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  • 51.
    Claeson, Anna-Sara
    et al.
    Umeå universitet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Lind, Nina
    Swedish Univ Agr Sci, Dept Econ, Uppsala, Sweden.
    Human exposure to acrolein: Time -dependence and individual variation in eye irritation2016Ingår i: Environmental Toxicology and Pharmacology, ISSN 1382-6689, E-ISSN 1872-7077, Vol. 45, s. 20-27Artikel i tidskrift (Refereegranskat)
  • 52. Crowley, James
    et al.
    Mudgal, Poorva
    Nordin Adolfsson, Annelie
    Umeå universitet.
    Åberg, Karolina
    Alaerts, Maaike
    Genovese, Giulio
    McCarroll, Steven
    Del-Favero, Jurgen
    Adolfsson, Rolf
    Umeå universitet.
    Sullivan, Patrick
    The genomics of bipolar and schizophrenic disorders in a large pedigree from a northern Swedish isolate2019Ingår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, s. S902-S903Artikel i tidskrift (Övrigt vetenskapligt)
  • 53.
    Cuklev, Filip
    et al.
    Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Kristiansson, Erik
    Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden och Chalmers University of Technology and University of Gothenburg, Göteborg, Sweden.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Asker, Noomi
    Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden och Faculty of Science, University of Gothenburg, Göteborg, Sweden.
    Förlin, Lars
    Faculty of Science, University of Gothenburg, Göteborg, Sweden.
    Larsson, D G Joakim
    Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
    Diclofenac in fish: blood plasma levels similar to human therapeutic levels affect global hepatic gene expression2011Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 30, nr 9, s. 2126-2134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diclofenac is a non-steroidal anti-inflammatory drug frequently found in the aquatic environment. Previous studies have reported histological changes in the liver, kidney and gills of fish at concentrations similar to those measured in treated sewage effluents (approximately 1 µg/L). Analyses or predictions of blood plasma levels in fish allow a direct comparison with human therapeutic plasma levels, and may therefore be used to indicate a risk for pharmacological effects in fish. To relate internal exposure to a pharmacological interaction we investigated global hepatic gene expression together with bioconcentration in blood plasma and liver of rainbow trout (Oncorhynchus mykiss) exposed to waterborne diclofenac. At the highest exposure concentration (81.5 µg/L) the fish plasma concentration reached approximately 88% of the human therapeutic levels (C(max) ) after two weeks. Using an oligonucleotide microarray followed by quantitative PCR we found extensive effects on hepatic gene expression at this concentration, and some genes were found to be regulated down to the lowest concentration tested (1.6 µg/L) corresponding to approximately 1.5% of the human C(max) . Thus, at concentrations detected in European surface waters, diclofenac can affect the expression of multiple genes in exposed fish. Functional analysis of differentially expressed genes revealed effects on biological processes such as inflammation and immune response, in agreement with the mode of action of diclofenac in mammals. In contrast to some previously reported results, the bioconcentration factor was found to be stable (4.02 ± 0.75 for blood plasma and 2.54 ± 0.36 for liver) regardless of the water concentration. Environ. Toxicol. Chem. © 2011 SETAC.

  • 54. Deplano, Alessandro
    et al.
    Cipriano, Mariateresa
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Moraca, Federica
    Novellino, Ettore
    Catalanotti, Bruno
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Onnis, Valentina
    Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors2019Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 34, nr 1, s. 562-576Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

  • 55. Deplano, Alessandro
    et al.
    Morgillo, Carmine Marco
    Demurtas, Monica
    Björklund, Emmelie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Cipriano, Mariateresa
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Svensson, Mona
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Hashemian, Sanaz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Cabiddu, Maria G.
    Novellino, Ettore
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Catalanotti, Bruno
    Onnis, Valentina
    Novel propanamides as fatty acid amide hydrolase inhibitors2017Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, s. 523-542Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.

  • 56. Eduardo Roa-Coria, Jose
    et al.
    Navarrete-Vazquez, Gabriel
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Javier Flores-Murrieta, Francisco
    Deciga-Campos, Myrna
    Granados-Soto, Vinicio
    N-(4-Methoxy-2-nitrophenyl)hexadecanamide, a palmitoylethanolamide analogue, reduces formalin-induced nociception2012Ingår i: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 91, nr 25-26, s. 1288-1294Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: To investigate the local antinociceptive effect as well as the possible mechanisms of action of a novel analogue of palmitoylethanolamide (PEA) N-(4-methoxy-2-nitrophenyl)hexadecanamide (HD) in the rat formalin test.

    Main methods: The formalin test was used to assess the antinociceptive activity of HD in vivo. The hydrolysis of anandamide catalyzed by fatty acid amide hydrolase (FAAH) was used to determine the action of HD on FAAH activity in vitro.

    Key findings: Local peripheral ipisilateral, but not contralateral, administration of HD (10-100 mu g/paw) produced a dose-dependent antinociceptive effect in rats. The CB1 and CB2 receptor antagonists AM281 (0.3-30 mu g/paw) and SR144528 (0.3-30 mu g/paw), respectively, reduced the antinociceptive effect of HD (100 mu g/paw). In addition, methiothepin (0.03-0.3 mu g/paw) and naloxone (5-50 mu g/paw) significantly reduced HD-induced antinociception (100 mu g/paw). In vitro, HD reduced only to a minor extent the hydrolysis of anandamide catalyzed by FAAH.

    Significance: HD local administration produces antinociception that probably results from an indirect activation of peripheral CB1 and CB2 cannabinoid receptors. Data suggest that 5-HT1 and opioid receptors also participate in the antinociceptive effect of this compound. HD may have potential as analgesic drug.

    (C) 2012 Elsevier Inc. All rights reserved.

  • 57. Ekman, Elisabet
    et al.
    Bäckström, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk farmakologi.
    Attitudes among hospital physicians to the reporting of adverse drug reactions in Sweden2009Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 65, nr 1, s. 43-46Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: This study was designed to investigate attitudes to and incentive for reporting adverse drug reactions (ADRs) in general and towards nurses as reporters of ADRs in particular in a sample of hospital physicians. METHOD: A questionnaire was sent to 1,201 randomly selected hospital physicians. RESULTS: The main factors for the decision to report an ADR were the severity of the reaction, a reaction to a new drug, and an unusual reaction. The most important factor for refraining from reporting was that the reaction was well known. There were no significant differences between males and females or between age groups in these aspects. A majority were positive or neutral to nurses as reporters. Only 6% stated that their willingness to report ADRs would be affected in a negative way if nurses were involved in the program for reporting. CONCLUSIONS: The results of this survey showed that inclusion of hospital nurses as reporters will not decrease the reporting rate from the physicians.

  • 58. Ekstrand-Hammarström, Barbro
    et al.
    Magnusson, Roger
    Österlund, Camilla
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Andersson, Britt M.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för tillämpad fysik och elektronik.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Wingfors, Håkan
    Oxidative stress and cytokine expression in respiratory epithelial cells exposed to well-characterized aerosols from Kabul, Afghanistan2013Ingår i: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 27, nr 2, s. 825-833Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study aerosol samples collected in an Asian mega-city (Kabul, Afghanistan) were compared to PM samples collected in a European location with traffic (Umea, Sweden) and a reference urban dust material (SRM 1649b). The toxicity of each sample towards normal human bronchial epithelial (NHBE) cells and a human bronchial epithelial cell line (BEAS-2B) was tested along with their ability to induce reactive oxygen species (ROS) formation and inflammatory responses. The extracts' morphology and elemental composition was studied by SEM-EDXRF, and filter samples were analyzed for metals and organic compounds. The PM from Kabul contained a larger fraction of fine particles, 19 times more polyaromatic hydrocarbons (PAH) and 37 times more oxygenated PAH (oxy-PAH) compared to samples from timed. The PM-samples from Kabul and the reference material (SRM 1649b) induced significantly stronger oxidative stress responses than the samples from Umea. Furthermore, samples collected in Kabul induced significantly higher secretion of the cytokines IL-6, IL-8 and GM-CSF while SRM1649b induced a cytokine pattern more similar to samples collected in Umea. Several properties of the particles could potentially explain these differences, including differences in their size distribution and contents of PAH and oxy-PAH, possibly in combination with their relative transition metal contents. 

  • 59. Elinder, Carl-Gustaf
    et al.
    Nordberg, Gunnar F
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Yrkes- och miljömedicin.
    Re: Byber et al. in Critical Reviews in Toxicology 2016;46:191-2402017Ingår i: Critical reviews in toxicology, ISSN 1040-8444, E-ISSN 1547-6898, Vol. 47, nr 10, s. 904-905Artikel i tidskrift (Refereegranskat)
  • 60.
    Elmi, Adrian
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Idahl, Lars-Åke
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Sehlin, Janove
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Histologi med cellbiologi.
    Modulation of islet ATP content by inhibition or stimulation of the Na(+)/K(+) pump2001Ingår i: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 426, nr 1-2, s. 139-143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    High (30 mM) K(+), known to cause beta-cell membrane depolarisation, significantly decreased the islet total ATP content, supporting the view that beta-cell membrane depolarisation can activate the ATP-consuming Na(+)/K(+) pump. Ouabain (1 mM) did not change the islet ATP content after 5-15 min of incubation in the absence or presence of 3 mM glucose but reduced it after 30 min, and in the presence of 20 mM glucose, the reduction by ouabain occurred already after 15 min. Incubation of islets with ouabain for 60 min decreased the islet ATP content in the presence of 3, 10 or 20 mM glucose or 30 mM K(+). Also, the islet glucose oxidation rate was decreased by ouabain. When K(+) deficiency was used to inhibit the Na(+)/K(+) pump, no change in ATP content was observed irrespective of glucose concentration, although K(+) deficiency caused a slight inhibition of the glucose oxidation rate. Diazoxide reduced the islet glucose oxidation rate and increased the islet ATP content in the presence of 20 mM glucose. There may exist a feedback mechanism decreasing the flow of glucose metabolism in response to reduced ATP consumption by the Na(+)/K(+) pump.

  • 61. Eriksson, Anna L.
    et al.
    Böttiger, Ylva
    Ekman, Agneta
    Reis, Margareta
    Persson, Katarina
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Wallerstedt, Susanna M.
    Läkemedelsarbete behöver vara integrerat i klinisk utbildning: Att göra många läkemedelsgenomgångar ökar trygghet och reflektion över patientens behandling, visar enkätstudie2019Ingår i: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 116, artikel-id FHCTArtikel i tidskrift (Refereegranskat)
    Abstract [en]

    A prerequisite for rational use of medicines is adequate prescribing skills; drug treatment is a complex task requiring diagnostic competence combined with pharmacologic knowledge and patient communication skills. Acquiring professional confidence in the art of prescribing is essential during medical training. The results of this questionnaire study, conducted in four medical schools in Sweden after the course in internal medicine (252 respondents; response rate: 74%; median age: 24 years, 61% female), show that 45% and 62% were confident in performing medication reviews and writing medication summary reports, respectively, i.e. the basics of prescribing. The confidence increased by the number of reviews and reports performed, i.e. the extent of practice (correlation coefficients: 0.41 and 0.38, respectively, both p<0.0001), as did the extent of the students' reflection on important aspects of drug treatment such as adherence, adverse reactions, renal function, dosing, and drug interactions. In multivariate regression analyses, major predictors for confidence in performing medication reviews were extent of practice and extent of clinical supervision. The results suggest that these factors are keys to acquiring professional confidence in the art of prescribing.

  • 62.
    Eriksson, S
    et al.
    Department of Physiology, Karolinska Institute, Stockholm, Sweden.
    Andersson, B
    Gunnarsson, Ulf
    Department of Physiology, Karolinska Institute, Stockholm, Sweden.
    Rundgren, M
    Hypertension and thirst outlasting renal vasoconstriction as effects of a brief evaluation of systemic angiotensin II in sheep.1994Ingår i: Acta Physiologica Scandinavica, ISSN 0001-6772, E-ISSN 1365-201X, Vol. 150, nr 2, s. 181-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The influence of 10 min intracarotid (i.c.) and intravenous (i.v.) infusions of angiotensin II (Ang II; 20 pmol kg-1 min-1) on carotid blood pressure (cBP) and renal blood flow (RBF) was studied in unanaesthetized ewes without and with pre-treatment with the alpha 1- and beta-adrenoceptor blocker labetalol. RBF was also monitored during 30 min intracerebroventricular (ICV) infusions of Ang II at 2 pmol kg-1 min-1. The i.c. infusions of Ang II induced about 50 mmHg rise in cBP. A steep decline occurred during 5 min post-infusion, followed by a much slower reduction with the cBP remaining above control level at 40 min post-infusion. The pressure elevation induced by i.v. Ang II was less pronounced but exhibited a similar pattern. Labetalol significantly reduced the pressor response to i.c. as well as i.v. Ang II. The i.c. and i.v. infusions of Ang II conspicuously reduced the RBF regardless of whether the ewes were labetalol-treated or not. At 5 min after the infusions RBF had returned to control level. The ICV infusions did not influence the RBF. Ang II i.c. elicited thirst in 50% of the ewes with the urge to drink remaining at 40 min post-infusion. The dipsogenic response was not reduced by labetalol pretreatment. The results imply that no cerebral component contributes to the reduction in RBF induced by systemic Ang II. However, a centrally mediated action seems to be the cause of the long-lasting post-infusion cBP elevation and dipsogenic response.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 63. Faroni, Alessandro
    et al.
    Mobasseri, S. Atefeh
    Kingham, Paul J.
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB), Anatomi.
    Reid, Adam J.
    Peripheral nerve regeneration: experimental strategies and future perspectives2015Ingår i: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 82-83, s. 160-167Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering. 

  • 64.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Delta9-tetrahydrocannabinol and cannabidiol as potential curative agents for cancer: a critical examination of the preclinical literature2015Ingår i: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 97, nr 6, s. 587-596Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An Internet search with search words "cannabis cures cancer" produce a wealth of sites claiming that cannabis has this effect. These sites are freely accessible to the general public and thus contribute to public opinion. But do delta9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) cure cancer? In the absence of clinical data other than a safety study and case reports, preclinical data should be evaluated in terms of its predictive value. Using a strict approach where only concentrations and/or models relevant to the clinical situation are considered, the current preclinical data do not yet provide robust evidence that systemically administered Δ9-THC will be useful for the curative treatment of cancer. There is more support for an intratumoral route of administration of higher doses of Δ9-THC. CBD produces effects in relevant concentrations and models, although more data are needed concerning its use in conjunction with other treatment strategies.

  • 65.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Has FLAT fallen flat?2014Ingår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 35, nr 2, s. 51-52Artikel i tidskrift (Övrigt vetenskapligt)
  • 66.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Monoacylglycerol lipase: a target for drug development?2012Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 166, nr 5, s. 1568-1585Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. Drugable selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents.

  • 67.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    NSAIDs: eNdocannabinoid stimulating anti-inflammatory drugs?2012Ingår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 33, nr 9, s. 468-473Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Read any pharmacology textbook and the message is clear: nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of cyclooxygenase (COX) and thereby the production of prostaglandins. However, evidence is accumulating that NSAIDs involve the endocannabinoid system in their actions, and that such effects may pave the way towards the design of new analgesics that are not plagued with the gastrointestinal and cardiovascular adverse actions that are associated with this class of drugs. In this Opinion article, our current understanding of the involvement of the endocannabinoid system in the actions of NSAIDs is described, and the ways in which this can lead to novel drug development is discussed.

  • 68.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view2015Ingår i: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 25, nr 6, s. 749-762Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover. Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling. In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view. It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone. Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of "cannabis-like" behaviours.

  • 69.
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The Potential of Inhibitors of Endocannabinoid Metabolism for Drug Development: A Critical Review2015Ingår i: Endocannabinoids / [ed] Roger G. Pertwee, Springer International Publishing , 2015, Vol. 231, s. 95-128Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    The endocannabinoids anandamide and 2-arachidonoylglycerol are metabolised by both hydrolytic enzymes (primarily fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL)) and oxygenating enzymes (e.g. cyclooxygenase-2, COX-2). In the present article, the in vivo data for compounds inhibiting endocannabinoid metabolism have been reviewed, focussing on inflammation and pain. Potential reasons for the failure of an FAAH inhibitor in a clinical trial in patients with osteoarthritic pain are discussed. It is concluded that there is a continued potential for compounds inhibiting endocannabinoid metabolism in terms of drug development, but that it is wise not to be unrealistic in terms of expectations of success.

  • 70.
    Fowler, Christopher J.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Björklund, Emmelie
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Lichtman, Aron H.
    Naidu, Pattipati S.
    Congiu, Cenzo
    Onnis, Valentina
    Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide2013Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 28, nr 1, s. 172-182Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A dual-action cyclooxygenase (COX)-fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4'-isobutylphenyl) propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 mu M respectively. The corresponding values for COX-1 were similar to 29, similar to 50 and similar to 60 mu M, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of similar to 6, similar to 10 and similar to 19 mu M, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.

  • 71.
    Fowler, Christopher J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Naidu, P S
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
    Lichtman, A
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
    Onnis, V
    Department of Toxicology, Unit of Medicinal Chemistry, University of Cagliari, Cagliari, Italy.
    The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV12009Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 156, nr 3, s. 412-419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory 'load'. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.

  • 72.
    Fowler, Christopher J
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Rojo, Maria Luisa
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Rodriguez-Gaztelumendi, Antonio
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Modulation of the endocannabinoid system: neuroprotection or neurotoxicity?2010Ingår i: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 224, nr 1, s. 37-47Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    There is now a large volume of data indicating that compounds activating cannabinoid CB(1) receptors, either directly or indirectly by preventing the breakdown of endogenous cannabinoids, can protect against neuronal damage produced by a variety of neuronal "insults". Given that such neurodegenerative stimuli result in increased endocannabinoid levels and that animals with genetic deletions of CB(1) receptors are more susceptible to the deleterious effects of such stimuli, a case can be made for an endogenous neuroprotective role of endocannabinoids. However, this is an oversimplification of the current literature, since (a) compounds released together with the endocannabinoids can contribute to the neuroprotective effect; (b) other proteins, such as TASK-1 and PPARalpha, are involved; (c) the CB(1) receptor antagonist/inverse agonist rimonabant has also been reported to have neuroprotective properties in a number of animal models of neurodegenerative disorders. Furthermore, the CB(2) receptor located on peripheral immune cells and activated microglia are potential targets for novel therapies. In terms of the clinical usefulness of targeting the endocannabinoid system for the treatment of neurodegenerative disorders, data are emerging, but important factors to be considered are windows of opportunity (for acute situations such as trauma and ischemia) and the functionality of the target receptors (for chronic neurodegenerative disorders such as Alzheimer's disease).

  • 73.
    Franzen, Lisa
    et al.
    Swedish Poisons Information Centre, Stockholm, Sweden.
    Tusic, Marinela
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Beck, Olof
    Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden.
    Hulten, Peter
    Swedish Poisons Information Centre, Stockholm, Sweden.
    Accuracy of on-site urine drug tests: an experimental study2013Ingår i: Clinical Toxicology, ISSN 1556-3650, E-ISSN 1556-9519, Vol. 51, nr 4, s. 348-349Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Objective: On-site drug tests (ODTs) are frequently used in hospitals to screen the urine of patients admitted for suspected poisoning. The purpose of this study is to evaluate the accuracy of such tests used in emergency departments in Sweden.

    Methods: Two brands, ColibriCheck™ and Concateno™, were tested for detecting amphetamine, benzodiazepines, opiates and tetrahydrocannabinol (THC) in urine. The results were compared with laboratory screening (CEDIA) and confirmation method (GC-MS). The study was conducted from December 2011 to March 2012 using samples from drug dependence clinics; 400 positive (100 in each drug group) and 200 negative (applied to all drug groups).

    Results: High specificity (Table 1) implies that most true negative samples are detected, but the risk of missing a true positive sample is high (6–26%). The incidence of false positive test results was low ( 1%). Limitations: inadequate blinding of the analysing procedure, emergency department samples were not included and GC-MS was performed on positive but not negative samples.

    Conclusion: The implications of this study are that positive ODTs are fairly reliable whereas negative ODTs neglect 6–26% of true drug presence. Consequently patients might be overlooked if treatment depended on the test result. ODTs’ intrinsic problems e.g. cross-reactivity and limited spectrum of analytes1, that are not addressed in our study, could further influence the reliability of test results.

    Reference

    1. Krasowski MD, Pizon AF, Siam MG, et al. Using molecular similarity to highlight the challenges of routine immunoassay-based drug of abuse/toxicology screening in emergency medicine. BMC Emerg Med 2009; 9:5.

  • 74. Fraqueza, G.
    et al.
    Carvalho, L.
    Marques, P.
    Ohlin, C. Andre
    Casey, W.
    Aureliano, M.
    Functional and structural interactions of Nb, V, Mo and W oxometalates with the sarcoplasmic reticulum Ca2(+) -ATPase reveal new insights into inhibition processes: a combination of NMR, Raman, AA and EPR spectroscopie with kinetic studies2012Ingår i: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 279, nr 1, SIArtikel i tidskrift (Refereegranskat)
  • 75. Fraqueza, Gil
    et al.
    Batista de Carvalho, Luis A. E.
    Marques, M. Paula M.
    Maia, Luisa
    Ohlin, C. Andre
    Casey, William H.
    Aureliano, Manuel
    Decavanadate, decaniobate, tungstate and molybdate interactions with sarcoplasmic reticulum Ca2+-ATPase: quercetin prevents cysteine oxidation by vanadate but does not reverse ATPase inhibition2012Ingår i: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, Vol. 41, nr 41, s. 12749-12758Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Recently we demonstrated that the decavanadate (V-10) ion is a stronger Ca2+-ATPase inhibitor than other oxometalates, such as the isoelectronic and isostructural decaniobate ion, and the tungstate and molybdate monomer ions, and that it binds to this protein with a 1 : 1 stoichiometry. The V-10 interaction is not affected by any of the protein conformations that occur during the process of calcium translocation (i.e. E1, E1P, E2 and E2P) (Fraqueza et al., J. Inorg. Biochem., 2012). In the present study, we further explore this subject, and we can now show that the decaniobate ion, [Nb-10 = Nb10O28](6-), is a useful tool in deducing the interaction and the non-competitive Ca2+-ATPase inhibition by the decavanadate ion [V-10 = V10O28](6-). Moreover, decavanadate and vanadate induce protein cysteine oxidation whereas no effects were detected for the decaniobate, tungstate or molybdate ions. The presence of the antioxidant quercetin prevents cysteine oxidation, but not ATPase inhibition, by vanadate or decavanadate. Definitive V(IV) EPR spectra were observed for decavanadate in the presence of sarcoplasmic reticulum Ca2+-ATPase, indicating a vanadate reduction at some stage of the protein interaction. Raman spectroscopy clearly shows that the protein conformation changes that are induced by V-10, Nb-10 and vanadate are different from the ones induced by molybdate and tungstate monomer ions. Here, Mo and W cause changes similar to those by phosphate, yielding changes similar to the E1P protein conformation. The putative reduction of vanadium(V) to vanadium(IV) and the non-competitive binding of the V-10 and Nb-10 decametalates may explain the differences in the Raman spectra compared to those seen in the presence of molybdate or tungstate. Putting it all together, we suggest that the ability of V-10 to inhibit the Ca2+-ATPase may be at least in part due to the process of vanadate reduction and associated protein cysteine oxidation. These results contribute to the understanding and application of these families of mono-and polyoxometalates as effective modulators of many biological processes, particularly those associated with calcium homeostasis.

  • 76. Fraqueza, Gil
    et al.
    Ohlin, C. Andre
    Casey, William H.
    Aureliano, Manuel
    Sarcoplasmic reticulum calcium ATPase interactions with decaniobate, decavanadate, vanadate, tungstate and molybdate2012Ingår i: Journal of Inorganic Biochemistry, ISSN 0162-0134, E-ISSN 1873-3344, Vol. 107, nr 1, s. 82-89Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Over the last few decades there has been increasing interest in oxometalate and polyoxometalate applications to medicine and pharmacology. This interest arose, at least in part, due to the properties of these classes of compounds as anti-cancer, anti-diabetic agents, and also for treatment of neurodegenerative diseases, among others. However, our understanding of the mechanism of action would be improved if biological models could be used to clarify potential toxicological effects in main cellular processes. Sarcoplasmic reticulum (SR) vesicles, containing a large amount of Ca(2+)-ATPase, an enzyme that accumulates calcium by active transport using ATP, have been suggested as a useful model to study the effects of oxometalates on calcium homeostasis. In the present article, it is shown that decavanadate, decaniobate, vanadate, tungstate and molybdate, all inhibited SR Ca(2+)-ATPase, with the following IC(50) values: 15, 35, 50, 400 mu M and 45 mM, respectively. Decaniobate (Nb(10)), is the strongest P-type enzyme inhibitor, after decavanadate (V(10)). Atomic-absorption spectroscopy (AAS) analysis, indicates that decavanadate binds to the protein with a 1:1 decavanadate:Ca(2+)-ATPase stoichiometry. Furthermore, V10 binds with similar extension to all the protein conformations, which occur during calcium translocation by active transport, namely El, El P, E2 and E2P, as analysed by MS. In contrast, it was confirmed that the binding of monomeric vanadate (H(2)VO(4)(2-):V(1)) to the calcium pump is favoured only for the E2 and E2P conformations of the ATPase, whereas no significant amount of vanadate is bound to the E1 and E1P conformations. Scatchard plot analysis, confirmed a 1:1 ratio for decavanadate-Ca(2+)-ATPase, with a dissociation constant, k(d) of 1 mu M(-1). The interaction of decavanadate V(10)O(28)(6-) (V(10)) with Ca(2+)-ATPase is prevented by the isostructural and isoelectronic decaniobate Nb(10)O(28)(6-) (Nb(10)), whereas no significant effects were detected with ATP or with heparin, a known competitive ATP binding molecule, suggesting that V(10) binds non-competitively, with respect to ATP, to the protein. Finally, it was shown that decaniobate inhibits SR Ca(2+)-ATPase activity in a non competitive type of inhibition, with respect to ATP. Taken together, these data demonstrate that decameric niobate and vanadate species are stronger inhibitors of the SR calcium ATPase than simple monomeric vanadate, tungstate and molybdate oxometalates, thus affecting calcium homeostasis, cell signalling and cell bioenergetics, as well many other cellular processes. The ability of these oxometalates to act either as phosphate analogues, as a transition-state analogue in enzyme-catalysed phosphoryl group transfer processes and as potentially nucleotide-dependent enzymes modulators or inhibitors, suggests that different oxometalates may reveal different mechanistic preferences in these classes of enzymes. (C) 2011 Elsevier Inc. All rights reserved.

  • 77.
    Fredriksson Sundbom, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Characterisation of anandamide uptake in resting and activated murine cells2015Självständigt arbete på avancerad nivå (masterexamen), 20 poäng / 30 hpStudentuppsats (Examensarbete)
    Abstract [en]

    Modifying the metabolism of the body’s own endocannabinoids is a novel approach for analgesia. Two key catabolic enzymes are fatty acid amide hydrolase (FAAH) and inflammation-inducible cyclooxygenase 2 (COX-2). The cellular uptake of the key endocannabinoid anandamide (AEA) has been found to be regulated by its FAAH-catalysed intracellular degradation, but COX-2 has not been investigated in this respect. We aimed to find out whether or not COX-2 in an in vitro inflammation setting would be able to gate AEA uptake. To achieve this, C6 cells and Raw 264.7 cells were stimulated with LPS/INF-γ and lysates then analyzed by immunoblot in order to verify COX-2 expression. AEA cellular uptake was quantified using a radioassay with [3H]-AEA. It was found that COX-2 was not inducible in C6 cells using the LPS/INF-γ conditions studied, while it was inducible in Raw 264.7 cells. AEA uptake in the COX-2-induced Raw 264.7 cells was not reduced by inhibitors of this enzyme. FAAH appeared to be down-regulated in the stimulated Raw 264.7 cells, and this was reflected in an overall lower AEA uptake. Our interpretation of the data points to FAAH as gating AEA uptake. Additional experiments are required to validate our findings by verifying significance.  

  • 78.
    Gabrielsson, Linda
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gouveia-Figueira, Sandra
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Häggström, Jenny
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Alhouayek, Mireille
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The anti-inflammatory compound palmitoylethanolamide inhibits prostaglandin and hydroxyeicosatetraenoic acid production by a macrophage cell line2017Ingår i: Pharmacology Research & Perspectives, ISSN 2052-1707, Vol. 5, nr 2, artikel-id UNSP e00300Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The anti-inflammatory agent palmitoylethanolamide (PEA) reduces cyclooxygenase (COX) activity in vivo in a model of inflammatory pain. It is not known whether the compound reduces prostaglandin production in RAW264.7 cells, whether such an action is affected by compounds preventing the breakdown of endogenous PEA, whether other oxylipins are affected, or whether PEA produces direct effects upon the COX-2 enzyme. RAW264.7 cells were treated with lipopolysaccharide and interferon-c to induce COX-2. At the level of mRNA, COX-2 was induced > 1000-fold following 24 h of the treatment. Coincubation with PEA (10 mu mol/L) did not affect the levels of COX-2, but reduced the levels of prostaglandins D-2 and E-2 as well as 11- and 15-hydroxyeicosatetraenoic acid, which can also be synthesised by a COX-2 pathway in macrophages. These effects were retained when hydrolysis of PEA to palmitic acid was blocked. Linoleic acidderived oxylipin levels were not affected by PEA. No direct effects of PEA upon the oxygenation of either arachidonic acid or 2-arachidonoylglycerol by COX-2 were found. It is concluded that in lipopolysaccharide and interferon-c-stimulated RAW264.7 cells, PEA reduces the production of COX-2-derived oxylipins in a manner that is retained when its metabolism to palmitic acid is inhibited.

  • 79. Gaehrs, Maike
    et al.
    Roos, Robert
    Andersson, Patrik L.
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Schrenk, Dieter
    Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes2013Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 272, nr 1, s. 77-85Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polychlorinated biphenyls (PCBs) are among the most ubiquitously detectable 'persistent organic pollutants'. In contrast to 'dioxinlike' (DL) PCBs, less is known about the molecular mode of action of the larger group of the 'non-dioxinlike' (NDL) PCBs. Owing to the life-long exposure of the human population, a carcinogenic, i.e., tumor-promoting potency of NDL-PCBs has to be considered in human risk assessment. A major problem in risk assessment of NDL-PCBs is dioxin-like impurities that can occur in commercially available NDL-PCB standards. In the present study, we analyzed the induction of CYP2B1 and CYP3A1 in primary rat hepatocytes using a number of highly purified NDL-PCBs with various degrees of chlorination and substitution patterns. Induction of these enzymes is mediated by the nuclear xenobiotic receptors CAR (Constitutive androstane receptor) and PXR (Pregnane X receptor). For CYP2B1 induction, concentration-response analysis revealed a very narrow window of EC50 estimates, being in the range of 1-4 mu M for PCBs 28 and 52, and between 0.4 and 1 mu M for PCBs 101, 138, 153 and 180. CYP3A1 induction was less sensitive to NDL-PCBs, the most pronounced induction being achieved at 100 mu M with the higher chlorinated congeners. Using okadaic acid and small interfering RNAs targeting CAR and PXR, we could demonstrate that CAR plays a major role and PXR a minor role in NDL-PCB-driven induction of CYPs, both effects showing no stringent structure-activity relationship. As the only obvious relevant determinant, the degree of chlorination was found to be positively correlated with the inducing potency of the congeners. (C) 2013 Elsevier Inc. All rights reserved.

  • 80.
    Ghafouri, Nazdar
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Endocannabinoids and N-acylethanolamines in translational pain research: from monoacylglycerol lipase to muscle pain2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    In the early nineties cannabinoid receptors, the main target for Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana were identified. Shortly after their endogenous ligands, N-arachidonoylethanolamine (anandamide, AEA) and 2-diacylglycerol (2-AG) were characterized. The enzymes primarily responsible for catalysing the degradation of AEA and 2-AG are fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL) respectively. AEA is a member of the N-acylethanolamine (NAE) class of lipids, which depending on the acyl chain length and number of double bonds can act as ligands for a variety of biological targets. Exogenous cannabinoids have long been reported to have analgesic effects, however the clinical usefulness of such substances is limited by their psychoactive effects. Inhibition of endocannabinoid degradation would mean enhancing the therapeutic effects without producing these unwanted side effects. In order to succeed in developing such compounds the pharmacology of the enzymes responsible for the degradation of endocannabinoids has to be thoroughly understood. When the preclinical part of this thesis was planned, FAAH had been well characterized whereas little was known as to the pharmacology of MGL. A series of compounds were tested in this first study aiming to find MGL-selective compounds. Although no compounds showed selectivity for MGL over FAAH, several interesting agents affecting both enzymes were identified.

    In order to increase the knowledge concerning which patient group would benefit from such treatment strategies it is important to investigate in which pain states the endocannabinoids/NAEs are altered. Thus the general aim of the clinical part of this thesis was to investigate the levels of endocannabinoids/NAEs in the interstitium of the trapezius muscle in women suffering from chronic neck/shoulder pain (CNSP) and chronic wide spread pain (CWP) and in healthy pain-free controls. Furthermore for the CNSP the effect of training, which is a commonly recommended treatment for these patients, on the levels of endocannabinoids/NAEs was also investigated. Microdialysis technique in the trapezius muscle was used for sampling and masspectrometry was used for analysing. Two NAEs,

    N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA), could be repeatedly measured. The levels of these two lipids were significantly higher in CNSP compared to CON. The result showed also that PEA and SEA mobilize differently in CWP compared to both CNSP and CON. Taken together the results presented in thesis represent an early characterization of the pharmacology of MGL and provides novel information on NAEs in chronic muscle pain.

  • 81.
    Ghafouri, Nazdar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ghafouri, Bijar
    Britt, Larsson
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Stensson, Niclas
    Gerdle, Björn
    Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder painManuskript (preprint) (Övrigt vetenskapligt)
  • 82.
    Ghafouri, Nazdar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ghafouri, Bijar
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Larsson, Britt
    Turkina, Maria V
    Karlsson, Linn
    Gerdle, Björn
    Effects of two different specific neck training programs on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck-shoulder painManuskript (preprint) (Övrigt vetenskapligt)
  • 83.
    Ghafouri, Nazdar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi. Rehabilitation Medicine, Department of Medicine and Health Sciences, Linköping University, SE 581 85 Linköping, Sweden and Pain and Rehabilitation Centre, UHL, County Council of Östergötland, SE 581 85 Linköping, Sweden .
    Ghafouri, Bijar
    Larsson, Britt
    Stensson, Niclas
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gerdle, Bjorn
    Palmitoylethanolamide and stearoylethanolamide levels in the interstitium of the trapezius muscle of women with chronic widespread pain and chronic neck-shoulder pain correlate with pain intensity and sensitivity2013Ingår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 154, nr 9, s. 1649-1658Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic widespread pain (CWP) is a complex condition characterized by central hyperexcitability and altered descending control of nociception. However, nociceptive input from deep tissues is suggested to be an important drive. N-Acylethanolamines (NAEs) are endogenous lipid mediators involved in regulation of inflammation and pain. Previously we have reported elevated levels of the 2 NAEs, the peroxisome proliferator-activated receptor type-alpha ligand N-palmitoylethanolamine (PEA) and N-stearoylethanolamine (SEA) in chronic neck/shoulder pain (CNSP). In the present study, the levels of PEA and SEA in women with CWP (n = 18), CNSP (n = 34) and healthy controls (CON, n = 24) were investigated. All subjects went through clinical examination, pressure pain threshold measurements and induction of experimental pain in the tibialis anterior muscle. Microdialysis dialysate of the trapezius was collected before and after subjects performed a repetitive low-force exercise and analyzed by mass spectrometry. The levels of PEA and SEA in CNSP were significantly higher post exercise compared with CWP, and both pre and post exercise compared with CON. Levels of both NAEs decreased significantly pre to post exercise in CWP. Intercorrelations existed between aspects of pain intensity and sensitivity and the level of the 2 NAEs in CWP and CNSP. This is the first study demonstrating that CNSP and CWP differ in levels of NAEs in response to a low-force exercise which induces pain. Increases in pain intensity as a consequence of low-force exercise were associated with low levels of PEA and SEA in CNSP and CWP. These results indicate that PEA and SEA have antinociceptive roles in humans. (c) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  • 84.
    Ghafouri, Nazdar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Tiger, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Razdan, Raj K
    Mahadevan, Anu
    Pertwee, Roger G
    Martin, Billy R
    Fowler, Christopher J
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol2004Ingår i: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 143, nr 6, s. 774-784Artikel i tidskrift (Refereegranskat)
  • 85.
    Gouveia-Figueira, Sandra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Karlsson, Jessica
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Deplano, Alessandro
    Hashemian, Sanaz
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Svensson, Mona
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Fredriksson Sundbom, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Congiu, Cenzo
    Onnis, Valentina
    Fowler, Christopher J.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor2015Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, nr 9, artikel-id e0139212Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. Methodology/Principal Findings COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon gamma-stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manner, with IC50 values in the absence of a preincubation phase of: (R)-Flu-AM1, COX-1 (arachidonic acid) 6 mu M; COX-2 (arachidonic acid) 20 mu M; COX-2 (2-AG) 1 mu M; (S)-Flu-AM1, COX-1 (arachidonic acid) 3 mu M; COX-2 (arachidonic acid) 10 mu M; COX-2 (2-AG) 0.7 mu M. The compounds showed no enantiomeric selectivity in their FAAH inhibitory properties. (R)-Flu-AM1 (10 mu M) greatly inhibited the production of prostaglandin D2 and E2 in both unstimulated and lipopolysaccharide + interferon.-stimulated RAW 264.7 macrophage cells. Levels of 2-AG were not affected either by (R)-Flu-AM1 or by 10 mu M flurbiprofen, either alone or in combination with the FAAH inhibitor URB597 (1 mu M). Conclusions/Significance Both enantiomers of Flu-AM1 are more potent inhibitors of 2-AG compared to arachidonic acid oxygenation by COX-2. Inhibition of COX in lipopolysaccharide + interferon.-stimulated RAW 264.7 cells is insufficient to affect 2-AG levels despite the large induction of COX-2 produced by this treatment.

  • 86. Gruden, M. A.
    et al.
    Davydova, T. V.
    Fomina, V. G.
    Vetrile, L. A.
    Morozova-Roche, Ludmilla A.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk kemi och biofysik.
    Sewell, R. D. E.
    Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice2017Ingår i: Bulletin of experimental biology and medicine, ISSN 0007-4888, E-ISSN 1573-8221, Vol. 162, nr 4, s. 430-432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Chronic intranasal administration of fibrillar structures of proinflammatory S100A9 protein impaired passive avoidance learning in old C57Bl/6 mice. Combined treatment with S100A9 fibrils and antibodies to glutamate was followed by an increase in horizontal locomotor activity of animals in the open-field test and did not disturb spatial memory.

  • 87. Grundmark, B.
    et al.
    Garmo, H.
    Zethelius, B.
    Stattin, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Lambe, M.
    Holmberg, L.
    Anti-androgen prescribing patterns, patient treatment adherence and influencing factors; results from the nationwide PCBaSe Sweden2012Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 68, nr 12, s. 1619-1630Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Adherence has not been studied in male oncology populations. The aim of this study on both the prescriber and user perspectives in prostate cancer treatment was to analyse real-life prescribing patterns of anti-androgens (AA), primarily bicalutamide, and factors influencing the patients' adherence to treatment. A nationwide clinical cohort of incident prostate cancer, PCBaSe, was linked to the Swedish Prescribed Drug Register. Men with a planned first line monotherapy AA treatment were identified; dosages and extent of off-label treatment were investigated. Cumulative incidence proportions for reasons for drug discontinuation were calculated. Factors potentially influencing adherence were explored using the medical possession ratio based on the individual prescribed daily dose. First line monotherapy AA was planned in 4.4 % of all incident cases and in 2.1 % of low risk disease cases. Among 1,406 men prescribed bicalutamide, 1,109 (79 %) received the approved daily dose of 150 mg. Discontinuation reasons differed with disease severity. Off-label, low-dose prescription associated with age above 75 years and disease categorised as low risk was noted in 297 men (21 %). Sixty percent of the men adhered well, i.e. to a parts per thousand yen80 %. Age above 75 years and less severe disease were both negatively associated with adherence. Patient age and tumour risk group influenced the prescriber's choice of dose, pointing to important issues for critical reflection. Possible over-treatment was noted in low risk disease. Interventions to increase adherence in older men and in men with less severe disease are worth considering after critically reviewing the appropriateness of the treatment indication, especially in the latter case.

  • 88. Gulin-Sarfraz, Tina
    et al.
    Jonasson, Sofia
    Wigenstam, Elisabeth
    von Haartman, Eva
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. CBRN Defence and Security, Swedish Defence Research Agency, Umeå, Sweden.
    Rosenholm, Jessica M.
    Feasibility Study of Mesoporous Silica Particles for Pulmonary Drug Delivery: Therapeutic Treatment with Dexamethasone in a Mouse Model of Airway Inflammation2019Ingår i: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, nr 4, artikel-id 149Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diseases in the respiratory tract rank among the leading causes of death in the world, and thus novel and optimized treatments are needed. The lungs offer a large surface for drug absorption, and the inhalation of aerosolized drugs are a well-established therapeutic modality for local treatment of lung conditions. Nanoparticle-based drug delivery platforms are gaining importance for use through the pulmonary route. By using porous carrier matrices, higher doses of especially poorly soluble drugs can be administered locally, reducing their side effects and improving their biodistribution. In this study, the feasibility of mesoporous silica particles (MSPs) as carriers for anti-inflammatory drugs in the treatment of airway inflammation was investigated. Two different sizes of particles on the micron and nanoscale (1 mu m and 200 nm) were produced, and were loaded with dexamethasone (DEX) to a loading degree of 1:1 DEX:MSP. These particles were further surface-functionalized with a polyethylene glycol-polyethylene imine (PEG-PEI) copolymer for optimal aqueous dispersibility. The drug-loaded particles were administered as an aerosol, through inhalation to two different mice models of neutrophil-induced (by melphalan or lipopolysaccharide) airway inflammation. The mice received treatment with either DEX-loaded MSPs or, as controls, empty MSPs or DEX only; and were evaluated for treatment effects 24 h after exposure. The results show that the MEL-induced airway inflammation could be treated by the DEX-loaded MSPs to the same extent as free DEX. Interestingly, in the case of LPS-induced inflammation, even the empty MSPs significantly down-modulated the inflammatory response. This study highlights the potential of MSPs as drug carriers for the treatment of diseases in the airways.

  • 89.
    Gunnarsson, Lina
    et al.
    Department of Neuroscience and Physiology, the Sahlgrenska Academy at University of Göteborg, Box 434, SE-405 30 Göteborg, Sweden.
    Kristiansson, Erik
    Department of Neuroscience and Physiology, the Sahlgrenska Academy at University of Göteborg, Box 434, SE-405 30 Göteborg, Sweden.
    Rutgersson, Carolin
    Department of Neuroscience and Physiology, the Sahlgrenska Academy at University of Göteborg, Box 434, SE-405 30 Göteborg, Sweden.
    Sturve, Joachim
    Department of Zoology, University of Göteborg, SE-405 30 Göteborg, Sweden.
    Fick, Jerker
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
    Förlin, Lars
    Department of Zoology, University of Göteborg, SE-405 30 Göteborg, Sweden.
    Larsson, D G Joakim
    Department of Neuroscience and Physiology, the Sahlgrenska Academy at University of Göteborg, Box 434, SE-405 30 Göteborg, Sweden.
    Pharmaceutical industry effluent diluted 1:500 affects global gene expression, cytochrome P4501A activity and plasma phosphate in fish2009Ingår i: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 28, nr 12, s. 2639-2647Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patancheru, near Hyderabad, India, is a major production site for the global bulk drug market. Approximately 90 manufacturers send their wastewater to a common treatment plant in Patancheru. Extraordinary high levels of a wide range of pharmaceuticals have recently been demonstrated in the treated effluent. As little as 0.2% of this effluent can strongly reduce the growth rate of tadpoles, but the underlying mechanisms of toxicity are not known. To begin addressing how the effluent affects aquatic vertebrates, rainbow trout (Oncorhynchus mykiss) were exposed to 0.2% effluent for five days. Several physiological endpoints, together with effects on global hepatic gene expression patterns, were analyzed. The exposed fish showed both an induction of hepatic cytochrome P450 1A (CYP1A) gene expression, as well as enzyme activity. Clinical blood chemistry analyses revealed an increase in plasma phosphate levels, which in humans indicates impaired kidney function. Several oxidative stress-related genes were induced in the livers; however, no significant changes in antioxidant enzyme activities or in the hepatic glutathione levels were found. Furthermore, estrogen-regulated genes were slightly up-regulated following exposure, and moderate levels of estriol were detected in the effluent. The present study identifies changes in gene expression triggered by exposure to a high dilution of the effluent, supporting the hypothesis that these fish are responding to chemical exposure. The pattern of regulated genes may contribute to the identification of mechanisms of sub-lethal toxicity, as well as illuminate possible causative agents.

  • 90.
    Gunnarsson, Ulf
    et al.
    Department of Physiology and Pharmacology, Karolinska Institute, Stockholm.
    Hjelmqvist, H
    Rundgren, M
    Centrally mediated influences of hypertonic NaCl and angiotensin II on regional blood flow and hemodynamic responses to hypotensive hemorrhage in conscious sheep.1994Ingår i: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 2, nr 1, s. 60-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The influence of separate and combined intracerebroventricular (ICV) infusions of hypertonic (.5 M) NaCl (HTNa) at .02 mL min-1 and angiotensin II (ANG II) at 1 pmol kg-1 min-1 on tolerance to hemorrhage, accompanying systemic hemodynamic changes, and regional blood flow was studied in adult conscious sheep. Corresponding measurements during ICV .9% NaCl served as controls. The hemorrhage volume needed to lower the blood pressure to about 50 mmHg was significantly larger during treatment with HTNa and HTNa/ANG II (27.8 +/- 2.2 and 28.3 +/- 2.5 mL kg-1, respectively; p < .001; about 45% of estimated blood volume) as well as during ANG II (20.1 +/- 1.3 mL kg-1; p < .01) compared to controls (15.1 +/- .7 mL kg-1; about 25% of estimated blood volume). In spite of a larger hemorrhage volume, the lowering of the cardiac output was not accentuated, and its subsequent recovery was not impaired during ICV infusion of HTNa or HTNa/ANG II. Similarly, the posthemorrhage restoration of the systemic blood pressure was not negatively affected by the more pronounced hypovolemia induced during the ICV treatments compared to controls. In contrast to ANG II, HTNa infusion, alone or in combination with ANG II, was accompanied by a significantly lower renal blood flow, and a higher renovascular resistance, during the posthemorrhage period. The femoral blood flow was maintained or even slightly elevated after hemorrhage in all experiments. The integrated results of the study imply differentiated hemodynamic effects of centrally administered HTNa and ANG II.(ABSTRACT TRUNCATED AT 250 WORDS)

  • 91.
    Gustafsson, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Mattsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Gallego, Gisselle
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Students' satisfaction with a web-based pharmacy program in a re-regulated pharmacy market2017Ingår i: Pharmacy, ISSN 2226-4787, E-ISSN 1913-4711, Vol. 5, nr 3, artikel-id E47Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In response to the shortage of pharmacists in Northern Sweden, a web-based Bachelor of Science in Pharmacy program was established at Umeå University in 2003. In 2009, the Swedish pharmacy market was re-regulated from a state monopoly to an open market, but it is unknown what impact this has had on education satisfaction. The objectives of this study were to examine the level of satisfaction among graduates from a web-based pharmacy program and to describe what subjects and skills students would have liked more or less of in their education. A secondary objective was to compare the level of satisfaction before and after the Swedish pharmacy market was re-regulated. A cross-sectional survey was conducted in 2015 with all alumni who had graduated from the pharmacy program between 2006 and 2014 (n = 511), and responses to questions about graduates' satisfaction with the program were analyzed (n = 200). Most graduates (88%) agreed or strongly agreed that the knowledge and skills acquired during their education were useful in their current job. The graduates stated that they would have wanted more applied pharmacy practice and self-care counselling, and fewer social pharmacy and histology courses. Further, 82% stated that they would start the same degree program if they were to choose again today, and 92% agreed or strongly agreed that they would recommend the program to a prospective student. Graduates were more likely to recommend the program after the re-regulation (p = 0.007). In conclusion, pharmacy graduates were very satisfied with their education, and no negative effects of the re-regulation could be observed on program satisfaction.

  • 92.
    Gustafsson, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi. Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Sandman, Per-Olof
    Department of Neurobiology, Care Sciences and Society, Division of Nursing, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Karlsson, Stig
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad.
    Isaksson, Ulf
    Umeå universitet, Medicinska fakulteten, Institutionen för omvårdnad. Umeå universitet, Arktiskt centrum vid Umeå universitet (Arcum).
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Sjölander, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Lövheim, Hugo
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Reduction in the use of potentially inappropriate drugs among old people living in geriatric care units between 2007 and 20132015Ingår i: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 71, nr 4, s. 507-515Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: The aims of this study were to investigate trends in the prevalence of potentially inappropriate drug use among old people living in geriatric care units in the county of Västerbotten between 2007 and 2013 using six national quality indicators and to assess the impact of medication reviews on those quality indicators.

    METHODS: Data were collected concerning potentially inappropriate drug use, function in the activities of daily living (ADL) and cognitive function, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). A comparison was made between the years 2007 and 2013, comprising 2772 and 1902 people, respectively, living in geriatric care in the county of Västerbotten, Sweden. We conducted a parallel investigation of a separate corresponding population in Västerbotten County from 2012, where potentially inappropriate drug use was measured before and after 895 medication reviews which involved a clinical pharmacist.

    RESULTS: After controlling for age, sex, ADL and cognitive impairment, there was a significant improvement in five out of six quality indicators between 2007 and 2013. While 44 % of the people were exposed to one or more potentially inappropriate medications in 2007, this number had declined to 26 % by 2013. In the separate population from 2012, the frequency of potentially inappropriate drug use was significantly reduced amongst the people who had a medication review performed.

    CONCLUSION: The extent of potentially inappropriate drug use declined between 2007 and 2013 according to the quality indicators used. Medication reviews involving clinical pharmacists might be an important factor in reducing potentially inappropriate drug use and improving drug treatment among old people.

  • 93.
    Gustafsson, Maria
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Sjölander, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Pfister, Bettina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Schneede, Jörn
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Lövheim, Hugo
    Umeå universitet, Medicinska fakulteten, Institutionen för samhällsmedicin och rehabilitering, Geriatrik.
    Effects of pharmacists' interventions on inappropriate drug use and drug-related readmissions in people with dementia: a secondary analysis of a randomized controlled trial2018Ingår i: Pharmacy, ISSN 2226-4787, E-ISSN 1913-4711, Vol. 6, nr 1, artikel-id E7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Age-associated physiological changes and extensive drug treatment including use of potentially inappropriate medications (PIMs) pose a significant risk of drug-drug interactions and adverse drug events among elderly people with dementia. This study aimed at analysing the effects of clinical pharmacists' interventions on use of PIMs, risk of emergency department visits, and time to institutionalization. Furthermore, a descriptive analysis was conducted of circumstances associated with drug-related readmissions. This is a secondary analysis of data from a randomized controlled intervention study conducted in two hospitals in Northern Sweden. The study included patients (n = 460) 65 years or older with dementia or cognitive impairment. The intervention consisted of comprehensive medication reviews conducted by clinical pharmacists as part of a healthcare team. There was a larger decrease in PIMs in the intervention group compared with the control group (p= 0.011). No significant difference was found in time to first all-cause emergency department visits (HR = 0.994, 95% CI = 0.755-1.307 p = 0.963, simple Cox regression) or time to institutionalization (HR = 0.761, 95% CI = 0.409-1.416 p = 0.389, simple Cox regression) within 180 days. Common reasons for drug-related readmissions were negative effects of sedatives, opioids, antidepressants, and anticholinergic agents, resulting in confusion, falling, and sedation. Drug-related readmissions were associated with living at home, heart failure, and diabetes. Pharmacist-provided interventions were able to reduce PIMs among elderly people with dementia and cognitive impairment.

  • 94.
    Gustafsson, Sofia
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Cannabinoids as modulators of cancer cell viability, neuronal differentiation, and embryonal development2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Cannabinoids (CBs) are compounds that activate the CB1 and CB2 receptors. CB receptors mediate many different physiological functions, and cannabinoids have been reported to decrease tumor cell viability, proliferation, migration, as well as to modulate metastasis.

    In this thesis, the effects of cannabinoids on human colorectal carcinoma Caco-2 cells (Paper I) and mouse P19 embryonal carcinoma (EC) cells (Paper III) were studied.  In both cell lines, the compounds examined produced a concentration- and time-dependent decrease in cell viability. In Caco-2-cells, HU 210 and the pyrimidine antagonist 5-fluorouracil produced synergistic effects upon cell viability. The mechanisms behind the cytocidal effects of cannabinoids appear to be mediated by other than solely the CB receptor, and a common mechanism in Caco-2 and P19 EC cells was oxidative stress. However, in P19 EC cells the CB receptors contribute to the cytocidal effects possibly via ceramide production.

    In paper II, the association between CB1 receptor immunoreactivity (CB1IR) and different histopathological variables and disease-specific survival of colorectal cancer (CRC) was investigated. In microsatellite stable (MSS) cases there was a significant positive association of the tumor grade with the CB1IR intensity. A high CB1IR is indicative of a poorer prognosis in MSS with stage II CRC patients.

    Paper IV focused on the cytotoxic effects of cannabinoids during neuronal differentiation. HU 210 affected the cell viability, neurite formation and produced a decreased intracellular AChE activity. The effects of cannabinoids on embryonic development and survival were examined in Paper V, by repeated injection of cannabinoids in fertilized chicken eggs. After 10 days of incubation, HU 210 and cannabidiol (without CB receptor affinity), decreased the viability of chick embryos, in a manner that could be blocked by α-tocopherol (antioxidant) and attenuated by AM251 (CB1 receptor antagonist).

    In conclusion, based on these studies, the cannabinoid system may provide a new target for the development of drugs to treat cancer such as CRC. However, the CBs also produce seemingly unspecific cytotoxic effects, and may have negative effects on the neuronal differentiation process. This may be responsible for, at least some of, the embryotoxic effects found in ovo, but also for the cognitive and neurotoxic effects of cannabinoids in the developing and adult nervous system.

  • 95.
    Gustafsson, Sofia B
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Lindgren, Theres
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jonsson, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig OP
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Cannabinoid receptor-independent cytotoxic effects of cannabinoids in human colorectal carcinoma cells: synergism with 5-fluorouracil2009Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 63, nr 4, s. 691-701Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cannabinoids (CBs) have been found to exert antiproliferative effects upon a variety of cancer cells, including colorectal carcinoma cells. However, little is known about the signalling mechanisms behind the antitumoural effect in these cells, whether the effects are shared by endogenous lipids related to endocannabinoids, or whether such effects are synergistic with treatment paradigms currently used in the clinic. The aim of this preclinical study was to investigate the effect of synthetic and endogenous CBs and their related fatty acids on the viability of human colorectal carcinoma Caco-2 cells, and to determine whether CB effects are synergistic with those seen with the pyrimidine antagonist 5-fluorouracil (5-FU). The synthetic CB HU 210, the endogenous CB anandamide, the endogenous structural analogue of anandamide, N-arachidonoyl glycine (NAGly), as well as the related polyunsaturated fatty acids arachidonic acid and eicosapentaenoic acid showed antiproliferative and cytotoxic effects in the Caco-2 cells, as measured by using [3H]-thymidine incorporation assay, the CyQUANT proliferation assay and calcein-AM fluorescence. HU 210 was the most potent compound examined, followed by anandamide, whereas NAGly showed equal potency and efficacy as the polyunsaturated fatty acids. Furthermore, HU 210 and 5-FU produced synergistic effects in the Caco-2 cells, but not in the human colorectal carcinoma cell lines HCT116 or HT29. The compounds examined produced cytotoxic, rather than antiproliferative effects, by a mechanism not involving CB receptors, since the CB receptor antagonists AM251 and AM630 did not attenuate the effects, nor did pertussis toxin. However, α-tocopherol and the nitric oxide synthase inhibitor L-NAME attenuated the CB toxicity, suggesting involvement of oxidative stress. It is concluded that the CB system may provide new targets for the development of drugs to treat colorectal cancer.

  • 96.
    Gustafsson, Sofia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Ghasimi, Soma
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Popova, Dina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Krzemien, J
    Wallenius, Anders
    Jacobsson, Stig OP
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    The effects of cannabinoids on the viability and differentiation of neurons derived from retinoic acid-induced  P19 embryonal carcinoma cellsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Cannabinoids and cannabinoid receptors play an important role in development and differentiation of the nervous system, but the mechanisms behind that role have not been fully elucidated. We have examined the effects of synthetic and endogenous cannabinoids and related polyunsaturated fatty acids upon mouse embryonal carcinoma P19 stem cell viability - before, during and after retinoic acid (RA)-induced neural differentiation. Experiments were also performed to investigate whether the cannabinoids affect the differentiation of P19-derived neurons by measuring the development and growth of neurites and intracellular acetylcholinesterase activity.

    Both synthetic and endogenous cannabinoids as well as related fatty acids produced a concentration-dependent decrease in undifferentiated P19 cell viability, but induction of the neural pathway reduced the sensitivity to the cytotoxic effects, and in differentiated neurons anandamide and related fatty acids showed no cytotoxicity. However, synthetic cannabinoids such as HU 210, HU 211 and WIN 55,212-2 produced cytotoxicity in both undifferentiated and differentiated cells, but there was a right-shifted concentration-effect curve in RA-induced cells and differentiated neurons compared with the undifferentiated cells.

    HU 210 produced a time- and concentration-dependent decrease in cell number, percentage of cells expressing neurites, number of neurites per cell and neurite length. Statistically significant inhibition was seen at a concentration of 1 µM to 3 µM, and this was confirmed by the measurement of intracellular acetylcholinesterase activity, an enzyme that is dramatically increased during the differentiation process, where HU 210 significantly decreased the activity after six and nine days of exposure. However, these effects of HU 210 could only be observed in the same concentration range as those affecting neuronal viability. Anandamide, on the other hand, had modest effect on measured markers of neuronal differentiation but decreased the fraction of neurite expressing cells and neurite length after nine days of exposure at a concentration ≥ 10 µM. No effect on the acetylcholinesterase activity was observed.

    It is concluded that cannabinoids and related fatty acids have cytotoxic effects in undifferentiated P19 embryonal carcinoma cells, but induction of the neuronal pathway reduces the sensitivity to the cytotoxic effects. The synthetic cannabinoids are more potent than the endogenous cannabinoids and fatty acids in causing cytotoxicity in differentiated neurons, but the CB-induced decrease in neurite formation and acetylcholinesterase activity in RA-induced P19-derived neurons occurs only at concentrations that cause measurable neuronal cell death. 

  • 97.
    Gustafsson, Sofia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig OP
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Effects of cannabinoids on the development of chick embryos in ovo2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 13486Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have examined the effects of the synthetic cannabinoids HU 210 and HU 211, the plant-derived cannabidiol and the endogenous cannabinoid anandamide on the viability and development of chick embryos. Fertilized White Leghorn chicken eggs were injected with the test compounds or carrier vehicle, via a drilled small hole in the egg, directly into the egg yolk. After nine days of exposure, the embryonal viability, length and wet weight of embryos, and wet weight of brains were measured, and the development stages were assessed according to the Hamburger and Hamilton (HH) scale. The potent synthetic cannabinoid receptor agonist HU 210 and the non-psychotropic cannabidiol were embryotoxic at the highest concentrations examined (10µM and 50µM, respectively), with no viable embryos after the HU 210 injection, and 20% viability after the cannabidiol injections. The efects of HU 210 on the chick embryo were attenuated by α-tocopherol and the cannabinoid receptor antagonist AM251, whereas only α-tocopherol gave a statistically signifcant protection against the embryotoxic efects of cannabidiol. This study shows that exposure to plant-derived or synthetic cannabinoids during early embryonal development decreases embryonal viability. Extrapolation of data across species is of course difcult, but the data would argue against the use of cannabinoids, be it recreationally or therapeutically, during pregnancy

  • 98.
    Gustafsson, Sofia
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Wallenius, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Zackrisson, H
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Popova, Dina
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Plym Forshell, Linus
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Jacobsson, Stig OP
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells2013Ingår i: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 87, nr 11, s. 1939-1951Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Compounds acting on the cannabinoid (CB) receptors are involved in the control of cell fate, and there is an emerging consensus that CBs have anticancer effects. However, the CB-mediated effects are contradictory since some studies suggest stimulatory effects on cancer cell proliferation, and CBs have been shown to stimulate both proliferation and differentiation of other mitotic cells such as stem and progenitor cells. In this study, the concentration-dependent effects of synthetic and endogenous CBs on the viability of mouse P19 embryonal carcinoma (EC) cells have been examined by using fluorescence assays of cell membrane integrity, cell proliferation, oxidative stress, and detection of apoptosis and necrosis. All compounds examined produced a concentration-dependent decrease in cell viability in the micromolar range, with the potent CB receptor agonist HU 210 and the enantiomer HU 211(with no CB receptor activity) being the most potent compounds examined with apparent IC50 values of 1 µM and 0.6 µM, respectively. The endogenous CB anandamide showed similar potency and efficacy as structurally related polyunsaturated fatty acids with no reported activity at the CB receptors. The rapid (within hours) decrease in cell viability induced by the examined CBs suggests cytocidal rather than antiproliferative effects, and is dependent on the plating cell population density with the highest toxicity around 100 cells/mm2. The CB-induced cytotoxicity, that appears to involve CB receptors and the sphingomyelin-ceramide pathway, is a mixture of both apoptosis and necrosis that can be blocked by the antioxidants α-tocopherol and N-acetylcysteine. In conclusion, both synthetic and endogenous CBs, produce seemingly unspecific cytotoxic effects in the P19 EC cells.

  • 99.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden.
    Bergström, Ulrika
    Ågren, Lina
    Österlund, Lars
    Sandström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. Swedish Def Res Agcy, Div CBRN Def & Secur, SE-90182 Umea, Sweden.
    Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles2015Ingår i: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 288, nr 1, s. 1-11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.

  • 100.
    Gustafsson, Åsa
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bergström, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Ågren, Lina
    FOI.
    Österlund, Lars
    Ångström Laboratory, Uppsala University.
    Sandström, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin.
    Bucht, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Lungmedicin. FOI.
    Mice with established airway inflammation exert differential cellular responses to inhaled hematite nanoparticles than healthy miceManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The aim of this study was to investigate the inflammatory and immunological responses in the airways and the lung-draining lymph nodes, following lung exposure to hematite nanoparticles (NPs). The responses to hematite NPs were evaluated in both non-sensitized healthy mice, and allergen-sensitized mice, in which the latter represent a group of sensitive individuals with allergic airway disease. This allergic airway disease was induced by sensitization and aerosol challenge to a respiratory allergen resulting in an established eosinophilic and lymphocytic airway inflammation at the time of NP exposure. The mice received either hematite NPs or vehicle (PBS) intratracheally and the cellular responses were evaluated on day 1, 2, and 7, following exposure.

    Intratracheal instillation of hematite NPs induced an increase of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on day 1 and 2 following exposure. At these time-points the lymphocytes in the lymph nodes were also increased. In contrast, exposure to hematite NPs in sensitized mice induced a rapid and unspecific cellular reduction in the alveolar space on the first day after exposure. A similar decrease of lymphocytes was also observed in the mediastinal lymph nodes draining the airways. The study did not indicate a reduction of inflammatory cells in the lung tissue or a translocation of cells from alveolar space to lung tissue. Although, mucociliary cellular clearance could be a possible explanation, our finding of cellular decrease also in lung draining lymph nodes point at cell death as the most likely cause to this unspecific cellular reduction.

    The results indicate that cells in the airways and lymph nodes of individuals with established airway inflammation undergo cell death when exposed to iron oxide NPs. A possible reason to the toxic response is extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways, which is further catalyzed by Fe ions released by the hematite NPs, or by generation of ROS at the surface of the NPs. Such cell toxic response was not detected in healthy non-sensitized individuals. This study clearly demonstrates the different response of sensitized and non-sensitized mice, and highlights the importance of including individuals with respiratory disorders, such as allergic asthma, when evaluating health effects of inhaled nanomaterials.

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