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  • 1.
    Abdulbasid Samad, Delan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Farmaceut-patientkommunikation på öppenvårdsapotek i Kurdistan: En observationsstudie som undersöker i vilken omfattning apotekspersonalen informerar om läkemedelsanvändningen och dess verkan.2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Apotekens riktlinjer har utvecklats från att ha begränsat farmaceuter ideras utdelning av medicin till att ge råd eller erbjuda rådgivning om patientens medicinering. Det är viktigt att farmaceuter ger rådgivning kring patienters medicinering då det ger effektivt behandlingsresultat, ökad följsamhet och minskar konfusion och osäkerhet hos patienten. Studier har visat att den farmaceutiska rådgivningen varierar mycket på apotek. En svensk studie har visat att samtalet mellan farmaceut och patient fokuserar mer på ekonomi och regelverk än att ge farmaceutiskrådgivning. Det har tidigare inte gjorts studier på hur kommunikation samt den farmaceutiska rådgivningen fungerar i mellanöstern.

    Syfte: Syftet med den här studien är att undersöka kommunikationen mellan farmaceut och patient på öppenvårdsapotek i Kurdistan, Irak. Kommunikationen kommer att undersökas utifrån hur lång tid patientmötena tar och innehåll. Det som studeras är i vilken utsträckning apotekspersonalen konsulterar patienter samt den information som tillhandahålls till patienterna ur ett farmaceutiskt perspektiv.

    Metod: En kvantitativ och icke- deltagande observationsstudie där patientmöten observerades utifrån innehåll och tidsmätning av mötet. Observatören bockade avämnen som tas upp under mötet utefter en empirisk fastställd observationsmall.

    Resultat: 4 apotek deltog i studien och det gjordes sammanlagt 90 observationer varav 85 stycken inkluderades i studien. Apotekmiljön har en negativ påverkan på patientmötena, exempelvis att det saknas ett avskilt ställe för ett privatsamtal medpatienter, bullret i omgivningen och dålig organiserad läkemedel. Den stora delen av den medicinska konsulteringen är information om administrering, lite om läkemedelsverkan och nästan inget om biverkningar. Det icke-medicinska innehållet var frågor om pris och tillgänglighet av läkemedel.

    Diskussion: Det finns säkert många anledningar för varför kommunikationen inte är fokuserad på konsultering till patienter. En orsak kan vara otillräcklig kunskap bland informatörerna som konsultering kring biverkningar och läkemedels verkan exkluderas i kommunikationen. En annan förklaring kan vara att rådgivningen tar mer tid och at tapoteksägare upplever rådgivning som en dyr tjänst och av den anledningen inteprioriterar sin uppmärksamhet på läkemedelsrådgivning. Försäljningen som uppenbarligen inte ligger i att ge läkemedelsrådgivning till patienterna.

    Slutsats: Den här observationsstudien visade att mycket lite tid (medeltid 125,5 smin7 s/max 427 s) tillägnas till rådgivning kring patientens medicinering. Läkemedel är en stor behandlingsmetod inom hälso- och sjukvården av den orsaken borde farmaceutisk rådgivning vara tillgänglig för personer som besöker apotek. Resultatet avden här studien visar att dagens patientmöten på öppenvårdapotek i Kurdistan inte fokuserar på konsultering kring läkemedel. Eventuellt kommer patienten inte få ett nyttigt behandlingsresultat.

  • 2.
    Abed, Shahla
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Is adiponectin secreted via caveolae?: The importance of caveolae for stimulated adiponectin secretion in obesity2018Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 3.
    Abramsson, Linnea
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Följsamhet till behandling med bisfosfonater: En intervjustudie på ortopedavdelningen vid Norrlands Universitetssjukhus, Umeå2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 4.
    Aden, Hassan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Apotekssystem i Kanada och Storbritannienrelaterat till Sveriges utveckling i enomreglerad apoteksmarknad2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 5.
    Ahmed Nazad, Zina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    MicroRNAs as biomarkers in some cardiovascular diseases: A bioinformatics and review study2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 6.
    Akhatova, Elena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Information och rådgivningvid e-handelpå apotek i Sverige.2018Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 7.
    Akpan, Joyce
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The Prevalence of Potentially Inappropriate Drug Prescription among Elderly Patients Registered in Balder Clinic in Åmål, Sweden2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 8.
    Al-ameri, Khalid
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effektskillnad mellanmåldos och lågdos vidhjärtsviktsbehandling2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 9.
    Alfredji, Kaothar
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effekt av tillskott av vitamin D på vårt immunförsvar2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 10. Alhayali, Amani
    et al.
    Tavelin, Staffan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Velaga, Sitaram
    Dissolution and precipitation behavior of ternary solid dispersions of ezetimibe in biorelevant media2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 1, p. 79-88Article in journal (Refereed)
    Abstract [en]

    The effects of different formulations and processes on inducing and maintaining the supersaturation of ternary solid dispersions of ezetimibe (EZ) in two biorelevant media fasted-state simulated intestinal fluid (FaSSIF) and fasted-state simulated gastric fluid (FaSSGF) at different temperatures (25 °C and 37 °C) were investigated in this work.

    Ternary solid dispersions of EZ were prepared by adding polymer PVP-K30 and surfactant poloxamer 188 using melt-quenching and spray-drying methods. The resulting solid dispersions were characterized using scanning electron microscopy, differential scanning calorimetry (DSC), modulated DSC, powder X-ray diffraction and Fourier transformation infrared spectroscopy. The dissolution of all the ternary solid dispersions was tested in vitro under non-sink conditions.

    All the prepared solid dispersions were amorphous in nature. In FaSSIF at 25 °C, the melt-quenched (MQ) solid dispersions of EZ were more soluble than the spray-dried (SD) solid dispersions and supersaturation was maintained. However, at 37 °C, rapid and variable precipitation behavior was observed for all the MQ and SD formulations. In FaSSGF, the melting method resulted in better solubility than the spray-drying method at both temperatures.

    Ternary solid dispersions show potential for improving solubility and supersaturation. However, powder dissolution experiments of these solid dispersions of EZ at 25 °C may not predict the supersaturation behavior at physiologically relevant temperatures.

  • 11.
    Al-Obaidi, Mays
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effekt av vitamin A-tillskott på mortalitet och morbiditet hos barn mellan 6 månader och 6 års ålder: En litteraturstudie med fokus på effekter av vitaminA-tillskott på dödlighet och sjuklighet i diarré och luftvägsinfektioner hos barn i utvecklingsländer2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 12. Anand, Praveen
    et al.
    Whiteside, Garth
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hohmann, Andrea G
    Targeting CB2 receptors and the endocannabinoid system for the treatment of pain2009In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 60, no 1, p. 255-266Article in journal (Refereed)
    Abstract [en]

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

  • 13.
    Anderholm, Louise
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Behandling av beteendemässiga ochpsykiska symtom med fokus påagitation hos äldre med Alzheimerssjukdom.: En jämförelse mellan neuroleptika ochacetylkolinesterashämmare2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Inledning: År 2030 uppskattas det vara ungefär 230 000 stycken människor i Sverige somhar drabbats av någon typ av demenssjukdom. Sjukdomens stadier delas in i begynnande,mild, måttlig och svår demens. Där första symtomen i den begynnande fasen brukar vara attden drabbade inte kommer ihåg vart den lagt sina saker. I den svåra fasen av sjukdomen ärpatienten förmodligen beroende av dygnet runt vård, patienten brukar även ha svårt attprata, enstaka ord eller meningar brukar upprepas. Beteendemässiga och psykiska symtom(BPSD) hos demenssjuka är symtom som kan orsaka lidande hos patienten och dessanhöriga. Symtomen delas in i fyra undergrupper affektiva, psykossymtom, hyperaktivitetoch apati. Riskfaktorn med högst evidens är Apolipoprotein E (ApoE), ApoEε4-allelen.Riskfaktorer med lägre evidensgrad är t.ex. låg utbildning och släktskap.

    Sjukdomen orsakas av att nervcellerna i hjärnan dör, framförallt i delen av hjärnan därminnet sitter. En röntgen av hjärnan visar onormala proteininlagringar, amyloida plack.Amyloidhypotesen påstår att det blir en överproduktion av amyloid-beta proteinet vilken trosvara den patologiska händelsen vid Alzheimers sjukdom. Tauproteinet hyperfosfyleras till enisoform som är tre gånger större än i en frisk hjärna, om överproduktion av tau på specifikaställen eller hela hjärnan orsakar sjukdomen har forskarna inte kommit fram till ännu. Mildtill måttlig Alzheimers sjukdom behandlas med acetylkolinesterashämmarna donepezil,rivastagmin och galantamin. Svår Alzheimers sjukdom behandlas med en NMDAreceptoragonist,memantin.

    Syfte: Att undersöka om acetylkolinesterashämmare eller neuroleptika fungerar bäst vidsymtom som uppkommer vid BPSD, samt undersöka vilka biverkningar som är vanligast.

    Metod: PubMed har använts för att hitta studier som stämmer in på inklusionskriterierna.Studier som exkluderas är de som undersökt fel substans, fel indikation eller fel preparat t.ex.omega-3.

    Resultat: De vanligaste biverkningarna som rapporterats hos acetylkolinesterashämmarnaär bland annat illamående och kräkningar. Av neuroleptika preparaten verkar det varasömnighet som är den mest rapporterade biverkningen. Studierna som undersökteneuroleptika kom fram till ungefär samma sak, att preparaten kan förbättra symtomen. Av destudier som undersökte acetylkolinesterashämmarna var det tre studier som drog slutsatsenatt de kan ha effekt. En studie säger att det inte sågs någon skillnad mellan donepezil ochplacebo vid dessa typer av symtom.

    Diskussion: Då de olika studierna som använts i arbetet har undersökt olika effektmått hardet varit svårt att göra en rättvis bedömning om läkemedlen fungerar eller ej. Då i de flestafall bara gått och jämföra ett effektmått från studierna. Hade jag bestämt vilka effektmåttsom fick finnas i varje studie redan från början och sedan gjort en exkludering utifrån det,hade det varit enklare att jämföra studierna och därefter kommit fram till en bra slutsats. Viden jämförelse mellan de olika substanserna ur neuroleptikagruppen, är sömnighet denvanligaste biverkningen i tre av fyra grupper. Viktökning är också en av de vanligastebiverkningarna i två av grupperna där ungefär 32% drabbades av just denna biverkning.Varför patienterna ökat i vikt framgår inte i studierna.

    Slutsats: Acetylkolinesterashämmare och neuroleptika kan ha effekt vid symtom somuppkommer vid BPSD. Acetylkolinesterashämmarna bör provas i första hand om intebehandlingen redan är insatt.

  • 14. Andersen, Toril
    et al.
    Bleher, Stefan
    Flaten, Goril Eide
    Tho, Ingunn
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Skalko-Basnet, Natasa
    Chitosan in Mucoadhesive Drug Delivery: Focus on Local Vaginal Therapy2015In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 13, no 1, p. 222-236Article in journal (Refereed)
    Abstract [en]

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

  • 15. Andersen, Toril
    et al.
    Mishchenko, Ekaterina
    Flaten, Gøril Eide
    Ericson Sollid, Johanna U.
    Mattsson, Sofia
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Tho, Ingunn
    Škalko-Basnet, Nataša
    Chitosan-Based Nanomedicine to Fight Genital Candida Infections: Chitosomes2017In: Marine Drugs, ISSN 1660-3397, E-ISSN 1660-3397, Vol. 15, no 3, article id 64Article in journal (Refereed)
    Abstract [en]

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

  • 16.
    Arakji Jawad, Ola
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effekter av begränsad förpackningsstorlek för paracetamol2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 17.
    Asi Rebatti, Lava
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Premedicinering av barn: - en jämförelse mellan alfa-2-adrenoceptoragonister ochmidazolam2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Premedicinering innebär att en patient behandlas med lugnande läkemedel inför enoperation eller ett ingrepp för att dämpa dennes oro och smärta. Inom den pediatriskapopulationen är detta vanligt då yngre patienter kan uppleva oro eftersom de inte alltidförstår syftet med ingreppet och kan känna rädsla då de ska separeras från sinaföräldrar. Bensodiazepinet midazolam har länge använts inom premedicinering tillbarn och har väl dokumenterad effekt. Det har dock påvisats att läkemedlet kan geupphov till så kallade paradoxala reaktioner, en biverkan som innebär att barnen fåroväntade reaktioner i form av t ex agitation. Det har därför föreslagits att substansenbör ersättas med alfa-2-adrenoceptoragonister som t ex klonidin eller dexmedetomidin,vilka har samma indikationer som midazolam, men utan att orsaka paradoxalareaktioner.

    Syftet med detta examensarbete är att undersöka om alfa-2-adrenoceptoragonister äröverlägsna midazolam vid premedicinering av barn. Arbetet är en litteraturstudie somfrämst jämfört resultaten från kliniska prövningar av olika läkemedelsbehandlingar isamband med premedicinering av barn avseende effekt och kvalitet, samt uppkomst avbiverkningar mellan de tre substanserna midazolam, klonidin och dexmedetomidin. Deprimära parametrar som jämförts är sedationsdjup, tillslagstid, substansernasanxiolytiska effekt och återhämtningsprofil. De sekundära parametrarna är hanteringav separation från föräldrar, föräldrarnas betyg samt läkemedels-/maskacceptans.

    Resultatet visar att de två alfa-2-adrenoceptoragonisterna klonidin ochdexmedetomidin är bättre än midazolam vad gäller sedationsdjup, separation frånföräldrar, läkemedelsacceptans och återhämtningsprofil, samt var denläkemedelsgrupp som gavs högst betyg av föräldrarna. Anxiolytisk effekt ochmaskacceptans var likvärdiga mellan de två grupperna, medan midazolam hadesnabbast tillslagstid. Paradoxala reaktioner förekom i relativt hög frekvens vidmidazolamsedering, medan alfa-2-adrenoceptoragonisterna gav biverkningar i form avhemodynamiska förändringar som sänkt blodtryck och puls.

    Avslutningsvis visar resultaten i denna studie att alfa-2-adrenoceptoragonister är attföredra framför midazolam. Speciellt avsaknaden av paradoxala reaktioner vid sederingmed alfa-2-adrenoceptoragonister gör att den gruppen av läkemedel har en stor fördelframför midazolam vid sedering av barn. Men i de fall där barnet har hemodynamiskabesvär i form av exempelvis bradykardi, bör man undvika alfa-2-adrenoceptoragonisteroch istället premedicinera med midazolam.

  • 18.
    Attebäck, Maria
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Är metformin ett effektivt och säkert behandlingsalternativ till insulin vid graviditetsdiabetes?: - En litteraturstudie av det vetenskapliga kunskapsläget2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 19. Benetou, V.
    et al.
    Orfanos, P
    Feskanich, D
    Michaëlsson, K
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ahmed, L A
    Peasey, A
    Wolk, A
    Brenner, H
    Bobak, M
    Wilsgaard, T
    Schöttker, B
    Saum, K-U
    Bellavia, A
    Grodstein, F
    Klinaki, E
    Valanou, E
    Papatesta, E-M
    Boffetta, P
    Trichopoulou, A
    Education, marital status, and risk of hip fractures in older men and women: the CHANCES project2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, no 6, p. 1733-1746Article in journal (Refereed)
    Abstract [en]

    The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk.

    INTRODUCTION: The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA.

    METHODS: A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models.

    RESULTS: Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05).

    CONCLUSIONS: The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.

  • 20. Benetou, Vassiliki
    et al.
    Orfanos, Philippos
    Feskanich, Diane
    Michaëlsson, Karl
    Pettersson-Kymmer, Ulrika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Eriksson, Sture
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation.
    Grodstein, Francine
    Wolk, Alicja
    Bellavia, Andrea
    Ahmed, Luai A
    Boffeta, Paolo
    Trichopoulou, Antonia
    Fruit and Vegetable Intake and Hip Fracture Incidence in Older Men and Women: The CHANCES Project2016In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 31, no 9, p. 1743-1752Article in journal (Refereed)
    Abstract [en]

    The role of fruit and vegetable intake in relation to fracture prevention during adulthood and beyond is not adequately understood. We investigated the potential association between fruit and vegetable intake and hip fracture incidence in a large sample of elderly from Europe and United States. A total of 142,018 individuals (among which 116,509 women), aged ≥60 years old, from five cohorts, were followed-up prospectively for 1,911,482 person-years accumulating 5,552 hip fractures. Fruit and vegetable intake was assessed by validated, cohort-specific, food-frequency questionnaires. Ηip fractures were ascertained through national patient registers or telephone interviews/questionnaires. Adjusted hazard ratios (HR) derived by Cox proportional-hazards regression were estimated for each cohort and subsequently pooled using random-effects meta-analysis. Intake of ≤ 1 servings/day of fruit and vegetables combined was associated with 39% higher hip fracture risk [pooled adjusted HR:1.39, 95% Confidence Intervals (CIs): 1.20, 1.58] in comparison to moderate intake (>3 and ≤5 servings/day) (pfor heterogeneity  = 0.505), whereas higher intakes (>5 servings/day) were not associated with lower risk in comparison to the same reference. Associations were more evident among women. We concluded that a daily intake of one or less servings of fruits and vegetables was associated with increased hip fracture risk in relation to moderate daily intakes. Older adults with such low fruit and vegetable consumption may benefit from raising their intakes to moderate amounts in order to reduce their hip fracture risk. 

  • 21.
    Berg, Emma
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Utvärdering av farmaceutiska tjänster – en litteraturstudie2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    En farmaceuts roll på ett öppenvårdsapotek är att erbjuda trygga och effektivaprodukter samt kunna ge råd om dessa. Genom sin kompetens inom läkemedel är öppenvårdsapotek är en viktig del i sjukvårdssektorn. Apoteken i Sverige är till stordel privatägda och de olika kedjorna konkurrera med varandra. Det är därför av intresse för apoteken att inte bara kunna erbjuda bra produkter utan även att generera vinst.

    Syftet med studien är att undersöka vilka metoder och resultat som används för att utvärdera farmaceutiska tjänster på öppenvårdsapotek.

    Studien är en litteraturstudie och litteraturen som användes bestod till största delen av artiklar som hämtades från sökmotorn PubMed. Olika nyckelord användes i olika kombinationer vid sökning och artiklarna valdes ut efter relevans i rubrik och”abstract”. Från de relevanta artiklarna kunde också relaterade artiklar hittas. Utöver artiklarna och några av deras källor användes en rapport från Läkemedelsverket ochen C-uppsats.

    Resultaten från artiklarna delades in i fem kategorier: kliniskt utfall, livskvalitetsförändringar, följsamhet till läkemedelsanvändning, apotekskundens upplevelse och farmaceutens upplevelse. Under kategorin kliniskt utfall hittades studier som genom sjukhuskontroll kunde visa på att ökad farmaceutisk vård gav bättre kliniskt utfall. Den ökade farmaceutiska vården gjorde att användning av läkemedel förbättrades vilket gjorde att deltagarnas sjukdomsbild förändrades till det bättre. Vid livskvalitetsförändringar visade en studie att deltagarna hade fått bättre hälsa och mindre risker för ytterligare sjukdomar genom att de fått ökad farmaceutisk vård och bättre användning av läkemedel. Studien använde sig av självrapportering och sjukhuskontroll. För att visa på förbättrad följsamhet till läkemedelsanvändning användes självrapportering och räkning av läkemedel där mängden läkemedel som användes jämfördes med mängden som borde ha används. Här kunde två av studierna visa på en positiv förändring av följsamheten medan en tredje studie inte visade på någon skillnad av följsamheten med ökad farmaceutiskvård. För att mäta apotekskundens och farmaceutens upplevelse användes kundmöten och intervjuer. Här mättes deltagarnas upplevelse utifrån om de varnöjda och i studierna som användes var resultatet positivt, både för kunder och förfarmaceuter, då ökad farmaceutisk vård användes.

    De resultat som visar kliniskt utfall, livskvalitetsförändringar och följsamhet till läkemedelsanvändning ger ett konkret värde som visar på positiva förändringar efteråtgärder. De visar dock inte deltagarnas upplevelse. De resultat som visar apotekskundens och farmaceutens upplevelse visar inte om användningen av läkemedel förbättrats och om den ökade farmaceutiska vården gav resultat. De flesta av resultaten i studierna visade positiva förändringar vid ökad farmaceutisk vård. För att införa ökad farmaceutisk vård på öppenvårdsapotek i Sverige krävs vissa resurser.

    Genom att kombinera flera metoder kan bättre resultat för att utvärdera farmaceutiska tjänster ges. Resultaten av de olika metoderna ger olika typer av utfall. Denna studie kan utgöra underlag för att kunna lägga mer resurser på att öka den farmaceutiska vården och ge farmaceuter en större roll inom hälso- och sjukvård. Detskulle leda till bättre läkemedelsanvändning och förbättrad hälsa för kunder och patienter.

  • 22.
    Berglund, Nadja
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inkjet Printing and Personalised Medicine:Possibilities and Practicalities2018Independent thesis Basic level (professional degree), 10 credits / 15 HE creditsStudent thesis
  • 23.
    Bergqvist, Tanja
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Minitabletter till barn: Acceptans och formulering vid oral administrering2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 24.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundgren, Per
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Löfgren, Magnus
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Ragagnin, Gianna
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Taube, Magdalena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Turkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wang, Ming-De
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Neuroactive steroid effects on cognitive functions with a focus on the serotonin and GABA systems.2006In: Brain Research Reviews, ISSN 0165-0173, E-ISSN 1872-6321, Vol. 51, no 2, p. 212-239Article in journal (Refereed)
  • 25.
    Birzniece, Vita
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Türkmen, Sahruh
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lindblad, Charlotte
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Zhu, Di
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Johansson, Inga-Maj
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Wahlström, Göran
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    GABA(A) receptor changes in acute allopregnanolone tolerance2006In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 535, no 1-3, p. 125-134Article in journal (Refereed)
    Abstract [en]

    To study acute tolerance, rats were anesthetized with interrupted i.v. allopregnanolone infusions where the "silent second" in the electroencephalogram (EEG) was the target. Animals were killed either directly at the first silent second or at the silent second level after 30 or 90 min of anaesthesia. Acute tolerance was demonstrated at 90 min of anaesthesia as earlier shown. In situ hybridization showed a decreased expression of the gamma-aminobutyric acid(A) (GABA(A)) receptor subunit alpha4mRNA amount in the thalamus ventral-posteriomedial nucleus of the tolerant rats. A parallel change in the abundance of the alpha4 subunit was detected with immunohistochemistry. The increase in maintenance dose rate (MDR) was significantly negatively correlated with the alpha4mRNA in the thalamus ventral-posteriomedial nucleus, and positively correlated with alpha2mRNA in different hippocampal subregions. There was also a positive relationship between the alpha1mRNA amounts in the different hippocampal subregions, with significant differences between groups. These changes in GABA(A) receptor subunits mRNA expression and protein (alpha4) might be of importance for the development of acute tolerance to allopregnanolone.

  • 26.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The endocannabinoid system: a translational study from Achilles tendinosis to cyclooxygenase2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The endogenous cannabinoids anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) exert their effect by activating cannabinoid receptors (CB). These receptors mediate a broad range of physiological functions such as beneficial effects in pain and inflammation, although little is known about the expression of CB receptors in human pain conditions. AEA and 2-AG are short- lived molecules due to their rapid cellular accumulation and metabolism. The enzymes primarily responsible for their degradation are fatty acid amide hydrolase (FAAH) for AEA and monoacylglycerol lipase (MGL) for 2-AG. Inhibition of endocannabinoid metabolism is a potential approach for drug development, and there is a need for the identification of novel compounds with inhibitory effects upon FAAH and MGL.

    In Paper I of this thesis, the expression of CB1 receptors in human Achilles tendon was examined. We found expression of CB1 receptors in tenocytes, blood vessel wall as well as in the perineurium of the nerve. A semi-quantitative analysis showed an increase of CB1 receptors in painful human Achilles tendinosis.

    In papers II and III, termination of AEA signalling was investigated via inhibition of FAAH. In Paper II, Flu-AM1, an analogue of flurbiprofen, was investigated. The compound inhibited both FAAH and the oxygenation of 2-AG by cyclooxygenase-2. In Paper III the antifungal compound ketoconazole was shown to inhibit the cellular uptake of AEA in HepG2, CaCo-2 and C6 cell lines in a manner consistent with inhibition of FAAH.

    The role of FAAH in gating the cellular accumulation of AEA was investigated in Paper IV. FAAH has been shown to control the concentration gradient of AEA across the plasmamembrane in RBL2H3 cells, whereas no such effect is seen in other FAAH-expressing cell lines. To determine whether this effect is assay dependent or due to intrinsic differences between the cell lines, we assayed four cell lines with different levels of FAAH expression using the same methodology. We found that the sensitivity of FAAH uptake inhibition was not dependent on the expression level of FAAH, suggesting that factors other than FAAH are important for uptake.

    Paper V is focused on the inhibition of MGL. Prior to this study no selective inhibitors of the enzyme had been described. Thus, we screened a number of compounds for their inhibitory effect on MGL. Troglitazone was found to be an inhibitor of MGL, although its potency was dependent upon the enzyme assay used. 

  • 27.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Blomqvist, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Joel, Hedlin
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103479-Article in journal (Refereed)
    Abstract [en]

    Background:

    The endocannabinoid ligand anandamide (AEA) is removed from the extracellular space by a process ofcellular uptake followed by metabolism. In many cells, such as the RBL-2H3 cell line, inhibition of FAAH activity reduces theobserved uptake, indicating that the enzyme regulates uptake by controlling the intra- : extracellular AEA concentrationgradient. However, in other FAAH-expressing cells, no such effect is seen. It is not clear, however, whether these differencesare methodological in nature or due to properties of the cells themselves. In consequence, we have reinvestigated the roleof FAAH in gating the uptake of AEA.Methodology/Principal Findings: The effects of FAAH inhibition upon AEA uptake were investigated in four cell lines: AT1rat prostate cancer, RBL-2H3 rat basophilic leukaemia, rat C6 glioma and mouse P19 embryonic carcinoma cells. SemiquantitativePCR for the cells and for a rat brain lysate confirmed the expression of FAAH. No obvious expression of atranscript with the expected molecular weight of FLAT was seen. FAAH expression differed between cells, but all four couldaccumulate AEA in a manner inhibitable by the selective FAAH inhibitor URB597. However, there was a difference in thesensitivities seen in the reduction of uptake for a given degree of FAAH inhibition produced by a reversible FAAH inhibitor,with C6 cells being more sensitive than RBL-2H3 cells, despite rather similar expression levels and activities of FAAH. Thefour cell lines all expressed FABP5, and AEA uptake was reduced in the presence of the FABP5 inhibitor SB-FI-26, suggestingthat the different sensitivities to FAAH inhibition for C6 and RBL2H3 cells is not due to differences at the level of FABP-5.Conclusions/Significance: When assayed using the same methodology, different FAAH-expressing cells display differentsensitivities of uptake to FAAH inhibition.

  • 28.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Forsgren, Sture
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Alfredson, Håkan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Increased expression of cannabinoid CB(1) receptors in achilles tendinosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24731-Article in journal (Refereed)
    Abstract [en]

    Background: The endogenous cannabinoid system is involved in the control of pain. However, little is known as to the integrity of the cannabinoid system in human pain syndromes. Here we investigate the expression of the cannabinoid receptor 1 (CB(1)) in human Achilles tendons from healthy volunteers and from patients with Achilles tendinosis.

    Methodology: Cannabinoid CB(1) receptor immunoreactivity (CB(1)IR) was evaluated in formalin-fixed biopsies from individuals suffering from painful Achilles tendinosis in comparison with healthy human Achilles tendons.

    Principal Findings: CB(1)IR was seen as a granular pattern in the tenocytes. CB(1)IR was also observed in the blood vessel wall and in the perineurium of the nerve. Quantification of the immunoreactivity in tenocytes showed an increase of CB(1) receptor expression in tendinosis tissue compared to control tissue.

    Conclusion: Expression of cannabinoid receptor 1 is increased in human Achilles tendinosis suggesting that the cannabinoid system may be dysregulated in this disorder.

  • 29.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Larsson, Therese N. L.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Jacobsson, Stig O. P.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ketoconazole Inhibits the Cellular Uptake of Anandamide via Inhibition of FAAH at Pharmacologically Relevant Concentrations2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e87542-Article in journal (Refereed)
    Abstract [en]

    Background: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). Methodology/Principal Findings: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 mu M, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 mu M. Conclusions/Significance: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer.

  • 30.
    Björklund, Emmelie
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Norén, E
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Nilsson, J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of monoacylglycerol lipase by troglitazone, N-arachidonoyl dopamine and the irreversible inhibitor JZL184: comparison of two different assays2010In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 161, no 7, p. 1512-1526Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Drugs used clinically usually have a primary mechanism of action, but additional effects on other biological targets can contribute to their effects. A potentially useful additional target is the endocannabinoid metabolizing enzyme monoacylglycerol lipase (MGL). We have screened a range of drugs for inhibition of MGL and compared the observed potencies using different MGL enzyme assays.

    EXPERIMENTAL APPROACH: MGL activity was screened using recombinant human MGL (cell lysates and purified enzyme) with 4-nitrophenyl acetate (NPA) as substrate. 2-Oleolyglycerol metabolism by rat cerebellar cytosolic MGL and by recombinant MGL was also investigated.

    KEY RESULTS: Among the 96 compounds screened in the NPA assay, troglitazone, CP55,940, N-arachidonoyl dopamine and AM404 inhibited NPA hydrolysis by the lysates with IC(50) values of 1.1, 4.9, 0.78 and 3.1µM, respectively. The potency for troglitazone is in the same range as its primary pharmacological activity, activation of peroxisome proliferator-activated receptor (PPAR) γ. Among PPARγ ligands, the potency order towards human MGL was troglitazone > ciglitazone > rosiglitazone > 15-deoxy-Δ(12,14) -prostaglandin J(2) ≈ CAY 10415 > CAY 10514. In contrast to the time-dependent inhibitor JZL184, the potency of troglitazone was dependent upon the enzyme assay system used. Thus, troglitazone inhibited rat cytosolic 2-oleoylglycerol hydrolysis less potently (IC(50) 41µM) than hydrolysis of NPA by the human MGL lysates.

    CONCLUSIONS AND IMPLICATIONS: 'Hits' in screening programmes for MGL inhibitors should be assessed in different MGL assays. Troglitazone may be a useful lead for the design of novel, dual action MGL inhibitors/PPARγ activators.

  • 31.
    Blomqvist, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Characterisation and regulation of the uptake of the endocannabinoid anandamide in RBL2H3 and AT-1 cell lines2012Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
  • 32. Boldrup, Linda
    et al.
    Wilson, Sandy J
    Barbier, Ann J
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    A simple stopped assay for fatty acid amide hydrolase avoiding the use of a chloroform extraction phase.2004In: J Biochem Biophys Methods, ISSN 0165-022X, Vol. 60, no 2, p. 171-7Article in journal (Refereed)
  • 33. Brengdahl, Johan
    et al.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    A novel assay for monoacylglycerol hydrolysis suitable for high-throughput screening.2006In: Anal Biochem, ISSN 0003-2697, Vol. 359, no 1, p. 40-4Article in journal (Refereed)
  • 34.
    Börjesson, Pernilla
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Den skriftliga patientinformationen: -en jämförelse av bipacksedlar för enalapril2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Introduktion

    När läkemedel säljs följer det med en bipacksedel som användaren uppmanas att läsa i sin helhet. Denna bipacksedel är obligatorisk och baseras på produktresumén som är en sammanfattning av läkemedlet, och krävs för att läkemedlet ska kunna godkänns. När läkemedelsbehandlingar blir långvariga, tex vid hypertoni, kan olika generika inom samma utbytbarhetsgrupp expedieras på apoteket när kunden kommer för att hämta sin medicin. Apoteket erbjuder den förpackning som Tandvårds- och Läkemedelsförmånsverket utsetts till att vara periodens vara. Trots att förpackning och utseende kan variera är läkemedlen likvärdiga och har samma indikation och biverkningsprofil. När bipacksedeln läses igenom kan det uppfattas som att detta inte stämmer, i synnerhet när biverkningar och varningar läses. Enalapril som är ett läkemedel mot hypertoni och hjärtsvikt, har för närvarande tio generika som betraktas som utbytbara. Sedan 1998 finns det inom EU gemensamma riktlinjer för hur en bipacksedel ska utformas och mallar att följa. Bland annat anges där vilka rubriker som ska vara med och i vilken ordning de ska komma. Läkemedelsverket ansvarar för översynen av innehållet i bipacksedeln i Sverige. Trots gemensamma regler och harmoniseringsprocesser som ska göra informationen mer enhetlig, kan skillnader förekomma i texten och det kan se ut som om till exempel biverkningsprofilen är annorlunda.

    Syfte

    Detta arbete studerar om det finns skillnader i hur den skriftliga informationen som följer med generika kan skilja sig åt och vad det kan bero på.

    Metod

    Undersökningen är en kvalitativ studie av bipacksedlars text hos 10 generika av enalapril som ingår i samma utbytbarhetsgrupp.

    Resultat

    Det förekommer skillnader i både innehåll och placering av text. Den största skillnaden beror dock på att ordvalen skiljer sig åt vilket gör att det kan tolkas som olika varningar eller biverkningar.

    Diskussion

    När medicinska termer används utan förklaring i en text finns risken att det uppfattas som olika biverkningar. Ett exempel är när man väljer att använda den medicinska termen anorexi istället för aptitförlust. Det förekommer också att information hamnar på olika platser i olika dokument eller att information helt uteblir.

    Slutsats

    De flesta skillnader mellan innehållet i bipacksedlarna för enalapril berodde på att ordvalen varierade samt att informationens placering inte alltid var enhetlig. Det behövs ytterligare förenkling i språket i många bipacksedlar samt en mer enhetligt utformad text för att den ska upplevas utbytbar. Dessutom skulle information vad gäller etniska skillnader behöva en egen rubrik så att det är mer överskådligt i texten.

  • 35.
    Cassel, Gudrun
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cyanide and central nervous system: a study with focus on brain dopamine1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The brain is a major target site in acute cyanide intoxication, as indicated by several symptoms and signs. Cyanide inhibits the enzyme cytochrome oxidase. This inhibition causes impaired oxygen utilization in all cells affected, severe metabolic acidosis and inhibited production of energy. In this thesis, some neurotoxic effects of cyanide, in particular, the effects on dopaminergic pathways were studied.

    In a previous study, decreased levels of striatal dopamine and HVA were found after severe cyanide intoxication (5-20 mg/kg i.p.). However, increased striatal dopamine were found in rats showing convulsions after infusion of low doses of cyanide (0.9 mg/kg i.v.), at the optimal dose rate (the dose rate that gives the treshold dose).

    Increased striatal dopamine synthesis was observed in rats after cyanide treatment and in vitro. Furthermore, in rat, as well as in pig striatal tissue, cyanide dose- dependently increased the oxidative deamination of 5-HT (MAO-A) and DA (MAO-A and -B) but not that of PEA (MAO-B). Thus cyanide affects both the synthesis and metabolism of dopamine.

    In rats, sodium cyanide (2.0 mg/kg, i.p.) decreased the striatal dopamine Dj- and D2-receptor binding 1 hour after injection. Increased extracellular levels of striatal dopamine and homovanillic acid were also shown after cyanide (2.0 mg/kg; i.p.). DOPAC and 5-HIAA were slightly decreased. This indicates an increased release or an extracellular leakage of dopamine due to neuronal damage caused by cyanide. Thus the effects of cyanide on dopamine Dj- and D2~receptors could in part be due to cyanide-induced release of dopamine.

    Because of reported changes in intracellular calcium in cyanide-treated animals, the effects of cyanide on inositol phospholipid breakdown was studied. Cyanide seemed not to affect the inositol phospholipid breakdown in vitro.

    The effects of cyanide on the synthesis and metabolism of brain GAB A were also examined. A decreased activity of both GAD and GAB A-T were found in the rat brain tissue. The reduced activity of GAB A-T, but not that of GAD returned to the control value after adding PLP in the incubation media. The cyanide-produced reduction of GABA levels will increase the susceptibility to convulsions, and could partly be due to GAD inhibition.

    In conclusion, cyanide affects the central nervous system in a complex manner. Some effects are probably direct. The main part, however, appears to be secondary, e.g. hypoxia, seizures, changes in calcium levels or transmitter release produced by cyanide.

  • 36.
    Cassini Bäckström, Cristina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Safety and efficacy ofguanfacine in treating ADHD in children and adolescents: current status of knowledge: A literature study including important factors to consider as a pharmacist in a patient-counselling role2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 37.
    Ceylan, Kamile
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    PROVTAGNINGSTJÄNST: Ett pilotprojekt mellan Apoteket AB och Min Doktor2018Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 38. Chandyo, Ram K.
    et al.
    Ulak, Manjeswori
    Sommerfelt, Halvor
    Schneede, Jørn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per M.
    Strand, Tor A.
    Nutritional Intake and Status of Cobalamin and Folate among Non-Pregnant Women of Reproductive Age in Bhaktapur, Nepal2016In: Nutrients, ISSN 2072-6643, E-ISSN 2072-6643, Vol. 8, no 6, article id 375Article in journal (Refereed)
    Abstract [en]

    Cobalamin and folate are especially important for women of childbearing age due to their ubiquitous role in fetal growth and development. Population-based data on cobalamin and folate status are lacking from Nepal, where diets are mostly vegetarian. The objectives of the study were to investigate cobalamin and folate intake and status, and to explore associations with socio-demographics, anthropometrics, anemia, and dietary habits. Following a random selection of geographical clusters, we collected blood samples from 500 non-pregnant women and 24-h dietary recalls and food frequency questionnaires from a subsample of 379 women. Twenty percent of the women did not consume any food containing cobalamin during the days recalled, and in 72% nutritional cobalamin intake was <1 mu g/day. Eighty-four percent of the women had cobalamin intake lower than the estimated average requirement (EAR) (< 2 mu g/day). In contrast, only 12% of the women had a folate intake less than 100 mu g per day, whereas 62% had intake between 100 and 320 mu g. Low plasma cobalamin (< 150 pmol/L) was found in 42% of the women, most of whom (88%) also had elevated levels of methylmalonic acid. Our results indicated a high prevalence of nutritional cobalamin deficiency, while folate deficiency was uncommon.

  • 39. Chung, Sui Chu
    et al.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Granfors, Torvald
    Egevad, Lars
    Mancini, Giacomo
    Lutz, Beat
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    A high cannabinoid CB(1) receptor immunoreactivity is associated with disease severity and outcome in prostate cancer2009In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 45, no 1, p. 174-182Article in journal (Refereed)
    Abstract [en]

    In the light of findings indicating that cannabinoids can affect the proliferation of a number of cancer cell types and that cannabinoid receptor expression is higher in prostate cancer cell lines than in non-malignant cells, we investigated whether the level of cannabinoid 1 receptor immunoreactivity (CB(1)IR) in prostate cancer tissues is associated with disease severity and outcome. Formalin-fixed paraffin-embedded non-malignant and tumour tissue samples from patients who were diagnosed with prostate cancer at a transurethral resection for voiding problems were used. CB(1)IR, which was scored in a total of 399 cases, was associated with the epithelial cell membranes, with little staining in the stroma. Patients with a tumour CB(1)IR score greater or equal to the median (2) had a significantly higher proportion of Gleason scores 8-10, metastases at diagnosis, tumour size and rate of cell proliferation at diagnosis than patients with a score<2. For 269 cases, tumour CB(1)IR was measured for patients who only received palliative therapy at the end stages of the disease, allowing the influence of CB(1)IR upon the disease outcome to be determined. Receiver operating characteristic (ROC) curves showed an area under the curve of 0.67 (95% confidence limits 0.59-0.74) for CB(1)IR in the tumour. CB(1)IR in non-malignant tissue was not associated with disease outcome. A tumour CB(1)IR score >or=2 was associated with a significantly lower disease specific survival. A Cox proportional hazards regression indicated that the tumour CB(1)IR score and the Gleason score were independent prognostic variables. It is concluded that a high tumour CB(1)IR score is associated with prostate cancer severity and outcome.

  • 40.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wilson, Alan A.
    Congiu, Cenzo
    Onnis, Valentina
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen2013In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 720, no 1-3, p. 383-390Article in journal (Refereed)
    Abstract [en]

    Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH/cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl) amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [H-3]anandamide by rat brain homogenates with IC50 values of 044 and 0.74 mu M. The corresponding values for flurbiprofen and naproxen were 29 and > 100 mu M, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K-slope(i) and K-intercept(i) values of 0.21 and 1.4 mu M, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol > COX-1 vs. arachidonic acid > COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than Flu-AM 1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low micromolar concentrations inhibited the FAAH-driven uptake of [H-3]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [F-18]DOPP to brain FAAH. It is concluded that Flu-AM 1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.

  • 41.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nording, Malin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells.2014In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 7, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Background: It has been reported that direct activation of the cannabinoid CB1 receptor in epidermal growth factor (EGR)-stimulated PC-3 prostate cancer cells results in an anti-proliferative effect accompanied by a down-regulation of EGF receptors (EGFR). In the present study, we investigated whether similar effects are seen following inhibition of the endocannabinoid hydrolytic enzyme monoacylglycerol lipase (MGL).

    Results: CB1 receptor expression levels were found to differ greatly between two experimental series conducted using PC-3 cells. The monoacylglycerol lipase inhibitor JZL184 increased levels of 2-arachidonoylglycerol in the PC-3 cells without producing changes in the levels of anandamide and related N-acylethanolamines. In the first series of experiments, JZL184 produced a small mitogenic effect for cells that had not been treated with EGF, whereas an anti-proliferative effect was seen for EGF-treated cells. An anti-proliferative effect for the EGF-treated cells was also seen with the CB receptor agonist CP55,940. In the second batch of cells, there was an interaction between JZL184 and CB1 receptor expression densities in linear regression analyses with EGFR expression as the dependent variable.

    Conclusions: Inhibition of MGL by JZL184 can affect EGFR expression. However, the use in our hands of PC-3 cells as a model to investigate the therapeutic potential of MGL inhibitors and related compounds is compromised by their variability of CB1 receptor expression.

  • 42.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65798-Article in journal (Refereed)
    Abstract [en]

    Background: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.

    Methodology/Principal Findings: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.

    Conclusions/Significance: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative.

  • 43. Cisneros, Jose A.
    et al.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gonzalez-Gil, Ines
    Hu, Yanling
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Canales, Angeles
    Medrano, Francisco J.
    Romero, Antonio
    Ortega-Gutierrez, Silvia
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Lopez-Rodriguez, Maria L.
    Structure-Activity Relationship of a New Series of Reversible Dual Monoacylglycerol Lipase/Fatty Acid Amide Hydrolase Inhibitors2012In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 55, no 2, p. 824-836Article in journal (Refereed)
    Abstract [en]

    The two endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), play independent and nonredundant roles in the body. This makes the development of both selective and dual inhibitors of their inactivation an important priority. In this work we report a new series of inhibitors of monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Among them, (+/-)-oxiran-2-ylmethyl 6-(1,1'-biphenyl-4-yl)hexanoate (8) and (2R)-(-)-oxiran-2-ylmethyl(4-benzylphenyl)acetate (30) stand out as potent inhibitors of human recombinant MAGL (IC(50) (8) = 4.1 mu M; IC(50) (30) = 2.4 mu M), rat brain monoacylglycerol hydrolysis (IC(50) (8) = 1.8 mu M; IC(50) (30) = 0.68 mu M), and rat brain FAAH (IC(50) (8) = 5.1 mu M; IC(50) (30) = 0.29 mu M). Importantly, and in contrast to the other previously described MAGL inhibitors, these compounds behave as reversible inhibitors either of competitive (8) or noncompetitive nature (30). Hence, they could be useful to explore the therapeutic potential of reversible MAGL inhibitors.

  • 44.
    Claeson, Anna-Sara
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Nording, Malin L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Perceived stress, sensory irritation and levels of prostaglandin F2 alpha in plasma after acrolein exposure: a pilot study2017In: Chemical Senses, ISSN 0379-864X, E-ISSN 1464-3553, Vol. 42, no 2, p. E28-E28Article in journal (Refereed)
  • 45.
    Claeson, Anna-Sara
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Nording, Malin L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Levels of oxylipins, endocannabinoids and related lipids in plasma before and after low-level exposure to acrolein in healthy individuals and individuals with chemical intolerance2017In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 121, p. 60-67Article in journal (Refereed)
    Abstract [en]

    Oxylipins and endocannabinoids play important biological roles, including effects upon inflammation. It is not known whether the circulating levels of these lipids are affected by inhalation of the environmental pollutant acrolein. In the present study, we have investigated the consequences of low-level exposure to acrolein on oxylipin, endocannabinoid and related lipid levels in the plasma of healthy individuals and individuals with chemical intolerance (CI), an affliction with a suggested inflammatory origin. Participants were exposed twice (60 min) to heptane and a mixture of heptane and acrolein. Blood samples were collected before exposure, after and 24 h post-exposure. There were no overt effects of acrolein exposure on the oxylipin lipidome or endocannibinoids detectable in the bloodstream at the time points investigated. No relationship between basal levels or levels after exposure to acrolein and CI could be identified. This implicates a minor role of inflammatory mediators on the systemic level in CI.

  • 46.
    Curic, Emina
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Vilka negativa effekter uppkommer av NSAID-användning hos patienter som är drabbade av hjärtsvikt?: - En jämförelse mellan de 6 mest använda receptbelagda NSAID i Sverige2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 47.
    Dahlqvist, Solbritt Rantapää
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mjörndal, Tom
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Acetylator phenotypes in rheumatoid-arthritis patients with or without adverse drug-reactions to sodium-aurothiomalate or d-penicillamine1987In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 16, no 4, p. 235-239Article in journal (Refereed)
    Abstract [en]

    The acetylator phenotype was determined in 59 patients with classical, seropositive and erosive rheumatoid arthritis (RA) treated with sodium-aurothiomalate or d-penicillamine. Patients with adverse drug reactions (ADR) leading to drug withdrawal (n=29) were compared with a group of patients without ADR (n=30). The frequency of slow acetylators was significantly (p< 0.05) increased in all RA patients, irrespective of the presence of ADR, particularly in the male patients, compared with a control population. No association was found between acetylator phenotype and clinical data or secondary Sjögrens's syndrome (SS).

  • 48.
    Dahlqvist, Solbritt Rantapää
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
    Mjörndal, Tom
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Östberg, Yngve
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Acetylator phenotypes in primary Sjögren's syndrome1994In: British Journal of Rheumatology, ISSN 0263-7103, E-ISSN 1460-2172, Vol. 33, no 4, p. 405-406Article in journal (Refereed)
  • 49. De Lago, Eva
    et al.
    Gustafsson, Sofia B
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Fernández-Ruiz, Javier
    Nilsson, Jonas
    Umeå University, Faculty of Science and Technology, Molecular Biology (Faculty of Science and Technology).
    Jacobsson, Stig O P
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Pharmacology.
    Acyl-based anandamide uptake inhibitors cause rapid toxicity to C6 glioma cells at pharmacologically relevant concentrations.2006In: J Neurochem, ISSN 0022-3042, Vol. 99, no 2, p. 677-88Article in journal (Refereed)
    Abstract [en]

    Compounds blocking the uptake of the endogenous cannabinoid anandamide (AEA) have been used to explore the functions of the endogenous cannabinoid system in the CNS both in vivo and in vitro. In this study, the effects of four commonly used acyl-based uptake inhibitors [N-(4-hydroxyphenyl)arachidonylamide (AM404), N-(4-hydroxy-2-methylphenyl) arachidonoyl amide (VDM11), (5Z,8Z,11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707) and (9Z)-N-[1-((R)-4-hydroxybenzyl)-2-hydroxyethyl]-9-octadecen-amide (OMDM2)] and the related compound arvanil on C6 glioma cell viability were investigated. All five compounds reduced the ability of the cells to accumulate calcein, reduced the total nucleic acid content and increased the activity of lactate dehydrogenase recovered in the cell medium. AM404 (10 microm) and VDM11 (10 microm) acted rapidly, reducing cell viability after 3 h of exposure when cell densities of 5,000 per well were used. In contrast, UCM707 (30 microm), OMDM2 (10 microm) and the related compound arvanil (10 microm) produced a more slowly developing effect on cell viability, although robust effects were seen after 6-9 h of exposure. At higher cell densities, the toxicities of AM404 and UCM707 were reduced. Comparison of the compounds with arachidonic acid, arachidonic acid methyl ester, AEA, arachidonoyl glycine and oleic acid suggested that the toxicity of the arachidonoyl-based compounds was related primarily to the acyl side-chain rather than the head group. A variety of pre-treatments blocking possible metabolic pathways and receptor targets were tested, but the only consistent protective treatment against the effects of these compounds was the antioxidant N-acetyl-L-cysteine. It is concluded that AM404, VDM11, UCM707 and OMDM2 produce a rapid loss of C6 glioma cell viability over the same concentration range as is required for the inhibition of AEA uptake in vitro, albeit with a longer latency. Such effects should be kept in mind when acyl-derived compounds are used to probe the function of the endocannabinoid system in the CNS, particularly in chronic administration protocols.

  • 50. Deplano, Alessandro
    et al.
    Morgillo, Carmine Marco
    Demurtas, Monica
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hashemian, Sanaz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Cabiddu, Maria G.
    Novellino, Ettore
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Catalanotti, Bruno
    Onnis, Valentina
    Novel propanamides as fatty acid amide hydrolase inhibitors2017In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, p. 523-542Article in journal (Refereed)
    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.

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