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  • 201. Nordberg, Monica
    et al.
    Nordberg, Gunnar F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Toxicology and biological monitoring of metals2009Ingår i: General and Applied Toxicology: volume 6, part thirteen: Toxicology of specific groups of substances / [ed] Bryan Ballantyne, Timothy C. Marrs and Tore Syversen, Wiley , 2009, 3Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    There are 67 elements classified as metals and the present chapter presents a review of the toxicology and evidence for useful biological monitoring of 29 of these elements and their various chemical compounds. Introductory sections of the chapter deals with general aspects of metal toxicology. Emphasis is given to the fundamental importance of speciation of metals. The chemical species is defined as the specific form of an element defined as to isotopic composition, electronic or oxidation state and /or complex or molecular structure. Consideration of specific chemical species is of fundamental importance in toxicology and biological monitoring. Advances in chemical analytical methods has made it possible in recent years to use biological monitoring i.e., repeated measurements of metallic compounds in tissues or biological fluids in order to evaluate occupational or environmental exposures and health risks. For all the elements dealt with in this chapter the importance of chemical species is considered when reviewing the uptake, metabolism and excretion; toxic effects and dose-response relationships; carcinogenicity; genotoxicity as well as biological monitoring. The following metals and their compounds are covered in the present chapter: Aluminium, Antimony, Arsenic, Barium, Beryllium, Bismuth, Cadmium, Chromium, Cobalt, Copper, Gallium and Semiconductor compounds, Germanium, Indium, Iron, Lead, Manganese, Mercury, Molybdenum, Nickel, Palladium, Platinum, Selenium, Silver, Tellurium, Thallium, Tin, Titanium, Tungsten and Zinc.

  • 202.
    Norqvist-Sjöberg, Astrid
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Amine oxidases in dental pulp: a study with special regard to a semicarbazide-sensitive amine oxidase with catalytic potency towards serotonin1988Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The amine oxidizing capacity of piglet dental pulp tissue has been investigated. At least six separate enzyme activities could be distinguished:

    - a soluble semicarbazide-sensitive (SSAO) activity towards benzylamine, most likely to be derived from the content of blood plasma within the pulp tissue;

    - a soluble pulp tissue SSAO activity with most properties in common with the plasma enzyme, however with great efficiency not only regarding benzylamine but also tryptamine;

    - a tissue bound SSAO activity with activity towards benzylamine, tryptamine, tyramine and ß-phenylethylamine;

    - a tissue bound semicarbazide-sensitive activity towards serotonin (SSA0-5HT) (a combination of properties never reported before);

    - a mitochondrially bound and clorgyline-sensitive monoamine oxidase-A (MAO-A) activity with activity towards serotonin;

    - a mitochondrially bound and deprenyl-sensitive MAO-B activity with activity towards e.g. benzylamine, tryptamine, tyramine and ß-phenylethylamine.

    The relative importance of the various activities for the metabolism of some monoamines has been investigated.

    Although the SSAO enzymes had lower K values with most substrates than the MAO, the bulk of ïhe compounds was likely to be metabolized by MAO-B because of higher V values. K values and values with serotonin, howSver,

    were rather similar for rfle MAO and the SSAO membrane-bound enzyme(s).

    The thermal sensitivity of membrane-bound SSAO activities was found to be considerably lower than that for MAO-B.

    The SSAO-5HT activity was found to be localized to the plasma membrane with a greater activity towards the perifery of the pulp tissue than towards the centre.

    No great difference in the various amine oxidase activities was found when pulp tissues of varying degrees of maturity were compared.

    The occurrence of membrane-bound SSAO and MAO activities was investigated and compared between pig, ox and human dental pulp. All activities were found to be present in about the same order of magnitude in all three species with the exception of a higher MAO-A activity in the ox pulp and the absence of this enzyme activity in the human dental pulp.

  • 203. Olofsson, Sara
    et al.
    Wickström, Anne
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Glenngard, Anna Huger
    Persson, Ulf
    Svenningsson, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Effect of treatment with natalizumab on ability to work in people with multiple sclerosis: productivity gain based on direct measurement of work capacity before and after 1 year of treatment2011Ingår i: BioDrugs, ISSN 1173-8804, E-ISSN 1179-190X, Vol. 25, nr 5, s. 299-306Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Sweden is a high endemic region for multiple sclerosis (MS), a neurologic disorder characterized by repeated inflammatory episodes affecting the CNS. The disease has its peak age of onset at approximately 30 years and affects women twice as often as men. The young age of onset makes MS one of the major causes of reduced capacity to work due to neurologic disease in Western society. Natalizumab (Tysabri(R)) is among the new generation of biologic drugs for the treatment of MS. Clinical studies have demonstrated that natalizumab is an effective treatment for preventing relapses and inflammatory activity.

    Objective: The aim of the study was to estimate the monetary value of treatment with natalizumab on the ability to work in patients with MS in Sweden, based on a direct measurement of weekly hours worked before and after 1 year of treatment with natalizumab.

    Methods: A sample of patients, consisting of all patients who had started treatment with natalizumab during the period June 2007 May 2008, was identified through the Swedish Multiple Sclerosis Register (SMSreg). Data about sex, age, disease severity, and disease duration were collected from the register. Data about type of work and work capacity (number of hours worked per week) were collected retrospectively through a postal questionnaire. The average hours worked per week was estimated at baseline (2 weeks before treatment started) and at follow-up (50 weeks after treatment started), and the change was assigned an economic value using the human capital approach.

    Results: This study showed that after 50 weeks of treatment with natalizumab, people with MS increased their productivity by 3.3 hours per week on average (p<0.01), which corresponded to an economic value of 3216 per person per year (year 2007 values). A shorter duration of illness or being 25-35 years old was significantly associated with a greater productivity gain (p = 0.025 and p = 0.002, respectively). Conclusion: A shorter duration of illness and a lower age at the start of treatment were significantly associated with a greater productivity gain after 50 weeks of treatment with natalizumab, which indicates that it is more beneficial to initiate efficient therapy early in patients with MS.

  • 204. Onnis, Valentina
    et al.
    Congiu, Cenzo
    Björklund, Emmelie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hempel, Franziska
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Söderström, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Synthesis and evaluation of paracetamol esters as novel fatty acid amide hydrolase inhibitors.2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 5, s. 2286-2298Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) is the key hydrolytic enzyme for the endogenous cannabinoid receptor ligand anandamide. The synthesis and evaluation for their FAAH inhibitory activities of a series of 18 paracetamol esters are described. Structure-activity relationship studies indicated that the ester (33) with a 2-(4-(2-(trifluoromethyl)pyridin-4-ylamino)phenyl)acetic acid substituent was the most potent analogue in this series. The compound inhibited FAAH activity in a competitive manner with a K(i) value of 0.16 microM. The compound was also able to inhibit the FAAH activity in rat basophilic leukemia cells as assessed by measuring either the hydrolysis of anandamide, the FAAH-dependent cellular accumulation of anandamide, or the FAAH-dependent recycling of tritium to the cell membranes. The compound also inhibited the activity of monoacylglycerol lipase (MGL), the enzyme responsible for the hydrolysis of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol, with an IC(50) value of 1.9 microM. It is concluded that the compound may be a useful template for the design of potent novel inhibitors of FAAH.

  • 205. Orre, R
    et al.
    Bate, Andrew
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Arnborg, S
    Edwards, IR
    A Bayesian recurrent neural network approach for finding dependencies in large incomplete data setsManuskript (preprint) (Övrigt vetenskapligt)
  • 206.
    Ott, Michael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Mannchen, Julie K.
    Jamshidi, Fariba
    Werneke, Ursula
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Sunderby Research Unit.
    Management of severe arterial hypertension associated with serotonin syndrome: a case report analysis based on systematic review techniques2019Ingår i: Therapeutic Advances in Psychopharmacology, ISSN 2045-1253, E-ISSN 2045-1261, Vol. 9, s. 1-32Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Serotonin syndrome is thought to arise from serotonin excess. In many cases, symptoms are mild and self-limiting. But serotonin syndrome can become life threatening, when neuromuscular hyperexcitability spins out of control. Uncontainable neuromuscular hyperexcitability may lead to cardiovascular complications, linked to extreme changes in blood pressure. Currently, there is little guidance on how to control blood pressure in hyperserotonergic states. We report a case with treatment-resistant arterial hypertension, followed by a clinical review (using systematic review principles and techniques) of the available evidence from case reports published between 2004 and 2016 to identify measures to control arterial hypertension associated with serotonin syndrome. We conclude that classic antihypertensives may not be effective for the treatment of severe hypertension associated with serotonin syndrome. Benzodiazepines may lower blood pressure. Patients with severe hypertension not responding to benzodiazepines may benefit from cyproheptadine, propofol or both. In severe cases, higher cyproheptadine doses than currently recommended may be necessary.

  • 207.
    Ott, Michael
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Salander Renberg, Ellinor
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Werneke, Ursula
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Sunderby Research Unit – Psychiatry.
    Prognosis and outcome of severe lithium poisoning: authors' reply2017Ingår i: Journal of Psychopharmacology, ISSN 0269-8811, E-ISSN 1461-7285, Vol. 31, nr 9, s. 1275-1277Artikel i tidskrift (Refereegranskat)
  • 208. Palmér, Robert
    et al.
    Mäenpää, Jukka
    Jauhiainen, Alexandra
    Larsson, Bengt
    Mo, John
    Russell, Muir
    Root, James
    Prothon, Susanne
    Chialda, Ligia
    Forte, Pablo
    Egelrud, Torbjörn
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Stenvall, Kristina
    Gardiner, Philip
    Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure-Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects2018Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, nr 6, s. 1155-1164Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neutrophil serine proteases (NSPs), such as neutrophil elastase (NE), are activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation. High NSP levels can be detrimental, particularly in lung tissue, and inhibition of NSPs is therefore an interesting therapeutic opportunity in multiple lung diseases, including chronic obstructive pulmonary disease (COPD) and bronchiectasis. We conducted a randomized, placebo-controlled, first-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of the DPP1 inhibitor AZD7986 in healthy subjects. Pharmacokinetic and pharmacodynamic data were analyzed using nonlinear mixed effects modeling and showed that AZD7986 inhibits whole blood NE activity in an exposure-dependent, indirect manner-consistent with in vitro and preclinical predictions. Several dose-dependent, possibly DPP1-related, nonserious skin findings were observed, but these were not considered to prevent further clinical development. Overall, the study results provided confidence to progress AZD7986 to phase II and supported selection of a clinically relevant dose.

  • 209. Patel, Jayendra Z.
    et al.
    Parkkari, Teija
    Laitinen, Tuomo
    Kaczor, Agnieszka A.
    Saario, Susanna M.
    Savinainen, Juha R.
    Navia-Padanius, Dina
    Cipriano, Mariateresa
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Leppanen, Jukka
    Koshevoy, Igor O.
    Poso, Antti
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Laitinen, Jarmo T.
    Nevalainen, Tapio
    Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors2013Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, nr 21, s. 8484-8496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.

  • 210. Paul, Carsten
    et al.
    Reunamo, Anna
    Lindehoff, Elin
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå marina forskningscentrum (UMF). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Bergkvist, Johanna
    Mausz, Michaela A.
    Larsson, Henrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå marina forskningscentrum (UMF).
    Richter, Hannes
    Wangberg, Sten-Ake
    Leskinen, Piia
    Bamstedt, Ulf
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Umeå marina forskningscentrum (UMF). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för ekologi, miljö och geovetenskap.
    Pohnert, Georg
    Diatom Derived Polyunsaturated Aldehydes Do Not Structure the Planktonic Microbial Community in a Mesocosm Study2012Ingår i: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 10, nr 4, s. 775-792Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several marine and freshwater diatoms produce polyunsaturated aldehydes (PUA) in wound-activated processes. These metabolites are also released by intact diatom cells during algal blooms. Due to their activity in laboratory experiments, PUA are considered as potential mediators of diatom-bacteria interactions. Here, we tested the hypothesis that PUA mediate such processes in a close-to-field mesocosm experiment. Natural plankton communities enriched with Skeletonema marinoi strains that differ in their PUA production, a plankton control, and a plankton control supplemented with PUA at natural and elevated concentrations were observed. We monitored bacterial and viral abundance as well as bacterial community composition and did not observe any influence of PUA on these parameters even at elevated concentrations. We rather detected an alternation of the bacterial diversity over time and differences between the two S. marinoi strains, indicating unique dynamic bacterial communities in these algal blooms. These results suggest that factors other than PUA are of significance for interactions between diatoms and bacteria.

  • 211. Pencikova, K.
    et al.
    Vondracek, J.
    Dvorak, Z.
    Novotna, A.
    Andersson, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Machala, M.
    Differential responses to PAHs and dioxin-like compounds in human and rat AhR-dependent reporter gene cell models2015Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, nr 2, s. S59-S60Artikel i tidskrift (Övrigt vetenskapligt)
  • 212. Petrelli, Riccardo
    et al.
    Orsomando, Giuseppe
    Sorci, Leonardo
    Maggi, Filippo
    Ranjbarian, Farahnaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Nya, Prosper C. Biapa
    Petrelli, Dezemona
    Vitali, Luca A.
    Lupidi, Giulio
    Quassinti, Luana
    Bramucci, Massimo
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cappellacci, Loredana
    Biological Activities of the Essential Oil from Erigeron floribundus2016Ingår i: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 21, nr 8, artikel-id 1065Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Erigeron floribundus (Asteraceae) is an herbaceous plant widely used in Cameroonian traditional medicine to treat various diseases of microbial and non-microbial origin. In the present study, we evaluated the in vitro biological activities displayed by the essential oil obtained from the aerial parts of E. floribundus, namely the antioxidant, antimicrobial and antiproliferative activities. Moreover, we investigated the inhibitory effects of E. floribundus essential oil on nicotinate mononucleotide adenylyltransferase (NadD), a promising new target for developing novel antibiotics, and Trypanosoma brucei, the protozoan parasite responsible for Human African trypanosomiasis. The essential oil composition was dominated by spathulenol (12.2%), caryophyllene oxide (12.4%) and limonene (8.8%). The E. floribundus oil showed a good activity against Staphylococcus aureus (inhibition zone diameter, IZD of 14 mm, minimum inhibitory concentration, MIC of 512 mu g/mL). Interestingly, it inhibited the NadD enzyme from S. aureus (IC50 of 98 mu g/mL), with no effects on mammalian orthologue enzymes. In addition, T. brucei proliferation was inhibited with IC50 values of 33.5 mu g/mL with the essential oil and 5.6 mu g/mL with the active component limonene. The essential oil exhibited strong cytotoxicity on HCT 116 colon carcinoma cells with an IC50 value of 14.89 mu g/mL, and remarkable ferric reducing antioxidant power (tocopherol-equivalent antioxidant capacity, TEAC = 411.9 mu mol.TE/g).

  • 213. Petrelli, Riccardo
    et al.
    Ranjbarian, Farahnaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Dall'Acqua, Stefano
    Papa, Fabrizio
    Iannarelli, Romilde
    Ngahang Kamte, Stephane L.
    Vittori, Sauro
    Benelli, Giovanni
    Maggi, Filippo
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Cappellacci, Loredana
    An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis2017Ingår i: Parasitology international, ISSN 1383-5769, E-ISSN 1873-0329, Vol. 66, nr 2, s. 146-151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Among natural products, sesquiterpenes have shown promising inhibitory effects against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing human African trypanosomiasis (HAT). Smyrnium olusatrum (Apiaceae), also known as Alexanders or wild celery, is a neglected horticultural crop characterized by oxygenated sesquiterpenes containing a furan ring. In the present work we explored the potential of its essential oils obtained from different organs and the main oxygenated sesquiterpenes, namely isofuranodiene, germacrone and β-acetoxyfuranoeudesm-4(15)-ene, as inhibitors of Trypanosoma brucei. All essential oils effectively inhibited the growth of parasite showing IC50 values of 1.9–4.0 μg/ml. Among the main essential oil constituents, isofuranodiene exhibited a significant and selective inhibitory activity against T. brucei (IC50 of 0.6 μg/ml, SI = 30), with β-acetoxyfuranoeudesm-4(15)-ene giving a moderate potentiating effect. These results shed light on the possible application of isofuranodiene as an antiprotozoal agent to be included in combination treatments aimed not only at curing patients but also at preventing the diffusion of HAT.

  • 214.
    Popova, Dina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    In vitro cellular models for neurotoxicity studies: neurons derived from P19 cells2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Humans are exposed to a variety of chemicals including environmental pollutants, cosmetics, food preservatives and drugs. Some of these substances might be harmful to the human body. Traditional toxicological and behavioural investigations performed in animal models are not suitable for the screening of a large number of compounds for potential toxic effects. There is a need for simple and robust in vitro cellular models that allow high-throughput toxicity testing of chemicals, as well as investigation of specific mechanisms of cytotoxicity. The overall aim of the thesis has been to evaluate neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) as a model for such testing. The model has been compared to other cellular models used for neurotoxicity assessment: retinoic acid-differentiated human neuroblastoma SH-SY5Y cells and nerve growth factor-treated rat pheochromocytoma PC12 cells. The chemicals assessed in the studies included the neurotoxicants methylmercury, okadaic acid and acrylamide, the drug of abuse MDMA (“ecstasy”) and a group of piperazine derivatives known as “party pills”. Effects of the chemicals on cell survival, neurite outgrowth and mitochondrial function have been assessed.

    In Paper I, we describe a fluorescence-based microplate method to detect chemical-induced effects on neurite outgrowth in P19 neurons immunostained against the neuron-specific cytoskeletal protein βIII-tubulin. In Paper II, we show that P19 neurons are more sensitive than differentiated SH-SY5Y and PC12 cells for detection of cytotoxic effects of methylmercury, okadaic acid and acrylamide. Additionally, in P19 neurons and differentiated SH-SY5Y cells, we could demonstrate that toxicity of methylmercury was attenuated by the antioxidant glutathione. In Paper III, we show a time- and temperature-dependent toxicity produced by MDMA in P19 neurons. The mechanisms of MDMA toxicity did not involve inhibition of the serotonin re-uptake transporter or monoamine oxidase, stimulation of 5-HT2A receptors, oxidative stress or loss of mitochondrial membrane potential. In Paper IV, the piperazine derivatives are evaluated for cytotoxicity in P19 neurons and differentiated SH-SY5Y cells. The most toxic compound in both cell models was TFMPP. In P19 neurons, the mechanism of action of TFMPP included loss of mitochondrial membrane potential. In conclusion, P19 neurons are a robust cellular model that may be useful in conjunction with other models for the assessment of chemical-induced neurotoxicity.

  • 215.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Forsblad, Andréas
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hashemian, Sanaz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig O. P.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Non-Serotonergic Neurotoxicity by MDMA (Ecstasy) in Neurons Derived from Mouse P19 Embryonal Carcinoma Cells2016Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 11, artikel-id e0166750Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) is a commonly abused recreational drug that causes neurotoxic effects in both humans and animals. The mechanism behind MDMA-induced neurotoxicity is suggested to be species-dependent and needs to be further investigated on the cellular level. In this study, the effects of MDMA in neuronally differentiated P19 mouse embryonal carcinoma cells have been examined. MDMA produces a concentration-, time- and temperature-dependent toxicity in differentiated P19 neurons, as measured by intracellular MTT reduction and extracellular LDH activity assays. The P19-derived neurons express both the serotonin reuptake transporter (SERT), that is functionally active, and the serotonin metabolizing enzyme monoamine oxidase A (MAO-A). The involvement of these proteins in the MDMA-induced toxicity was investigated by a pharmacological approach. The MAO inhibitors clorgyline and deprenyl, and the SERT inhibitor fluoxetine, per se or in combination, were not able to mimic the toxic effects of MDMA in the P19-derived neurons or block the MDMA-induced cell toxicity. Oxidative stress has been implicated in MDMA-induced neurotoxicity, but pre-treatment with the antioxidants α-tocopherol or N-acetylcysteine did not reveal any protective effects in the P19 neurons. Involvement of mitochondria in the MDMA-induced cytotoxicity was also examined, but MDMA did not alter the mitochondrial membrane potential (ΔΨm) in the P19 neurons. We conclude that MDMA produce a concentration-, time- and temperature-dependent neurotoxicity and our results suggest that the mechanism behind MDMA-induced toxicity in mouse-derived neurons do not involve the serotonergic system, oxidative stress or mitochondrial dysfunction.

  • 216.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Forsblad, Andréas N. P.
    Umeå universitet.
    Jacobsson, Stig O. P.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    In vitro studies on the neurotoxic effects of piperazine-derived designer drugs and 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy")2013Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 221, nr Suppl. S, s. S151-S151Artikel i tidskrift (Övrigt vetenskapligt)
  • 217.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig O. P.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    A fluorescence microplate screen assay for the detection of neurite outgrowth and neurotoxicity using an antibody against βIII-tubulin2014Ingår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 28, nr 3, s. 411-418Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The majority of environmental and commercial chemicals have not been evaluated for their potential to cause neurotoxicity. We have investigated if neuron specific anti-βIII-tubulin antibodies are useful in a microplate assay of neurite outgrowth of retinoic acid-induced neurons from mouse P19 embryonal carcinoma cells. By incubating the P19-derived neurons with the primary anti-βIII-tubulin antibody and a secondary Alexa Fluor 488-conjugated antibody, followed by measuring the fluorescence in a microplate reader, a time-dependent increase in anti-βIII-tubulin immunofluorescence was observed. The relative fluorescence units increased by 4.3-fold from 2 to 10 days in culture. The results corresponded well with those obtained by semi-automatic tracing of neurites in fluorescence microscopy images of βIII-tubulin-labeled neurons. The sensitivity of the neurite outgrowth assay using a microplate reader to detect neurotoxicity produced by nocodazole, methyl mercury chloride and okadaic acid was significantly higher than for a cell viability assay measuring intracellular fluorescence of calcein-AM. The microplate-based method to measure toxicity targeting neurites using anti-βIII-tubulin antibodies is however less sensitive than the extracellular lactate dehydrogenase activity assay to detect general cytotoxicity produced by high concentrations of clomipramine, or glutamate-induced excitotoxicity. In conclusion, the fluorescence microplate assay for the detection of neurite outgrowth by measuring changes in βIII-tubulin immunoreactivity is a rapid and sensitive method to assess chemical- or toxin-induced neurite toxicity.

  • 218.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Karlsson, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig O. P.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Comparison of neurons derived from mouse P19, rat PC12 and human SH-SY5Y cells in the assessment of chemical- and toxin-induced neurotoxicity2017Ingår i: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, artikel-id 42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Exposure to chemicals might be toxic to the developing brain. There is a need for simple and robust in vitro cellular models for evaluation of chemical-induced neurotoxicity as a complement to traditional studies on animals. In this study, neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) were compared with human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells for their ability to detect toxicity of methylmercury (MeHg), okadaic acid and acrylamide. Methods: Retinoic acid-treated P19 and SH-SY5Y cells and nerve growth factor-stimulated PC12 cells, allowed to differentiate for 6 days, were exposed to MeHg, okadaic acid and acrylamide for 48 h. Cell survival and neurite outgrowth were assessed with the calcein-AM assay and fluorescence detection of antibodies against the cytoskeletal neuron-specific protein beta III-tubulin, respectively. The effects of glutathione (GSH) and the potent inhibitor of GSH synthesis buthionine sulfoximine (BSO) on the MeHg induced-toxicity were assessed using the PrestoBlue (TM) cell viability assay and the TMRE mitochondrial membrane potential assay. Results: Differentiated P19 cells developed the most extensive neuronal network among the three cell models and were the most sensitive neuronal model to detect neurotoxic effects of the test compounds. MeHg produced a concentration-dependent toxicity in differentiated P19 cells and SH-SY5Y cells, with statistically significant effects at concentrations from 0.1 mu M in the P19 neurons and 1 mu M in the SH-SY5Y cells. MeHg induced a decrease in the cellular metabolic activity and mitochondrial membrane potential (Delta Psi m) in the differentiated P19 cells and SH-SY5Y cells, that were attenuated by GSH. Okadaic acid and acrylamide also showed statistically significant toxicity in the P19 neurons, but not in the SH-SY5Y cells or the P12 cells. Conclusions: P19 neurons are more sensitive to detect cytotoxicity of MeHg, okadaic acid and acrylamide than retinoic acid-differentiated SH-SY5Y cells and nerve growth factor-treated PC12 cells. P19 neurons are at least as sensitive as differentiated SH-SY5Y cells to detect the loss of mitochondrial membrane potential produced by MeHg and the protective effects of extracellular GSH on MeHg toxicity. P19 neurons may be a useful model to study neurotoxic effects of chemicals.

  • 219.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Karlsson, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Stig O.P., Jacobsson
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Comparison of neurons derived from mouse P19, rat PC12 and human SH-SY5Y cells in the assessment of chemical- and toxin-induced neurotoxicityManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Exposure to chemicals might be toxic to the developing brain. There is a need for simple and robust in vitro cellular models for evaluation of chemical-induced neurotoxicity as a complement to traditional studies on animals. In this study, neuronally differentiated mouse embryonal carcinoma P19 cells (P19 neurons) were compared with human neuroblastoma SH-SY5Y cells and rat adrenal pheochromocytoma PC12 cells for their ability to detect toxicity of methylmercury (MeHg), okadaic acid and acrylamide.

    Methods: Retinoic acid-treated P19 and SH-SY5Y cells and nerve growth factor-stimulated PC12 cells, allowed to differentiate for six days, were exposed to MeHg, okadaic acid and acrylamide for 48 h. Cell survival and neurite outgrowth were assessed with the calcein-AM assay and fluorescence detection of antibodies against the cytoskeletal neuron-specific protein βIII-tubulin, respectively. The effects of glutathione (GSH) and the potent inhibitor of GSH synthesis buthionine sulfoximine (BSO) on the MeHg induced-toxicity were assessed using the PrestoBlue™ cell viability assay and the TMRE mitochondrial membrane potential assay.

    Results: Differentiated P19 cells developed the most extensive neuronal network among the three cell models and were the most sensitive neuronal model to detect neurotoxic effects of the test compounds. MeHg produced a concentration-dependent toxicity in differentiated P19 cells and SH-SY5Y cells, with statistically significant effects at concentrations from 0.1 µM in the P19 neurons and 1 µM in the SH-SY5Y cells. MeHg induced a decrease in the cellular metabolic activity and mitochondrial membrane potential (ΔΨm) in the differentiated P19 cells and SH-SY5Y cells, that were attenuated by GSH. Okadaic acid and acrylamide also showed statistically significant toxicity in the P19 neurons, but not in the SH-SY5Y cells or the P12 cells.

    Conclusions: P19 neurons are more sensitive to detect cytotoxicity of MeHg, okadaic acid and acrylamide than retinoic acid-differentiated SH-SY5Y cells and nerve growth factor-treated PC12 cells. P19 neurons are at least as sensitive as differentiated SH-SY5Y cells to detect the loss of mitochondrial membrane potential produced by MeHg and the protective effects of extracellular GSH on MeHg toxicity. P19 neurons may be a useful model to study neurotoxic effects of chemicals.

  • 220.
    Popova, Dina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Stig O.P., Jacobsson
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    In vitro toxicity of piperazine-derived designer drugs in differentiated neural cell linesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Piperazine derivatives are common ingredients in recreational “party pills” which are used to provide a stimulant, euphoric effect akin to that of methylenedioxymethamphetamine (MDMA, “ecstasy”). There is a potential for significant toxicity associated with the use of these compounds, and the aim of the present study was to investigate if the common piperazine derivatives N-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP), 1-(4-methoxyphenyl)piperazine (MeOPP) and 1-(4-fluorophenyl)piperazine (pFPP), were toxic to retinoic acid-treated neuronally differentiated mouse P19 embryonic carcinoma stem cells and differentiated human neuroblastoma SH-SY5Y cells. Immunofluorescence of the neuron-specific protein βIII-tubulin, fluorescence of intracellular calcein, assays of mitochondrial membrane potential (∆ψm), MTT reduction and extracellular levels of LDH were used to estimate concentration-dependent cell toxicity of the piperazine derivatives and MDMA. All piperazine derivatives were toxic to the P19 neurons, but TFMPP was the most potent cytotoxic compound, producing a major decrease in mitochondrial membrane potential, cellular MTT reduction and fluorescence of calcein and βIII-tubulin, with a simultaneous increase in LDH release. The toxicity of piperazine derivatives is not restricted to differentiated P19 cells, since BZP and TFMPP were also cytotoxic in SH-SY5Y cells and human colon adenocarcinoma Caco-2 cells.

  • 221.
    Pourazar, Jamshid
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Blomberg, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Kelly, Frank J
    Davies, Donna E
    Wilson, Susan J
    Holgate, Stephen T
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Diesel exhaust increases EGFR and phosphorylated C-terminal Tyr 1173 in the bronchial epithelium2008Ingår i: Particle and Fibre Toxicology, ISSN 1743-8977, E-ISSN 1743-8977, Vol. 5, artikel-id 8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Epidemiological studies have demonstrated adverse health effects of environmental pollution. Diesel exhaust (DE) is a major contributor to particulate matter pollution. DE exposure has been shown to induce a pronounced inflammatory response in the airways, together with an enhanced epithelial expression of cytokines such as IL-8, Gro-alpha, IL-13 and activation of redox sensitive transcription factors (NFkappaB, AP-1), and MAP kinases (p38, JNK). The aim of the present investigation was to elucidate the involvement of the epidermal growth factor receptor (EGFR) signalling pathway in the epithelial response to DE in-vivo.

    RESULTS: Immunohistochemical staining was used to quantify the expression of the EGFR, phosphorylated Tyrosine residues, MEK and ERK in the bronchial epithelium of archived biopsies from 15 healthy subjects following exposure to DE (PM10, 300 mug/m3) and air. DE induced a significant increases in the expression of EGFR (p = 0.004) and phosphorylated C-terminal Tyr 1173 (p = 0.02). Other investigated EGFR tyrosine residues, Src related tyrosine (Tyr 416), MEK and ERK pathway were not changed significantly by DE.

    CONCLUSION: Exposure to DE (PM10, 300 mug/m3) caused enhanced EGFR expression and phosphorylation of the tyrosine residue (Tyr 1173) which is in accordance with the previously demonstrated activation of the JNK, AP-1, p38 MAPK and NFkB pathways and associated downstream signalling and cytokine production. No effects were seen on the MEK and ERK pathway suggesting that at the investigated time point (6 hours post exposure) there was no proliferative/differentiation signalling in the bronchial epithelium. The present findings suggest a key role for EGFR in the bronchial response to diesel exhaust.

  • 222.
    Qin, Liena
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Vo, Duc-Duy
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Nakhai, Azadeh
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Andersson, C. David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Elofsson, Mikael
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Diversity-Oriented Synthesis of Libraries Based on Benzofuran and 2,3-Dihydrobenzofuran Scaffolds2017Ingår i: ACS Combinatorial Science, ISSN 2156-8952, Vol. 19, nr 6, s. 370-376Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Benzofuran and 2,3-dihydrobenzofuran scaffolds are core components in a large number of biologically active natural and synthetic compounds including approved drugs. Herein, we report efficient synthetic protocols for preparation of libraries based on 3-carboxy 2-aryl benzofuran and 3-carboxy 2-aryl trans-2,3-dihydrobenzofuran scaffolds using commercially available salicylaldehydes, aryl boronic acids or halides and primary or secondary amines. The building blocks were selected to achieve variation in physicochemical properties and statistical molecular design and subsequent synthesis resulted in 54 lead-like compounds with molecular weights of 299-421 and calculated octanol/water partition coefficients of 1.9-4.7.

  • 223.
    Ranjbarian, Farahnaz
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Targets and strategies for drug development against human African sleeping sickness2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Trypanosoma brucei is a causative agent of African sleeping sickness. It is an extracellular parasite which circulates in the blood, lymph and eventually invades the central nervous system. There is a great need for new medicines against the disease and specific properties of nucleoside kinases in the pathogen can be exploited as targets for chemotherapy. 

    T. brucei contains a gene where two thymidine kinase sequences are fused into a single open reading frame. These types of tandem thymidine kinases were found only in different types of parasites, which made us to believe that it might be beneficial for them. Each thymidine kinase sequence in these tandem enzymes are here referred to as a domain. By cloning and expressing each domain from T. brucei separately, we found that domain 1 was inactive and domain 2 was as active as the full-length enzyme. T. brucei thymidine kinase phosphorylated the pyrimidine nucleosides thymidine and deoxyuridine and to some extent purine nucleosides like deoxyinosine and deoxyguanosine. Human thymidine kinase increases the affinity to its substrates when it forms oligomers. Similarly, the T. brucei two thymidine kinase sequences, which can be viewed as a pseudodimer, had a higher affinity to its substrates than domain 2 alone. 

    T. brucei lacks de novo purine biosynthesis and it is therefore dependent on salvaging the required purine nucleotides for RNA and DNA synthesis from the host. Purine salvage is considered as a target for drug development. It has been shown that in the presence of deoxyadenosine in the growth medium, the parasites accumulate high levels of dATP and the extensive phosphorylation of deoxyadenosine leads to depleted ATP pools. Initially, we wondered if deoxyadenosine could be used as a drug against T. brucei. However, we found that T. brucei is partially protected against deoxyadenosine because it was cleaved by the enzyme methylthioadenosine phosphorylase (MTAP) to adenine and ribose-1-phosphate. At higher concentration of deoxyadenosine, 3 the formed adenine was not efficiently salvaged into ATP and started to inhibit MTAP instead. The deoxyadenosine was then instead phosphorylated by adenosine kinase leading to accumulation of dATP. The MTAP reaction makes deoxyadenosine itself useless as a drug and instead we focused on finding analogues of deoxyadenosine or adenosine that were cleavage-resistant and at the same time good substrates of T. brucei adenosine kinase. Our best hit was then 9-(2-deoxy-2-fluoro-ß-D-arabinofuranosyl) adenine (FANA-A). An additional advantage of FANA-A as a drug was that it was taken up by the P1 nucleoside transporter family, which makes it useful also against multidrug resistant parasites that often have lost the P2 transporter function and take up their purines solely by the P1 transporter. In parallel with our study of nucleoside metabolism in T. brucei, we also have a collaboration project where we screen essential oils from plants which are used in traditional medicine. If the essential oils are active against the trypanosomes, we further analyze the different components in the oils to identify new drugs against African sleeping sickness. One such compound identified from the plant Smyrnium olusatrum is isofuranodiene, which inhibited T. brucei proliferation with an IC50 value of 3 μM.

  • 224.
    Ranjbarian, Farahnaz
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Vodnala, Munender
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Alzahrani, Khalid J. H.
    Ebiloma, Godwin U.
    de Koning, Harry P.
    Hofer, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance2017Ingår i: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, nr 6, artikel-id e02719-16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. brucei-infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects T. brucei against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC(50)s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.

  • 225. Ringbäck Weitoft, G
    et al.
    Ericsson, Ö
    Löfroth, Emil
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Centre for Epidemiology, Swedish National Board of Health and Welfare, 106 30, Stockholm, Sweden .
    Rosén, Måns
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. The Swedish Council on Technology Assessment in Health Care, Stockholm, Sweden .
    Equal access to treatment? Population-based follow-up of drugs dispensed to patients after acute myocardial infarction in Sweden.2008Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, nr 4, s. 417-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and Objective The establishment of national guidelines is one approach to creating equity in terms of access to care, and both internationally and in Sweden, guidelines have been developed for coronary heart disease. We have analysed drug treatment in Sweden according to national guidelines after acute myocardial infarction (AMI). The aim was to investigate whether there are differences between population groups according to sex, education, country of birth and diabetes.

    Methods Information was obtained from the Swedish Prescribed Drug Register on drugs dispensed between July and October 2005 for incident cases of AMI during the period 2003-2004 (n=28,168). Data on socio-economic and demographic conditions were included. Dispensed drugs after AMI were compared to the recommended drug treatment according to Swedish and European guidelines - acetylsalicylic acid (ASA), beta-blockers, lipid-lowering drugs and angiotensin-converting enzyme inhibitors (ACE inhibitors).

    Results We found that, in general, there were only small differences between the sexes and between educational groups. The greatest differences were found in comparisons between regions of birth. In particular, foreign-born patients resident in Sweden but originally from outside the EU25 countries used fewer drugs than Swedish-born patients. The OR (odds ratio) for ASA was 0.73 [95% confidence interval (CI) 0.63-0.85], for beta-blockers, 0.72 (0.63-0.83), for lipid-lowering drugs, 0.75 (0.65-0.86) and for ACE inhibitors, 0.76 (0.67-0.86).

    Conclusions In general, we found only slight differences - or none at all - between population groups in terms of drug treatment after AMI. Only among immigrants from outside the EU25 countries was there a tendency towards a lesser use of the recommended drugs according to the national guidelines.

  • 226.
    Rodriguez-Gaztelumendi, Antonio
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Alvehus, Malin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Andersson, Therése
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Comparison of the effects of nicotine upon the transcellular electrical resistance and sucrose permeability of human ECV304/rat C6 co-cultures and human CaCo2 cells2011Ingår i: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 207, nr 1, s. 1-6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is now well established that nicotine adversely affects the integrity of the blood–brain barrier (BBB). In contrast, nicotine has been reported to increase the transendothelial electrical resistance (TEER) of CaCo2 colon cancer cells. In the present study, the effects of nicotine upon the TEER and sucrose permeability of ECV304/C6 co-cultures and, for comparative purposes, CaCo2 cells has been investigated. Neither ECV304 nor C6 cells were found to express measurable membrane levels of nicotinic acetylcholine receptors, as assessed by [3H]–epibatidine binding. Nicotine treatment (0.01–1 µM) for up to 48 h had little or no effect upon the TEER or sucrose permeability of either ECV304/C6 co-cultures or CaCo2 cells. It is concluded that in contrast to the situation for the BBB, ECV304 cells lack nicotinic acetylcholine receptors and the barrier properties of ECV304/C6 co-cultures are not affected to any important extent by nicotine. This study underlines the conclusions made by other authors that the ECV304/C6 co-culture system is of limited validity as a model of the BBB.

  • 227.
    Rojo, Maria Luisa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Söderström, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Olsson, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Fower, Christopher
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Changes in cannabinoid CB(1) receptor functionality in the female rat prefrontal cortex following a high fat diet.2013Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 92, nr 13, s. 757-762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: A high fat diet (HFD) has been found to affect neurotransmission in the prefrontal cortex, but the effects of this dietary regime upon the endocannabinoid system has not been studied in this brain region. In consequence, in the present study, we have investigated the effect of HFD for up to 20 weeks upon the endocannabinoid system in the prefrontal cortex of female rats.

    Main methods: CB1 receptor functionality was measured using CP55,940-stimulated [S-35] GTP gamma S autoradiography. Fatty acid amide hydrolase and monoacylglycerol lipase activities were analysed in brain regions by assessing rates of [H-3] anandamide and JZL184-sensitive [H-3]2-oleoylglycerol hydrolysis, respectively.

    Key findings: In the prefrontal cortex, a significantly greater stimulation of [S-35] GTP gamma S binding by CP55,940 was seen following 4-12, but not 16-20 weeks of HFD. No significant changes were seen for the caudate-putamen, CA1-CA3 region of the hippocampus or the dentate gyrus. The increased response for the 12 week animals was not accompanied by a significant change in the receptor density, measured with [H-3]CP55,940 autoradiography. No significant changes in the activity of the endocannabinoid hydrolytic enzymes fatty acid amide or monoacylglycerol lipase were seen in the prefrontal cortex, hippocampus, amygdala or hypothalamus following either 12 or 20 weeks of HFD.

    Significance: It is concluded that HFD produces an increased CB1 receptor functionality in the prefrontal cortex of female rats. Given that the endocannabinoid system regulates neurotransmission in the prefrontal cortex, the present data would implicate this system in the disturbed prefrontal cortical activity in this region following a high fat diet.

  • 228. Rundle, Andrew
    et al.
    Richie, John
    Steindorf, Karen
    Peluso, Marco
    Overvad, Kim
    Raaschou-Nielsen, Ole
    Clavel-Chapelon, Francoise
    Linseisen, Jacob P.
    Boeing, Heiner
    Trichopoulou, Antonia
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Panico, Salvatore
    Bueno-De-Mesquita, Hendrik B.
    Peeters, Petra H.
    Lund, Eiliv
    Gonzalez, Carlos A.
    Martinez, Carmen
    Dorronsoro, Miren
    Barricarte, Aurelio
    Jose Tormo, M.
    Quiros, Jose R.
    Agudo, Antonio
    Berglund, Goran
    Järvholm, Bengt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Bingham, Sheila
    Key, Timothy J.
    Gormally, Emmanuelle
    Saracci, Rodolfo
    Kaaks, Rudolf
    Riboli, Elio
    Vineis, Paolo
    Physical activity and lung cancer among non-smokers: a pilot molecular epidemiological study within EPIC2010Ingår i: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 15, nr 1, s. 20-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The association between physical activity, potential intermediate biomarkers and lung cancer risk was investigated in a study of 230 cases and 648 controls nested within the European Prospective Investigation of Cancer and Nutrition. Data on white blood cell aromatic-DNA adducts by 32P-post-labelling and glutathione (GSH) in red blood cells were available from a subset of cases and controls. Compared with the first quartile, the fourth quartile of recreational physical activity was associated with a lower lung cancer risk (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.90), higher GSH levels (+1.87 μmol GSH g-1 haemoglobin, p = 0.04) but not with the presence of high levels of adducts (OR 1.05, 95% CI 0.38-2.86). Despite being associated with recreational physical activity, in these small-scale pilot analyses GSH levels were not associated with lung cancer risk (OR 0.95, 95% CI 0.84-1.07 per unit increase in GSH levels). Household and occupational activity was not associated with lung cancer risk or biomarker levels.

  • 229. Rutgersson, Carolin
    et al.
    Gunnarsson, Lina
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Kristiansson, Erik
    Larsson, D. G. Joakim
    Oral exposure to industrial effluent with exceptionally high levels of drugs does not indicate acute toxic effects in rats2013Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 32, nr 3, s. 577-584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The Patancheru area near Hyderabad in India is recognized as a key link in the global supply chain for many bulk drugs. A central treatment plant receives wastewater from approximately 90 different manufacturers, and the resulting complex effluent has contaminated surface, ground, and drinking water in the region. Ecotoxicological testing of the effluent has shown adverse effects for several organisms, including aquatic vertebrates, at high dilutions. In addition, a recent study of microbial communities in river sediment indicated that the contamination of antibiotic substances might contribute to the emergence and spread of antibiotic resistance genes. In an attempt to start investigating how exposure to effluent-contaminated water may directly affect humans and other terrestrial vertebrates, rats were tube-fed effluent. Several pharmaceuticals present in the effluent could be detected in rat blood serum at low concentrations. However, results from exploratory microarray and quantitative polymerase chain reaction assays indicated no marked effects on hepatic gene transcription after 5 d of exposure. Neither did clinical analysis of blood serum constituents, used as biomarkers for human disease, reveal any significant changes, nor was there any weight gain. Taken together, the authors could not find evidence for any acute toxicity in the rat; however, the authors cannot rule out that higher doses of effluent or a longer exposure time may still be associated with risks for terrestrial vertebrates. 

  • 230. Sacchet, Matthew D.
    et al.
    Ho, Tiffany C.
    Connolly, Colm G.
    Tymofiyeva, Olga
    Lewinn, Kaja Z.
    Han, Laura K.M.
    Henje Blom, Eva
    Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden; Department of Psychiatry, Division of Child and Adolescent Psychiatry, University of California San Francisco, San Francisco, CA, USA.
    Tapert, Susan F.
    Max, Jeffrey E.
    Frank, Guido K.W.
    Paulus, Martin P.
    Simmons, Alan N.
    Gotlib, Ian H.
    Yang, Tony T.
    Large-scale hypoconnectivity between resting-state functional networks in unmedicated adolescent major depressive disorder2016Ingår i: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, nr 12, s. 2951-2960Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Major depressive disorder (MDD) often emerges during adolescence, a critical period of brain development. Recent resting-state fMRI studies of adults suggest that MDD is associated with abnormalities within and between resting-state networks (RSNs). Here we tested whether adolescent MDD is characterized by abnormalities in interactions among RSNs. Participants were 55 unmedicated adolescents diagnosed with MDD and 56 matched healthy controls. Functional connectivity was mapped using resting-state fMRI. We used the network-based statistic (NBS) to compare large-scale connectivity between groups and also compared the groups on graph metrics. We further assessed whether group differences identified using nodes defined from functionally defined RSNs were also evident when using anatomically defined nodes. In addition, we examined relations between network abnormalities and depression severity and duration. Finally, we compared intranetwork connectivity between groups and assessed the replication of previously reported MDD-related abnormalities in connectivity. The NBS indicated that, compared with controls, depressed adolescents exhibited reduced connectivity (p<0.024, corrected) between a specific set of RSNs, including components of the attention, central executive, salience, and default mode networks. The NBS did not identify group differences in network connectivity when using anatomically defined nodes. Longer duration of depression was significantly correlated with reduced connectivity in this set of network interactions (p=0.020, corrected), specifically with reduced connectivity between components of the dorsal attention network. The dorsal attention network was also characterized by reduced intranetwork connectivity in the MDD group. Finally, we replicated previously reported abnormal connectivity in individuals with MDD. In summary, adolescents with MDD show hypoconnectivity between large-scale brain networks compared with healthy controls. Given that connectivity among these networks typically increases during adolescent neurodevelopment, these results suggest that adolescent depression is associated with abnormalities in neural systems that are still developing during this critical period.

  • 231. Sadovski, Oleg
    et al.
    Hicks, Justin W
    Parkes, Jun
    Raymond, Roger
    Nobrega, Jose
    Houle, Sylvain
    Cipriano, Mariateresa
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Vasdev, Neil
    Wilson, Alan A
    Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase2013Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 21, nr 14, s. 4351-4357Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an F-18-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [F-18]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [F-18]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [F-18]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [H-18]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [F-18]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

    (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  • 232. Salome, Nicolas
    et al.
    Haage, David
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Fysiologi.
    Perrissoud, Daniel
    Moulin, Aline
    Demange, Luc
    Egecioglu, Emil
    Fehrentz, Jean-Alain
    Martinez, Jean
    Dickson, Suzanne L
    Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats2009Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 612, nr 1-3, s. 167-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 mu g) in a dose-dependent manner with a total blockade at concentraions of 0.4 mu g and 8 mu g for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 mu g). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 mu M)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fast mass in clincal studies.

  • 233.
    Samuelsson, Eva
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Hedenmalm, Karin
    Persson, Ingemar
    Mortality from venous thromboembolism in young Swedish women and its relation to pregnancy and use of oral contraceptives: an approach to specifying rates2005Ingår i: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 20, nr 6, s. 509-516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Pregnancy and use of combined oral contraceptives (COCs) are major risk factors for venous thromboembolism (VTE) in young women and we wanted to obtain accurate VTE mortality data overall, by age, associated with the use of COCs and pregnancy. METHODS: From the Swedish Cause of Death Register (CDR) we identified women aged 15-44 with VTE as underlying or contributory cause of death during the period 1990-1999. We scrutinized medical records and included verified VTE cases without active cancer or terminal disease. Pregnancy statistics and COC utilization data were obtained from national databases. RESULTS: Of the 120 cases included, 9 (8%) were associated with pregnancy and 28 (23%) with current COC use. The overall refined VTE mortality rate in current COC users was 7.5[4.7; 10.3] per million user-years and the corresponding pregnancy-related rate was 8.9[4.1;17.0] per million pregnancy years, rates increasing with age. For ages 15-24, the rate was significantly higher in current COC users than in non-pregnant women not using COCs: 6.0[3.1; 10.5] per million user-years vs. 0.3[0.0; 1.2] per million woman years. Underlying cause mortality data included 82% of VTE deaths associated with COCs, and 56% of maternal deaths had a pregnancy-related code. CONCLUSION: Mortality figures from VTE associated with the use of COCs and pregnancy were similar. COC use had an important impact on the total VTE mortality in the youngest age group. Standard mortality statistics do not allow accurate monitoring of VTE mortality in young women due to missing data, misdiagnoses and coding rules.

  • 234.
    Samuelsson, Eva
    et al.
    Uppsala universitet.
    Hägg, S
    Bäckström, M
    Granberg, K
    Mjörndal, T
    [Thrombosis caused by oracl contraceptives. Underreporting to the adverse effects registry].1996Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 93, nr 37, s. 3117-8, 3121Artikel i tidskrift (Refereegranskat)
  • 235.
    Sandqvist, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi. Uppsala universitet.
    Vardenafil and methylarginines in pulmonary hypertension2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway.

    Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects.

    Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects.

    Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05).

    Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.

  • 236.
    Sandqvist, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Henrohn, Dan
    Egeröd, Hanna
    Hedeland, Mikael
    Wernroth, Lisa
    Bondesson, Ulf
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Wikström, Gerhard
    Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension2015Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, nr 10, s. 1165-1173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: 

    Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine.

    METHODS: 

    A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria.

    RESULTS: 

    Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders.

    CONCLUSIONS: 

    Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

  • 237.
    Sandqvist, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Kling, Anders
    Påverkar glukosamin blod­sockret?: Kan glukosamin påverka blodsockret? Finns det någ­ra samband?2008Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, nr 39, s. 2706-Artikel i tidskrift (Refereegranskat)
  • 238.
    Sandqvist, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ottander, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Laktos i läkemedel normalt inget problem för laktosintoleranta2015Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, nr 27-28, s. 1234-1234Artikel i tidskrift (Refereegranskat)
  • 239.
    Sandqvist, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Henrohn, Dan
    Kylhammar, David
    Lundgren, Jakob
    Hedeland, Mikael
    Bondesson, Ulf
    Rådegran, Göran
    Wikström, Gerhard
    Differences in plasma L-arginine and dimethylarginines in diagnosis and treatment of pulmonary arterial hypertension: a prospective observational studyManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Introduction Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance in vasoactive substances and remodelling of pulmonary vasculature. Asymmetric dimethylarginine (ADMA) inhibits the enzyme nitric oxide synthase, which generates nitric oxide (NO), a molecule causing smooth muscle cell relaxation. Our aim was to investigate the plasma concentrations of ADMA, symmetrical dimethylarginine (SDMA), L-arginine, L-ornithine and L- citrulline at diagnosis and during PAH-specific treatment in patients with PAH compared to patients with left heart failure (LVHF) and healthy subjects.

    Methods This is an observational, prospective multicentre study of 21 PAH patients. For comparison 14 patients with LVHF and 27 healthy subjects were investigated. Blood samples were collected and ADMA, SDMA, L-arginine, L-ornithine and L-citrulline were analysed with liquid chromatography – tandem mass spectrometry (LC-MS/MS).

    Results Baseline plasma concentrations of ADMA and SDMA were higher whereas the L-arginine concentrations and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p<0.001). Patients with PAH had lower L-arginine concentration than patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to L-arginine and L- arginine/ADMA in PAH at baseline (p<0.05). At follow-up, patients on mono- or combination therapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on phosphodiesterase type-5 inhibitors (PDE5-inhibitors) had higher ADMA levels compared to patients without PDE5-inhibitor treatment (p<0.05).

    Conclusion Concentrations of L-arginine were decreased and dimethylarginines were increased in PAH compared to healthy subjects. L-arginine was decreased in PAH compared to LVHF. L- arginine/ADMA ratio correlated to WHO functional class and L-arginine and L-arginine/ADMA ratio correlated to 6MWD. PAH-specific treatment influences the levels of L-arginine and dimethylarginines. 

  • 240.
    Schliamser, Silvia E.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Neurotoxicity of β-lactam antibiotics: experimental kinetic and neurophysiological studies1988Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The neurotoxic potential of intravenous administered benzylpenicillin (BPC) was studied in rabbits with intact blood-CNS barriers and rabbits with experimental E. coli meningitis. At onset of epileptogenic EEG activity or seizures, serum, CSF and brain tissue were collected for assay of BPC. Based on the fact that, in tissues, BPC seems to remain extracellularly, brain concentrations of BPC were expressed as brain tissue fluid (BTF) levels, calculated as lOx the concentration in whole brain tissue. Neurotoxicity could be precipitated in all rabbits. In normal rabbits BTF levels of BPC were considerably higher than those in CSF indicating a better penetration across the blood-brain barrier (BBB). BPC penetrated better to CSF and BTF in meningitic rabbits than in normal controls, suggesting some degree of damage of the BBB concomitant with meningeal inflammation. E. coli meningitis did not increase the neurotoxicity of BPC. In control rabbits the intracistemal injection of saline resulted in some degree of pleocytosis. Unmanipulated animals are therefore preferable as controls. Epileptogenic EEG-changes was the most precise of the two variables used for demonstration of neurotoxicity. EEG-changes were therefore used as neurotoxicity criterion in the following rabbit experiments. To evaluate the effect of uraemia alone and uraemia plus meningitis on the neurotoxity of BPC in rabbits, cephaloridine was used to induce uraemia. Meningitis was induced by intracistemal inoculation of a cephalosporinresistant strain of E. cloacae. Untreated  rabbits were used as controls. Uraemia resulted in increased BTF penetration of BPC, possibly explained by permeability changes in the BBB and/or decreased binding of BPC to albumin. Uraemia did not result in increased penetration of BPC into the CSF of non-meningitic rabbits. Uraemic non-meningitic rabbits had the highest BTF levels of BPC at the criterion, indicating that cephaloridine-induced renal failure increased the epileptogenic threshold in these rabbits. The combination of uraemia and meningitis increased the neurotoxicity of BPC since the criterion was reached at considerably lower BTF levels of BPC. Meningitis, either alone or together with uraemia, did not increase the neurotoxicity in comparison to control rabbits. Higher BTF levels of BPC were found in meningitic rabbits than in controls with intact blood-CNS barriers at onset of EEG-changes. In all groups of rabbits there was a pronounced variability of BPC levels in the CSF while the intra-group variations in BTF levels were much smaller. Thus, BTF and not CSF levels were decisive for the neurotoxicity of BPC. Using   the same EEG-model, the neurotoxic potential of imipenem/cilastatin (I) and a new penem derivative, FCE 22101 were compared in a cross-over study. Both I and FCE 22101 were significantly more neurotoxic than BPC. While BTF levels of the three antibiotics could be detected in all tested rabbits, detectable CSF levels were only found in one of twelve rabbits treated with I or FCE 22101, indicating that BTF concentrations rather than CSF ones are decisive for neurotoxicity of ß-lactam antibiotics. The EEG-model used was found to be a suitable model for cross-over studies of intravenously administered antibiotics. Using the "silent-second" as EEG-threshold, a CNS interaction between intraperitoneally administered BPC and intravenous thiopental was demonstrated in rats. The most probably site for this interaction is the organic acid transport system out of the CNS. Thiopental distribution in the rat brain seemed to depend not only on its lipid solubility.

  • 241.
    Schug, Alexander
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Onuchic, José N
    Center for Theoretical Biological Physics, University of California San Diego, San Diego, USA.
    From protein folding to protein function and biomolecular binding by energy landscape theory2010Ingår i: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 10, nr 6, s. 709-714Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Protein folding and function are inherently linked sharing a joined funneled energy landscape. In this theoretical framework, the integration of simulations, structural information, and sequence data has led to quantitatively explore, understand, and predict biomolecular binding and recognition, key processes in pharmacology, as a natural extension of the selective self-binding found in protein folding. Computer simulations based on these principles have made valuable contributions to understanding protein and RNA folding, protein-protein interactions, and protein-metabolite/RNA-metabolite interactions.

  • 242.
    Seidel, Pia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    [Keppra in pregnancy. Generally lower risk of birth defects in monotherapy.]2012Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, nr 22, s. 1099-1099Artikel i tidskrift (Refereegranskat)
  • 243. Semenza, Jan C.
    et al.
    Trinanes, Joaquin
    Lohr, Wolfgang
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Sudre, Bertrand
    Löfdahl, Margareta
    Martinez-Urtaza, Jaime
    Nichols, Gordon L.
    Rocklöv, Joacim
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Epidemiologi och global hälsa.
    Environmental Suitability of Vibrio Infections in a Warming Climate: An Early Warning System2017Ingår i: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, nr 10, artikel-id UNSP 107004Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Some Vibrio spp. are pathogenic and ubiquitous in marine waters with low to moderate salinity and thrive with elevated sea surface temperature (SST). OBJECTIVES: Our objective was to monitor and project the suitability of marine conditions for Vibrio infections under climate change scenarios. METHODS: The European Centre for Disease Prevention and Control (ECDC) developed a platform (the ECDC Vibrio Map Viewer) to monitor the environmental suitability of coastal waters for Vibrio spp. using remotely sensed SST and salinity. A case-crossover study of Swedish cases was conducted to ascertain the relationship between SST and Vibrio infection through a conditional logistic regression. Climate change projections for Vibrio infections were developed for Representative Concentration Pathway (RCP) 4.5 and RCP 8.5. RESULTS: The ECDC Vibrio Map Viewer detected environmentally suitable areas for Vibrio spp. in the Baltic Sea in July 2014 that were accompanied by a spike in cases and one death in Sweden. The estimated exposure response relationship for Vibrio infections at a threshold of 16 degrees C revealed a relative risk (RR) = 1.14 (95% CI: 1.02, 1.27; p=0.024) for a lag of 2 wk; the estimated risk increased successively beyond this SST threshold. Climate change projections for SST under the RCP 4.5 and RCP 8.5 scenarios indicate a marked upward trend during the summer months and an increase in the relative risk of these infections in the coming decades. CONCLUSIONS: This platform can serve as an early warning system as the risk of further Vibrio infections increases in the 21st ritui due to climate change.

  • 244.
    Shadmanesh, Javad
    et al.
    Department Of Chemistry, National and Kapodostrian University Of Athens, Panepistimiopolis, Athens, Greece .
    Jadid, Aiyoub Parchehbaf
    Department of Applied Chemistry, Ardabil Branch, Islamic Azad University, Ardabil, Iran.
    Azari, Zhila
    Young Researchers and Elite Club, Ardabil Branch, Islamic Azad University, Ardabil, Iran .
    Niazi, Mehri
    Young Researchers and Elite Club, Ardabil Branch, Islamic Azad University, Ardabil, Iran .
    Aghbolagh, Mahdi Shahmohammadi
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    QSAR study of active human glucagon receptor antagonists by SW-MLR and SW-SVM methods2014Ingår i: Medicinal Chemistry Research, ISSN 1054-2523, E-ISSN 1554-8120, Vol. 23, nr 5, s. 2639-2650Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A linear quantitative structure-activity relationship model is given for modelling and predicting of human glucagon receptor activities. A dataset containing 37 human glucagon receptors with their corresponding inhibition activities were used. The whole dataset was divided into training and testing set by using hierarchical clustering technique. Seven variables were selected by the stepwise variable selection procedure. Multiple linear regressions (MLR) and support vector machine (SVM) were applied to model the relationship between biological activities and molecular descriptors. Both models could suggest satisfactory prediction results: MLR method presented squared correlation coefficients of R (2) for the training and test sets of 0.894 and 0.776, namely, and squared correlation coefficient of 0.999 and 0.824 was obtained for training and testing sets by SVM model, respectively. The prediction result of the SVM was superior to that obtained by MLR model. The given models have suitable predictability and stability and can culminate in designing novel and potent human glucagon receptor activities.

  • 245.
    Sjölander, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Eriksson, Marie
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Glader, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Few sex differences in the use of drugs for secondary prevention after stroke: a nationwide observational study2012Ingår i: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 21, nr 9, s. 911-919Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: This observational study describes the sex differences in the use of secondary preventive drugs after ischemic stroke in terms of prescribing and persistence. Also, sex differences in patient- and treatment-related factors associated with drug use were investigated.

    METHODS: In this nationwide register-based study, the Swedish Stroke Register was linked to the Swedish Prescribed Drug Register for information on drugs prescribed for, and bought by, stroke patients. Background factors were included from the Swedish Stroke Register.

    RESULTS: Included in the database were 9331 men and 9018 women. Men were more often prescribed statins, 48.8% versus 38.1% [age-adjusted prevalence ratio (PR) = 0.86, 95%CI = 0.82-0.91], and warfarin, 38.4% versus 26.4% after stroke (age-adjusted PR = 0.88, 95%CI = 0.79-0.97). There were no differences in prescribing of antihypertensive or antiplatelet drugs. No sex differences were seen regarding not continuing drug treatment after discharge (primary non-adherence). Women had slightly higher persistence to antihypertensive treatment 2 years after discharge, 76.3% versus 71.9% for men (age-adjusted PR = 1.05, 95%CI = 1.00-1.09), but there were no differences in persistence to antiplatelet, warfarin or statin treatments. Similar factors were related to statin and warfarin prescribing for both men and women. Only antihypertensive treatment before stroke was associated to persistence to antihypertensive treatment, and this increased persistence for both men and women.

    CONCLUSIONS: This study showed few differences between men and women after stroke. Patients' use of secondary preventive drugs needs to be improved, and from a public health perspective, poor persistence is probably a greater problem than differences between the sexes. Copyright © 2011 John Wiley & Sons, Ltd.

  • 246.
    Sjölander, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Eriksson, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Glader, Eva-Lotta
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Few sex differences in use of drugs for secondary prevention after stroke: a nationwide observational study2011Ingår i: Abstracts 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management Hyatt Regency Chicago: Chicago, Illinois, USA August 14–17, 2011, Wiley , 2011, Vol. 20, s. S110-S110Konferensbidrag (Refereegranskat)
    Abstract [en]

    Background: Secondary preventive drug treatment after stroke is important to prevent further development of disease. Although recommendations for secondary prevention are the same for men and women, reality is not always in accordance with recommendations.

    Objectives: This observational study intended to describe the differences between men and women in the use of secondary preventive drugs after ischemic stroke in terms of prescribing and continuous use. The purpose was also to investigate differences in patient and treatment related factors associated with drug use.

    Methods: In this nationwide register - based study, the Swedish Stroke Register was linked to the Swedish Prescribed Drug Register for information on drugs prescribed for, and bought by, stroke patients. Background factors were included from the Stroke Register.

    Results: Men were more often prescribed statins after stroke, 45.2% versus 33.8% (p<0.001). There were no differences in prescribing of antihypertensive or antithrombotic drugs. No differences were seen between the sexes regarding not continuing drug treatment after discharge (primary non - adherence). Women had a slightly higher persistence rate to antihypertensive treatment 2 years after discharge from hospital, 76.3% versus 71.9% for men (p<0.001), but there were no differences in persistence to antithrombotic or lipid - lowering treatments. The same factors were related to statin prescribing for both men and women. Factors associated to persistence to antihypertensive treatment were the same for both sexes except for a follow - up visit to hospital which was associated with increased persistence for men; age was associated with increased persistence and dissatisfaction with care was associated with decreased persistence for women.

    Conclusions: This study showed small or no differences between men and women after stroke. Patients' use of secondary preventive drugs needs to be improved. Men and women do not have to be treated differently.

  • 247.
    Skagerlind, Malin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad. Department of Nephrology, Centre of Medicine, University Hospital of Umeå, Umeå, Sweden.
    Stegmayr, Bernd
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis2018Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, nr 3, s. 267-274Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intensive care participants that need dialysis frequently suffer from increased risk of bleeding. Standard intermittent haemodialysis (SHD) includes anticoagulation to avoid clotting of the dialysis system. The aim of this study was to clarify which of four different low-dose anticoagulant modes was preferable in reducing the exposure to i.v. unfractionated heparin (heparin) and maintaining patency of the dialysis circuit. Twenty-three patients on SHD were included to perform haemodialysis with four modes of low-dose anticoagulation. For comparative analyses, patients served as their own control. Haemodialysis with a single bolus of tinzaparin at the start was compared to haemodialysis initiated without i.v. heparin but priming with (1) heparin in saline (H), (2) heparin and albumin in saline (HA), (3) heparin and albumin in combination with a citrate-containing dialysate (HAC), (4) saline and usinga heparin-coated filters (EvodialA (R)). The priming fluid was discarded before dialysis started. Blood samples were collected at 0, 30 and 180 min during haemodialysis. Smaller bolus doses of heparin (500 Units/dose) were allowed during the modes to avoid interruption by clotting. The mean activated partial thromboplastin (APTT) time as well as the doses of anticoagulation administered was highest with SHD and least with HAC and EvodialA (R). Mode H versus SHD had the highest rate of prematurely interrupted dialyses (33%, p = 0.008). The urea reduction rate was less with EvodialA (R) vs. SHD (p < 0.01). One hypersensitivity reaction occurred with EvodialA (R). Changes in blood cell concentrations and triglycerides differed between the modes. If intermittent haemodialysis is necessary in patients at risk of bleeding, anticoagulation using HAC and EvodialA (R) appeared most preferable with least administration of heparin, lowest APTT increase and lowest risk for prematurely clotted dialyzers in contrast to the least plausible H mode.

  • 248. Skerfving, Staffan
    et al.
    Bergdahl, Ingvar A.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkesmedicin.
    Lead2007Ingår i: Handbook on the Toxicology of Metals, 3rd Edition / [ed] Gunnar F. Nordberg, Bruce A. Fowler, Monica Nordberg and Lars T. Friberg, San Diego: Elsevier, 2007, 3, s. 599-643Kapitel i bok, del av antologi (Övrigt vetenskapligt)
    Abstract [en]

    Inorganic lead is certainly the most extensively studied of all toxic agents. Occupational exposure occurs in a wide variety of settings. There is also widespread exposure in the general environment. However, after the ban of lead addition to petrol, the exposure has decreased dramatically in several parts of the world. Exposure and risk are usually assessed by biological monitoring, mainly by blood-lead concentration (B-Pb). However, B-Pb has limitations, because there is saturation at high exposure. Lead accumulates in teeth and in the skeleton, where it may be determined by in vivo methods, which reflect long-term uptake. Toxic effects may occur in the central and peripheral nervous systems, blood (including inhibition of heme synthesis, which also affects other cells), kidney, and cardiovascular, endocrine and immune systems, gastrointestinal tract, and male reproduction (sperm quality). Lead causes increase of blood pressure; slight effects may occur in adults with a mean B-Pb of 0.4 mu mol/L. Furthermore, lead passes the placenta and may cause effects on the nervous system of the fetus. Lead in the skeleton is mobilized during pregnancy and lactation and is transferred to both the fetus and the lactating infant. Slight (but adverse) effects on the mental development of infants and children have repeatedly been reported at a mean B-Pb of 0.5 mu mol/L, or even less, in the pregnant woman or the child. Lead is carcinogenic in animal experiments, but there is only limited evidence for carcinogenicity in humans. The most important organolead compounds are tetraethyl and tetramethyl lead, which have been used in enormous quantities in leaded petrol. They are easily absorbed through inhalation and through the skin and may cause acute encephalopathia.

  • 249.
    Souihi, Nabil
    et al.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Reynolds, Gavin
    Tajarobi, Pirjo
    Wikström, Håkan
    Haeffler, Gunnar
    Josefson, Mats
    Trygg, Johan
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Roll compaction process modeling: transfer between equipment and impact of process parameters2015Ingår i: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 484, nr 1-2, s. 192-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study the roll compaction of an intermediate drug load formulation was performed using horizontally and vertically force fed roll compactors. The horizontally fed roll compactor was equipped with an instrumented roll technology allowing the direct measurement of normal stress at the roll surface, while the vertically fed roll compactor was equipped with a force gauge between the roll axes. Furthermore, characterization of ribbons, granules and tablets was also performed. Ribbon porosity was primarily found to be a function of normal stress, exhibiting a quadratic relationship thereof. A similar quadratic relationship was also observed between roll force and ribbon porosity of the vertically fed roll compactor. The predicted peak pressure (Pmax) using the Johanson model was found to be higher than the measured normal stress, however, the predicted Pmax correlated well with the ribbon relative density/porosity and the majority of downstream properties of granules and tablets, demonstrating its use as a scale-independent parameter. A latent variable model was developed for both the horizontal and vertical fed roll compactors to express ribbon porosity as a function of geometric and process parameters. The model validation, performed with new data, resulted in overall good predictions. This study successfully demonstrated the scale up/transfer between two different roll compactors and revealed that the combined use of design of experiments, latent variable models and in silico predictions result in better understanding of the critical process parameters in roll compaction.

  • 250. Spulber, S.
    et al.
    Raciti, M.
    Dulko-Smith, B.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
    Lupu, D.
    Ruegg, J.
    Nam, Kwangho
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
    Ceccatelli, S.
    Methylmercury interferes with glucocorticoid receptor: Potential role in the mediation of developmental neurotoxicity2018Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 354, s. 94-100Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Methylmercury (MeHg) is a widespread environmental contaminant with established developmental neurotoxic effects. Computational models have identified glucocorticoid receptor (GR) signaling to be a key mediator behind the birth defects induced by Hg, but the mechanisms were not elucidated. Using molecular dynamics simulations, we found that MeHg can bind to the GR protein at Cys736 (located close to the ligand binding site) and distort the conformation of the ligand binging site. To assess the functional consequences of MeHg interaction with GR, we used a human cell line expressing a luciferase reporter system (HeLa AZ-GR). We found that 100 nM MeHg does not have any significant effect on GR activity alone, but the transactivation of gene expression by GR upon Dex (a synthetic GR agonist) administration was reduced in cells pre-treated with MeHg. Similar effects were found in transgenic zebrafish larvae expressing a GR reporter system (SR4G). Next we asked whether the effects of developmental exposure to MeHg are mediated by the effects on GR. Using a mutant zebrafish line carrying a loss-of-function mutation in the GR (grs(357)) we could show that the effects of developmental exposure to 2.5 nM MeHg are mitigated in absence of functional GR signaling. Taken together, our data indicate that inhibition of GR signaling may have a role in the developmental neurotoxic effects of MeHg.

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