. The irreversible binding of 3-MeSO2–DDE previously demonstrated in vivo was successfully reproduced and could be inhibited by the CYP-inhibitors etomidate, ketoconazole and metyrapone. Surprisingly, o,p′-DDD reached similar levels of binding as 3-MeSO2–DDE. The binding of o,p′-DDD was sensitive to etomidate and ketoconazole, but not to metyrapone. Moreover, GSH depletion increased the binding of 3-MeSO2–DDE, but not of o,p′-DDD, indicating an important role of GSH conjugation in the detoxification of the 3-MeSO2–DDE-derived reactive metabolite. In addition, the specificity of CYP11B1 in activating 3-MeSO2–DDE was investigated using structurally analogous compounds. None of the analogues produced histopathological lesions in the mouse adrenal in vivo following a single i.p. injection of 100 mg/kg body weight, but two of the compounds were able to decrease the irreversible binding of 3-MeSO2–DDE to Y-1 cells. These results indicate that the bioactivation of 3-MeSO2–DDE by CYP11B1 is highly structure-dependent. In conclusion, both 3-MeSO2–DDE and o,p′-DDD bind irreversibly to Y-1 cells despite differences in binding and adrenotoxicity in mice in vivo. This reveals a notable in vitro/in vivo discrepancy, the contributing factors of which remain unexplained. We consider the Y-1 cell line as appropriate for studies of the cellular mechanisms behind the adrenocortical toxicity of these substances.

    Keywords
    Adrenal cortex, Cytochrome P450, Metabolic activation, Toxicity, Y-1
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-14330 (URN)10.1007/s00204-007-0206-5 (DOI)000250537400006 ()17487473 (PubMedID)
    Available from: 2008-05-15 Created: 2008-05-15 Last updated: 2017-12-11Bibliographically approved
    3. Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
    Open this publication in new window or tab >>Biphasic hormonal responses to the adrenocorticolytic DDT metabolite 3-methylsulfonyl-DDE in human cells
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    2010 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 242, no 3, p. 281-289Article in journal (Refereed) Published
    Abstract [en]

    The DDT metabolite 3-methylsulfonyl-DDE (3-MeSO(2)-DDE) has been proposed as a lead compound for an improved adrenocortical carcinoma (ACC) treatment. ACC is a rare malignant disorder with poor prognosis, and the current pharmacological therapy o,p'-DDD (mitotane) has limited efficacy and causes severe adverse effects. 3-MeSO(2)-DDE is bioactivated by cytochrome P450 (CYP) 11B1 in mice and causes formation of irreversibly bound protein adducts, reduced glucocorticoid secretion, and cell death in the adrenal cortex of several animal species. The present study was carried out to assess similarities and differences between mice and humans concerning the adrenocorticolytic effects of 3-MeSO(2)-DDE. The results support previous indications that humans are sensitive to the adrenocorticolytic actions of 3-MeSO(2)-DDE by demonstrating protein adduct formation and cytotoxicity in the human adrenocortical cell line H295R. However, neither the irreversible binding nor the cytotoxicity of 3-MeSO(2)-DDE in H295R cells was inhibited by the CYP11B1 inhibitor etomidate. We also report biphasic responses to 3-MeSO(2)-DDE in cortisol and aldosterone secretion as well as in mRNA levels of the steroidogenic genes StAR, CYP11B1 and CYP11B2. Hormone levels and mRNA levels were increased at lower concentrations of 3-MeSO(2)-DDE, while higher concentrations decreased hormone levels. These biphasic responses were not observed with o,p'-DDD or with the precursor DDT metabolite p,p'-DDE. Based on these results, 3-MeSO(2)-DDE remains a viable lead compound for drug design, although the adrenocorticolytic effects of 3-MeSO(2)-DDE in human cells seem more complex than in murine cells.

    Keywords
    Adrenocorticolytic DDT metabolites, Endocrine disruption, Adrenocortical cancer (ACC), Biphasic responses, Steroidogenesis, H295R
    National Category
    Pharmacology and Toxicology
    Research subject
    Ecotoxicology
    Identifiers
    urn:nbn:se:uu:diva-112583 (URN)10.1016/j.taap.2009.10.018 (DOI)000273832500006 ()19900470 (PubMedID)
    Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2018-01-12
    4. Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    Open this publication in new window or tab >>Chiral effects in adrenocorticolytic action of o,p'-DDD (mitotane) in human adrenal cells
    2010 (English)In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 3, p. 177-183Article in journal (Refereed) Published
    Abstract [en]

    Adrenocortical carcinoma (ACC) is a rare malignant disease with poor prognosis. The main pharmacological choice, o,p'-DDD (mitotane), produces severe adverse effects. Since o,p'-DDD is a chiral molecule and stereoisomers frequently possess different pharmacokinetic and/or pharmacodynamic properties, we isolated the two o,p'-DDD enantiomers, (R)-(+)-o,p'-DDD and (S)-(-)-o,p'-DDD, and determined their absolute structures. The effects of each enantiomer on cell viability and on cortisol and dehydroepiandrosterone (DHEA) secretion in the human adrenocortical cell line H295R were assessed. We also assayed the o,p'-DDD racemate and the m,p'- and p,p'-isomers. The results show small but statistically significant differences in activity of the o,p'-DDD enantiomers for all parameters tested. The three DDD isomers were equally potent in decreasing cell viability, but p,p'-DDD affected hormone secretion slightly less than the o,p'- and m,p'-isomers. The small chiral differences in direct effects on target cells alone do not warrant single enantiomer administration, but might reach importance in conjunction with possible stereochemical effects on pharmacokinetic processes in vivo.

    National Category
    Pharmaceutical Sciences Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-112582 (URN)10.3109/00498250903470230 (DOI)000274882900002 ()20044879 (PubMedID)
    Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2018-01-12
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