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  • 301.
    Rambaran, Theresa F.
    et al.
    Department of Chemistry, Faculty of Science and Technology, The University of the West Indies, Mona Campus, Kingston 7, Jamaica.
    Mckenzie, Joette
    Natural Products Institute, Faculty of Science and Technology, The University of the West Indies, Mona Campus, Kingston 7, Jamaica.
    Murray, JeAnn
    Natural Products Institute, Faculty of Science and Technology, The University of the West Indies, Mona Campus, Kingston 7, Jamaica.
    Delgoda, Rupika
    Natural Products Institute, Faculty of Science and Technology, The University of the West Indies, Mona Campus, Kingston 7, Jamaica.
    Bowen-Forbes, Camille S.
    Department of Chemistry, Faculty of Science and Technology, The University of the West Indies, Mona Campus, Kingston 7, Jamaica.
    Rubus rosifolius varieties as antioxidant and potential chemopreventive agents2017In: Journal of Functional Foods, ISSN 1756-4646, E-ISSN 2214-9414, Vol. 37, p. 49-57Article in journal (Refereed)
    Abstract [en]

    Two Rubus rosifolius raspberry varieties described as ‘Red’ and ‘Wine Red’ were analyzed for their phytochemical constituents, impact on cytochromes P450 (CYP) enzyme activity, and antioxidant properties. Ellagic acid was the most predominant of the phenolics analyzed. Three compounds were isolated from the methanol extract of the ‘Red’ variety. β-sitosterol D-glucoside-6′-acetate and trachelosperogenin A were among the six compounds isolated from the ‘Wine Red’ EtOAc extract, and, to the best of our knowledge, are being reported in the genus for the first time. Euscaphic acid demonstrated the highest antioxidant activity (175.3 AE/100 mg fresh weight, FW). Pomolic acid demonstrated moderate inhibitory activity (IC50 = 9.4 µM) against the carcinogen-activating CYP1B1 enzyme, while cyanidin 3-O-glucoside was identified as a moderate, uncompetitive inhibitor of the same enzyme (Ki = 2.3 µM). Ellagic acid, quercetin and kaempferol were important contributors to the CYP1B1 inhibitory activity of the methanol extracts, indicating potential for chemopreventive effects.

  • 302.
    Ranjbarian, Farahnaz
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Targets and strategies for drug development against human African sleeping sickness2017Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 303.
    Ranjbarian, Farahnaz
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vodnala, Munender
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Alzahrani, Khalid J. H.
    Ebiloma, Godwin U.
    de Koning, Harry P.
    Hofer, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance2017In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 61, no 6, article id e02719-16Article in journal (Refereed)
    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.

  • 304.
    Rankin, Linda
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chronic pain: from the study of student attitudes and preferences to the in vitro investigation of a novel treatment strategy2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic pain will affect one in five adults during their lifetime, and it exerts a heavy burden on society with major physiological, psychological, social, and economic impacts. The current chronic pain curriculum taught to medical students in most settings is fragmented, inconsistent and inadequate and a vast majority of general practitioners considered their undergraduate training in chronic pain incomplete. Attitudes and beliefs amongst health care personnel are important and have shown to have impact on clinical management. There is currently a knowledge gap that needs to be addressed in this matter. In this thesis, through an online survey, the attitudes and beliefs of medical students in Sweden and Australia were surveyed. Additionally, we explored which factors influence chronic pain management amongst medical students in Sweden and Australia and Swedish general practitioners. We found that Swedish final year students have a more positive attitude towards chronic pain patients compared to Australian students. Both student cohorts perceived chronic pain management education in need of improvement. Furthermore, we found that the relative importance of factors that influence treatment decisions are formed early during undergraduate training, which further underlines the importance of improving pain curricula during undergraduate medical education in order to give the emerging workforce appropriate tools to manage chronic pain.

    Management of chronic pain urgently requires novel, well-tolerated pharmacological treatment strategies. Palmitoylethanolamide (PEA) is a potential candidate for managing chronic pain. Its analgesic and anti-inflammatory effects have been observed in a range of experimental animal models and clinical trials. However, questions remain as to how PEA exerts its effects and how levels of PEA and its congeners are changed in states of pain and inflammatory disorders in humans. Treatment with PEA decreases cyclooxygenase 2 (COX-2) activity in animal models, but we found that PEA did not have direct effects upon the kinetic properties of COX-2 in a cell free system. However, COX-2 derived eicosanoid levels were reduced by PEA in lipopolysaccharide and interferon-g-stimulated RAW 264.7 cells. With respect to changes in PEA levels in a chronic inflammatory disorder, we investigated PEA levels, in addition to its synthesizing and hydrolysing enzymes in biopsies from patients with oral lichen planus (OLP). We found that the ratio of prostaglandins to PEA was increased in the OLP biopsy samples. Furthermore, PTGS2 mRNA levels (coding for COX-2) were increased in OLP-patients compared to controls relative to NAPEPLD mRNA levels (coding for a key enzyme in the synthesis of PEA). These results suggest that there is a relative deficit of PEA in OLP, raising the possibility that PEA might be useful for the treatment of this disorder.

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  • 305. Rankin, Linda
    et al.
    Gouveia-Figueira, Sandra
    Danielsson, Karin
    Fowler, Christopher
    On the balance between prostaglandins and anti-inflammatory N-acylethanolamines in oral lichen planusManuscript (preprint) (Other academic)
  • 306. Ringbäck Weitoft, G
    et al.
    Ericsson, Ö
    Löfroth, Emil
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Centre for Epidemiology, Swedish National Board of Health and Welfare, 106 30, Stockholm, Sweden .
    Rosén, Måns
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. 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.2008In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 64, no 4, p. 417-424Article in journal (Refereed)
    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.

  • 307. Rocksén, David
    et al.
    Elfsmark, Daniel
    Heldestad, Victoria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neurophysiology.
    Wallgren, Karin
    Cassel, Gudrun
    Göransson Nyberg, Ann
    An animal model to study health effects during continuous low-dose exposure to the nerve agent VX2008In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 250, no 1, p. 32-38Article in journal (Refereed)
    Abstract [en]

    In the present study, we have developed an animal model to study long-term health effects of continuous exposure of toxic chemical agents, in awake, freely moving rats. The aim was to evaluate the effect of low-dose exposure of the nerve agent VX, and to find specific biomarkers for intoxication. To exclude the influence of stress, we used an implanted radio-telemetric device for online registration of physiological parameters, and an osmotic pump, implanted subcutaneously, for continuous exposure of the toxic agent. Our results showed that the lowest observable effect dose of VX in Wistar rats was 5 microg/kg/24 h, after continuous exposure by the osmotic pump. Although we observed significant inhibition of acetylcholinesterase (AChE) in blood and a significant decrease in body weight gain at this dose, no change in blood pressure, heart rate or respiratory rate was registered. However, a significant decrease in the thyroid hormone, free T4, was measured in blood after 8 weeks, indicating that low doses of VX might affect the thyroid function. Rats given repeated daily injections were more sensitive to VX and needed only 1/10 of the concentration to reach a similar level of AChE inhibition, compared to animals exposed by the osmotic pump. Moreover, the results showed that exposure of VX in our experimental design, does not induce an increase in corticosterone blood levels. Thus, the model used in this investigation renders minimal stress and will not cause unnecessary pain to the animals, indicating that this model could be a useful tool to study long-term effects of various toxic substances in freely moving rats.

  • 308.
    Rodriguez-Gaztelumendi, Antonio
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Alvehus, Malin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Andersson, Therése
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Comparison of the effects of nicotine upon the transcellular electrical resistance and sucrose permeability of human ECV304/rat C6 co-cultures and human CaCo2 cells2011In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 207, no 1, p. 1-6Article in journal (Refereed)
    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.

  • 309.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderström, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fower, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Changes in cannabinoid CB(1) receptor functionality in the female rat prefrontal cortex following a high fat diet.2013In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 92, no 13, p. 757-762Article in journal (Refereed)
    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.

  • 310.
    Rosendahl, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Eklund, Michaela
    Umeå University, Faculty of Medicine, Department of Odontology.
    Holm, Cecilia Koskinen
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Marcus J. O.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Kindstedt, Elin
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Odontology.
    Lindquist, Susanne
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice2021In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 296, article id 100177Article in journal (Refereed)
    Abstract [en]

    Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C–C chemokine receptor 3 (CCR3) is dramatically upregulated during osteoclastogenesis, but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages derived from adult male CCR3-proficient and CCR3-deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices, and altered mRNA expression of related chemokine receptors and ligands. In addition, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator–related gene, receptor activator of nuclear factor kappa-B ligand, and osteoblast differentiation–associated genes. Microcomputed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the total number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endocortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.

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  • 311.
    Rullo, Mariagrazia
    et al.
    Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy.
    Cipolloni, Marco
    TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy.
    Catto, Marco
    Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy.
    Colliva, Carolina
    TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy.
    Miniero, Daniela Valeria
    Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", via Orabona, 4, Bari, Italy.
    Latronico, Tiziana
    Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari "Aldo Moro", via Orabona, 4, Bari, Italy.
    De Candia, Modesto
    Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy.
    Benicchi, Tiziana
    TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy.
    Linusson, Anna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Giacchè, Nicola
    TES Pharma s.r.l., Corso Vannucci 47, Perugia, Italy.
    Altomare, Cosimo Damiano
    Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy.
    Pisani, Leonardo
    Department of Pharmacy Pharmaceutical Sciences, University of Bari "Aldo Moro", via Orabona 4, Bari, Italy.
    Probing Fluorinated Motifs onto Dual AChE-MAO B Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Early-ADME Studies2022In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 65, no 5, p. 3962-3977Article in journal (Refereed)
    Abstract [en]

    Bioisosteric H/F or CH2OH/CF2H replacement was introduced in coumarin derivatives previously characterized as dual AChE-MAO B inhibitors to probe the effects on both inhibitory potency and drug-likeness. Along with in vitro screening, we investigated early-ADME parameters related to solubility and lipophilicity (Sol7.4, CHI7.4, log D7.4), oral bioavailability and central nervous system (CNS) penetration (PAMPA-HDM and PAMPA-blood–brain barrier (BBB) assays, Caco-2 bidirectional transport study), and metabolic liability (half-lives and clearance in microsomes, inhibition of CYP3A4). Both specific and nonspecific tissue toxicities were determined in SH-SY5Y and HepG2 lines, respectively. Compound 15 bearing a −CF2H motif emerged as a water-soluble, orally bioavailable CNS-permeant potent inhibitor of both human AChE (IC50 = 550 nM) and MAO B (IC50 = 8.2 nM, B/A selectivity > 1200). Moreover, 15 behaved as a safe and metabolically stable neuroprotective agent, devoid of cytochrome liability.

  • 312. 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 University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    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 EPIC2010In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 15, no 1, p. 20-30Article in journal (Refereed)
    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.

  • 313. Rutgersson, Carolin
    et al.
    Gunnarsson, Lina
    Fick, Jerker
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Kristiansson, Erik
    Larsson, D. G. Joakim
    Oral exposure to industrial effluent with exceptionally high levels of drugs does not indicate acute toxic effects in rats2013In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 32, no 3, p. 577-584Article in journal (Refereed)
    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. 

  • 314.
    Saarinen, Marcus
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Mantas, Ioannis
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Flais, Ivana
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Basal and Clinical Neuroscience, King’s College London, London, United Kingdom.
    Ågren, Richard
    Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Sahlholm, Kristoffer
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Millan, Mark J.
    Neuroinflammation Therapeutic Area, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, France and Institute of Neuroscience and Psychology, College of Medicine, Vet and Life Sciences, Glasgow University, Scotland, Glasgow, United Kingdom.
    Svenningsson, Per
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Basal and Clinical Neuroscience, King’s College London, London, United Kingdom.
    TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-3838562022In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 47, p. 2319-2329Article in journal (Refereed)
    Abstract [en]

    SEP-383856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT1A). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gαs recruitment (pEC50: 6.08 ± 0.22 EMAX: 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT1A receptor, while it partially inhibited recruitment of D2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.

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  • 315. 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 disorder2016In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 41, no 12, p. 2951-2960Article in journal (Refereed)
    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.

  • 316. Sadovski, Oleg
    et al.
    Hicks, Justin W
    Parkes, Jun
    Raymond, Roger
    Nobrega, Jose
    Houle, Sylvain
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Vasdev, Neil
    Wilson, Alan A
    Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase2013In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 21, no 14, p. 4351-4357Article in journal (Refereed)
    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.

  • 317.
    Sadr-Azodi, Omid
    et al.
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Unit of Upper Gastrointestinal Surgery, Saint Goran Hospital, Stockholm, Sweden; Centre for Clinical Research Sörmland, Uppsala University, Eskilstuna, Sweden.
    Ljung, Rickard
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Lindblad, Mats
    Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Department of Upper Abdominal Surgery, Karolinska University Hospital, Stockholm, Sweden.
    Oskarsson, Viktor
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Antipsychotic drugs and risk of acute pancreatitis: a nationwide case–control study2023In: Acta Psychiatrica Scandinavica, ISSN 0001-690X, E-ISSN 1600-0447, Vol. 148, no 2, p. 199-207Article in journal (Refereed)
    Abstract [en]

    Introduction: Use of antipsychotic drugs, especially second-generation agents, has been suggested to cause acute pancreatitis in multiple case reports; however, such an association has not been corroborated by larger studies. This study examined the association of antipsychotic drugs with risk of acute pancreatitis.

    Methods: Nationwide case–control study, based on data from several Swedish registers and including all 52,006 cases of acute pancreatitis diagnosed in Sweden between 2006 and 2019 (with up to 10 controls per case; n = 518,081). Conditional logistic regression models were used to calculate odds ratios (ORs) in current and past users of first-generation and second-generation antipsychotic drugs (dispensed prescription <91 and ≥91 days of the index date, respectively) compared with never users of such drugs.

    Results: In the crude model, first-generation and second-generation antipsychotic drugs were associated with increased risk of acute pancreatitis, with slightly higher ORs for past use (1.58 [95% confidence interval 1.48–1.69] and 1.39 [1.29–1.49], respectively) than for current use (1.34 [1.21–1.48] and 1.24 [1.15–1.34], respectively). The ORs were largely attenuated in the multivariable model—which included, among others, alcohol abuse and the Charlson comorbidity index—up to the point where only a statistically significant association remained for past use of first-generation agents (OR 1.18 [1.10–1.26]).

    Conclusion: There was no clear association between use of antipsychotic drugs and risk of acute pancreatitis in this very large case–control study, indicating that previous case report data are most likely explained by confounding.

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  • 318. Salehi, Alireza M.
    et al.
    Nilsson, Ida A. K.
    Figueira, João
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Thornton, Laura M.
    Abdulkarim, Israa
    Pålsson, Erik
    Bulik, Cynthia M.
    Landén, Mikael
    Serum profiling of anorexia nervosa: A 1H NMR-based metabolomics study2021In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 49, p. 1-10Article in journal (Refereed)
    Abstract [en]

    Our understanding of pathophysiological mechanisms underlying anorexia nervosa (AN) is incomplete. The aim was to conduct a metabolomics profiling of serum samples from women with AN (n = 65), women who have recovered from AN (AN-REC, n = 65), and age-matched healthy female controls (HC, n = 65). Serum concentrations of 21 metabolites were measured using proton nuclear magnetic resonance (1H NMR). We used orthogonal partial least-squares discriminant analysis (OPLS-DA) modeling to assign group classification based on the metabolites. Analysis of variance (ANOVA) was used to test for metabolite concentration differences across groups. The OPLS-DA model could distinguish between the AN and HC groups (p = 9.05 × 10–11 R2Y = 0.36, Q2 = 0.37) and between the AN-REC and HC groups (p = 8.47 × 10–6, R2Y = 0.36, Q2 = 0.24,), but not between the AN and AN-REC groups (p = 0.63). Lower methanol concentration in the AN and AN-REC group explained most of the variance. Likewise, the strongest finding in the univariate analyses was lower serum methanol concentration in both AN and AN-REC compared with HC, which withstood adjustment for body mass index (BMI). We report for the first time lower serum concentrations of methanol in AN. The fact that low methanol was also found in recovered AN suggests that low serum concentration of methanol could either be trait marker or a scar effect of AN.

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  • 319. Salome, Nicolas
    et al.
    Haage, David
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    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 rats2009In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 612, no 1-3, p. 167-173Article in journal (Refereed)
    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.

  • 320.
    Samuelsson, Eva
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    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 rates2005In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 20, no 6, p. 509-516Article in journal (Refereed)
    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.

  • 321.
    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].1996In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 93, no 37, p. 3117-8, 3121Article in journal (Refereed)
  • 322.
    Sandqvist, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology. Uppsala universitet.
    Vardenafil and methylarginines in pulmonary hypertension2016Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 323.
    Sandqvist, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Henrohn, Dan
    Egeröd, Hanna
    Hedeland, Mikael
    Wernroth, Lisa
    Bondesson, Ulf
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wikström, Gerhard
    Acute vasodilator response to vardenafil and clinical outcome in patients with pulmonary hypertension2015In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, no 10, p. 1165-1173Article in journal (Refereed)
    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.

  • 324.
    Sandqvist, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Kling, Anders
    Påverkar glukosamin blod­sockret?: Kan glukosamin påverka blodsockret? Finns det någ­ra samband?2008In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 105, no 39, p. 2706-Article in journal (Refereed)
  • 325.
    Sandqvist, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ottander, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Laktos i läkemedel normalt inget problem för laktosintoleranta2015In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, no 27-28, p. 1234-1234Article in journal (Refereed)
  • 326.
    Sandqvist, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    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 studyManuscript (preprint) (Other academic)
    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. 

  • 327.
    Sandvig, Ioanna
    et al.
    Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Sandvig, Axel
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Clinical Sciences. Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
    Editorial: Criticality in neural network behavior and its implications for computational processing in healthy and perturbed conditions2022In: Frontiers in Neural Circuits, E-ISSN 1662-5110, Vol. 16, article id 1041250Article in journal (Other academic)
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  • 328.
    Sapounidou, Maria
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Norinder, Ulf
    Department of Computer and Systems Sciences, Stockholm University, Kista, Sweden; MTM Research Centre, School of Science and Technology, Örebro University, Örebro, Sweden; Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Predicting endocrine disruption using conformal prediction: a prioritization strategy to identify hazardous chemicals with confidence2023In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 36, no 1, p. 53-65Article in journal (Refereed)
    Abstract [en]

    Receptor-mediated molecular initiating events (MIEs) and their relevance in endocrine activity (EA) have been highlighted in literature. More than 15 receptors have been associated with neurodevelopmental adversity and metabolic disruption. MIEs describe chemical interactions with defined biological outcomes, a relationship that could be described with quantitative structure-activity relationship (QSAR) models. QSAR uncertainty can be assessed using the conformal prediction (CP) framework, which provides similarity (i.e., nonconformity) scores relative to the defined classes per prediction. CP calibration can indirectly mitigate data imbalance during model development, and the nonconformity scores serve as intrinsic measures of chemical applicability domain assessment during screening. The focus of this work was to propose an in silico predictive strategy for EA. First, 23 QSAR models for MIEs associated with EA were developed using high-throughput data for 14 receptors. To handle the data imbalance, five protocols were compared, and CP provided the most balanced class definition. Second, the developed QSAR models were applied to a large data set (∼55,000 chemicals), comprising chemicals representative of potential risk for human exposure. Using CP, it was possible to assess the uncertainty of the screening results and identify model strengths and out of domain chemicals. Last, two clustering methods, t-distributed stochastic neighbor embedding and Tanimoto similarity, were used to identify compounds with potential EA using known endocrine disruptors as reference. The cluster overlap between methods produced 23 chemicals with suspected or demonstrated EA potential. The presented models could be utilized for first-tier screening and identification of compounds with potential biological activity across the studied MIEs.

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  • 329.
    Savard, Josephine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Anova, Karolinska University Hospital, Stockholm, Sweden.
    Görts Öberg, Katarina
    Chatzittofis, Andreas
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Medical School, University of Cyprus, Nicosia, Cyprus.
    Dhejne, Cecilia
    Arver, Stefan
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Naltrexone in Compulsive Sexual Behavior Disorder: A Feasibility Study of Twenty Men2020In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 17, no 8, p. 1544-1552Article in journal (Refereed)
    Abstract [en]

    Background: Compulsive sexual behavior disorder (CSBD) is a common disorder affecting different areas of life, although studies focusing on pharmacological treatment are sparse.

    Aim: To investigate whether the opioid receptor antagonist naltrexone is feasible and tolerable and can provide symptom reduction in CSBD.

    Methods: Twenty men aged 27-60 years (mean = 38.8 years, standard deviation = 10.3) with CSBD seeking treatment in an outpatient nonforensic clinic received four weeks of naltrexone 25-50 mg. Measurements were made before, during, and four weeks after treatment.

    Outcomes: The self-assessment Hypersexual Disorder: Current Assessment Scale (HD: CAS) score was the primary outcome measure, and secondary outcomes were the Hypersexual Behavior Inventory (HBI) score, reported adverse effects, adherence to treatment, and dropouts.

    Results: There was significant decrease on both HD: CAS and HBI scores during treatment with naltrexone. Even though some of the effects remained after treatment, the increased scores on HD: CAS indicated worsening of CSBD symptoms. The most reported side effects were fatigue (55%), nausea (30%), vertigo (30%), and abdominal pain (30%). However, there were no serious adverse effects leading to discontinuation of naltrexone.

    Clinical Implications: Despite side effects being common, naltrexone seems to be feasible in the treatment of CSBD.

    Strengths & Limitations: Being the first nonforensic prospective trial on naltrexone in CSBD, this study provides novel insights on a pharmacological intervention. However, owing to the small sample size and the lack of a control group, conclusions of effectiveness should be interpreted with caution.

    Conclusion: Naltrexone is feasible and tolerable and may reduce symptoms of CSBD; nevertheless, future studies should ensure a randomized controlled procedure to evaluate possible effectiveness.

  • 330.
    Savard, Josephine
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Anova Clinic, Karolinska University Hospital, Stockholm, Sweden.
    Görts Öberg, Katarina
    Anova Clinic, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dhejne, Cecilia
    Anova Clinic, Karolinska University Hospital, Stockholm, Sweden; Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
    Jokinen, Jussi
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    A randomised controlled trial of fluoxetine versus naltrexone in compulsive sexual behaviour disorder: presentation of the study protocol2022In: BMJ Open, E-ISSN 2044-6055, Vol. 12, no 6, article id e051756Article in journal (Refereed)
    Abstract [en]

    Background: Compulsive sexual behaviour disorder is a new disorder in the International Classification of Diseases (ICD-11), and is associated with negative consequences in different areas of life. Evidence for pharmacological treatment of compulsive sexual behaviour disorder is weak and treatment options are limited. This proposed study will be the largest and the first randomised controlled trial comparing the efficacy and tolerability of two active drugs in compulsive sexual behaviour disorder.

    Methods and analysis: Eighty adult participants with compulsive sexual behaviour disorder according to ICD-11 will be randomised to receive either naltrexone 25-50 mg or fluoxetine 20-40 mg for 8 weeks, followed by 6 weeks without treatment. The study will be conducted in a subspecialised outpatient sexual medicine unit at Karolinska University Hospital, Stockholm, Sweden. The study is financed by grants and entirely independent of the manufacturers. Exclusion criteria include severe psychiatric or psychical illness, changes to concurrent medication and non-compatible factors contraindicating the use of either drug. The primary outcome measure is the Hypersexual Disorder: Current Assessment Scale (HD: CAS), and tolerability will be assessed by the Udvalg for Kliniske Undersogelser side effect rating scale (UKU), drug accountability, adherence to treatment and drop-out rate. Participants will complete questionnaires at regular intervals, with the main endpoint for efficacy after 8 weeks (end of treatment) and after 14 weeks (follow-up). Blood chemistry will be repeatedly collected as a safety precaution and for research purposes. The results will be analysed using an appropriate analysis of variance model or a mixed model, depending on the distribution of HD: CAS and the extent of missing data.

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  • 331. Schillemans, Tessa
    et al.
    Shi, Lin
    Donat-Vargas, Carolina
    Hanhineva, Kati
    Tornevi, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Koponen, Jani
    Kiviranta, Hannu
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Landberg, Rikard
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health. Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Åkesson, Agneta
    Brunius, Carl
    Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes: A nested case-control study2021In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 146, article id 106180Article in journal (Refereed)
    Abstract [en]

    Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations. We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D. PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1-0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3-2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk.

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  • 332.
    Schliamser, Silvia E.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Neurotoxicity of β-lactam antibiotics: experimental kinetic and neurophysiological studies1988Doctoral thesis, comprehensive summary (Other academic)
    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.

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  • 333.
    Schmidtchen, Artur
    et al.
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden; Copenhagen Wound Healing Center, Bispebjerg Hospital, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
    Mirza, Haris
    Department of Immunobiology, Yale University School of Medicine, CT, New Haven, United States.
    van der Plas, Mariena J. A.
    Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
    Nadeem, Aftab
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Puthia, Manoj
    Division of Dermatology and Venereology, Department of Clinical Sciences, Lund University, Lund, Sweden.
    Editorial: methods and applications in inflammation pharmacology2022In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 13, article id 1108263Article in journal (Other academic)
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  • 334.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Milestones in the discovery of pernicious anemia and its treatment2017In: Vitamin B12: advances and insights / [ed] Rima Obeid, Boca Raton: CRC Press, 2017, p. 1-29Chapter in book (Refereed)
    Abstract [en]

    Pernicious anemia, an extreme form of vitamin B12-deficiency, was most likely first portrayed in 1822 by James Combe, a Scottish physician from Edinburgh. Vitamin B12 in the liver extract was able to enhance the growth of the bacteria, and the growth rate could be used as a measure of the amount of the unknown factor in the extract. Vitamin B12 is essential for cell growth and replication and participates in transmethylation reactions during the synthesis of methionine, choline, creatinine and nucleic acids. To understand the feasibility of oral vitamin B12-treatment it is necessary to recognize the clinical pharmacology of vitamin B12, which is quite complex. Oral supplementation reduces the risk of injection complications such as infections or cyst formations and nerve injuries are avoided. Vitamin B12-treatment was from the very beginning not just a matter of clinical effectiveness, but also cost-effectiveness.

  • 335.
    Schug, Alexander
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    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 theory2010In: Current opinion in pharmacology (Print), ISSN 1471-4892, E-ISSN 1471-4973, Vol. 10, no 6, p. 709-714Article in journal (Refereed)
    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.

  • 336.
    Seidel, Pia
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Rolander, Bo
    Futurum-Academy for Healthcare, Region Jönköping County, Jönköping, Sweden; Department of Behavioral Science and Social Work, School of Health Sciences, Jönköping University, Jönköping, Sweden.
    Eriksson, Anna L.
    Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Pharmacology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Lindahl, Ulf
    Region Västernorrland, Härnösand, Sweden.
    Wallerstedt, Susanna M.
    Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; HTA-Centrum, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hägg, Staffan
    Futurum-Academy for Healthcare, Region Jönköping County, Jönköping, Sweden; Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Kling, Anders
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Child and Adolescent Psychiatry.
    Drug information sources in professional work - a questionnaire study on physicians’ usage and preferences (the drug information study)2023In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 79, no 6, p. 767-774Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aimed to explore physicians’ use of drug information in professional work, with special focus on those working in primary care, and also in relation to personal characteristics of physicians.

    Methods: A web-based questionnaire was distributed by e-mail to physicians in five regions in Sweden. The questions concerned drug-related queries at issue when searching for information, sources used, and factors of importance for the choice of source, as well as responder characteristics.

    Results: A total of 3254 (85%) out of 3814 responding physicians stated that they searched for drug information every week. For physicians working in primary health care, the corresponding number was 585 (96%). The most common drug-related issues searched for by 76% of physicians every week concerned pharmacotherapeutic aspects (e.g., dosing), followed by adverse drug reactions (63%). For 3349 (88%) physicians, credibility was the most important factor for the choice of sources of drug information, followed by easy access online (n = 3127, 82%). Further analyses among physicians in primary care showed that some personal characteristics, like seniority, sex, and country of education, as well as research experience, were associated with usage and preferences of drug information sources.

    Conclusions: This study confirms that physicians often use drug information sources in professional work, in particular those who work in primary health care. Credibility and easy access are key factors for usage. Among physicians in primary care, personal factors influenced the choice of drug information sources.

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  • 337.
    Seidel, Pia
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    [Keppra in pregnancy. Generally lower risk of birth defects in monotherapy.]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 22, p. 1099-1099Article in journal (Refereed)
  • 338. Selley, Liza
    et al.
    Schuster, Linda
    Marbach, Helene
    Forsthuber, Theresa
    Forbes, Ben
    Gant, Timothy W.
    Sandström, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Camina, Nuria
    Athersuch, Toby J.
    Mudway, Ian
    Kumar, Abhinav
    Brake dust exposure exacerbates inflammation and transiently compromises phagocytosis in macrophages2020In: Metallomics, ISSN 1756-5901, E-ISSN 1756-591X, Vol. 12, no 3, p. 371-386Article in journal (Refereed)
    Abstract [en]

    Studies have emphasised the importance of combustion-derived particles in eliciting adverse health effects, especially those produced by diesel vehicles. In contrast, few investigations have explored the potential toxicity of particles derived from tyre and brake wear, despite their significant contributions to total roadside particulate mass. The objective of this study was to compare the relative toxicity of compositionally distinct brake abrasion dust (BAD) and diesel exhaust particles (DEP) in a cellular model that is relevant to human airways. Although BAD contained considerably more metals/metalloids than DEP (as determined by inductively coupled plasma mass spectrometry) similar toxicological profiles were observed in U937 monocyte-derived macrophages following 24 h exposures to 4–25 μg ml−1 doses of either particle type. Responses to the particles were characterised by dose-dependent decreases in mitochondrial depolarisation (p ≤ 0.001), increased secretion of IL-8, IL-10 and TNF-α (p ≤ 0.05 to p ≤ 0.001) and decreased phagocytosis of S. aureus (p ≤ 0.001). This phagocytic deficit recovered, and the inflammatory response resolved when challenged cells were incubated for a further 24 h in particle-free media. These responses were abrogated by metal chelation using desferroxamine. At minimally cytotoxic doses both DEP and BAD perturbed bacterial clearance and promoted inflammatory responses in U937 cells with similar potency. These data emphasise the requirement to consider contributions of abrasion particles to traffic-related clinical health effects.

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  • 339. Semenza, Jan C.
    et al.
    Trinanes, Joaquin
    Lohr, Wolfgang
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sudre, Bertrand
    Löfdahl, Margareta
    Martinez-Urtaza, Jaime
    Nichols, Gordon L.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Environmental Suitability of Vibrio Infections in a Warming Climate: An Early Warning System2017In: Journal of Environmental Health Perspectives, ISSN 0091-6765, E-ISSN 1552-9924, Vol. 125, no 10, article id 107004Article in journal (Refereed)
    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.

  • 340.
    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 University, Faculty of Science and Technology, Department of Chemistry.
    QSAR study of active human glucagon receptor antagonists by SW-MLR and SW-SVM methods2014In: Medicinal Chemistry Research, ISSN 1054-2523, E-ISSN 1554-8120, Vol. 23, no 5, p. 2639-2650Article in journal (Refereed)
    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.

  • 341.
    Sikora, K.
    et al.
    Sumy State University, Sumy, Ukraine.
    Lyndin, M.
    Sumy State University, Sumy, Ukraine; University of Duisburg-Essen, Essen, Germany.
    Sikora, V.
    Sumy State University, Sumy, Ukraine; University of Foggia, Foggia, Italy.
    Hyriavenko, N.
    Sumy State University, Sumy, Ukraine.
    Piddubnyi, Artem
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Sumy State University, Sumy, Ukraine; Ukrainian-Swedish research center SUMEYA, Sumy, Ukraine.
    Lyndina, Y.
    Sumy State University, Sumy, Ukraine.
    Awuah, W.A.
    Sumy State University, Sumy, Ukraine.
    Abdul-Rahman, T.
    Sumy State University, Sumy, Ukraine.
    Korobchanska, A.
    Kharkiv National Medical University, Kharkiv, Ukraine.
    Alexiou, A.
    Novel Global Community Educational Foundation, Hebersham, Australia; AFNP Med Austria, Wien, Austria.
    Romaniuk, A.
    Sumy State University, Sumy, Ukraine.
    Heavy metals effect on the rat uterus and effectiveness of vitamin E treatment2023In: Jordan Journal of Biological Sciences, ISSN 1995-6673, Vol. 16, no 3, p. 455-465Article in journal (Refereed)
    Abstract [en]

    Environmental pollution by heavy metals (HMs) is an increasingly critical problem that is posing a growing threat to reproductive health. Consequently, the aim of the current research was to study changes in rat uterus under 90 days of HMs exposure and estimate the efficacy and benefits of vitamin E treatment. Female rats were randomly divided into three groups: untreated animals (control group); animals orally treated with the HMs mixture (HM group); and animals treated simultaneously with HMs and vitamin E (HM+E group). The toxic effects of the HMs (comprising Zn, Cu, Mn, Fe, Pb, and Cr) on the uterus of rats were investigated by histological, morphometrical, spectrophotometrical, and statistical methods.

    Long-term HMs exposure triggered pathological (degenerative, inflammation, and atrophic) changes in the rat uterus together with a significant reduction of the uterine-wall thickness (37.99%, p<0.0001) compared to the control. In contrast, there was a lower intensity of morphological lesions and wall thickness decrease (26.03%, p<0.0001) in the uterus, in rats that underwent treatment with vitamin E. A substantial bioaccumulation of zinc, copper, manganese, iron, lead, and chromium general levels in the rat uterus was demonstrated in both the HM group (74.46%, p<0.0001) and the HM+E group (49.81%, p<0.0001), as compared to the control group. The lowest accumulative potential belonged to Zn and the highest to Pb. The results obtained showed a significant decline in the weight of animals treated by HMs in both HM (18,21%, p<0.01) and HM+E (13,09%; p<0.05) groups compared to the control. Our findings have demonstrated that treatment with vitamin E in HM-induced intoxication has a significant restrain of HMs accumulation (up to 16.46%, p<0.0001) together with morphometric variations (less on 16.17%, p<0.01).

    In summary, long-term exposure to the HMs mixture had a pernicious toxic effect on the morphology and chemical content of the uterus of rats (strong negative correlations). Treatment with vitamin E significantly reversed the HMs impact on the uterus but did not demonstrate absolute protection.

  • 342.
    Sjölander, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Eriksson, Marie
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Glader, Eva-Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Few sex differences in the use of drugs for secondary prevention after stroke: a nationwide observational study2012In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 21, no 9, p. 911-919Article in journal (Refereed)
    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.

  • 343.
    Sjölander, Maria
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Marie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Glader, Eva-Lotta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Few sex differences in use of drugs for secondary prevention after stroke: a nationwide observational study2011In: Abstracts 27th International Conference on Pharmacoepidemiology & Therapeutic Risk Management Hyatt Regency Chicago: Chicago, Illinois, USA August 14–17, 2011, Wiley , 2011, Vol. 20, p. S110-S110Conference paper (Refereed)
    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.

  • 344.
    Skagerlind, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Nursing. Department of Nephrology, Centre of Medicine, University Hospital of Umeå, Umeå, Sweden.
    Stegmayr, Bernd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    An evaluation of four modes of low-dose anticoagulation during intermittent haemodialysis2018In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 74, no 3, p. 267-274Article in journal (Refereed)
    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.

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  • 345. Skerfving, Staffan
    et al.
    Bergdahl, Ingvar A.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational Medicine.
    Lead2007In: 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, p. 599-643Chapter in book (Other academic)
    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.

  • 346.
    Souihi, Nabil
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Reynolds, Gavin
    Tajarobi, Pirjo
    Wikström, Håkan
    Haeffler, Gunnar
    Josefson, Mats
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Roll compaction process modeling: transfer between equipment and impact of process parameters2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 484, no 1-2, p. 192-206Article in journal (Refereed)
    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.

  • 347. Spulber, S.
    et al.
    Raciti, M.
    Dulko-Smith, B.
    Umeå University, Faculty of Science and Technology, Department of Chemistry. University of Texas at Arlington, Department of Chemistry and Biochemistry, Arlington, TX, USA.
    Lupu, D.
    Ruegg, J.
    Nam, Kwangho
    Umeå University, Faculty of Science and Technology, Department of Chemistry. 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 neurotoxicity2018In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 354, p. 94-100Article in journal (Refereed)
    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.

  • 348.
    Stafberg, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jessica, Karlsson
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Christopher, Fowler
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The mRNA expression of endocannabinoid-related enzymes in rat prostate AT-1 cells following exposure to lactate and interleukin-6Manuscript (preprint) (Other academic)
    Abstract [en]

    The endocannabinoid system is dysregulated in prostate cancer but the mechanisms responsible for this dysregulation are not known. We hypothesise that the dysregulation is secondary to factors in the tumour microenvironment. In this study we investigated the effects of lactic acid induced low pH and interleukin-6 (IL-6) treatment upon the expression of endocannabinoid related enzymes and the functional effects upon anandamide degradation and cell viability in Dunning R3327 rat prostate AT-1 cancer cells. Cells were exposed for 3 h at 37 °C to Krebs-Ringer-HEPES/bicarbonate buffer at either pH 7.4 or at pH 6.6 (due to the presence of 40 mM lactic acid), and to 0, 25 or 100 ng/ml of IL-6. Neither low pH (pH 6.6) nor IL-6 induced any changes in the mRNA levels of the anandamide metabolic enzymes. However, the expression of the 2- arachidonoylglycerol-synthesizing enzyme DAGLα was increased by low pH and the expression of CB2 receptor mRNA was decreased at the low pH. The DAGL inhibitor orlistat increased extracellular LDH levels after 24 h of incubation of AT-1 cells, suggesting a higher frequency of cell death. It is concluded that under the conditions used, exposure to lactate and IL-6 do not affect the expression of the anandamide metabolic enzymes in AT-1 cells, but do modify the expression of an enzyme involved in the synthesis of 2-arachidonoylglycerol. 

  • 349.
    Stan, Tiberiu Loredan
    et al.
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Ronaghi, Abdolaziz
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Barrientos, Sebastian A.
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Halje, Pär
    The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Censoni, Luciano
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Garro-Martínez, Emilio
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Nasretdinov, Azat
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Malinina, Evgenya
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology.
    Hjorth, Stephan
    Integrative Research Laboratories Sweden AB, Göteborg, Sweden.
    Svensson, Peder
    Integrative Research Laboratories Sweden AB, Göteborg, Sweden.
    Waters, Susanna
    Integrative Research Laboratories Sweden AB, Göteborg, Sweden.
    Sahlholm, Kristoffer
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.
    Petersson, Per
    Umeå University, Faculty of Medicine, Department of Medical and Translational Biology. The Group for Integrative Neurophysiology and Neurotechnology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
    Neurophysiological treatment effects of mesdopetam, pimavanserin and clozapine in a rodent model of Parkinson's disease psychosis2024In: Neurotherapeutics, ISSN 1933-7213, Vol. 21, no 2, article id e00334Article in journal (Refereed)
    Abstract [en]

    Psychosis in Parkinson's disease is a common phenomenon associated with poor outcomes. To clarify the pathophysiology of this condition and the mechanisms of antipsychotic treatments, we have here characterized the neurophysiological brain states induced by clozapine, pimavanserin, and the novel prospective antipsychotic mesdopetam in a rodent model of Parkinson's disease psychosis, based on chronic dopaminergic denervation by 6-OHDA lesions, levodopa priming, and the acute administration of an NMDA antagonist. Parallel recordings of local field potentials from eleven cortical and sub-cortical regions revealed shared neurophysiological treatment effects for the three compounds, despite their different pharmacological profiles, involving reversal of features associated with the psychotomimetic state, such as a reduction of aberrant high-frequency oscillations in prefrontal structures together with a decrease of abnormal synchronization between different brain regions. Other drug-induced neurophysiological features were more specific to each treatment, affecting network oscillation frequencies and entropy, pointing to discrete differences in mechanisms of action. These findings indicate that neurophysiological characterization of brain states is particularly informative when evaluating therapeutic mechanisms in conditions involving symptoms that are difficult to assess in rodents such as psychosis, and that mesdopetam should be further explored as a potential novel antipsychotic treatment option for Parkinson psychosis.

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  • 350.
    Stergiou, George
    et al.
    Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, Athens, Greece.
    Brunström, Mattias
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    MacDonald, Thomas
    Director of MEMO Research, Ninewells Hospital & Medical School, University of Dundee, United Kingdom.
    Kyriakoulis, Konstantinos G.
    Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, Athens, Greece.
    Bursztyn, Michael
    Hypertension Clinic, Hadassah-Hebrew University Medical Center, Faculty of Medicine, Hadassah-Hebrew University School of Medicine, Department of Medicine D, Beilinson Hospital, Israel.
    Khan, Nadia
    Department of Medicine, University of British Columbia, Center for Health Evaluation and Outcomes Sciences, Vancouver, Canada.
    Bakris, George
    Department of Medicine, University of Chicago Medicine, IL, Chicago, United States.
    Kollias, Anastasios
    Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, Athens, Greece.
    Menti, Ariadni
    Hypertension Center STRIDE-7, National and Kapodistrian University of Athens, School of Medicine, Third Department of Medicine, Sotiria Hospital, Athens, Greece.
    Muntner, Paul
    School of Public Health, University of Alabama at Birmingham, AL, Birmingham, United States.
    Orias, Marcelo
    Yale University, CT, New Haven, United States.
    Poulter, Neil
    Imperial Clinical Trials Unit, School of Public Health, Imperial College London, Stadium House, London, United Kingdom.
    Shimbo, Daichi
    Columbia Hypertension Center and Lab, Department of Medicine, Columbia University Irving Medical Center, NY, United States.
    Williams, Bryan
    Institute of Cardiovascular Science, University College London, London, United Kingdom.
    Adeoye, Abiodun Moshood
    Cardiovascular Genetics and Genomic Research Unit, Institute of Cardiovascular Diseases, Faculty of Clinical Sciences, College of Medicine, University of Ibadan, Ibadan, Nigeria.
    Damasceno, Albertino
    Faculty of Medicine, Eduardo Mondlane University, Maputo, Mozambique.
    Korostovtseva, Lyudmila
    Almazov National Medical Research Centre, St Petersburg, Russian Federation.
    Li, Yan
    Department of Cardiovascular Medicine, Shanghai Institute of Hypertension, Shanghai Key Lab of Hypertension, National Research Centre for Translational Medicine, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
    Muxfeldt, Elizabeth
    , Universidade Federal do Rio de Janeiro - Hospital Universitário Clementino Fraga Filho, Rio de Janeiro, Brazil.
    Zhang, Yuqing
    Department of Cardiology, Fu Wai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
    Mancia, Giuseppe
    University of Milano-Bicocca, Milan, Italy.
    Kreutz, Reinhold
    Charité - Universitätsmedizin Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin, Germany.
    Tomaszewski, Maciej
    Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester; Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
    Bedtime dosing of antihypertensive medications: systematic review and consensus statement: International Society of Hypertension position paper endorsed by World Hypertension League and European Society of Hypertension2022In: Journal of Hypertension, ISSN 0263-6352, E-ISSN 1473-5598, Vol. 40, no 10, p. 1847-1858Article, review/survey (Refereed)
    Abstract [en]

    Antihypertensive drug therapy is one of the most efficient medical interventions for preventing disability and death globally. Most of the evidence supporting its benefits has been derived from outcome trials with morning dosing of medications. Accumulating evidence suggests an adverse prognosis associated with night-time hypertension, nondipping blood pressure (BP) profile and morning BP surge, with increased incidence of cardiovascular events during the first few morning hours. These observations provide justification for complete 24-h BP control as being the primary goal of antihypertensive treatment. Bedtime administration of antihypertensive drugs has also been proposed as a potentially more effective treatment strategy than morning administration. This Position Paper by the International Society of Hypertension reviewed the published evidence on the clinical relevance of the diurnal variation in BP and the timing of antihypertensive drug treatment, aiming to provide consensus recommendations for clinical practice. Eight published outcome hypertension studies involved bedtime dosing of antihypertensive drugs, and all had major methodological and/or other flaws and a high risk of bias in testing the impact of bedtime compared to morning treatment. Three ongoing, well designed, prospective, randomized controlled outcome trials are expected to provide high-quality data on the efficacy and safety of evening or bedtime versus morning drug dosing. Until that information is available, preferred use of bedtime drug dosing of antihypertensive drugs should not be routinely recommended in clinical practice. Complete 24-h control of BP should be targeted using readily available, long-acting antihypertensive medications as monotherapy or combinations administered in a single morning dose.

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