Download 1 Avdeling for farmakologi

Årsrapport 2014 Avdeling for farmakologi Klinikk for diagnostikk og intervensjon Innhold 1 Avdeling for farmakologi ......................................................................................................3 2 Klinisk farmakologi .............................................................................................................4 3 Seksjon Klinisk forskningspost (KFP) ....................................................................................9 4 Seksjon Legemiddelkomité og –sikkerhet .............................................................................12 5 Seksjon Regionalt legemiddel-informasjonssenter (RELIS) Sør-Øst ..........................................15 6 Seksjon Norges laboratorium for dopinganalyse ....................................................................18 7 Seksjon Farmakologisk institutt ..........................................................................................20 8 Research activity ..............................................................................................................22 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10 9 Publications 2010 – 2014 ...................................................................................................46 9.1 9.2 9.3 9.4 9.5 10 Research group on receptors, signalling and cardiac pharmacology ....................................................22 Research group on cellular signal transduction and cancer pharmacology (per 2013) .........................28 Neuropharmacology – Alzheimer’s disease research ...........................................................................31 Therapeutic Drug Monitoring Group ......................................................................................................32 Clinical Pharmacology & Pharmacogenomics Research Group ...........................................................34 Epilepsy Research Group - Clinical pharmacology of antiepileptic drugs .............................................36 Research group: Individualizing immune modulation and chemotherapy (i2mc) ..................................40 Clinical Research Group .......................................................................................................................43 Norges laboratorium for dopinganalyse ................................................................................................44 Regionalt legemiddelinformasjonssenter (RELIS) Sør-Øst ...................................................................45 Articles and reviews ............................................................................................................................46 Book chapters .......................................................................................................................................58 Books ....................................................................................................................................................61 Publikasjoner i norske tidsskrifter ..........................................................................................................61 Doctoral theses 1970-2014 ...................................................................................................................64 Ansatte pr 31.12.2014 ........................................................................................................68 Side 2 av 70 1 Avdeling for farmakologi Avdeling for farmakologi er tilknyttet Klinikk for diagnostikk og intervensjon (KDI) ved Oslo universitetssykehus (OUS) og omfatter den samlede farmakologiske kompetanse og virksomhet ved OUS og ved Universitetet i Oslo (UiO). Avdeling for farmakologis overordnede oppgave er å fremme rasjonell og sikker medikamentell behandling og å forebygge og kontrollere bruk av rus- og dopingmidler. Avdelingens oppgaveportefølje omfatter analyse av legemidler, rusmidler, intoksikasjonsstoffer og dopingmidler, basal og klinisk forskning, legemiddelinformasjon, bivirkningsarbeid, legemiddelkomitéarbeid, undervisning, veiledning og rådgivning. Avdelingen er organisert i åtte seksjoner. Fagområdet klinisk farmakologi er fordelt på tre seksjoner: Medisinskfaglig seksjon, Seksjon for utvikling og Driftsseksjon. De øvrige fem seksjonene omfatter Seksjon legemiddelkomité og – sikkerhet og Seksjon klinisk forskningspost, som er finansiert over sykehusets driftsbudsjett, Seksjon Farmakologisk institutt, som er universitetstilknyttet og Seksjon Norges laboratorium for dopinganalyse og Seksjon Regionalt legemiddelinformasjonssenter Sør-Øst (RELIS) som får sine oppdrags- og tildelingsbrev fra henholdsvis Kulturdepartementet og Helse- og omsorgsdepartementet via Statens legemiddelverk. Organisasjonsstrukturen er vist i figur 1. Denne årsrapporten gir en oversikt over avdelingens aktivitet i 2014 samt en detaljert beskrivelse av avdelingens forskningsgrupper. En oversikt over doktoravhandlinger fra de involverte fagmiljøene fra 1970 – 2014 samt publikasjoner fra 2005 - 2014 er inkludert til slutt i rapporten. Avdeling for Farmakologi Avdelingsleder: Berit Muan Lederassistent Marianne Spalder Larsen Medisinskfaglig rådgiver Kvalitetsleder Per Wiik Johansen Bente Heesch Klinisk farmakologi Driftsseksjon Klinisk farmakologi Seksjon for utvikling Bente Heesch Stein Bergan Klinisk farmakologi Medisinsk- Seksjon: Seksjon: Seksjon: Klinisk forskningspost Legemiddelkomite og –sikkerhet Farmakologisk institutt med FoU Hassan Khiabani Per W Johansen Finn Olav Levy [Forskningsleder] faglig seksjon Ingebjørg Gustavsen Seksjon: RELIS Regionalt legemiddelinformasjonssenter Sør-Øst Tone Westergren Seksjon: Norges laboratorium for dopinganalyse Peter Hemmersbach Enhet for driftsstøtte Lise-Marit Amlie Enhet for farmakologiske analyser; SSE Marianne L. Schmidt Forskningsgrupper Enhet for farmakologiske analyser; Rikshospitalet Torunn Skogseth Enhet for farmakologiske analyser; Ullevål Hanne Britt Johansen Figur 1. Organisasjonskart for Avdeling for farmakologi. Side 3 av 70 2 Klinisk farmakologi Virksomhetsområdet klinisk farmakologi er organisert i Medisinskfaglig seksjon, Seksjon for utvikling og Driftsseksjonen. Driftsseksjonen har laboratorieenheter ved Ullevål (US), Rikshospitalet (RH) og Avdeling for kompleks epilepsi (SSE). Det er tett samarbeid mellom de tre seksjonene, og Medisinskfaglig seksjon og Seksjon for utvikling jobber på tvers av lokasjonene. Virksomheten innen klinisk farmakologi omfatter Analyse av legemidler og toksiske substanser og faglig vurdering og fortolkning av analyseresultater Farmakogenetiske analyser og faglig vurdering og fortolkning av analyseresultater ”Therapeutic drug monitoring” – farmakologisk monitorering Medisinskfaglige råd knyttet til farmakologisk profylakse og behandling av sykdommer, intoksikasjon, rus og påvirkning av fysiologiske funksjoner Kontakt med rekvirenter og annet helsepersonell om rekvirering og prøvesvar Utvikling av nye og forbedring av etablerte analysemetoder Kvalitetssikringsarbeid Utdanning av spesialister i klinisk farmakologi Undervisning av medisinske studenter i farmakologi Praksisveiledning av bioingeniørstudenter Forskning og utvikling i klinisk farmakologi Avdeling for farmakologi har ansvar for drift og utvikling samt medisinskfaglig ansvar for farmakologiske analyser som utføres på avdelingens driftsenheter på US, RH og SSE. I tillegg er avdelingen medisinskfaglig ansvarlig for farmakogenetiske analyser som utføres ved Avdeling for medisinsk biokjemi (MBK), samt enkelte farmakologiske analyser som utføres på MBKs stormaskin med tilgjengelighet 24-7. Laboratorieenhetene ved US, RH og SSE har et analyserepertoar som er tilpasset de tre sykehuslokalisasjonenes pasientgrupper. Analyserepertoaret velges ut i samarbeid med klinikere ut fra hvilke analytter som trengs som ledd i diagnostikk og behandling av ulike sykdommer. I 2014 har vi arbeidet videre med organisering og implementering av den analytiske virksomheten etter at avdelingen overtok driftsansvaret for analysene i 2013. Det har vært særlig fokus på organisering av fagområdene farmakogenetikk og antiepileptika. Dette er viktige fagområder for OUS og Avdeling for farmakologi, og organisering og plassering av disse fagene vil ha stor betydning også utenfor avdelingens grenser. Endelige beslutninger vedrørende organisering av disse fagområdene er foreløpig ikke tatt. Året ble også preget av arbeid med utvikling av nytt regionalt laboratoriedatasystem og nytt journalsystem. Det nye journalsystem (DIPS) ble implementert i OUS høsten 2014. Implementeringen ble grundig forberedt og krevde betydelige ressurser også fra klinisk farmakologi. Vi hadde et vellykket oppfølgingsbesøk fra Norsk Akkreditering våren 2014 som konkluderte med opprettholdt akkreditering etter ISO standard 15189 (2007). Akkrediteringen gjelder for virksomheten på RH og US, og omfatter prøvetaking (M30), klinisk farmakologi (M04) og fleksibel akkreditering (M31). Side 4 av 70 Klinisk farmakologi – Driftsseksjonen Driftsseksjonen er bemannet med bioingeniører og ingeniører som har sin daglige arbeidsplass på laboratorieenheten på enten US, RH eller SSE. Noen av bioingeniørene har også deltatt i blodprøvetaking og annet preanalytisk arbeid i Avdeling for medisinsk biokjemi. Seksjonen hadde 24 årsverk i 2014. Klinisk farmakologi - Seksjon for utvikling Seksjon for utvikling er bemannet med overingeniører, farmasøyter og forskere og hadde i 2014 ni årsverk fordelt på de tre lokasjonene. En av de ansatte har professor II stilling ved Farmasøytisk institutt, Universitetet i Oslo. Hovedoppgaven til seksjonen er utvikling av nye og forbedring av eksisterende analysemetoder og analytisk rådgivning og problemløsning i forbindelse med rutineanalysene. Repertoar og omfang fremgår av beskrivelsen for laboratorieenhetene ved hver av lokasjonene. Utredninger i forbindelse med fornyelse av avansert analyseutstyr er også en vesentlig oppgave for seksjonen. Ved Rikshospitalet er det Utviklingsseksjonen som ivaretar kommentering av analyseresultater, kontakt med klinikere internt og eksternt samt utarbeidelse og presentasjon av informasjon til brukerne. Seksjonen driver også forskning og fagutvikling i samarbeid med Driftsseksjonen og Medisinskfaglig seksjon og andre samarbeidspartnere i og utenfor OUS. To av avdelingens forskningsgrupper er forankret med gruppeledere og medarbeidere fra denne seksjonen. Klinisk farmakologi - Medisinskfaglig seksjon Medisinskfaglig seksjon har det medisinskfaglige ansvaret for analysene i klinisk farmakologi. Dette innebærer blant annet ansvar for å ha et klinisk relevant analyserepertoar, fortolking av analysesvar og tett samarbeid og kontakt med både laboratorium og rekvirenter. Seksjonen har fire overlegestillinger og fire LiS-stillinger (Lege i Spesialisering). I løpet av 2014 har seksjonen vært bemannet med tre-fire overleger og tre-fire LiS. Sommeren 2014 ble Ingebjørg Gustavsen ansatt som ny seksjonsleder, mens Mimi Stokke Opdal gikk over fra seksjonslederstilling til kombinert 1. amanuensis ved Universitetet i Oslo og overlege i seksjonen. Det første halvåret var to av LiSene plassert på Rikshospitalet, mens de øvrige hadde tilholdssted på Ullevål. Høsten 2014 ble alle legene i seksjonen samlet på Ullevål for å styrke fagmiljøet. Legenes hoved-rutineoppgaver på Ullevål har vært svarkommentering og besvarelse av vakttelefonen. Vakttelefonens pågang har vært jevnt økende med både eksterne og interne henvendelser i løpet av året. Mange av spørsmålene handler om rus. En av overlegene har i løpet av 2014 brukt mesteparten av sin tid på medisinskfaglig arbeid med antiepileptika (analyseres først og fremst ved SSE). Avdelingen er utdannelsessted for legespesialiteten klinisk farmakologi, og Medisinskfaglig seksjon har hovedansvaret for denne funksjonen. I november 2014 hadde avdelingen et vellykket besøk av Spesialitetskomiteen i klinisk farmakologi som fant utdanningen tilfredsstillende, og opprettholdt godkjennelsen av avdelingen som utdanningssted for hele spesialistforløpet. Seksjonen har for øvrig deltatt i undervisning av medisinstudenter og annet helsepersonell, og har bidratt i diverse underutvalg av Legemiddelkomiteen ved OUS. Seksjonen har i 2014 som i tidligere år samarbeidet med RELIS om bivirkninger og legemiddelrelaterte spørsmål på ukentlige møter. Side 5 av 70 Seksjonen leder nettverk i klinisk farmakologi i deler av Helse Sør-Øst. I tillegg til jevnlig kontakt med våre kontaktpersoner på de respektive sykehus, ble det avholdt felles nettverksmøte i løpet av 2014. Når det gjelder forskning, opprettet Mimi Stokke Opdal forskningsgruppen Therapeutic Drug Monitoring i 2014. Høsten 2014 ble Margrete Larsen Burns påmeldt doktorgradsprogrammet ved Universitetet i Oslo med Mimi Stokke Opdal som biveileder. Legene i seksjonen er for øvrig involvert i forskning innen antibiotika, intoksikasjoner og rus. Klinisk farmakologi - Ullevål Ved enheten utføres analyse av legemidler og rusmidler og farmakogenetiske analyser i prøver tatt fra inneliggende og polikliniske pasienter i og utenfor OUS. Indikasjon for prøvene er terapikontroll, intoksikasjoner og kontroll av rusmiddelbruk. Enheten har primært ansvar for analyse av medikamenter i behandling av infeksjon og psykiske lidelser, medikamenter, russtoffer og toksiske stoffer ved intoksikasjon og rus samt enkelte antiepileptika. Enheten fikk i 2014 to nye gasskromatografer koblet til massespektrometri. Et av instrumentene er satt i rutinedrift med analyse av alkoholer, på det andre utvikles metoder til analyse av forgiftningsstoffer. Enheten fikk også en pipetteringsrobot. Arbeid pågår for å få denne i rutinedrift. Det har i 2014 vært utført totalt 155 393 legemiddel- og rusmiddelanalyser ved enheten. Antall serumanalyser har gått noe ned de siste årene mens antall urinanalyser har økt (se figur 2). Analyser i serum og urin (US) 160 000 Antall analyser 140 000 120 000 100 000 80 000 Serum/Plasma 60 000 Urin 40 000 20 000 0 2009 2010 2011 2012 2013 2014 Figur 2. Antall prøver analysert for legemidler og rusmidler i serum og urin ved Enhet for farmakologiske analyser, Ullevål i årene 2009 – 2014. (Av serum/plasma-analysene ble 9 462 analysert i Avdeling for farmakologi mens 11 156 ble analysert i Avdeling for medisinsk biokjemi.) Side 6 av 70 Enheten har et bredt utvalg av farmakogenetiske analyser og antallet farmakogenetiske analyser økte i 2014 (se figur 3). Det har vært gjennomført studentveiledning innen farmakogenetikk på både bachelor-, master- og doktorgradsnivå. Avdeling for farmakologi står for forskning og utvikling, utfører det meste av rutineoppgavene og har det medisinskfaglige ansvaret for de farmakogenetiske analysene, mens driftsansvaret ligger i Avdeling for medisinsk biokjemi. Farmakogenetiske analyser 1200 Antall analyser 1000 800 600 400 200 0 2009 2010 2011 2012 2013 2014 Figur 3. Antall analyser i prøver av DNA fra hvite blodceller utført ved Enhet for farmakologiske analyser, Ullevål i årene 2009 - 2014. (Det er ikke justert for antall analyser innen samme CYP2C9.) Klinisk farmakologi – Rikshospitalet Enheten har sin største aktivitet i farmakologisk monitorering ("TDM") av legemidler knyttet til transplantasjonsvirksomheten, som er en landsfunksjon. Dette gjelder immundempende legemidler som takrolimus, ciklosporin, mykofenolat, everolimus og sirolimus. I forbindelse med kondisjonering for hematologisk stamcelletransplantasjon utføres også en avansert analyse og dosetilpasning av cellegiften busulfan. Videre utføres analyse av 6-tioguaninnukleotider (6-TGN) som er de aktive metabolittene av azatioprin og merkaptopurin. Disse brukes både som immundempende midler og cellegifter ved en rekke forskjellige immunsykdommer og ved leukemi. Enheten utfører også analyse av systemiske soppmidler som vorikonazol med flere. Dette er også legemidler som er spesielt aktuelle for pasienter med nedsatt immunforsvar. Utover disse analysene utførte enheten analyse av metotreksat, inntil analysen ble overført Avdeling for medisinsk biokjemi i september, samt noen andre legemidler, i tillegg til at røntgenkonstrastmidlet joheksol analyseres som ledd i evaluering av nyrefunksjon. For de fleste av de nevnte legemiddelanalysene har laboratoriet i praksis en landsfunksjon. Monitorering og individualisering av slik behandling blir i økende grad supplert med farmakogenetiske analyser som kan bidra til å forutsi og forklare avvikende dosebehov og respons hos den enkelte pasient. Det er Avdeling for medisinsk biokjemi som har driftsansvaret for de farmakogenetiske analysene. De mest sentrale farmakogenetiske analysene ved RH er tiopurin-metyltransferase (TPMT) og cytokrom-P450 (CYP). Side 7 av 70 Antallet analyser utført ved enheten er vist i figur 4. Analysevolum RH 35 000 Antall analyser 30 000 25 000 20 000 2010 15 000 2011 10 000 2012 2013 5 000 2014 0 Figur 4. Antall prøver analysert ved Enhet for farmakologiske analyser, Rikshospitalet i årene 2010 – 2014, samt farmakogenetiske analyser (antall varianter) - utført ved Avdeling for medisinsk biokjemi og Avdeling for farmakologi i samarbeid (2011-14). Forkortelser: Takro=takrolimus; Ciklosp=ciklosporin, Mykof=mykofenolat; mTOR-hemm=sirolimus og everollimus; 6-TGN=tioguaninnukleotider (inkl metyl-MP); Farmakogen=CYP'er, TPMT mfl. Analysene ciklosporin samt noen i gruppen Andre utføres på Hovedinstrument i Avdeling for medisinsk biokjemi. Persontilpasset eller individualisert legemiddelbehandling (personalized medicine) er ikke bare analyser og farmakokinetiske beregninger. Kommentering og informasjon rundt de enkelte prøvesvar samt mer generell informasjon er en stadig viktigere del av denne virksomheten. Enheten har i flere år drevet sin informasjon gjennom en webside (anx.no), dessuten er det tett kontakt med de viktigste rekvirentene bl.a. ved regelmessig deltagelse på møter, previsitter og annen løpende kontakt. Forskningsgruppen som utgår fra denne lab-enheten (i2mc "Individualizing immune modulation and chemotherapy") er beskrevet under kapittel 9.6. Den rommer også masterstudenter og stipendiater som i stor grad utfører sine og gruppens prosjekt i samme laboratorium som rutinevirksomheten. Forskningsgruppens nære samarbeid med de kliniske miljøene er i stor grad basert på samarbeid som har utgangspunkt i rutinevirksomheten. I en stor del av 2013-14 har laboratoriet vært preget av ombygging. Dette har vært krevende for personale og drift, men med stor evne til tilpasning og fleksibilitet i arbeidssituasjonen har medarbeiderne klart å utføre sine oppgaver på en sikker og god måte. Mot slutten av året var det meste av ombyggingen unnagjort, og installering av nye instrumenter – to UPLC-MSMSinstrumenter og en pipetteringsrobot – kunne begynne. Laboratoriet står foran en stor omlegging, idet de immunkjemiske metodene skal skiftes ut med massespektrometri i løpet av 2015. Side 8 av 70 Klinisk farmakologi - Avdeling for kompleks epilepsi (SSE) Laboratorieenheten ved SSE har landsdekkende tilbud for analyse og monitorering (TDM) av antiepileptika. Enheten driver forskning, metodeutvikling, undervisning og opplysningsvirksomhet, nasjonalt og internasjonalt, i samarbeid med laboratoriemiljøer og kliniske miljøer innen epileptologi. Forskningsaktiviteten er beskrevet i kapittel 9.5. Analyseproduksjonen ved SSE for sentrale antiepileptika er vist i figur 5. Det ble i 2014 utviklet forbedrede metoder for lamotrigin og levetiracetam. Det ble også foretatt strukturelle endringer på laboratoriet for å øke analysefrekvensen slik at svartiden for en del analyser ble redusert. Biokjemiske serum analyser ble overført til Avdeling for medisinsk biokjemi i august 2014, mens hematologi og SR fortsatt utføres ved SSE. Laboratoriet har i 2014 vært involvert i to kliniske prosjekter, der oppgaven har vært blodprøvetaking, -preparering, -lagring og forsendelse. Analysevolum antiepileptika 6000 5000 4000 3000 2010 2000 2011 1000 2012 0 2013 2014 Figur 5. Antall prøver av utvalgte antiepileptika analysert ved Enhet for farmakologiske analyser, Avdeling for kompleks epilepsi (SSE), Sandvika i årene 2010 – 2014. 3 Seksjon Klinisk forskningspost (KFP) Klinisk forskningspost (KFP) ved Avdeling for Farmakologi har fagkompetanse i planlegging og gjennomføring av kliniske intervensjonsstudier med hovedfokus på klinisk utprøving av legemidler i fase I (sikkerhet/toleranse) og II (dose/effekt). Forskning, undervisning, informasjon og faglig veiledning er også viktige oppgaver for KFP. Prosjekter og studier som nyttiggjør seg KFPs fasiliteter og kompetanse omfatter først og fremst pasientgrupper og behandlingsopplegg som ikke er tilgjengelig andre steder i regionen eller i landet forøvrig. KFP bidrar på tvers av fagdisipliner og pasientgrupper, og fasiliterer både stu dier initiert av interne forskere ved OUS og sponsorinitierte studier (oppdragsstudier initiert av legemiddelindustrien). Side 9 av 70 KFP er lokalisert til Rikshospitalet/Gaustad og ledes av spesialist i klinisk farmakologi. I tillegg har KFP en studiekoordinator/studiesykepleier i fast stilling. KFP deltar aktivt i nettverket for kliniske oppdragsstudier ved OUS og har fått én av fire koordinatorstillinger finansiert av Helse Sør-Øst (HSØ) for en tre års periode. Vedkommende fungerer også som studiesykepleier, og styrker dermed staben ved KFP. I 2014 fikk seksjonen også midler fra Nasjonalt kompetansenettverk for legemidler til barn for å ansette studiesykepleier i 30 % stilling, primært for å bistå kliniske legemiddelstudier innen barneonkologi. Klinisk forskningspost følger nasjonale lover og forskrifter og internasjonale retningslinjer som gjelder ved legemiddelutprøvinger, og har egne prosedyrer for gjennomføring av studiene. Prosedyrene (Standard Operating Procedures (SOPer)) ligger i sykehusets Kvalitetshåndbok (eHåndboken) og oppdateres regelmessig. KFP følger Nasjonale SOPer for kliniske studier (lansert 2011) sammen med egne prosedyrer. KFP har opprettet et Fagråd med medlemmer som representerer ulike fagmiljø ved OUS og UiO. Fagrådets mandat er å gi råd og støtte til seksjonsleder vedrørende postens drift og utvikling, prioritering av oppgaver, utarbeidelse av retningslinjer og bemanning samt å bistå ved rekruttering av nye studier. Det ble avholdt et formelt møte i Fagrådet på vårparten i 2014. Seksjonsleder har for øvrig kontinuerlig kontakt med Fagrådets medlemmer. KFP arrangerte et heldags forskningsseminar – ”Kliniske intervensjonsstudier” - ved OUS i november 2014. De fleste av Fagrådets medlemmer samt sentrale forskere ved OUS holdt innlegg. I 2014 har KFPs personale deltatt i totalt 12 studier, hvorav fem forskerinitierte studier og syv sponsorinitierte. Av de sponsorinitierte studiene var seks fase II studier og en fase III studie. Alle disse studiene fortsetter i 2015. I tillegg har forskningspostens fasiliteter vært brukt av forskere ved sykehuset til prosjekter som ikke har involvert postens personale. Totalt har KFP brukt 1 548 timer på pasientrettet arbeid og 154 pasienter har deltatt i studier ved forskningsposten. Flere av studiedeltagerne har vært innlagt på KFP over flere døgn. Slike studier er arbeidsintensive og ressurskrevende. Som tidligere år ble det også i 2014 lagt ned mye arbeid i planlegging av studier som sponsor besluttet å kansellere like før oppstart. Personalet ved KFP har i 2014 deltatt i ulike nasjonale og nordiske fora, med bl.a. presentasjon av KFP. Seksjonsleder deltar også på møter i regi av NorCRIN (Norwegian Clinical Research Infrastructure Network). Side 10 av 70 Antall studier ved Klinisk forskningspost Forskerinitierte studier 8 7 8 8 Sponsorinitierte studier 5 7 5 5 4 2007 4 2 2008 2009 2 2010 4 5 2011 2012 5 2 2013 2014 Figur 6. Antall forskerinitierte hhv sponsorinitierte studier som Klinisk forskningspost har vært involvert i årene 2007 – 2014. Antall studier ved Klinisk forskningspost Fase I 2 1 2 4 3 4 2007 2008 Fase II 1 2 6 6 2009 2010 Fase III Fase IV 1 2 2 3 2 1 2 2011 2012 2013 6 3 2014 Figur 7. Antall fase I, II, III og IV studier gjennomført ved Klinisk forskningspost i årene 2007 – 2014. Side 11 av 70 4 Seksjon Legemiddelkomité og –sikkerhet Seksjonen jobber for kostnadseffektivt legemiddelbruk ved OUS, herunder en effektiv legemiddelforsyning og forsvarlig legemiddelberedskap, samt en trygg legemiddelhåndtering. Seksjonen har ansvar for ledelse og daglig drift av sykehusets legemiddelkomité, som er rådgivende organ i legemiddelspørsmål ved Oslo universitetssykehus, og er sterkt involvert i pasientsikkerhetsarbeid innen legemiddelfeltet. Seksjonen ledes av overlege/spesialist i klinisk farmakologi og har i tillegg to sykehusfarmasøyter ansatt. Hovedoppgaver og aktiviteter i 2014 LMK Seksjonen innehar posisjonene som leder (seksjonsoverlege) og sekretær (sykehusfarmasøyt) i sykehusets legemiddelkomité (LMK), og seksjonens arbeid blir således tett knyttet opp mot denne virksomheten. Seksjonen står for mye av den daglige drift av legemiddelkomiteens arbeid, oppfølging av løpende legemiddelrelaterte saker, utarbeidelse av møteagendaer, og samarbeid med ledelsen (Stab medisin og helsefag) der mer overordnede føringer for arbeidet i LMK tas opp til diskusjon. Det har vært avholdt fire LMKmøter i 2014. LMKs underutvalg Seksjonen har i 2014 deltatt i følgende underutvalg til LMK: Legemiddelhåndteringsutvalget (MHU). Hovedoppgaven har til nå vært koordinering av prosedyreverket innen legemiddelhåndtering på nivå 1. Dette arbeidet nærmer seg slutten, men man må sikre at prosedyreverket følges opp og revideres, slik at det til enhver tid er i overensstemmelse med gjeldende faglige standarder og retningslinjer. Det har også vært jobbet mye med utarbeidelse av ny felles pasientkurve i papir (F1-kurve), og denne ble ferdigstilt og implementert i OUS medio mai 2014. Her har en av seksjonens sykehusfarmasøyter bidratt sterkt for å få dette på plass. LIS-utvalget (LegemiddelInnkjøpsSamarbeidet), som arbeider med å sikre OUS gode innkjøpsavtaler på legemidler. En av seksjonens sykehusfarmasøyter ble konstituert som sykehusets LIS-kontakt i september 2013, og har også hatt denne rollen i 2014. Hun har i løpet av 2014 hatt nyansatt økonom, som skal bli LIS kontakt, i opplæring. LMK og LISutvalget samarbeidet om informasjon vedrørende nye legemiddelavtaler med avtalestart 1.2.2014. Væskeutvalget. Det har ikke vært væskeanbud i 2014, og aktiviteten i dette utvalget har ligget noe nede, blant annet pga at lederen av utvalget har blitt pensjonist. Det skal utnevnes ny leder så snart som mulig, slik at væskeutvalget kan ta hånd om nytt væskeanbud som kommer i 2015. Psykofarmakautvalget. Seksjonen har sekretærfunksjon. Utvalgets viktigste oppgave har så langt vært å bidra i utviklingen av et godt kurstilbud på dette området for sykehusets ansatte. Utvalget vil også ta hånd om saker/spørsmål som dreier seg om bruk/håndtering av psykofarmaka. Pasientsikkerhet Seksjonen arbeider mye innen pasientsikkerhet, og er sterkt involvert i arbeidet med avviksmeldinger innen legemiddelområdet i OUS. Seksjonen samarbeider tett med ansatte i Stab pasientsikkerhet innen dette feltet. Det ble i 2014 registrert 1252 avviksmeldinger knyttet til legemidler og blodprodukter, dette utgjør 17,3 % av totalt antall avviksmeldinger i OUS. Side 12 av 70 En av sykehusfarmasøytene i seksjonen er medlem i Pasientsikkerhets- og kvalitetsutvalget i Kreft-, kirurgi- og transplantasjonsklinikken (KKT), og i Ernæringsrådet i OUS. I samarbeid med Sykehusapoteket Oslo (SAO) gjennomgås avvik som angår interaksjonen mellom apotek og sykehus, og forbedringstiltak iverksettes. Seksjonen initierte prosessen med å utarbeide OUS-retningslinje for opioidbruk på sengepost, etter flere fatale hendelser nasjonalt. Retningslinjen ”Opioidbruk på sengepost. Ordinering og overvåking” ble ferdigstilit i 2013 og foreligger nå i eHåndbok ved OUS. Seksjonen tok initiativ til et implementeringsmøte med nøkkelpersonell ved OUS i mai 2014, for å sikre god implementering og etterlevelse av denne viktige prosedyren, og bedre ivaretagelse av pasientsikkerheten knyttet til slik behandling. En av sykehusfarmasøytene i seksjonen arrangerte workshop innen legemiddelsikkerhet på den nasjonale pasientsikkerhetskonferansen. Revisjoner For å kontrollere etterlevelsen av prosedyreverket på legemiddelområdet gjennomfører seksjonen i samarbeid med OUS revisjoner. OUS deltok ikke i fellesrevisjonen som HSØ hadde i 2014, der det var fokus på samstemming av legemiddellister. Grunnen til dette var at dette området ikke var tilstrekkelig utbredt i OUS til at en slik revisjon ville ha noen verdi. Legemiddelberedskap På bakgrunn av arbeidet med nasjonal legemiddelberedskap som fant sted i 2012 i regi av Helsedirektoratet, der seksjonsleder deltok, er det etablert en lokal beredskapsgruppe ved OUS for å vurdere legemiddelberedskapen ved sykehuset. Seksjonsleder deltar i den lokale gruppen, som i tillegg består av beredskapsoverlegen ved OUS, spesial-rådgiver/LIS-kontakt fra innkjøp, sykehusfarmasøyt fra SAO og lege i spesialisering fra vår avdeling. Arbeidet startet i 2012, fortsatte i 2013 og ble kontinuert i 2014. Legemiddelberedskapsarbeidet skal gi anbefalinger mht hovedtyper og mengde av viktige og kritiske legemidler som bør beredskapssikres ved både akutte hendelser (ulykker m.v.) og langvarig forsyningssvikt. Dette arbeidet omfatter også hvor lageret skal ligge, og hvordan det skal driftes. Gruppen har fremlagt sin anbefaling for legemiddellager, og dette forslaget støttes av sykehusledelsen. Kostnader knyttet opp mot dette blir tatt med i budsjettprosessen for 2015. Det er ikke sikkert vi får alt på plass i 2015, men sykehusledelsen har anbefalt å ta dette stegvis over et par år. Apoteksamarbeid - Seksjonen samarbeider tett med Sykehusapoteket Oslo (SAO) på ulike områder, blant annet innen kvalitetssikkerhetsarbeidet ved OUS. Det avholdes regelmessige møter mellom seksjonen, Stab risiko og internkontroll og SAO, der man prioriterer oppgaver innen kvalitetsforbedrende tiltak på flere områder (fokus på prosedyrer, revisjonsarbeid, klinisk farmasi, undervisning etc). Dette forumet legger således føringer for det arbeidet SAOs tjenestefarmasøyter skal yte til OUS på legemiddelområdet for å sikre et optimalt samarbeid og en god interaksjon mellom organisasjonene. Det ble avholdt seks møter i 2014. - Seksjonens ansatte er, sammen med sykehusledelsen (Stab medisin, helsefag og utvikling) betydelig involvert i revisjonsarbeid rundt apotekavtalen som OUS har med SAO. Denne består av en stor portefølje av ulike avtaler, som må revideres og kvalitetssikres årlig. Dette skal bl.a. medvirke til effektiv og sikker legemiddelforsyning og adekvat lagerhold og beredskap av legemidler, samt en kostnadseffektiv bruk av ressurser. - Seksjonen har dialogmøter med SAOs ledelse der man utveksler informasjon om driftssituasjonen både ved OUS og SAO og oppfølging av apotekavtalene generelt. Side 13 av 70 - Samarbeidsforumet mellom OUS og SAO med fokus på legemiddelmangel, som startet opp i 2011, har pågått i hele 2014, og fortsetter videre. Dette forumet består av leder og sekretær i LMK, representant fra innkjøp/LIS kontakt (OUS) og sykehusfarmasøyt(er) fra SAO. Det avholdes ukentlige møter og representanter fra Statens legemiddelverk deltar en gang månedlig. Dette samarbeidet har vært en suksess ved at det holdes et kontinuerlig fokus på legemiddelmangel og de problemer dette avstedkommer, og sikrer at viktig informasjon når ut i hele OUS-organisasjonen. Informasjon fra dette arbeidet distribueres også nasjonalt via sykehusapoteksystemet. Seksjonen bidro som medarrangør (sammen med SLV og SAO) av et nasjonalt møte for ”legemiddelmangelkontakter” i de ulike HF’ene i januar 2014. Dette var et ”kick-off”-møte for å få på plass etablering av ”mangelkontakter” rundt i de ulike HF’ene med ansvar for å håndtere legemiddelmangel lokalt. Det planlegges et oppfølgingsmøte i 2015. Det planlegges også et nordisk møte om legemiddelmangel i løpet av våren 2015, med tanke på et nordisk samarbeid på dette feltet. - Seksjonen samarbeider tett med SAO ved utarbeidelsen av bytteliste for OUS, som ferdigstilles i februar/mars hvert år. Byttelisten er viktig for å sikre at legemiddelbytter i sykehuset er trygge og i tråd med avtalene sykehuset har inngått om legemiddelinnkjøp og gjeldende terapiretningslinjer. Byttelisten trykkes opp som en liten håndbok og ligger også i eHåndbok. - Seksjonen er involvert i et arbeid med oversettelse av preparatomtaler på en del uregistrerte legemidler som er i jevnlig bruk ved sykehuset. Arbeidet utføres av Tjenesteavdelingen i SAO i samarbeid med Avdeling for farmakologi. Preparatomtalene skal legges i eHåndbok. - Seksjonen samarbeider med SAO om hvordan legemiddelstatistikk skal presenteres i OUS (tertialrapportering). Deltagelse i ulike fora, både internt og eksternt Deltagelse på 3 LIS-anbudsseminarer årlig, hvorav to av disse omhandler biologiske legemidler (TNF-hemmere og MS-midler) – dette er viktige møter som legger føringer for de LIS-avtalene som inngås. ”Obligatorisk” for leder og sekretær i LMK. Seksjonen har, sammen med SAO, tatt initiativ til et møte med ansvarlige for sykepleierutdanningen ved HiOA, Diakonhjemmet og Lovisenberg diakonale høgskole. Dette er gjort med tanke på å gi innspill som skal bidra til å forbedre kvaliteten på den undervisningen som gis ved de ulike høgskolene. Dette tiltaket er basert på avviksmeldinger i avvikssystemet ved OUS, som viser manglende kompetanse på viktige felt (legemiddelhåndtering, legemiddelregning etc). Møtet er planlagt i januar 2015. En av sykehusfarmasøytene i seksjonen leder arbeidet med revidering av Cytostatikabokens kapittel om cytostatikahåndtering. En av sykehusfarmasøytene i seksjonen har deltatt i Helsedirektoratets arbeidsgruppe for rundskriv/veileder til den nye legemiddelhåndteringsforskriften. Følgende høringssvar er utarbeidet på vegne av stab Medisin, helsefag og utvikling: - Høringssvar til endring i Legemiddelhåndteringsforskriften - Seksjonsleder (seksjonsoverlege) har i 2014 deltatt på følgende områder: - Medlem/nestleder i Regionalt legemiddelforum (RLF), som bl.a. arbeider med harmonisering av arbeidet på legemiddelfeltet i HSØ. Det er avholdt tre RLFmøter i 2014. - Medlem i kurskomiteen og møteleder på årlig regional legemiddelkomitékonferanse i regi av RLF, Gardermoen. - Medlem i referansegruppe vedrørende persontilpasset medisin. Side 14 av 70 - - Medlem i Miljøfaggruppe for å bidra til sertifisering av OUS som Grønt sykehus. Seksjonen skal i denne sammenheng se på/vurdere retur/destruksjon av legemidler, og mulige miljøkonsekvenser av dette. Dette vil også skje i samarbeid med SAO. Revisjon av kapitler i Norsk legemiddelhåndbok. Revisjon av informasjonsgrunnlaget vedrørende nye antikoagulantia i regi av Helsedirektoratet. Sakkyndig vurdering (Oslo politikammer). Sakkyndig i Sør-Trøndelag Tingrett og Frostating Lagmannsrett (GILDE-saken) Foredragsvirksomhet i ulike fora, både eksternt og internt i OUS. - Sykehusfarmasøyter/spesialrådgivere har i 2014 deltatt på følgende områder: - Foredragsvirksomhet i ulike fora, både eksternt og internt i OUS. - Undervisning, kursutvalg. - Medlem i styringsgruppen for den nasjonale pasientsikkerhetskonferansen. - Medlem i ernæringsrådet i OUS. - Medlem i kursutvalg for kurs i psykofarmaka for sykepleiere. - Regionalt legemiddelhåndteringsutvalg. - Råd for metodevurdering i OUS når det er aktuelle legemiddelrelaterte saker. - Rådslag arrangert av Helsedirektoratet vedrørende Legemiddelmeldingen 2015. - LIS kontaktmøte - ESCP konferanse Flytting Planlagt flytting og samlokalisering av seksjonens ansatte til Forskningsveien 2B (Cbygningen, 4. etg). LMK-seksjonen blir der samlokalisert med RELIS. Mye møtevirksomhet i denne forbindelse for å tilrettelegge flytteprosessen best mulig for alle parter. 5 Seksjon Regionalt legemiddelinformasjonssenter (RELIS) Sør-Øst RELIS - Hjelp i legemiddelspørsmål RELIS - regionale legemiddelinformasjonssentre - skal bidra til riktig legemiddelbruk gjennom gratis, produsentuavhengig legemiddelinformasjon til helsepersonell og publikum. Mange legemidler, økt fokus på helse i samfunnet og økonomiske aspekter omkring behandling gjør det krevende for helsepersonell å holde seg faglig oppdatert i en stadig travlere klinisk hverdag. Myndighetene ønsker at pasienter i økende grad skal være aktive deltakere i sin egen behandling. Legemiddelinformasjon tilpasset målgruppens individuelle problemstillinger skal gi den nødvendige trygghet for å oppnå dette. RELIS Sør-Øst hadde i 2014 ca. 12 årsverk bestående av farmasøyter, leger og sekretær, og holdt til i kontorer i bygg 2, Ullevål (Søsterhjemmet). RELIS Sør-Øst er en del av et nettverk med fire regionale sentre, lokalisert ved de respektive universitetssykehusene i hver helseregion. Alle fire RELIS samarbeider tett med de klinisk farmakologiske fagmiljøene ved sykehusene, og har i tillegg et aktivt og bredt samarbeid med helsepersonell i de fire helseregionene. Sentrene er finansiert gjennom tilskudd fra Helse- og omsorgsdepartementet. Statens legemiddelverk er tilskuddsforvalter. RELIS tilbyr en spørsmål- og svartjeneste og bistår helsepersonell i alle typer legemiddelspørsmål. De fleste spørsmålene gjelder enkeltpasienter der generell informasjon om preparater og behandlingsretningslinjer ikke er tilstrekkelig detaljert for problemstillingen. Side 15 av 70 Målgruppe og brukere av tjenesten er i første rekke leger, men også farmasøyter, tannleger, sykepleiere, helsesøstre og jordmødre. De fleste svarene vi gir ut gjøres også fritt tilgjengelige i en søkbar database. RELIS besvarte 3 070 legemiddelspørsmål i 2014, en økning på 7 % fra 2013. Svarene er lagt inn i spørsmål- og svardatabasen, som er søkbar og gratis tilgjengelig på hjemmesiden. Av disse ble 1 404 utredet ved RELIS Sør-Øst (se figur 8). De fleste henvendelser kommer fra leger og det har vært en jevn økning de siste årene. De fleste legemiddelspørsmålene gjelder terapi (31 %), bivirkninger (26 %), graviditet/amming (16 %) og interaksjoner (15 %). Løpende saker, RELIS Sør-Øst 2014 1600 1400 Antall besvarte spørsmål Antall 1200 1000 Antall bivirkningsmeldinger 800 600 400 Antall svar i TryggMamma medisin 200 0 2009 2010 2011 2012 2013 2014 Figur 8. Antall besvarte spørsmål og mottatte bivirkningsmeldinger pr år ved RELIS Sør-Øst i årene 2009 – 2014. Bivirkningsarbeid En annen viktig oppgave er legemiddelovervåking. RELIS mottar bivirkningsmeldinger fra helsepersonell, vurderer hendelsesforløp og årsakssammenheng, og kommenterer i skriftlig tilbakemelding til melder. Bivirkningsrapportene registreres i en nasjonal bivirkningsdatabase, i nært samarbeid med Statens legemiddelverk. RELIS har i 12 år behandlet spontanrapporterte bivirkninger fra helsepersonell. Alle mottatte meldinger blir registrert i den nasjonale bivirkningsdatabasen og Statens legemiddelverk videreformidler informasjonen til Verdens helseorganisasjon (WHO) og europeiske legemiddelmyndigheter (EMA). På denne måten inngår meldingene både i nasjonal og internasjonal legemiddelovervåking. RELIS gir en faglig tilbakemelding til melder og publiserer jevnlig informasjon om bivirkninger på hjemmesiden, i enkelte tilfeller også i nasjonale og internasjonale tidsskrifter. Meldingene blir også brukt oi samarbeid med annet helsepersonell og i mastergradsoppgaver. På landbasis vurderte RELIS 1 174 bivirkningsmeldinger i 2014 mot 1 082 i 2013 (se figur 8). Av disse ble 655 behandlet ved RELIS Sør-Øst. Dette er en økning på 14 % fra 2013. Bivirkningsmeldingene i 2014 gjenspeilet den økende bruken av de nye orale antikoagulasjonsmidlene (NOAK). For å lære mest mulig om bivirkninger av NOAK har vi Side 16 av 70 også i 2014 kontaktet melder av bivirkningen for å få mer detaljert informasjon om hendelsen. Ved Oslo universitetssykehus samarbeider RELIS tett med legemiddelkomitéen i bivirkningsspørsmål og leder komitéens bivirkningsutvalg. Det er etablert en ordning der sykehusets ansatte kan melde om bivirkninger gjennom avvikssystemet. For mer informasjon om overvåking av legemidler henvises det til RELIS nettside og til Bivirkningsrapport 2014 som utarbeides av Statens legemiddelverk i samarbeid med RELIS og Folkehelseinstituttet (FHI). Utvikling av publikumstjenester Trygg Mammamedisin (www.tryggmammamedisin.no) er en gratis, nettbasert tjeneste der gravide og ammende kan stille spørsmål om legemidler. Tjenesten ble startet i juni 2011 og totalt er nå nesten 7 400 spørsmål besvart. De tre legemidlene vi fikk flest spørsmål om i 2014 var paracetamol, ibuprofen og cetirizin.. Oppdragsbrevet for 2014 inneholdt et eget punkt for særlige oppdrag: Forslag til plan for videreføring av en utvidet publikumstjeneste. En ny nettside tiltenkt publikum som har spørsmål om sine legemidler, uavhengig av type legemiddel eller terapiområde, var ferdigstilt ved årsskiftet 2013/2014. Tjenesten kalles Trygg Medisin (www.tryggmedisin.no) og er bygget opp på samme måte som Trygg Mammamedisin. En pilot for tjenesten ble gjennomført våren 2014. Tjenesten skal markedsføres og trappes opp ytterligere i 2015 før den blir evaluert. RELIS hjemmeside, applikasjon, nyhetsbrev og sosiale medier RELIS har i dag en rekke nettbaserte ressurser: Hjemmeside (www.relis.no) hvor fagartikler og nyheter legges ut. Søkbar spørsmål- og svardatabase (RELIS database) som er unik i sitt slag i Norge. Mobilvennlig utgave av hjemmesiden og databasen. Applikasjon for smarttelefon og nettbrett. Elektronisk nyhetsbrev. Eget nettsted for gravide og ammende: www.tryggmammamedisin.no. Eget nettsted for pasienter (pilot): www.tryggmedisin.no Egne profiler på sosiale medier som Twitter og Facebook. Side 17 av 70 Foredrag og undervisning RELIS arrangerer både regionale og nasjonale kurs og temakvelder, og opplever stor etterspørsel etter undervisning. De ansatte benyttes ofte som foredragsholdere på faglige arrangementer i regi av andre. RELIS Sør-Øst avholdt i februar 2014 sitt årlige kurs med tittelen ”Allmenn psykofarmakologi – hva er din strategi?” med ca 100 deltagere. Seksjonen har hatt undervisning og foredrag for leger, farmasøyter og annet helsepersonell på forskjellige faglige møter og kurs lokalt og nasjonalt. Det er gitt undervisning til medisinerog farmasistudenter ved universitetet i Oslo. Totalt ble det gitt ca 30 timer undervisning i 2014. I tillegg kommer hospitering i form av heldagsbesøk for ca. 30 studenter, med et faglig innhold som omfattet bivirkninger, interaksjoner og legemidler ved graviditet/amming. Seksjonen har hatt et medlem i kursutvalget for Legeforeningens kurs Farmakoterapi i allmennpraksis. Vi formidler regelmessig legemiddelinformasjon gjennom publisering i nasjonale og internasjonale medier og fagtidsskrifter. Vi er opptatt av å kunne kommunisere med våre brukere på nye møteplasser og nye elektroniske plattformer. RELIS deltar i forskningssamarbeid med universitet og helsevesen. RELIS Sør-Øst har i 2014 hatt en mastergradsstudent i farmasi og har vært involvert i diverse forskningsprosjekter, se kap. 8.10 6 Seksjon Norges laboratorium for dopinganalyse Norges laboratorium for dopinganalyse har siden 2010 vært tilknyttet Avdeling for farmakologi som en eksternt finansiert seksjon. Laboratoriet finansieres av Kulturdepartementet samt av inntekter fra analyseoppdrag. Norges laboratorium for dopinganalyse er akkreditert i henhold til WADAs regelverk. I tillegg til å fungere som Norges Wada-akkrediterte dopingkontrollaboratorium utfører laboratoriet analyseoppdrag for AntiDoping Danmark samt en del andre oppdragsgivere. Laboratoriet har på bakgrunn av gjennomførte WADA-tester i 2014 fått fornyet WADAakkreditering for 2015. Laboratoriet har også fått fornyet akkreditering i henhold til ISO/IEC 17025. Figur 10 viser antallet utførte dopinganalyser de siste fire årene. Antallet ”ikke-negative” prøver var i 2014 143, tilsvarende 2,8 % av totalt antall analyserte urinprøver. Andelen ”ikkenegative” prøver er noe høyere enn tidligere år, dette skyldes i hovedsak en del prøver fra treningssentermiljøet i Danmark, som har en større andel positive resultater. Av de rapporterte stoffene som ble funnet kan nevnes anabole stoffer, beta-2-agonister, hormonantagonister og metabolske modulatorer, diuretika og andre maskeringsmidler, stimulerende midler, cannabinoider og glukokortikoider. Side 18 av 70 Dopinganalyser 6 000 Antall analyser 5 000 4 000 3 000 2011 2012 2 000 2013 2014 1 000 0 Figur 10. Antall prøver analysert ved Norges laboratorium for dopinganalyse i 2011- 2014. Validering, videreutvikling og effektivisering av eksisterende analysemetoder er en permanent utfordring og er avgjørende for å beholde WADA-status og for å tilpasse laboratoriet til nye utfordringer. Etter at WADA overtok ansvaret for forbudslisten og laboratorieakkrediteringen i 2004 har det blitt mange forandringer på listen og nye krav er tilkommet gjennom ”The International Standard for Laboratories”, så også i 2014. Disse må innarbeides i laboratoriets etablerte metoder. I tillegg kommer det vanlige arbeidet med forbedringer, forenklinger og utvidelser av metoder som skjer kontinuerlig. I 2014 har laboratoriet videreutviklet påvisningsmetoder for EPO, overført analyse av store peptider og proteiner til LC-MS plattform, innført nytt assay for IGF-1 analyse, implementert nye stoffer i eksisterende screeningprosedyrer, forbedret IRMS analysen for å implementere nye analytter og utvidet med nye bekreftelsesmetoder på GC-MS/MS og LC-MS/MS Laboratoriet er lokalisert ved Aker sykehus og hadde pr. 31.12.2014 ca. 18 ansatte, hvorav en seksjonsleder, en enhetsleder, fire overingeniører (faglig ansvarlig), og to (helse)sekretærer, resterende avdelingsingeniører og kjemi-/bioingeniører. Laboratoriets seksjonsleder har en professor II-stilling ved Farmasøytisk institutt, UiO. Deltakelse i nasjonale og internasjonale fora Laboratoriets ansatte har i 2014 hatt følgende verv i nasjonale og internasjonale forbund/utvalg/arbeidsgrupper: - Medlem i WADAs arbeidsgruppe for EPO-analyser Meldem i IOC Medical Commission Games Group; deltagelse i OL i Sochi Medlem i Anti-Doping Commission for EAA (European Athletics Association) Side 19 av 70 - Medlem i Anti-Doping Commission for FIBT (International Bobsleigh and Skeleton Federation) Deltagelse i Antidoping Norges antidoping-nettverk Medlem og medgrunnlegger av NAPMU (Nordic Athlete Passport Management Unit) I likhet med tidligere år, har laboratoriets ansatte deltatt aktivt på nasjonale og internasjonale vitenskapelige møter og konferanser, og har holdt ca. 20 foredrag/presentasjoner. Laboratoriet har et utstrakt samarbeid med laboratorier verden over, og har i løpet av 2014 besøkt fire andre antidopinglaboratorier i Europa. Forskning Seksjonens forskningsprosjekter er omtalt i kapittel 8.9. 7 Seksjon Farmakologisk institutt Farmakologisk institutt driver både grunnforskning og anvendt forskning om legemidlenes basale mekanismer, kliniske effekter og anvendelse. Forskningen har vært konsentrert om følgende temaområder: - Reseptormedierte mekanismer i hjertets fysiologi, patofysiologi og farmakologi - Serotoninreseptorers molekylærbiologi, funksjon og farmakologi - Cellulær signaltransduksjon og cancerfarmakologi - Nevrofarmakologi og Alzheimer’s sykdom - Metabolisme i skjelettmuskulatur - Klinisk farmakologisk forskning Mer informasjon om disse forskningsområdene er gjengitt i kapittel 9. K.G. Jebsen senter for hjerteforskning ledes av prof. Finn Olav Levy og har funksjonstid ut 2015. Instituttet gjennomfører undervisning i det medisinske studiet og i etterutdannelsen av leger. I eksisterende studieplan (Oslo-96) undervises det i farmakologi i ni forskjellige semestre i det medisinske studiet (dvs. alle fra 3. til 12., unntatt 10. semester). Undervisningen gis i form av forelesninger, problembasert læring, seminarer og kurs, og omfatter både basale molekylære og cellulære aspekter, med vekt på mekanismene for medikamentenes virkninger og kliniske aspekter ved farmakologisk behandling. I løpet av medisinstudiet er det 113 timer undervisning i farmakologi (forelesninger, klinikker, seminarer), hvorav 70 timer er fagspesifikke forelesninger. Det er ikke egen eksamen i farmakologi, men det gis isteden eksamensspørsmål i farmakologi i alle skriftlige og stasjonsbaserte eksamener i semestre der faget er representert. Dette medfører at instituttets lærere er representert i eksamenskommisjoner eller gir og retter oppgaver i mange av medisinstudiets semestre, spesielt 3., 4., 5., 7., 9. og 12. semester. Undervisningen av medisinstudenter i Oslo-96 omfatter følgende undervisningsoppgaver: Forelesninger i semestrene 3, 4, 5, 6, 7, 8, 9, 11, 12 Integrerte klinikker i semestrene 4, 5, 6, 8, 9, 11, 12 PBL-undervisning i semestrene 1, 3, 4, 5, 8, 9 Eksamensarbeid i mange semestre, spesielt 3, 4, 5, 7, 9, 12 I den reviderte studieplanen Oslo-2014 vil hoveddelen av farmakologiundervisningen bli samlet i modulene 3, 4 og 5 (5. – 8. semester), med egen skriftlig eksamen i farmakologi i modul 5 (8. semester), sammen med eksamen i reseptlære. I tillegg vil det bli undervisning i Side 20 av 70 farmakologi i modul 6 (9. semester) vedrørende gynekologi, obstetrikk og pediatri og mer klinisk rettet farmakologi i modul 8 (11. – 12. semester). Arbeidet med revisjon av studieplanen har vært et av hovedinnsatsområdene i 2014 og vil fortsatt være det i 2015. På grunn av ubesattes stillinger kombinert med sykdom var den vitenskapelige bemanningen ved Farmakologisk institutt i 2014 kritisk lav. To faste vitenskapelige stillinger var ved utgangen av 2014 ubesatt med plan om utlysning i 2015. En førsteamanuensis i 20 % stilling kombinert med overlegestilling i Klinisk farmakologi - Medisinskfaglig seksjon ble tilsatt og en tilsvarende kombinert stilling ble lyst ut, med forventet tilsetting i 2015. I tillegg hadde instituttet i løpet av 2014 to forskere, tre postdoktorer og ni stipendiater ansatt i midlertidige stillinger hele eller deler av året. Instituttet hadde i 2014 seks ingeniører. Side 21 av 70 8 Research activity 8.1 Research group on receptors, signalling and cardiac pharmacology Leader: Finn Olav Levy, MD, PhD, Professor Scientific staff 2014 Name Finn Olav Levy Tor Skomedal Jan-Bjørn Osnes Kurt Krobert Kjetil Wessel Andressen Trond Bach Lise Román Moltzau Eirik Qvigstad Rizwan I. Hussain Caroline Bull Melsom Silja Meier Ornella Manfra Selene J. Sollie Øivind Ørstavik Andrea H. Ulsund Iwona Gutowska Schiander Marie Dahl Marianne Bjørnerem Henriette Andresen Kari S. Dugstad Halvard G. Hiis Gaia Calamera Degree MD, PhD MD, PhD MD, PhD MSc, PhD MScPharm, PhD MSc, PhD MSc, PhD MD, PhD MD MSc MSc MSc MSc MD MD Title Professor Professor Professor em. Senior researcher Asst. prof Postdoc PhD Consultant PhD student PhD student PhD student PhD student PhD student PhD student PhD student Engineer Engineer MSc student MSc student Student.res.fellow Student res. fellow MSc student (Erasmus) Institution/Employer UiO/OUH UiO UiO UiO UiO OUH UiO OUH External Nasjonalforeningen/UiO OUH OUH UiO Nasjonalforeningen Nasjonalforeningen UiO UiO UiO UiO UiO UiO UiO OUH=Oslo University Hospital Research area Mechanisms of receptor-mediated signalling in normal and failing hearts. Molecular properties of serotonin receptors. Aims To improve our understanding of receptor-mediated signalling in normal and failing hearts with the aim of providing the basis for development of novel principles for pharmacological therapy of heart failure. To improve our understanding of the molecular function and pharmacological importance of serotonin receptors. Ongoing projects in 2014 Importance of 5-HT4 serotonin receptors in heart failure Heart failure (HF) is characterised by impaired left ventricular function, increased peripheral and pulmonary vascular resistance and reduced exercise tolerance and dyspnea. With aging of the population and better survival of acute heart disease, the prevalence of HF is increasing. Our understanding and rationale for treatment of chronic HF has changed Side 22 av 70 dramatically from a hemodynamic model, aimed at correcting the hemodynamic defects, to a neurohumoral model, in which treatment is aimed at preventing the maladaptive, biological changes that occur in chronic HF. Research in our group revealed functional 5-HT2A and 5HT4serotonin receptors in failing myocardium. Both of these receptors can increase contractility, but through different mechanisms. The 5-HT4 receptor activates similar molecular mechanisms and elicits similar effects as the β-adrenoceptors, while the 5-HT2A receptor activates the same molecular mechanisms as the α1-adrenoceptors. Thus, we found a surprising analogy between adrenergic and serotonergic receptor systems in failing myocardium. Considering the importance of the adrenergic receptor systems, exploring the molecular mechanisms and role of the myocardial serotonin receptors has been an important project over several years. This new research field on the role of seretonin receptors in both development of HF and regulation of the failing heart may form the basis for a new treatment of chronic HF targeting the seretonin receptots. We have proposed that similar to betablockers, 5-HT4 antagonists can be used in the treatment of HF and have during the recent years conducted studies in rats and patients with HF to test this hypothesis. This work has also resulted in several related projects described below. Compartmentation of receptor-mediated cAMP and cGMP signalling in normal and failing hearts. Implications for treatment of heart failure It is well established that classical beta-adrenergic signalling is deleterious and increases mortality in chronic HF patients. Beta-adrenoceptors (β-AR) signal through cyclic AMP (cAMP) and several lines of evidence indicate that increasing cardiac contractility through cAMP-mediated signalling is energetically expensive and therefore should be avoided in chronic HF. However, other receptors (e.g. 5-HT4 serotonin receptors and prostaglandin receptors) also utilise cAMP as a second messenger. Whereas 5-HT4 receptors in many respects behave like β-AR, prostaglandin receptor stimulation gives different functional consequences, and recent research indicates that different receptors increase cAMP in different functional intracellular compartments. Our recent results indicate that cyclic GMP (cGMP), produced in the heart by stimulation of receptors for natriuretic peptides as well as nitric oxide (NO), also displays differential functional compartmentation with different functional consequences,as described below. Enhancement of cAMP-mediated signalling by natriuretic peptides (NP) in failing hearts Atrial (ANP), brain (BNP), and C-type (CNP) natriuretic peptide levels are increased in the myocardium of HF patients. NPs affect cardiac and non-cardiac cells through receptors (NPRs) which are membrane-bound guanylyl cyclases (GCs). Their activation causes increased cGMP production which is expected to exert beneficial cardiovascular effects, primarily through cGMP-dependent protein kinase (PKG). However, by competitive inhibition of cAMP degradation by phosphodiesterase 3 (PDE3), cGMP can theoretically also enhance cAMP-dependent signalling, e.g. following stimulation of β-ARs. While stimulation of NPR-A with ANP was recently demonstrated to have no effect on β-AR-mediated contractility despite a robust increase in cGMP, we found an unexpected enhancement of the cAMP-mediated inotropic effect of β-AR and 5-HT4 receptor stimulation by activation of NPR-B by CNP. Thus, cGMP produced following NPR-B, but not NPR-A receptor stimulation reduces the degradation of cAMP through phosphodiesterase inhibition and enhances potentially deleterious cAMP-mediated signalling. The expected beneficial cardiovascular effects of natriuretic peptides may thus have to be reconsidered. With the new methodology allowing studies of cAMP and cGMP production at the subcellular level combined with studies of protein-protein interaction, we are examining the intracellular compartmentation of cAMP and cGMP in cardiomyocytes following stimulation of different receptor systems and relating these different intracellular compartments of cAMP and cGMP to functional effects in the heart, primarily regulation of contractility. Results from animal Side 23 av 70 experiments are verified in human heart tissue and the research will have relevance for treatment of HF. Contractile effects of natriuretic peptides and the role of phosphodiesterases in cGMP compartmentation in failing rat hearts In addition to the enhancement of cAMP-mediated signalling described above, we found a negative inotropic and a positive lusitropic response to CNP in failing rat ventricle, presumably through PKG activation. This effect was also only elicited by cGMP from the NPR-B receptor,as BNP gave no effect. We found that the mechanism of the negative inotropic and positive lusitropic response to CNP was mainly explained by PKG-mediated phospholamban and troponin I phosphorylation. Further, we found that the functional responses to CNP were modestly regulated by PDE2 and PDE3, but in opposite directions. Both CNP- and BNP-induced cGMP increases were markedly and mainly regulated by PDE2, supported by high PDE2 activity in cardiomyocytes. The lack of functional responses to BNP could not be explained by PDE regulation. Different effects on contractility and downstream targets of CNP and BNP indicated differential compartmentation of the cGMP signals induced by the two natriuretic peptides. Three papers on the effects of natriuretic peptides on contractility and the role of PDEs in the regulation of both natriuretic peptide-induced cGMP and functional responses were published in 2013-14. Regulation of cardiac stiffness by regulating titn phosphorylation In patientssuffering from HF with preserved ejection fraction (HFpEF), the inability of stiff hearts to fully relax results in incomplete filling during the diastole. The cardiac stiffness may be due to less elasticity in extracellular matrix or cardiac myocytes. The main regulator of elasticity in cardiac myocytes during the diastole is titin, which main function is to keep the structural integrity of the sarcome intact, but also function as an elastic spring, contributing to passive tension within cardiac myocytes. The large protein titin can be phosphorylated on several residues, where in vitro, PKC seems to increase stiffness, whereas PKA and PKG reduce stiffness. In this project, we have determined the receptors responsible for the cGMPmediated reduction in stiffness of single cardiac myocytes. We have also determined which sites on titin are phosphorylated. Together, this may increase our knowledge on how to modulate myocardial stiffness by targeting these receptors in patients with HFpEF. High throughput screening in search for a novel NPR-B receptor antagonist Since enhanced cAMP-mediated signalling is deleterious in HF, we proposed that the cardioexcitatory effect of NPR-B stimulation may have long term harmful effects in HF patients. NPR-B antagonism may therefore serve as a new pharmacological treatment of HF, in addition to conventional treatment (e.g. β-adrenoceptor blockade). So far, there is no NPR-Bselective antagonist available for clinical use. Thus, we started this project aimed at developing a novel small molecule (non-peptide) NPR-B antagonist. We have set up an assay (Alpha Screen) for high throughput screening of low molecular weight compounds and screened a chemical library of about 20,000 compounds (<500 Da). Several compounds inhibited CNP-stimulated cGMP production in NPR-B- or NPR-A-expressing HEK293 cells. Six compounds of special interest were selected for further studies. Three of them show selective NPR-B inhibition, two show partially selective NPR-B inhibition and one shows NPR A/B non-selective inhibition. The compounds mediate reversible and noncompetitive inhibition and most likely act as allosteric inhibitors binding outside the agonist binding site of NPR-B. We also found that the cardio-excitatory effect of NPR-B stimulation in ventricular muscle strips can be attenuated by these compounds. A paper describing these results was published in 2014, and further work, based on the six most interesting compounds, aims to identify new compounds with improved properties.. Side 24 av 70 Scrutiny of the cardiac effects of levosimendan and omecamtiv mecarbil Traditional inotropic agents evoke inotropic responses through increased cAMP production primarily through β-AR stimulation (e.g. dobutamine) or through a reduction of cAMP degradation through inhibition of PDE3 (e.g. milrinone). However, other agents which induce inotropic responses independent of cAMP are sought for, as they can potentially evoke inotropic effects without inefficiently increasing myocardial energy demand and oxygen consumption. As such, the primary objective of these studies was to characterize the effects and certain aspects of the mechanisms of action of two such novel drugs that are currently being evaluated as possible therapeutic agents for the treatment of chronic HF patients, namely levosimendan and omecamtiv mecarbil (OM). These substances are claimed to interfere with the calcium binding component of the troponin complex (troponin C, TnC) directly (levosimendan) or with the myosin ATPase (OM). Levosimendan was marketed as a true Ca2+ sensitizer, evoking inotropic effects through an energy-neutral mechanism of action. However, the positive clinical results of levosimendan may result from the activation of several mechanisms operating alone or in combination. The results of our studies indicate that the inotropic responses to levosimendan and its active metabolite OR-1896 can be accounted for exclusively by inhibition of PDE3, increasing cAMP levels and potentiating inotropic effects of the β-AR system. As such, in the long term, this drug may prove detrimental for the treatment of chronic HF patients. OM is proposed to evoke inotropic effects by activating directly and binding selectively to the S1 domain of cardiac myosin, reducing the threshold for activation of the cardiac myosin ATPase. This results in a prolonged contraction-relaxation cycle thereby increased contractility. The results of these studies indicate OM exerts inotropic and negative lusitropic effects and has Ca2+ sensitizing effect. However, during increased heart frequencies OM may induce increased diastolic tension. These findings provide new insight into mechanistic effects of these two novel inotropes and potential interactions with adrenergic stimulation of the heart. It remains to be determined if these properties are beneficial or detrimental for the treatment of HF. Characterization of functional changes in prostanoid signalling in failing myocardium Despite favourable acute and long-term hemodynamic effects, long-term treatment of HF patients with prostanoid agonists increases mortality. Inhibition of prostanoid synthesis has also shown favourable effects in animal models of HF. Also, in clinical studies, inhibition of prostanoid synthesis with non-steroidal anti-inflammatory drugs and selective COX-2 inhibitors was deleterious in HF. The mechanisms causing the unfavourable effects of prostanoid-modulatory approaches in HF patients are incompletely understood, and a possible contributing factor is the direct effect of prostanoids on heart contractility. Stimulation of FP prostanoid receptor increases heart contractility in animal models but the effects of prostanoids upon human heart contractility remain unknown. Since prostanoids elevate cardiac cAMP levels in the heart and positive inotropic agents elevating cAMP levels generally increase mortality in HF patients, stimulation with prostanoids might be suspected to increase mortality. However, if prostanoids provide tonic inotropic support through cAMPindependent mechanisms, inhibition of the prostanoid synthesis with subsequent loss of inotropic support may be an additional factor contributing to increased mortality. We have concluded our studies and published two manuscripts documenting our results that addressed the initial objectives of this project 1) to determine if prostanoids could elicit direct inotropic responses in human cardiac left ventricle and, if so, elucidate the mechanism of action and 2) determine if prostanoid inotropic responses are modified in failing ventricle. In addition, we have completed and published a manuscript that details the effect of prostanoids to modulate the inotropic responsiveness of receptor systems that signal through cAMP. Lastly, we have concluded studies designed to elucidate the downstream signalling cascade that mediates FP receptor activation of Rho-kinase (ROCK), and whether this increases activity of the sodium hydrogen exchanger (NHE1). In addition, we determined if NHE1 activation is involved in regulation of myosin light chain (MLC-2) phosphorylation levels. Our data indicate that NHE1 activation can modify MLC-2 phosphorylation levels and contractility, Side 25 av 70 providing a molecular mechanistic point of convergence that possibly explains why both alkalinization and MLC-2 phosphorylation appear to mediate FP receptor-mediated inotropic effects. Role of inhibitory G protein (Gi) in heart failure: potential target for treatment Stimulation of β-adrenergic receptors (βAR) is deleterious and increases mortality in chronic HF patients. The muscarinic receptor system counteracts βAR responses through activation of inhibitory G protein (Gi) and enhancing Gi activity to inhibit βAR effects may prove beneficial in HF. Recent studies indicate that chronic vagus nerve stimulation (increasing muscarinic Gi activity) conferred cardioprotection, improved ventricular function and survival in animal HF models and HF patients. Currently in HF, the role of Gi is poorly understood and it is unknown if Gi activity contributes to the beneficial effects of vagal stimulation. Our aim is to elucidate the role of Gi and specific adenylyl cyclase (AC) subtypes to regulate βARmediated cAMP signalling, its compartmentation and effect upon contractile function in normal and HF hearts. We are coducting studies to determine if Gi exerts a tonic intrinsic inhibition upon AC and if there is a differential role of AC5 and AC6. The role of Gi in recruitment of phosphodiesterases is also being explored. Measures of contractile force are being done in whole heart, ventricular strips or cardiomyocytes from rat and AC5 and AC6 knockout mice. We are using intracellular sensors we developed that are bound to anchoring proteins or AC subtypes to measure local, intracellular cAMP concentrations by FRET. Clarifying the role of Gi may aid the identification of molecular targets that mediate the beneficial effects of vagal stimulation, allowing for development of a new drug therapy. Can cardiac tissue hypothyroidism contribute to changes in receptor functions in heart failure? Reports indicate that the failing myocardium exhibits local cardiac tissue hypothyroidism as revealed by reduction of the thyroid hormone receptor TR-α1 and of the thyroid hormones. There seem to be similar changes in receptor-effector signalling and myocardial contractility during development of HF and hypothyroidism. Myocardial foetal genes are activated both in HF and in hypothyroidism, and cardiac tissue hypothyroidism may be involved in some changes in receptor signalling in the failing myocardium. Studying inotropic responses to selective stimulation of various Gq/11/G12/13-protein coupled receptors (5-HT2A serotonin receptors, muscarinic acetylcholine receptors, FP prostanoid receptors, endothelin ET1 receptors, AT1 receptors, α1-adrenoceptors) revealed, however, that the hypothyroid rat model used, exhibited only a few similarities to the failing myocardium, and importantly clear differences such as lacking the 5-HT4 response that failing hearts develop. Thus, a local tissue hypothyroidism and the following activation of fetal genes cannot account for all changes in recetor signalling observed in the failing myocardium. Other factors at least in addition must be involved in the changes of phenotype occuring during development of HF. Molecular organization and interaction between receptors and G proteins In classic pharmacology, G-protein-coupled receptors (GPCRs), G proteins and effectors interact sequentially by random collision. Signalling through GPCRs is both specific and very rapid, indicating that the proteins are efficiently organized. Currently, there are two prevailing views on how receptors, G proteins and effectors are organized; either preassembled in one complex (preassociated/precoupled) or interacting after receptor-activation (collisioncoupling) in discrete microdomains. We have previously compared signalling of the Gscoupled 5-HT4 and 5-HT7 serotonin receptors which revealed fundamental differences in G protein activation. Whereas 5-HT4 receptor function is consistent with collision-coupling, the unusual pharmacological properties exhibited by 5-HT7 receptors can best fit a model with receptor and Gs preassociated in the absence of ligand, thus limiting the access of G protein for other receptors. The few receptors known to preassociate with G protein (Mel1a and CB1 receptors) are (like 5-HT7 receptors) known to be involved in circadian rhythm. Also, the expression of 5-HT7 receptors is regulated by glucocorticoids, and thereby its “control” of Gssignalling in the cell may vary during the day. Preassociation of receptors with G protein Side 26 av 70 might therefore serve as a way to regulate circadian rhythm by controlling the stimuli that will activate the cell. To demonstrate whether 5-HT7 receptors are preassociated with Gs, we have used Fluorescence Resonance Energy Transfer (FRET) to compare the interaction between fluorescently-labeled 5-HT4, 5-HT7 or β1-adrenergic receptors with fluorescentlylabeled G proteins. Agonist-activation of 5-HT4 or β1-adrenergic receptors increased FRET (indicating recruitment of Gs). In contrast, 5-HT7 receptor activation decreased FRET in a concentration-dependent manner. The dissociation of G protein from 5-HT7 receptors had kinetics identical to G protein activation (dissociation between Gα and Gβγ determined by FRET), but slower than recruitment of G protein to 5-HT4 and β1-adrenergic receptors. In addition, results from fluorescence recovery after acceptor photobleaching (FRAP) were consistent with a stable complex between 5-HT7 and G protein. Taken together, this suggests that 5-HT7 receptors preassociate with G protein, a property that likely accounts for the atypical signalling characteristics of 5-HT7 receptors. Effects of functional selectivity: Antagonist-mediated down-regulation of 5-HT7 serotonin receptors Traditionally, ligands of G-protein-coupled receptors have been classified primarily by their affinity and efficacy to activate a signal transduction pathway. More recent reports indicate that the efficacy of a particular ligand can vary depending on the receptor-mediated response measured. A traditional antagonist (when measuring G protein activation) could in fact activate MAP kinases or induce receptor desensitization and internalization and thereby be seen as an agonist on the latter processes. A single receptor can therefore undertake multiple receptor conformations that are responsible for the different effects. Every ligand that binds to the receptor stabilizes different receptor conformations, leading to differential effects. This is termed functional selectivity and has great importance in drug discovery, where ligands can be developed to activate only some specific conformations leading to beneficial effects, thus avoiding conformations that activate other effectors responsible for side effects. Functional selectivity can also explain why only certain drugs in a drug-class have greater effect or suffer from certain side-effects. Previously, we have demonstrated that various ligands behave as functionally selective ligands at 5-HT7 serotonin receptors. Interestingly, the important atypical antipsychotics clozapine and olanzapine not only blocked G protein activation (as expected), but induced both internalization and lysosomal degradation of 5-HT7 receptors. We have therefore determined the mechanism of clozapine- and olanzapine-mediated internalization and lysosomal targeting of 5-HT7 receptors. In the C-terminus of the 5-HT7 receptor we demonstrated that several motifs and conserved residues are involved in recruitment of specific lysosomal sorting proteins and thereby induce degradation of 5-HT7 receptors. Development of new method for detection of phosphoproteins Several of our projects involve quantification of post-translational modifications of proteins, especially protein phosphorylation. This has mainly been achieved using Western blotting, which has limited utility with very tiny tissue samples. We have therefore started a project to develop assays for detection of phosphoproteins based on a novel technology utilising isoelectric focussing in capillary nanotubes (“NanoPro” technology). The assay is a protein analysis technique with many attributes of Western blot analysis, but the use of capillarybased isoelectric focussing to separate various protein phosphorylation states enables detection of changes in protein phosphorylation with very small tissue samples. The relative phosphorylation level can be estimated by using a pan-specific antibody that recognizes all non-phosphorylated and phosphorylated isoforms of the protein. Unlike traditional analytical techniques, the technique is highly quantitative and extremely sensitive, and enables detailed characterization of proteins in small and precious samples. NanoPro assays also enable quantification of small changes in phosphorylated states of key proteins during different physiological/pathological states or during different conditions, below the detection limit of traditional analytical techniques. Side 27 av 70 National collaborators Center for Heart Failure Research, Faculty of Medicine, University of Oslo K.G. Jebsen Cardiac Research Centre, Faculty of Medicine, University of Oslo Lars Gullestad, Oslo Univ. Hospital - Rikshospitalet Ivar Sjaastad, Ole M. Sejersted, Oslo Univ. Hospital - Ullevaal Kjetil Taskén, The Biotechnology Centre of Oslo Jo Klaveness, Bjarne Brudeli, Drug Discovery Laboratory AS Eva Steinnes, Trygve Gulbrandsen, Serodus ASA International collaborators Alberto J. Kaumann, University of Cambridge, Cambridge, UK Peter Molenaar, University of Queensland, Brisbane, Australia Christian Torp-Pedersen, Lars Køber, Copenhagen, Denmark Martin J. Lohse, Würzburg, Germany Moritz Bünemann, Marburg, Germany Manuela Zaccolo, University of Oxford, UK Thomas Eschenhagen, Univ.klin. Eppendorf, Hamburg, Germany Adrian Hobbs, Queen Mary University of London, UK Thomas Wieland, Universität Heidelberg, Germany Kathleen Van Craenenbroeck, Ghent University, Ghent, Belgium Salvatore Guccione, Univ. of Catania, Catania, Italy Maria Waldhoer, Novo Nordisk, Copenhagen, Denmark 8.2 Research group on cellular signal transduction and cancer pharmacology (per 2013) Leader: Dagny Sandnes, PhD, Professor. Scientific staff Name Degree Title Institution/Employer Dagny Sandnes Thoralf Christoffersen Ingvild Brusevold Vegard Tjomsland Ingun Heiene Tveteraas John Ødegård Monica Aasrum MScPharm, PhD MD, PhD MScOdont, PhD MSc, PhD MD, PhD MD MSc Professor Professor emeritus Postdoc Postdoc PhD student PhD student Head Engineer UiO UiO UiO UiO UiO UiO UiO Research area Molecular mechanisms that convey and integrate receptor-mediated signalling Aims To increase understanding of targeted therapy of cancer, and to identify novel targets for pharmacological treatment of cancer. Ongoing projects in 2013 Intrinsic modulating mechanisms in EGFR and Met signalling pathways In previous studies of the role of several pathways downstream of EGFR and Met in mediating proliferative responses and migrating behaviour, we found, so far in two cell types, Side 28 av 70 that there are partly parallel and partly distinct mechanisms for these receptors. Pursuing these studies, we have started to investigate mechanisms within the signalling pathways that regulate the magnitude and pattern of the signals. Currently we are focusing particularly on the role of Gab1 as a modulator of signalling from EGFR and Met. The ‘Grb2-associated binder-1’ (Gab1) is a large docking protein known to be involved in signalling pathways from RTKs and cytokine receptors. In our experiments in rat hepatocytes, Gab1 is rapidly phosphorylated upon stimulation with either EGF or HGF. Knockdown of Gab1 expression using specific siRNA leads to reduced cyclin D1 expression and DNA synthesis. However, while Gab1 is recruited directly to Met, it interacts indirectly with EGFR, in a Grb2-dependent manner. Furthermore, in contrast to an EGFR-mediated parallel stimulation of the two adaptor proteins Shc and Gab1, Met dramatically prefers Gab1 (Fig 1), activating it at very low HGF concentrations without detectably stimulating Shc (Aasrum et al 2013). Figure 1. Schematic representation of differential involvement of Gab1 in activation of the Ras-Erk pathway downstream of EGFR and Met. Gab1 also mediates activation of the PI3K-Akt pathway (not shown). There are reports suggesting that Gab1 has an important role in the activation of the MEK/ERK and PI3K/Akt pathways downstream of EGFR, especially at low-intensity stimulation. No such studies exist for Met. In Gab1-depleted hepatocytes we have shown that Gab1 is essential for maximal activation of signalling pathways downstream of EGFR and Met, with an even more evident role downstream of Met compared to EGFR. Both EGF and HGF utilises Gab1 to exert signalling through the ERK pathway, in contrast to the Akt pathway, where only HGF-induced Akt activation is dependent on Gab1. In addition, the effect of Gab1 on the signalling pathways is dependent on the growth factor concentration for both EGF and HGF (Aasrum et al 2014, unpublished).We will extend these investigations to a panel of normal and neoplastic cells from oral mucosa, colon, and pancreas. Mechanisms integrating GPCR- and EGFR-mediated signals A major aim of this project line is to explore the molecular mechanisms that integrate signals from GPCRs and EGFR. So far we have identified several different patterns of interaction between signalling pathways from receptors of the GPCR family and EGFR (summarized in Fig 2). Figure 2. Different mechanisms of interaction between GPCR and EGFR signalling. The figure is based on our findings using different GPCR agonists in various normal and malignant cells. Depending on the cell type and the agonist used, one single or a combination of these mechanisms may be operating in integration of GPCR and EGFR signalling (see text). Side 29 av 70 Our studies have provided evidence that in some cells the promitogenic effects mediated via GPCRs involve upregulation of the expression of several genes and synergistic modulation of downstream signalling from the EGF receptor. These effects seem to be mediated via G proteins of both the Gi and Gq subtype (mechanisms 1 and 2 in Fig 2), and in some of the cells mitogenic signals may proceed from Gq through protein kinase C (PKC). On the other hand, in several of the cancer cells that we have investigated, GPCRs initiate cellular events leading to transactivation of EGFR (mechanism 3 in Fig 2). In these cells EGFR functions as a signal integrator. While transactivation of EGFR is a well-known phenomenon, we have tried to delineate the underlying mechanisms in much detail. In some of the cells (hepatocarcinoma, colon cancer) stimulated with PGE2 or neurotensin, we have evidence supporting the following sequence of events: binding to receptors that couple to Gq – activation of phospholipase C beta (PLCβ) – InsP3 and Ca2+ release (rather than PKC activation) – interaction with Src – and metalloproteinase-mediated shedding of mitogens of the EGF family. The above studies have included several different GPCR agonists. We will now pursue these investigations, focusing particularly on effects of prostaglandins and LPA in oral and pancreatic carcinoma cells, and on mechanisms integrating signalling from LPA receptors and EGFR. Mechanisms of LPA-induced cell migration in oral carcinoma cells Interference with LPA receptors and their signalling is a potential approach in novel therapeutic strategies. Using the oral cancer cell line E10 as a screening model, we found that LPA strongly induced migration, while several other GPCR agonists did not. LPA did also induce migration in pancreatic cell lines. It is notable that relatively little is known about the mechanisms of the tumour-promoting effects of LPA, particularly about the receptors involved. We will now examine if LPA induces migration independently of EGFR or through EGFR transactivation. Preliminary results indicate that the activation of EGFR is involved in at least some effects of LPA in both pancreatic and oral carcinoma cells. Thus we have seen that LPA induces migration in several of the above cells and that this effect can be inhibited by gefitinib, suggesting a role of EGFR in the underlying pathways. We will explore further the signalling pathways involved. LPA can activate six different LPA receptors, all belonging to the family of GPCRs. Presently, pharmacological tools for characterizing different LPA receptor-mediated effects are not very selective. By combining studies with agonists and antagonists, specific silencing with siRNAs, and measurement of receptor expression at the mRNA and protein level, we will explore these mechanisms. We have tentatively, and somewhat unexpectedly, identified LPAR3 as the receptor most likely responsible for migration-inducing signalling and EGFR transactivation by LPA. More studies along these lines are important in our further work. Mechanisms involved in tumour-stroma interactions in pancreatic duct cancer Pancreatic adenocarcinoma is the most lethal of all solid malignancies, with a 5 year survival of less than 5%. Surgical resection remains the only treatment with curative potential, but the majority of patients have unresectable or metastatic disease at the time of diagnosis. A particular feature of primary pancreatic adenocarcinoma is the extensive fibrotic stromal reaction known as tumour desmoplasia surrounding these tumours. Histologically, the extent of tumour desmoplasia, consisting of proliferating stromal fibroblasts, pancreatic stellate cells (PSCs) and various other cell types embedded in collagen is often greater than the epithelial tumour component. These observations have raised the possibility that targeting the stromal cells to interrupt paracrine stromal signalling mechanisms may represent a new treatment strategy in pancreatic cancer. Interleukin-1 (IL-1) is a pleiotropic cytokine that primarily affects inflammatory and immune responses, but it also has multiple effects in cancer development. Two agonist proteins, IL-1α and IL-1β, bind to the IL-1 receptor. The expression of IL-1α has been found to correlate with the clinical outcome of the patients and to be a major activator of PSCs, suggesting an essential role for IL-1α in the cross-talk Side 30 av 70 between cancer cells and the tumor stroma. Our aim is to inhibit the effects of IL-1 signaling between cancer cells and PSCs by identifying regulatory mechanisms involved in IL-1 signaling in PSCs and isolate IL-1α-induced factors in PSCs responsible for the enhanced migration and infiltration of cancer cells. Figure 3: Some of the interactions between pancreatic carcinoma cells and stellate cells. Our studies focus primarily on major pathways involving IL-1, TGFβ1, HGF/Met, and COX/prostaglandins, and they focus particularly on the interaction between these pathways. 8.3 Neuropharmacology – Alzheimer’s disease research Leader: Lars Nilsson, PhD, Professor. Scientific staff Name Lars Nilsson Charlotte Jendresen Kristi Henjum Vibeke Årskog, Degree MScPharm, PhD MSc MScPharm MSc Title Professor PhD student PhD student Engineer Institution/Employer UiO UiO OUH UiO OUH=Oslo University Hospital Research area Alzheimer’s disease and other dementia disorders Aims To investigate Alzheimer’s disease pathogenesis, and to explore novel targets and diagnostic principles based on enhanced pathogenic understanding. Ongoing projects in 2014 Mechanisms of extracellular matrix to amyloid formation Studies of genetics of Alzheimer’s disease have proved, mainly from in vitro experiments, that altered production and/or accumulation of aggregation-prone amyloid-β (Aβ) peptides in brain can cause early-onset Alzheimer’s disease. These mechanisms are likely important also to far more prevalent “sporadic” forms of Alzheimer’s disease. Little is known on the mechanism of Aβ-aggregation and deposition in brain, and how downstream pathobiology is instigated by Aβ leading to neuronal dysfuntion, demise and dementia. Heparan sulfate proteoglycans (HSPG) are glycoproteins which are primarily located at the extracellular matrix. Heparan sulphate (HS) is associated with amyloid deposits in Alzheimer’s disease and other amyloid disorders, but their pathogenic role remains unclear. We have access to a unique transgenic mouse model which overexpresses heparanase in the brain leading to structural changes of HSPGs with shortening of sulphated side-chains. The mice have been cross-bred with transgenic mice overexpressing human amyloid precursor protein (AβPP) with the Swedish AβPP mutation (tg-Swe). This AβPP-mutation always results in early-onset Side 31 av 70 Alzheimer’s disease in a Swedish family. We have recently found that heparanase overexpression markedly affects Aβ-deposition in crossed mice, and are now exploring the molecular mechanisms of the effect e.g. by injecting tissue extracts. We have also found that proinflammatory stimuli can change cytokine expression and differentially affects amyloid deposition in transgenic mice with or without heparanase. The project is done in collaboration with Prof. Jin-Ping Li and Dr. Xiao Zhang at Uppsala University. Pathogenic role and therapeutic potential of receptors regulating innate immuny Recent genetic and gene network analyses suggest that innate immunity is implicated in Alzheimer’s disease pathogenesis. We are exploring the role of peripheral monocytes cells migrating across the blood-brain barrier and patroling the central nervous system. In this process the cells can differentiate and become able to phagocytose and digest protein aggreagtes in brain e.g. Aβ-complexes. In order to detect Aβ-fragments and to measure Aβclearance by such cells in the brain a series of new Aβ-antibodies are being generated and evaluated. The intent is to quantity Aβ-clearance and to exploit the diagnostic potential of such a measure. We are examining pathogenic effects of wild-type and mutant Triggering Receptor Expressed on Myeloid cells 2 (TREM-2), a recently discovered risk factor gene for Alzheimer’s disease. TREM-2, a receptor protein that is expressed on monocytes and microglia, is functionally linked to innate immunity and neurodegenerative disease. We have developed and ELISA for soluble TREM and used that for CSF-analyses to check diagnostic potential. We have also developed a TREM-reporter signalleing assay to detect and assay agonist ligand to this receptor. These projects are done in collaboration with Prof Tormod Fladby, Dr. Reidun Torp and Assoc. Profs Michael Daws and Oskar Hansson. National collaborators Tormod Fladby, Professor, Oslo University Hospital Reidun Torp, Researcher, UiO Michael Daws, Assoc. professor, UiO International collaborators Jin-Ping Li, Professor, Uppsala University, Sweden Xiao Zhang, Researcher, Uppsala University, Sweden Oskar Hansson, Assoc. Professor, Lund University, Sweden 8.4 Therapeutic Drug Monitoring Group Leader: Mimi Stokke Opdal, MD, PhD Scientific staff Name Mimi Stokke Opdal, Peter Krajci Marianne K Kringen Hege-Merethe Krabseth Lill Dannevig Müller Margrete Larsen Burns Svein Ivar Johannessen Degree MD, PhD MD, PhD MSc, PhD MD MSc, PhD MD MSc, Dr.philos. Cecilie Johannessen Landmark MSciPharm, PhD Title Associate prof II Medical Adviser Researcher Doctor Senior engineer PhD student Senior researcher emeritus Associate prof. Institution/Employer OUH OUH OUH OUH OUH OUH OUH Oslo university college OUH=Oslo university hospital Side 32 av 70 Research area The research group is working on the optimization of drug therapy using therapeutic drug monitoring (TDM), pharmacogenetic analyses and other outcome measures. The main focus of the group is at present on opioids, antiepileptic drugs and ethanol. Ongoing projects in 2014 Methadone pharmacology and QT-time in methadone maintenance treatment patients with end stage kidney failure Oslo University Hospital is the largest centre for treatment of methadone maintenance treatment (MMT) patients in Norway. This project is performed in collaboration with clinicians at our hospital. In Norway such patients are treated with rather high dose of methadone, that is around 100 mg daily. Methadone is an opioid that primarily is removed by renal excretion. Some MMT patients develop kidney failure and need treatment with haemodialysis. Methadone treatment has also been associated with increased QT-time giving rise to fatal arrhythmias. Aim: To investigate methadone pharmacokinetics during four hours haemodilaysis in MMT patients with end-stage renal failure, particularly if methadone was removed in haemodialysis or in urine. We investigated possible effects on QT-time by recording ECG every 30 min during haemodialysis. In addition we perform certain clinical tests to assess opioid withdrawal, side effects and clinical impairment along with routine biochemistry tests including pharmacogenetics. Substitution of R,S-methadone with R-methadone in methadone maintenance treatment patients with known prolonged QT-time In studies by Anchersen et al. 2009 a subpopulation of MMT patients with prolonged QT-time on ECG has been detected. It has been reported that R-methadone has less effect on QTtime than R,S-methadone. Aim: To investigate serum levels of methadone and QT-time before and three hrs after daily R,S-methadone dose in patients at methadone steady state concentrations and with QT-time > 450 ms at inclusion. The patients will then switch to Rmethadone (half-dose of R,S-methadone) and at developed concentration of steady state we will again measure methadone serum concentration and QT at Cmin and Cmax of methadone. If R-methadone has less effect on QT-time in these patients they will be offered Rmethadone treatment instead of R,S-methadone. The pharmacogenetics regarding metabolizing enzymes (CYP3A4/5, CYP2D6, CYP2B6 and to a lesser degree CYP1A2) in the liver of importance for methadone metabolism will also be investigated in this study. TDM and clinical pharmacology of antiepileptic drugs We aim to study pharmacokinetic variability of newer antiepileptic drugs (AEDs) in patients with epilepsy, regarding factors that contribute to individual variability, such as age, physiological state and comedication. Implementation of therapeutic drug monitoring in the treatment of patients with refractory epilepsy at the National Center for Epilepsy, Sandvika is an important part of their treatment. Increased focus on and monitoring of individual variability will lead to more optimal treatment of the patients and avoidance of harmful adverse effects and toxicity. The TDM-database at the National Center for Epilepsy will be used to investigate individual variability in pharmacokinetics of newer antiepileptic drugs in patients with epilepsy, to elucidate factors that contribute to variability, as age, comedication and genetic factors. Focus on variability is essential for treatment and dosage adjustments in the individual patients for optimal efficacy and tolerability. Ongoing studies include pharmacokinetic variability and experience with clobazam. Further studies will include other newer AEDs that are established for routine TDM service, as well as the implementation of TDM in the treatment of gabapentin in various pain disorders and the pharmacokinetics of zonizamide during pregnancy. National collaborators Hassan Khiabani, MD, PhD, Section manager at The Clinical Research Unit, Department of Pharmacology Side 33 av 70 Knut Gjesdal, MD, PhD, Professor emeritus, University of Oslo/OUS Ullevål MDs at Department of Addiction and Dependence, OUS, Ullevå Solbjørg Sagedal, MD, PhD, Department of Nephrology, OUS Ullevål 8.5 Clinical Pharmacology & Pharmacogenomics Research Group Leader: Marianne K Kringen, MSc, PhD Scientific staff Name Degree Title Marianne K. Kringen Mimi Stokke Opdal Odd Brørs Gaut Gadeholt Sigrid Narum Per Wiik Johansen Kari B. Foss Haug Jens Petter Berg Camilla Stormo Armin Piehler MSc, PhD MD, PhD MD, PhD MD, PhD MD MD, PhD Dr.scient MD, PhD MSc MD, PhD Researcher Adjunct Asst. Prof. Adjunct Asst. Prof. emeritus Senior Consultant Senior Consultant Section manager/Senior Consultant Researcher Professor PhD student Senior Consultant Institution/ Employer OUH OUH OUH OUH Diakonhjemet OUH OUH OUH OUH Fürst Med Lab OUH= Oslo university hospital Research area 1) Cardiovascular disease; cholesterol lowering (statins), anti-platelets and anticoagulation medicines, 2) Cancer; cytostatics (5-FU, irinotecan) Aims Investigation of the role of clinical pharmacology and pharmacogenomic variation in pharmacokinetics, pharmacodynamics and clinical use of drugs Ongoing projects in 2014 1) Cholesterol lowering- and anticoagulation medicines Mortality among head trauma patients on anticoagulants or antiplatelet agents prior to trauma Anticoagulant therapy is increasingly common among older persons. As a consequence, the incidence of anticoagulant-associated intracerebral hemorrhage has increased. Whether the use of anticoagulants or platelet inhibitors affects the mortality after head trauma is not so well studied. Aim: To study the association of drug use on mortality among head trauma patients admittet to Oslo University Hospital between January 2004 and December 2006. Data are analysed and manuscript is under preparation. Platelets and leukocytes in GI bleeding Etiology and pathogenesis of gastrointestinal (GI) bleeding are often unclear/unknown. Among factors likely to contribute are erosions, ulcerations, venous varicosities, HP infection and ulcerating drugs. Drugs associated with GI bleeding such as aspirin, NSAIDs and anticoagulants may contribute by damaging the GI mucosal protective barrier and/or inhibiting hemostasis (e.g. platelet function or blood coagulation). Platelet function is of vital importance for hemostasis. Platelet activation (aggregation and CD11b expression) by ADP Side 34 av 70 is correlated with leukocyte count and thus appears to be at least partially dependent on platelet-leukocyte interaction. In a recent study of platelet function in patients with acute GI bleeding, we observed that arachidonic acid (AA)-induced aggregation and collagen-induced P-selectin expression were reduced compared to healthy control persons, the reductions being partially dependent on prior use of platelet inhibitors by the patients. Aim: To further investigate possible mechanisms contributing to bleeding tendency in patients with acute GI bleeding: 1) Investigate the contribution of leucocyte – platelet interaction on GI bleeding. 2) Investigate the contribution of leucocyte FcγRI receptor expression on GI bleeding. Alternative splicing in cholesterol metabolizing genes Cholesterol is essential for normal function and growth of human cells. However, elevated levels of cholesterol in plasma and tissues represent a major risk factor for development of cardiovascular disease. Statins is a class of lipid lowering drugs that targets genes involved in the cholesterol biosynthesis. Alternative splicing in a number of genes has been reported to be associated with variable statin response. Aim: The main objective of this project was to investigate how lipid lowering statin drugs (atorvastatin) affect the splicing pattern in cultured liver cells (HepG2). Results: RNA-seq analysis identified 121 genes and 98 specific splice variants to be differentially expressed upon statin treatment. In addition, 11 genes showed changes in the splicing pattern. These results were recently published and the article is included in Camilla Stormos doctoral thesis. Copy number variations of the ATP-binding cassette transporter ABCC6 and its pseudogenes The ATP-binding cassette transporter ABCC6 belongs to a large family of membrane proteins (ABC transporters) that are a highly conserved and present in all organisms from bacteria to man. ABCC6 is located on the long arm of chromosome 16 along with two shorter, almost identical (> 99% sequence identity), pseudogenes; ABCC6P1 and ABCC6P2. Single mutations in ABCC6 are known to cause the rare autosomal recessive disease pseudoxanthoma elasticum (PXE), a metabolic disorder characterized by ectopic mineralization of soft connective tissues. Interestingly, several studies have also shown an association of genetic ABCC6 variants and plasma cholesterol levels (low HDL-cholesterol in non-wildtype genotypes). Recently we found that copy number variation (CNV) of ABCC6 and ABCC6 pseudogenes are common in several populations. CNV of the ABCC6 pseudogenes are likely to influence the expression level of these pseudogenes, and therefore, may have an impact on ABCC6 including the genetic message, the protein level, the function of the protein and the PXE phenotype. Aim: To gain insight into the contribution of CNVs of ABCC6 and its pseudogenes on the PXE phenotype. Results are evaluated and manuscript is submitted. 2) Cytostatics Contribution of genetic variants to serum bilirubin levels in the NORIP population Genetic variants are known to contribute to decreased glucuronidation activity in the liver due to decreased promoter activity of the gene encoding UGT1A1. Decreased glucuronidation activity leads to increased bilirubin levels in otherwise healthy people (Gilbert’s syndrome) and represents a substantial risk factor for adverse drug reactions of certain drugs (e.g. irinotecan). The proposed study seeks to confirm previously published associations between certain genetic variants and bilirubin levels in a Nordic cohort (NORIP population). Moreover, the study aims at identifying novel SNPs in an extended promoter region of UGT1A1 associated with bilirubin levels in serum. The aims of this study were: 1) To confirm previously published associations between certain SNPs UGT1A1, SLCO1B3 etc. and bilirubin levels. 2) Evaluate associations of other SNPs (tagSNPs from the HapMap project) in an extended promoter region (about 30kb) upstream of UGT1A1. Results: Stepwise multivariate logistic regression analysis of all genetic variants together with age, sex, country Side 35 av 70 of origin and fasting time, showed that the repeat variants of UGT1A1 TA6>TA7 and SLCO1B3 rs2117032 T>C were the only variants significantly associated with higher bilirubin concentrations. Most individuals with high bilirubin levels were homozygous for the TA7repeat (74%) while only 3% were homozygous for the TA7-repeat in individuals with normal bilirubin levels. Among individuals heterozygous for the TA7-repeat, a low frequent UGT1A1diplotype harbouring the rs7564935 G-variant was associated with higher bilirubin levels. These results were recently published. Copy number variation and alternative mRNA-splicing of Carboxylesterase 1 and its pseudogenes Human carboxylesterase 1 is the major hydrolase in human livers and is responsible for the metabolism of many drugs; anticoagulants (i.e. clopidogrel and dabigatran) and cyostatica (i.e. irinotecan and 5-FU (capecitabine) and endogenous substances. The enzyme is encoded by the CES1 gene which is located on chromosome 16, in a region with a lot of chromosomal instability. Aim: 1) To determine the frequency of CES1 copy number variation in different populations and to gain insight into the contribution of CNVs on drug metabolism. 2) To identify novel CES1 splice variants. Results: The copy number of CES1 vary between populations and having copy numbers of 3 or 4 is rather common in Chinese. Three new CES1 splice variants have been identified so far in this study. Further work will attempt to functionally characterize these splice variants. Results from this study have resulted in one MSc-thesis and one BSc-thesis (HiOA). National collaborators Lipid Clinic, OUS, Rikshospitalet (Kjetil Retterstøl, Martin Bogsrud) Center for Clinical Heart Research, Department of Cardiology, OUS, Ullevål (Arnesen/Seljeflot) Department of of Medical Gastroenterology, OUS, Ullevål (I. Lygren) University of Agder; UiA, Camilla Stormo Ragnhild Augustson, HiOA Toril Tefre, HiOA International collaborators PXE-international, USA (Sharon Terry) Institute of Laboratory and Transfusion Medicine of the Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany (Doris Hendig) 8.6 Epilepsy Research Group - Clinical pharmacology of antiepileptic drugs Leader: Svein I. Johannessen, MSc, PhD Scientific staff Name Svein Ivar Johannessen Degree MSc, Dr.philos. Cecilie Johannessen Landmark, MScPharm, PhD Title Senior researcher emeritus Associate prof. Side 36 av 70 Institution/Employer OUH Oslo university college Research area Epilepsy and clinical pharmacology of antiepileptic drugs. Aims Get insight into trends in the utilization of antiepileptic drugs in epilepsy and other indications in the entire population in Norway II. To improve our knowledge for better individual treatment of patients with antiepileptic drugs I. Background From population to the individual – for optimal treatment of the individual patient Pharmacoepidemiological studies by the use of the Norwegian Prescription Registry contribute to new insight in pharmacological treatment of subpopulations and patient groups. We investigate changes in prescription patterns over time for specific drugs and combinations of drugs. Many drugs used in combination may lead to harmful effects over time, and often they are not discovered in clinical studies. Such studies thus contribute to improved pharmacovigilance of drug treatment in a national and international scale. Population based studies may therefore improve our knowledge for better treatment of patients on the individual level, that will benefit subgroups of patients, e.g. in epilepsy or psychiatric disorders. Special patient groups that need individualized treatment include children, pregnant women and the elderly, due to extensive individual variability in pharmacokinetics, polytherapy and interactions, other individual factors or comorbid disorders. This variability may be accounted for by the implementation of therapeutic drug monitoring (TDM). Genetic variability may also be discovered, as a base of ”tailored therapy”. Ongoing projects 2014 I) Population-based studies: Use of the National Prescription database to study drug utilization in the population 1) Antiepileptic drugs in epilepsy vs non-epilepsy indications We investigate the utilization of various classes of drugs in the entire population regarding their use in epilepsy and psychiatric disorders (antiepileptic drugs, antidepressants, antipsychotics) from 2004 to 2012. During the last years, antiepileptic drugs are increasingly used in other disorders than epilepsy. In neurology and psychiatry they are used in migraine, neuropathic pain, bipolar disorder, mania, schizofrenia, anxiety etc. This trend is important to follow in the population, as new groups of patients with psychiatric disorders or pain often use these drugs, and most often in combination with other drugs that may cause adverse effects or insufficient pharmacological effect. Antiepileptic drugs have several mechanisms of action that may contribute to the clinical efficacy. Investigation of changes in the national prescription pattern over time may show how the use of the individual drugs may change over time. The national Prescription Registry is suitable to carry out pharmacoepidemiological population-based studies using reimbursement codes or diagnosis codes to investigate the use in various indications in the population 2) The elderly and the use of drugs in epilepsy and psychiatry The elderly often use polytherapy and have a decreased tolerance for drug combinations. Utilization of drugs that affect the central nervous system in the elderly, as compared to younger adults, polytherapy with various drug combinations, changes in prescription patterns of specific drugs over time, choice of drugs in various age groups etc. will be elucidated. Of special importance the utilization of antiepileptic drugs in elderly (> 60 yrs) as compared to the younger population (< 60 yrs) will be Side 37 av 70 elucidated. Details in prescriptions, reimbursement and the level of specialists involved in the prescriptions of these drugs in the elderly will be investigated. 3) Availability of antiepileptic drugs in Europe Based on our studies on national drug utilization, we initiated a study to investigate the utilization and possible treatment gap in epilepsy across Europe. The WHO has recently published a report that points to that the treatment of epilepsy has to be focused on. At present the documentation on the availability of antiepileptic drugs in the various countries in Europe is scarce. Many new antiepileptic drugs have been marketed in recent years, but there are several restrictions and differences in the availability, cost for the individual patient, reimbursement and availability in other indications than epilepsy (psychiatric disorder and pain), freedom of choice of the various antiepileptic drugs, availability of generic products etc. The documentation of the drug consumption in the population is an important part of pharmacovigilance in an international setting. The aim of the study is to document and evaluate the treatment choices, availability of antiepileptic drugs and the possible “treatment gap” in epilepsy in Europe. A quantitative study of the availability of antiepileptic drugs using an electronic questionnaire sent to all national Epilepsy Societies of the International League Against Epilepsy. This is important to document for the drug authorities in the respective countries if there is any major limitation of drugs and also for the European Drug Authorities (EMA) in order to improve the possibility for an equal treatment opportunity of all patients. II) Individual pharmacokinetic variability and use of antiepileptic drugs 1) Pharmacokinetic variability of antiepileptic drugs We aim at studying pharmacokinetic variability of newer antiepileptic drugs in patients with epilepsy, regarding factors that contribute to individual variability, as age, physiological state and comedication. Implementation of therapeutic drug monitoring in the treatment of patients with refractory epilepsy at the National Center for Epilepsy, Sandvika is an important part of their treatment. Increased focus on and monitoring of individual variability will lead to more optimal treatment of the patients and avoidance of harmful adverse effects and toxicity. The TDM-database at the National Center for Epilepsy will be used to investigate individual variability in pharmacokinetics of newer antiepileptic drugs in patients with epilepsy, to elucidate factors that contribute to variability, as age, comedication and genetic factors. Focus on variability is essential for treatment and dosage adjustments in the individual patients for optimal efficacy and tolerability. Ongoing studies include carbamazepine, oxcarbazepine and eslicarbazepine acetate. A collaborative study of eslicarbazepine acetate (SSE-OUH, St. Olavs hospital, Diakonhjemmet hospital) To investigate the implementation of therapeutic drug monitoring for eslicarbazepine acetate in clinical practice with focus on pharmacokinetic variability, pharmacokinetic interactions, tolerability and efficacy. This forms the basis to evaluate its suggested reference range (50-140 μmol/L). Retrospective data from therapeutic drug monitoring services from main laboratories in Norway during 2012-2013 are included. Eslicarbazepine acetate is analysed as oxcarbazepine where the racemic monohydroxy-derivative is measured. Supplementary clinical data were evaluated where possible and handled anonymously. Drug fasting samples at assumed steady state are used. The pharmacokinetic variability of eslicarbazepine acetate is extensive. Therapeutic drug Side 38 av 70 monitoring is implemented to evaluate the balance between efficacy and tolerability in the individual patient. 2) Pharmacological treatment of patients with MS - focus on polytherapy and antiepileptic drugs Patients with multiple sclerosis (MS) are often suffering from chronic pain. Pain is a debilitating symptom and treatment is associated with undesirable adverse reactions, especially long-term treatment where tolerance and dependence issues are concerning. Therefore, antiepileptic drugs are frequently being used in the management of chronic pain. Antiepileptic drugs are among the most susceptible drugs to be involved in pharmacokinetic as well as pharmacodynamic interactions. MS patients often use several different types of CNS-active drugs, yet little research has been done to highlight potential polypharmacy issues. The aim of this study was to investigate the pharmacological treatment of MS patients at MSSH with regards to current knowledge on polypharmacy, with particular focus on antiepileptic drugs. Medical records from 2009 to 2011 were reviewed and an overview of drug dosages and combinations used by patients at MSSH was created. The present study demonstrates that one third of MS patients used either an antiepileptic drug or antidepressants and that one fifth used two or more. There was no difference in age, gender or degree of disability of the patients using these drugs. Polytherapy was widespread, with up to 19 concomitant drugs in use. Although the antiepileptic drugs are well-known for their pharmacokinetic interactions, this is not of particular concern for MS patients since they mainly used newer antiepileptic drugs (pregabalin and gabapentin) with little propensity to interact. Pharmacodynamic interactions are of greater concern since more than half of the patients used an opioid, a benzodiazepine or baclofen in addition to their antiepileptic drugs and antidepressants therapy. One third of the patients were elderly and careful considerations regarding pharmacokinetics and possible excessive adverse effects are of importance. More focus on individualization of treatment by implementation of therapeutic drug monitoring of antiepileptic drugs and antidepressants and attention to potential pharmacodynamic interactions may be further treatment concerns. National collaborators Oliver Henning, MD, National Center for Epilepsy, OUH Torleiv Svendsen, MD, National Center for Epilepsy, OUH Erik Sætre, MD, PhD, National Center for Epilepsy, OUH Eylert Brodtkorb, Prof., MD, PhD., St. Olav’s Hospital, Trondheim Arne Reimers, MD, PhD., St. Olav’s Hospital, Trondheim Espen Molden, Prof., PhD, University of Oslo and Center for psychopharmacology, Diakonhjemmet hospital, Oslo Pål Gunnar Larsson, MD, PhD, Section Head, Department of Neurosurgery, OUH Antonie G. Beiske, MD, PhD, Center for MS rehabilitation, Hakadal Arton Baftiu, cand. pharm., PhD student Morten A. Mevåg, Master student, School of Pharmacy, University of Oslo (UiO International collaborators Prof. Torbjörn Tomson, MD, PhD, Karolinska Institutet, Stockholm, Sweden Prof. Philip N. Patsalos, PhD, Chalfont Epilepsy Center/The National Hospital for Neurology and Neurosurgery, London, UK Prof. Meir Bialer, PhD, MBA, Hebrew University, Jerusalem, Israel Prof. Emilio Perucca, MD, PhD, University of Pavia, Italy Side 39 av 70 8.7 Research group: Individualizing immune modulation and chemotherapy (i2mc) Leader: Stein Bergan, MScPharm, Dr. philos., Adjunct professor (Oslo University Hospital and School of Pharmacy, University of Oslo) Scientific staff Name Degree Title Stein Bergan Nils Tore Vethe Sara Bremer Anders Andersen Helge Rootwelt Ragnhild Heier Skauby Rolf A. Klaasen Mojgan Gharizadeh Ilona M. Jaszcz MScPharm, Dr.philos. MScPharm, PhD MScPharm, PhD BScChem MD, PhD MD MScPharm Section manager Researcher Researcher Analytical Chemist Senior Consultant PhD-student Master student, Pharmacy Master student, Pharmacy Institution/ Employer OUH/UiO OUH OUH OUH OUH OUH OUH UiO UiO OUH=Oslo university hospital Completed degrees Margrete Kasbo completed her thesis for the MSc in Pharmacy, School of Pharmacy, University of Oslo, in June 2014. Title: Individualisering av takrolimusbehandling hos nyretransplanterte pasienter – Muligheter ved farmakodynamiske og –genetiske analyser. Rolf Klaasen completed his thesis for the MSc in Pharmacy, School of Pharmacy, University of Oslo, in June 2014. Title: Biomolekylære markører hos de novo nyretransplanterte – Endringer i metabolsk aktivitet, puriner og IMPDH-kapasitet i ex vivo-aktiverte lymfocytter. Following the completion of his master degree, Klaasen has been part time employed in our department. Working group on biomarkers in transplantation (BWG): S. Bergan is now member of this working group which is organized under the IATDMCT (the International Association of TDM and Clinical Toxicology). This group arranged a symposium on the topic in Dec 2014 in Barcelona and also several roundtable sessions to prepare consensus documents for the status of biomarkers in (drug therapy related to) transplantation. These documents are now in preparation for publication. Research area For several diseases the transplantation of a healthy organ from a living or deceased donor is the best therapy available. When an organ is transplanted into a recipient from a donor that is not genetically identical, the immune system must be suppressed to avoid rejection of the organ. In most situations this is a critical part of the treatment, and the recipients will need life long immunosuppression. The use of immunosuppressive drugs is a delicate balance between sufficiently effective suppression to avoid rejection, and an exposure to those drugs that is low enough to avoid adverse effects, short and long term effects like infections, organ toxicities, increased risk of malignancies and other drug specific side effects. To obtain this balance, tools are needed that can enable the optimal dosing for each patient. Those are the methods and principles applied for individualizing the treatment, also known as 'personalized medicine'. The further refinement of these methods can best be achieved in a close collaboration between the clinicians that use these methods in treating their patients and the researchers who develop, establish, perform and interpret the necessary pharmacological, genetic and other kinds of tests in the laboratories. Side 40 av 70 The current projects of this research group exemplify translational research in a field that is central for Oslo University Hospital. Since the activity of solid organ transplantations is centralized to this hospital for the whole of Norway, it is a particular responsibility for all involved to keep this at a high international level. Therefore this research also complies well with the research strategy of the health region, namely that it should be highly relevant for an important field in the hospital and also may contribute to the advancement of multidisciplinary translational research. Successful individualization of immunosuppressive therapy has the potential to reduce the rate of complications, adverse effects and unwanted drug discontinuations and thereby improve graft function, the general prognosis short and long term as well as the quality of life for these patients. Ongoing projects in 2014 Glucocorticoid pharmacokinetics, pharmacodynamics and pharmacogenomics in children with ALL and in pediatric kidney transplant recipients. [Glucomix] This study addresses the pharmacokinetic, pharmacodynamic and pharmacogenetic aspects of glucocorticoid therapy in children with acute lymphoblastic leukemia and in children that undergo kidney transplantation. The results from this study are in preparation for publication. Immunosuppressants in islet transplantationThe disposition of immunosuppressants into pancreatic islets and the direct effects of these drugs on the islets. Islets are exposed to relatively high concentrations of immunosuppressive drugs in the liver. These high concentrations may be toxic to the islets and could impair revascularization and proliferation, but will also prevent the attack from the adaptive immune system. Specific studies are needed to determine whether the high concentrations are beneficial or detrimental to functional islet survival. This is a collaboration project with H.Scholz and coworkers. Results are in preparation for publication. Novel diagnostic markers in the management of graft function and monitoring of immune modulation following renal transplantation; – utilization of ex vivo activity assays, proteomics and molecular biomarkers [Mark-IT study] The main purpose of this study is to optimize and validate the conditions for the laboratory biomarker analyses and to provide in-depth knowledge about the mechanisms of action of the immunosuppressive drugs. In addition, relationships between molecular biomarkers and clinical outcome following renal transplantation will be assessed to generate hypotheses about candidate diagnostic biomarkers. It is of special interest to assess the relevance of biomarkers in ex vivo activated lymphocytes. Patient inclusion and one year follow-up is now completed. Large efforts are invested in these samples, providing opportunities for further sub-studies. So far, one objective has been to characterize NFAT-regulated gene expression in relation to tacrolimus (Tac) concentrations and clinical outcome. The preliminary results support the potential of NFAT-regulated gene expression as a tool for further improvement of Tac therapy. The gene expression of the drug transporter Pgp (gene: ABCB1) are also under investigation, and one goal is to relate this to the intracellular concentrations of immunosuppressants in lymphocytes. In other sub-studies, we have investigated the IMPDH activity in ex vivo-stimulated lymphocytes as well as other potential markers of the response to mycophenolic acid. Glutathione transferase gene variants influence busulfan pharmacokinetics and outcome after myeloablative conditioning. Busulfan (BU) is frequently used in high-dose conditioning regimens before hematopoietic stem cell transplantation (HSCT). Due to a narrow therapeutic range and large pharmacokinetic variability, BU dosing is usually guided by therapeutic drug monitoring. Side 41 av 70 Glutathione S-transferases (GST) play an important role in the metabolism of BU, and GST gene variants may explain some of the interindividual variability in pharmacokinetics. This study documented the association between GST gene variants, BU pharmacokinetics and clinical outcomes post-HSCT. The conclusion of this study is that genotyping GSTA1 prior to HSCT may allow better prediction of oral BU kinetics, reduce the need for dose adjustments and thereby improve clinical outcomes following high-dose BU conditioning. These results have been presented at meetings, and the paper is in press. We are also planning a prospective follow up study. Population pharmacokinetic modeling as a tool for improving dose individualization. [Tentative title] For many drugs, immunosuppressants included, recent advancements have provided a more detailed insight into the mechanisms and cofactors that determine the final response of a drug dose in an individual. At the same time, as this knowledge is getting increasingly complex, it will be difficult to take all such variables into account and to predict an individual dosage. Tools for advanced modeling are available, and we have started to apply these on data from our own lab. In collaboration with Åsberg and colleagues, and the group of Jelliffe and Neely (US), such models have been developed and validated for tacrolimus and this approach is being applied on mycophenolate as well as iohexol (for assessment of renal function). Bioequivalence study of tacrolimus in elderly transplant recipients. [Tentative title] Results from this study, in which we are collaborating with Åsberg, Midtvedt and colleagues at the Department of Medicine, are in preparation for publication. Using high throughput sequencing (HTS) to characterize variants in pharmacogenetics. [Tentative title] In collaboration with the Department of Genetics (Hughes & Undlien) we (Bremer, Rootwelt, Bergan) have initiated a project to explore the potential for detailed and efficient characterization of gene variants in pharmacogenetics, as an application of high throughput sequencing. National collaborators A. Hartmann, K. Midtvedt, A. Åsberg, H. Holdaas, P. D. Line, A. Foss, H. Scholz, Department of Specialized Medicine and Surgery, Oslo University Hospital H.S. Christensen and colleagues, School of Pharmacy, University of Oslo E. Ruud and A. Bjerre, Department of Paediatric Medicine, Oslo University Hospital Y. Fløisand and colleagues, Department of Hematology, Oslo University Hospital T. Hughes, D. Undlien, T. Grünfeld, Department of Medical Genetics, Oslo University Hospital C.B.N. Engen and B. Gjertsen, University of Bergen International collaborators M. N. Neely et al., Laboratory for Applied Pharmacokinetics, University of Southern California, CA, USA. T. van Gelder, D. Hesselink, Erasmus Medical Center, Rotterdam, Netherlands Side 42 av 70 8.8 Clinical Research Group Leader: Hassan Z. Khiabani (MD, PhD) Scientific staff Name Degree Title Gaut Gadeholt Per W. Johansen Jean Paul Bernard Thor Edvardsen Lars Gullestad Anders Hartmann Anders Åsberg Pål Aukrust Audun Stubhaug Thor Ueland Ragnhild Sørum Falk Ida Robertsen MD, PhD MD, PhD MD MD, PhD MD, PhD MD, PhD MScPharm, PhD MD, PhD MD, PhD PhD MSc MSc. PhD Senior Consultant Section manager/Senior Consultant PhD-student Department manager/Adjunct Professor Senior Consultant/Adjunct Professor Section manager/Adjunct Professor Laboratory manager/Adjunct Professor Senior Consultant/Adjunct Professor Department manager/Adjunct Professor Researcher Statistician Post doc Institution/ Employer OUH OUH Diakonhj OUH OUH OUH OUH OUH OUH OUH OUH OUH OUH=Oslo university hospital Research area Cardiovascular, inflammatory, immunological and renal disorders, pain, transplant medicine, methadone pharmacokinetic and pharmacodynamic Aims Advanced diagnostic approach and optimal treatment based on multidisciplinary clinical studies A. On going study Characteristics of methadone-related fatalities in Norway Studying the concentration range of methadone detected at post-mortem forensic analysis and the relationship of concentration to whether the deceased was prescribed methadone or not. This is a collaboration between UiO, Department of Pharmacology at OUH and Norwegian Institute of Public Health and the Centre for Psychopharmacology, Diakonhjemmet Hospital. B. Studies under planning 1. Cysteine and energy metabolism in humans Through a national and international collaborative effort, the effect of drugs that lower cysteine concentrations on energy metabolism will be examined. This is a collaboration between UiO, University of Oxford, Department of Physiology and Pharmacology, University of Alexandria, Egypt, Departments of Pharmacology and Transplant Medicine, Section of Nephrology at OUH. 2. Optimal management of patients with advanced heart failure (HF) and atrial fibrilation This project will be research collaboration between, Department of Pharmacology, Department of Cardiology, Section of Clinical Immunology and Infectious Disease, Unit of Biostatistics and Epidemiology, and Research Institute of Internal Medicine at OUH. Side 43 av 70 3. Intravenous infusion of Lidocaine in thoracic surgery perioperative; a comprehensive pharmacokinetic & pharmacodynamic study We will perform a comprehensive pharmacokinetic investigation of lidocaine infusion over time (up to 5 days) to elucidate the safety and efficacy of long-term intravenous lidocaine infusion before the randomized placebo-controlled efficacy study can be initiated. In the present study, we will develop a pharmacokinetic population model of lidocaine and the metabolite MEGX to allow for individually adapted dosing of long-term intravenous lidocaine infusion. The overall objective for the whole project (two studies) is to improve the postoperative pain therapy in patients undergoing thoracic surgery by perioperative administration of individualized dosed intravenous long-term lidocaine infusion.This project will be research collaboration between, Department of Pharmacology, Department of Anesthesiology, Department of Thoracic Surgery and Department of Transplant Medicine, Department of Lung medicine at OUH and Department of Pharmaceutical Biosciences, School of Pharmacy, UiO. 4. Substitution of R,S-methadone with R-methadone in methadone maintenance treatment patients with known prolonged QT-time This prosject will be research collaboration between Centre for Addiction Treatment, Department of Pharmacology - Clinical Pharmacology and Clinical Trial Unit at OUH. See TDM group, chapter 9.4 for details. 8.9 Norges laboratorium for dopinganalyse I henhold til World Anti-Doping Agency’s (WADA) regelverk skal våre forskningsaktiviteter (minst 7 % av vår totalaktivitet) være knyttet til å fremme antidopingarbeidet, nasjonalt og internasjonalt. Seksjonen hadde i 2014 ingen dedikerte forskerstillinger. Forskningsarbeidet ble utført av de faglig ansvarlige i seksjonen: Peter Hemmersbach, Dr. rer. nat., prof II ved Farmasøytisk institutt UiO Yvette Dehnes, PhD, faglig ansvarlig proteinhormoner, elektroforese, immunoassay Ingunn Hullstein, Cand. scient., faglig ansvarlig GC-MS Sebastian Rzeppa, Dr. rer. nat., faglig ansvarlig LC-MS Helle Malerød, PhD, faglig ansvarlig medikamentanalyse, peptider, LC-MS WADA definerer flere forskningsområder som er relevante i denne sammenheng: - Etablering av nye analysemetoder for å avsløre misbruk av forbudte stoffer og metoder (bl. a. økning av oksygentransport, anabole-androgene steroider, gendoping, vekstfremmende midler) - Utvikling av ny analyseteknologi - Farmakologiske egenskaper av dopingmidler - Identifikasjon av nye substanser/metoder som har et misbrukspotensial innen doping Vårt laboratorium er engasjert på flere av de nevnte områdene og i 2014 har vi hatt følgende prosjekter under arbeid: - Beta-2-adrenoreceptor agonist and elite athletes: Blood and urinary concentrations of terbutaline and salbutamol in asthmatic and non-asthmatic subjects. (Collaboration V. Backer, Copenhagen) - Master thesis: Analysis of doping substances and their metabolism in model systems. (Westfälische Wilhemls-Universität Münster) - Analysis and synthesis of sulphate conjugates of anabolic androgenic steroids. Side 44 av 70 Transfer of the analysis of large peptides and proteins to a LC-MS platform. Determination of peptidic drugs using LC-MS/MS. Carbon isotope ratio determination of seized nandrolone, boldenone and testosterone preparations in Norway. Characterization of erythropoietin (EPO) produced in liver, a potential source to atypical EPO profiles in doping samples. Individual profiles of Human Growth Hormone dependent markers, an indirect method for detecting the use of Recombinant Human Growth Hormone in sports. MAIIA EPO SeLect: Preparation for inter-laboratory WADA validation. Bidragsytere til vår forskningsaktivitet er Kulturdepartementet, Antidoping Norge og WADA. 8.10 Regionalt legemiddelinformasjonssenter (RELIS) SørØst Seksjonen har ingen dedikerte forskerstillinger. Forskningsarbeidet ble utført av enkelte ansatte parallelt med ordinære arbeidsoppgaver. I 2014 har seksjonen arbeidet med følgende prosjekter: - - - Ungdom og selvmedisinering med reseptfrie smertestillende midler. Samarbeidspartnere ved Institutt for allmenn- og samfunnsmedisin, og Avdeling for sykepleieutdanning, Høgskolen i Oslo. Botulinumtoksin A - Kvalitetssikring av preparatvalg. Samarbeidspartnere ved Barneavdeling for nevrofag, OUS. Risiko for gastrointestinale blødninger ved steroidbehandling. Samarbeidspartnere ved Farmakologisk institutt og Avdeling for psykofarmakologi, Diakonhjemmets sykehus. Bivirkninger ved bytte av digitalispreparat. Samarbeidspartnere ved Giftinformasjonen, Statens legemiddelverk og Klinisk farmakologi, FAR, OUS. Medikamentell behandling, erfaringer ved møte med helsetjenesten og psykososial byrde hos kvinner med ekstrem svangerskapskvalme i Norge (Mastergradsprosjekt, Sør-Øst). Samarbeid med Farmasøytisk Institutt, Universitetet i Oslo. Side 45 av 70 9 Publications 2010 – 2014 9.1 Articles and reviews 2014 Brudeli B, Navaratnarajah M, Andressen KW, Manfra O, Moltzau LR, Nilsen NO, Levy FO, Klaveness J: Discovery and pharmacological profile of new hydrophilic 5-HT4 receptor antagonists. Bioorganic & Medicinal Chemistry Letters 24:4598-4602, 2014 Brusevold IJ, Tveteraas IH, Aasrum M, Ødegård J, Sandnes DL, Christoffersen T: Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells. BMC Cancer 14, 2014 Dehnes Y, Myrvold L, Strøm H, Ericsson M, Hemmersbach PJ: MAIIA EPO SeLect – a rapid screening kit for the detection of recombinant EPO analogues in doping control: Interlaboratory prevalidation and normative study of athlete urine and plasma samples. Drug Testing and Analysis 6:1144-1150, 2014 De Raav GN, Bergan S, Baan CC, Weimar W, van Elder T, Hesselink DA: Therapeutic drug monitoring of belatacept in kidney transplantation. Therapeutic Drug Monitoring Dec 30, 2014 (Epub ahead of print) Henning OJ, Baftiu A, Johannessen SI, Landmark CJ: Withdrawal of antiepileptic drugs during presurgical video-EEG monitoring: An observational study for evaluation of current practice at a referral center for epilepsy. Acta Neurologica Scandinavica 129:243-251, 2014 Holst L, Havnen GC, Nordeng HME: Echinacea and elderberry - should they be used against upper respiratory tract infections during pregnancy? Frontiers in Pharmacology 5:31, 2014 Hostrup M, Kalsen A, Bangsbo J, Hemmersbach PJ, Karlsson S, Backer V: High-dose inhaled terbutaline increases muscle strength and enhances maximal sprint performance in trained men. European Journal of Applied Physiology, 114:2499-2508, 2014 Hullstein I, Sagredo C, Hemmersbach PJ: Carbon isotope ratios of nandrolone, boldenone, and testosterone preparations seized in Norway compared to those of endogenously produced steroids in a Nordic reference population. Drug Testing and Analysis 6:11631169, 2014 Høiseth G, Fjeld B, Burns ML, Strand DH, Vindenes V: Long-term stability of morphine, codeine, and 6-acetylmorphine in real-life whole blood samples, stored at -20°C. Forensic Science International 239:6-10, 2014 Jendresen CB, Cui H, Zhang X, Vlodavsky I, Nilsson L, Li JP: Overexpression of heparanase lowers amyloid burden in AbPP Transgenic mice. Journal of Biological Chemistry 290:5053-5064, 2014 Kalsen A, Hostrup M, Karlsson S, Hemmersbach PJ, Bangsbo J, Backer V: Effect of inhaled terbutaline on substrate utilization and 300-kcal time trial performance. Journal of applied physiology 117:1180-1187, 2014 Kilander MBC, Petersen J, Andressen KW, Ganji RS, Levy FO, Schuster J, Dahl N, Bryja V, Schulte G: Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. The FASEB Journal 28:2293-2305, 2014 Kong XY, Nesset CK, Damme M, Løberg EM, Lübke T, Mæhlen J, Andersson KB, Lorenzo PIO, Roos N, Thoresen HG, Rustan A, Kase ET, Eskild W: Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells. Disease Models and Mechanisms 7:351-362, 2014 Side 46 av 70 Kringen MK, Piehler AP, Grimholt RM, Opdal MS, Foss KB, Urdal P: Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TARepeat variants. PLoS ONE 9, 2014 Landmark CJ, Oliver H, Johannessen SI: Proconvulsant effects of antidepressants - what is the current evidence? Epileptology, 2014 Levinsen M, Rotevatn EØ, Rosthøj S, Nersting J, Abrahamsson J, Appell ML, Bergan S, Bechensteen AG, Harila-Saari A, Heyman M, Jonsson OG, Maxild JBC, Niemi M, Söderhäll S, Schmiegelow K: Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: Influence on cure rates and risk of second cancer. Pediatric Blood & Cancer 61:797-802, 2014 Liu F, Qimuge Q, Hao J, Yan H, Bach T, Fan L, Morigen M: AspC-mediated aspartate metabolism coordinates the Escherichia coli cell cycle. PLoS ONE 9, 2014 Lillehaug S, Syverstad GHE, Nilsson L, Bjaalie JG, Leergaard TB, Torp R: Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice. Neurobiology of Aging 35:556-564, 2014 Lunde I, Bremer S, Midtvedt K, Mohebi BU, Husvegg MD, Bergan S, Åsberg A, Christensen HS: The influence of CYP3A, PPARA and POR genetic variants on the pharmacokinetics of tacrolimus and cyclosporine in renal transplant recipients. European Journal of Clinical Pharmacology 70:685-693, 2014 Lærum H, Bremer S, Bergan S, Grüfeld T: A taste of individualized medicine: physicians' reactions to automated genetic interpretations. Journal of the American Medical Informatics Association 2, 2014 Melsom EMCB, Hussain R, Ørstavik Ø, Aronsen JM, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Krobert KA: Non-classical regulation of 1- and 2 adrenoceptor- mediated inotropic responses in rat ventricle by the G protein Gi. Naunyn-Schmiedeberg's Archives of Pharmacology 387:1177-1186, 2014 Melsom EMCBull, Ørstavik Ø, Osnes JB, Skomedal T, Levy FO, Krobert KA: Gi Proteins Regulate Adenylyl Cyclase Activity Independent of Receptor Activation. PLoS Medicine 2014 Moltzau LR, Meier S, Aronsen JM, Afzal F, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Qvigstad E: Differential regulation of C-type natriuretic peptide-induced cGMP and functional responses by PDE2 and PDE3 in failing myocardium. NaunynSchmiedeberg's Archives of Pharmacology 387:407-417, 2014 Moltzau LR, Aronsen JM, Meier S, Skogestad J, Ørstavik Ø, Lothe GB, Sjaastad I, Skomedal T, Osnes JB, Levy FO, Qvigstad E: Different compartmentation of responses to brain natriuretic peptide and C-type natriuretic peptide in failing rat ventricle. Journal of Pharmacology and Experimental Therapeutics 350:681-690, 2014 Narum S, Westergren T, Klemp M: Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open 4, 2014 Nuruddin S, Syverstad GHE, Lillehaug S, Leergaard TB, Nilsson L, Ropstad E, Krogenæs A, Haraldsen IH, Torp R: Elevated mRNA-Levels of Gonadotropin-Releasing Hormone and Its Receptor in Plaque-Bearing Alzheimer's Disease Transgenic Mice. PLoS ONE 9, 2014 Pomianowska E, Sandnes DL, Grzyb K, Schjølberg AR, Aasrum M; Tveteraas IH, Tjomsland, V, Christoffersen T, Gladhaug IP: Inhibitory effects of prostaglandin E2; on collagen synthesis and cell proliferation in human stellate cells from pancreatic head adenocarcinoma. BMC Cancer 14, 2014 Robertsen I, Åsberg A, Granseth T, Vethe NT, Akhlaghi F, Ghareeb M, Molden E, ReierNilsen M, Holdaas H, Midtvedt K: More potent lipid-lowering effect by rosuvastatin Side 47 av 70 compared with fluvastatin in everolimus-treated renal transplant recipients. Transplantation 97:1266-1272, 2014 Smith R, Solberg R, Jacobsen LL, Voreland A Larsen, Rustan A, Thoresen HG, Johansen HT: Simvastatin inhibits glucose metabolism and legumain activity in human myotubes. PLoS ONE 9, 2014 Stormo C, Kringen MK, Lyle R, Olstad OK, Sachse D, Berg JP, Piehler A: RNA-Sequencing Analysis of HepG2 Cells Treated with Atorvastatin. PLoS ONE 9, 2014 Størset E, Holford N, Midtvedt K, Bremer S, Bergan S, Åsberg A: Importance of hematocrit for a tacrolimus target concentration strategy. European Journal of Clinical Pharmacology 70:65-77, 2014 Størset E, Holford N, Hennig S, Bergmann TK, Bergan S, Bremer S, Åsberg A, Midtvedt K, Staatz C: Improved prediction of tacrolimus concentrations early after kidney transplantation using theory-based pharmacokinetic modelling. British Journal of Clinical Pharmacology 78:509-523, 2014 Sulheim D, Fagermoen FE, Winger A, Andersen AM, Godang K, Müller F, Rowe PC, Saul J P, Skovlund E, Øie MG, Wyller VB: Disease Mechanisms and Clonidine Treatment in Adolescent Chronic Fatigue Syndrome: A Combined Cross-sectional and Randomized Clinical Trial. JAMA pediatrics 168:351-360, 2014 Sæves I, Line PD, Bremer S, Vethe NT, Tveit RG, Meltevik TJ, Bergan S: Tacrolimus exposure and mycophenolate pharmacokinetics and pharmacodynamics early after liver transplantation. Therapeutic Drug Monitoring 36:46-53, 2014 Sørensen O, Andersen AM, Kristian A, Giercksky KE, Flatmark K: Impact of hyperthermia on pharmacokinetics of intraperitoneal mitomycin C in rats investigated by microdialysis. Journal of Surgical Oncology 109:521-526, 2014 Vethe NT, Ali AM, Reine PA, Andersen AM, Bremer S, Line PD, Rootwelt H, Bergan S: Simultaneous quantification of IMPDH activity and purine bases in lymphocytes using LCMS/MS: assessment of biomarker responses to mycophenolic acid. Therapeutic Drug Monitoring 36:108-118, 2014 Westergren T, Hjelmeland KJ, Kristoffersen B, Johannessen SI, Kalikstad B: Probable opiramate-induced diarrhea in a 2-month-old breast-fed child - A case report. Epilepsy and Behavior Case Reports 2:22-23, 2014 Ørstavik Ø, Ata SH, Riise J, Dahl CP, Andersen GØ, Levy FO, Skomedal T, Osnes JB, Qvigstad E: Inhibition of phosphodiesterase-3 by levosimendan is sufficient to account for its inotropic effect in failing human heart. British Journal of Pharmacology 171: 5169-5181, 2014 Åstrand OAH, Gikling I, Sylte I, Rustan A, Thoresen HG, Rongved P, Kase ET: Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models. European Journal of Medicinal Chemistry 74:258-263, 2014 Side 48 av 70 2013 Asberg A, Midtvedt K, van GM, Storset E, Bremer S, Bergan S, Jelliffe R, Hartmann A, Neely MN: Inclusion of CYP3A5 genotyping in a nonparametric population model improves dosing of tacrolimus early after transplantation. Transpl Int 26:1198-1207, 2013 Bach T, Bergholtz S, Riise J, Qvigstad E, Skomedal T, Osnes JB, Levy FO: Identification of small molecule NPR-B antagonists by high throughput screening - potential use in heart failure. Naunyn Schmiedebergs Arch Pharmacol 387:5-14, 2014 (Epub Dec 2013) Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS: Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI). Epilepsy Res 103:2-30, 2013 Brudeli B, Andressen KW, Moltzau LR, Nilsen NO, Levy FO, Klaveness J: Acidic biphenyl derivatives: synthesis and biological activity of a new series of potent 5-HT4 receptor antagonists. Bioorg Med Chem 21:7134-7145, 2013a Brudeli B, Moltzau LR, Nguyen CH, Andressen KW, Nilsen NO, Levy FO, Klaveness J: Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5HT4 antagonist. Eur J Med Chem 64:629-637, 2013b Christoffersen T: Cancer, cachexia, prostanoids, and NSAIDs. Acta Oncol 52:3-5, 2013 Dehnes Y, Shalina A, Myrvold L: Detection of recombinant EPO in blood and urine samples with EPO WGA MAIIA, IEF and SAR-PAGE after microdose injections. Drug Test Anal 5:861-869, 2013 Eibye K, Elers J, Pedersen L, Henninge J, Hemmersbach P, Dalhoff K, Backer V: Formoterol concentrations in blood and urine: the World Anti-Doping Agency 2012 regulations. Med Sci Sports Exerc 45:16-22, 2013 Feng YZ, Nikolic N, Bakke SS, Boekschoten MV, Kersten S, Kase ET, Rustan AC, Thoresen GH: PPARdelta activation in human myotubes increases mitochondrial fatty acid oxidative capacity and reduces glucose utilization by a switch in substrate preference. Arch Physiol Biochem 120:12-21, 2014 Gellynck E, Heyninck K, Andressen KW, Haegeman G, Levy FO, Vanhoenacker P, Van CK: The serotonin 5-HT7 receptors: two decades of research. Exp Brain Res 230:555-568, 2013 Gravning J, Ahmed MS, Qvigstad E, Krobert K, Edvardsen T, Moe IT, Hagelin EM, Sagave J, Valen G, Levy FO, Osnes JB, Skomedal T, Attramadal H: Connective tissue growth factor/CCN2 attenuates β-adrenergic receptor responsiveness and cardiotoxicity by induction of G protein-coupled receptor kinase-5 in cardiomyocytes. Mol Pharmacol 84:372-383, 2013 Grundtvig M, Hagen TP, Amrud ES, Reikvam A: Reduced life expectancy after an incident hospital diagnosis of acute myocardial infarction--effects of smoking in women and men. Int J Cardiol 167:2792-2797, 2013 Gu GJ, Wu D, Lund H, Sunnemark D, Kvist AJ, Milner R, Eckersley S, Nilsson LN, Agerman K, Landegren U, Kamali-Moghaddam M: Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease. J Alzheimers Dis 33:699-713, 2013 Gumucio A, Lannfelt L, Nilsson LN: Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging. BMC Neurosci 14:148-2013 Hamidi V, Ringerike T, Hagen G, Reikvam A, Klemp M: New anticoagulants as thromboprophylaxis after total hip or knee replacement. Int J Technol.Assess Health Care 29:234-243, 2013 Side 49 av 70 Haug JB, Reikvam A: WHO defined daily doses versus hospital-adjusted defined daily doses: impact on results of antibiotic use surveillance. J Antimicrob Chemother 68:2940-2947, 2013 Henning O, Baftiu A, Johannessen SI, Landmark CJ: Tapering of antiepileptic drugs during long-term EEG monotoring. Acta Neurol Scand (Epub Aug 2013) Hostrup M, Kalsen A, Auchenberg M, Rzeppa S, Hemmersbach P, Bangsbo J, Backer V: Urine concentrations of oral salbutamol in samples collected after intense exercise in endurance athletes. Drug Test Anal 2013 Hussain RI, Aronsen JM, Afzal F, Sjaastad I, Osnes JB, Skomedal T, Levy FO, Krobert KA: The functional activity of inhibitory G protein (G(i)) is not increased in failing heart ventricle. J Mol Cell Cardiol 56:129-138, 2013 Kalimo H, Lalowski M, Bogdanovic N, Philipson O, Bird TD, Nochlin D, Schellenberg GD, Brundin R, Olofsson T, Soliymani R, Baumann M, Wirths O, Bayer TA, Nilsson LN, Basun H, Lannfelt L, Ingelsson M: The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ. Acta Neuropathol Commun 1:60-2013 Karouni M, Henning O, Larsson PG, Johannessen SI, Johannessen LC: Pharmacological treatment of psychiatric comorbidity in patients with refractory epilepsy. Epilepsy Behav 29:77-81, 2013 Kase ET, Nikolic N, Bakke SS, Bogen KK, Aas V, Thoresen GH, Rustan AC: Remodeling of oxidative energy metabolism by galactose improves glucose handling and metabolic switching in human skeletal muscle cells. PLoS One 8:e59972-2013 Krefting EA, Jorde R, Christoffersen T, Grimnes G: Vitamin D and intraocular pressure results from a case -control and an intervention study. Acta Ophthalmol 2013 Lei P, Baysa A, Nebb HI, Valen G, Skomedal T, Osnes JB, Yang Z, Haugen F: Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia-reperfusion injury. Basic Res Cardiol 108:323-2013 Levay M, Krobert KA, Wittig K, Voigt N, Bermudez M, Wolber G, Dobrev D, Levy FO, Wieland T: NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors. J Pharmacol Exp Ther 347:69-79, 2013 Levy FO: Cardiac PDEs and crosstalk between cAMP and cGMP signalling pathways in the regulation of contractility. Naunyn Schmiedebergs Arch Pharmacol 386:665-670, 2013 Lillehaug S, Syverstad GH, Nilsson LN, Bjaalie JG, Leergaard TB, Torp R: Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice. Neurobiol Aging 35:556-564, 2014 Lillenes MS, Stoen M, Gomez-Munoz M, Torp R, Gunther CC, Nilsson LN, Tonjum T: Transient OGG1, APE1, PARP1 and Polβ expression in an Alzheimer's disease mouse model. Mech Ageing Dev 134:467-477, 2013 Lund H, Snilsberg AH, Halvorsen TG, Hemmersbach P, Reubsaet L: Comparison of newly developed immuno-MS method with existing DELFIA® immunoassay for human chorionic gonadotropin determination in doping analysis. Bioanalysis 5:623-630, 2013a Lund H, Snilsberg AH, Paus E, Halvorsen TG, Hemmersbach P, Reubsaet L: Sports drug testing using immuno-MS: clinical study comprising administration of human chorionic gonadotropin to males. Anal Bioanal Chem 405:1569-1576, 2013b Magnusson K, Sehlin D, Syvanen S, Svedberg MM, Philipson O, Soderberg L, Tegerstedt K, Holmquist M, Gellerfors P, Tolmachev V, Antoni G, Lannfelt L, Hall H, Nilsson LN: Specific Side 50 av 70 uptake of an amyloid-β protofibril-binding antibody-tracer in AβPP transgenic mouse brain. J Alzheimers Dis 37:29-40, 2013 Martinov V, Dehnes Y, Holmseth S, Shimamoto K, Danbolt NC, Valen G: A novel glutamate transporter blocker, LL-TBOA, attenuates ischaemic injury in the isolated, perfused rat heart despite low transporter levels. Eur J Cardiothorac Surg 45:710-716, 2014 (Epub Oct 2013) Molenaar P, Christ T, Hussain RI, Engel A, Berk E, Gillette KT, Chen L, Galindo-Tovar A, Krobert KA, Ravens U, Levy FO, Kaumann AJ: PDE3, but not PDE4, reduces β1- and β2 adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprololtreated patients. Br J Pharmacol 169:528-538, 2013 Moltzau LR, Aronsen JM, Meier S, Nguyen CH, Hougen K, Ørstavik Ø, Sjaastad I, Christensen G, Skomedal T, Osnes JB, Levy FO, Qvigstad E: SERCA2 activity is involved in the CNP-mediated functional responses in failing rat myocardium. Br J Pharmacol 170:366-379, 2013 Narum S, Solhaug V, Myhr K, Brørs O, Kringen MK: Characterisation of non-warfarinassociated bleeding events reported to the Norwegian spontaneous reporting system. Eur J Clin Pharmacol 69:1445-1452, 2013 Reine PA, Vethe NT, Kongsgaard UE, Andersen AM, Line PD, Ali AM, Bergan S: Mycophenolate pharmacokinetics and inosine monophosphate dehydrogenase activity in liver transplant recipients with an emphasis on therapeutic drug monitoring. Scand J Clin Lab Invest 73:117-124, 2013 Skarstein S, Rosvold EO, Helseth S, Kvarme LG, Holager T, Småstuen MC, Lagerløv P: High-frequency use of over-the-counter analgesics among adolescents: reflections of an emerging difficult life, a crossectional study. Scand J Caring Sci 2013. [Epub ahead of print]. Soland TM, Brusevold IJ: Prognostic molecular markers in cancer - quo vadis? Histopathology 63:297-308, 2013 Stormo C, Bogsrud MP, Hermann M, Asberg A, Piehler AP, Retterstol K, Kringen MK: UGT1A1*28 is associated with decreased systemic exposure of atorvastatin lactone. Mol Diagn Ther 17:233-237, 2013 Tvete IF, Bjorner T, Aursnes IA, Skomedal T: A 3-year survey quantifying the risk of dose escalation of benzodiazepines and congeners to identify risk factors to aid doctors to more rationale prescribing. BMJ Open 3:e003296-2013 Aas V, Bakke SS, Feng YZ, Kase ET, Jensen J, Bajpeyi S, Thoresen GH, Rustan AC: Are cultured human myotubes far from home? Cell Tissue Res 354:671-682, 2013 Aasrum M, Ødegard J, Sandnes D, Christoffersen T: The involvement of the docking protein Gab1 in mitogenic signalling induced by EGF and HGF in rat hepatocytes. 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PLoS One 7:e44740, 2012 Brattelid T, Qvigstad E, Moltzau LR, Bekkevold SVS, Sandnes DL, Birkeland JAK, Skomedal T, Osnes J-B, Sjaastad I, Levy FO: The 5-HT4 receptor – a foetal gene reactivated in heart failure. PLoS One 7:e45489, 2012 Brusevold IJ, Aasrum M, Bryne M, Christoffersen T: Migration induced by epidermal and hepatocyte growth factors in oral squamous carcinoma cells in vitro: role of MEK/ERK, p38 and PI-3 kinase/Akt. J Oral Pathol Med 41:547-58, 2012 Danese E, Montagnana M, Johnson JA, Rettie AE, Zambon CF, Lubitz SA, Suarez-Kurtz G, Cavallari LH, Zhao L, Huang M, Nakamura Y, Mushiroda T, Kringen MK, Borgiani P, Ciccacci C, Au NT, Langaee T, Siguret V, Loriot MA, Sagreiya H, Altman RB, Shahin MH, Scott SA, Khalifa SI, Chowbay B, Suriapranata IM, Teichert M, Stricker BH, Taljaard M, Botton MR, Zhang JE, Pirmohamed M, Zhang X, Carlquist JF, Horne BD, Lee MT, Pengo V, Guidi GC, Minuz P, Fava C: Impact of the CYP4F2 p.V433M polymorphism on coumarin dose requirement: systematic review and meta-analysis. Clin Pharmacol Ther 92:746-756, 2012 de Blasio BF, Neilson AR, Klemp M, Skjeldestad FE: Modeling the impact of screening policy and screening compliance on incidence and mortality of cervical cancer in the post-HPV vaccination era. 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Ther Drug Monit 34:440-445, 2012 Johannessen LC, Johannessen SI, Tomson T: Host factors affecting antiepileptic drug delivery-pharmacokinetic variability. Adv Drug Deliv Rev 64:896-910, 2012b Kringen MK, Stormo C, Grimholt RM, Berg JP, Piehler AP: Copy number variations of the ATP-binding cassette transporter ABCC6 gene and its pseudogenes. BMC Res Notes 5:425-2012 Landmark CJ, Johannessen SI: Safety aspects of antiepileptic drugs--focus on pharmacovigilance. Pharmacoepidemiol Drug Saf 21:11-20, 2012 Lei P, Baysa A, Nebb HI, Valen G, Skomedal T, Osnes JB, Yang Z, Haugen F: Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia-reperfusion injury. Basic Res Cardiol Epub 2012 Dec 25. Lund H, Snilsberg AH, Paus E, Halvorsen TG, Hemmersbach P, Reubsaet L: Sports drug testing using immuno-MS: clinical study comprising administration of human chorionic gonadotropin to males. 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Neurobiol Aging 33:1010.e1-13, 2012 Reikvam AG, Hustad S, Reikvam H, Apelseth TO, Nepstad I, Hervig TA: The effects of selective serotonin reuptake inhibitors on platelet function in whole blood and platelet concentrates. Platelets 23:299-308, 2012 Side 53 av 70 Riise J, Nguyen CH, Hussain RI, Dahl CP, Ege MS, Osnes JB, Skomedal T, Sandnes DL, Levy FO, Krobert KA: Prostanoid-mediated inotropic responses are attenuated in failing human and rat ventricular myocardium. Eur J Pharmacol 686:66-73, 2012 Riise J, Ørstavik Ø, Qvigstad E, Dahl CP, Osnes JB, Skomedal S, Levy FO, Krobert KA: Prostaglandin E1 facilitates inotropic effects of 5-HT4 serotonin receptors and βadrenoceptors in failing human heart. Bas Res Cardiol 107:295-304, 2012 Saeves I, Line PD, Bergan S: The pharmacokinetics of prednisolone and prednisone in adult liver transplant recipients early after transplantation. 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Lipids 47:483-93, 2012 Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T: Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol 30:1755-62, 2012 Tveteraas IH, Müller KM, Aasrum M, Odegård J, Dajani O, Guren T, Sandnes D, Christoffersen T: Mechanisms involved in PGE2-induced transactivation of the epidermal growth factor receptor in MH1C1 hepatocarcinoma cells. J Exp Clin Cancer Res 31:72, 2012 Viktil KK, Blix HS, Eek AK, Davies MN, Moger TA, Reikvam A: How are drug regimen changes during hospitalisation handled after discharge: a cohort study. BMJ Open 2:2012 Viktil KK, Blix HS, Eek AK, Davies MN, Moger TA, Reikvam Å: How are drug regimen changes during hospitalisation handled after discharge: a cohort study. BMJ Open 2:e001461, 2012 von Lueder TG, Gravning J, How OJ, Vinge LE, Ahmed MS, Krobert KA, Levy FO, Larsen TS, Smiseth OA, Aasum E, Attramadal H: Cardiomyocyte-restricted inhibition of G proteincoupled receptor kinase-3 (GRK3) attenuates cardiac dysfunction after chronic pressure overload. Am J Physiol Heart Circ Physiol 303:H66-74, 2012 Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M: Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open 2:e000653, 2012 Willoch K, Blix HS, Pedersen-Bjergaard AM, Eek AK, Reikvam A: Handling drug-related problems in rehabilitation patients: a randomized study Int J Clin Pharm 34:382-388, 2012 Willoch K, Blix HS, Pedersen-Bjergaard AM, Eek AK, Reikvam Å: Handling drug-related problems in rehabilitation patients: a randomized study. Int J Clin Pharm 34:382-8, 2012 Zhang X, Wang B, O'Callaghan P, Hjertström E, Jia J, Gong F, Zcharia E, Nilsson LN, Lannfelt L, Vlodavsky I, Lindahl U, Li JP: Heparanase overexpression impairs inflammatory response and macrophage-mediated clearance of amyloid-β in murine brain. Acta Neuropathol 124:465-78, 2012 Ødegård J, Aasrum M, Tveteraas IH, Bharath SP, Sandnes D, Christoffersen T: Role of ErbB2 in the prostaglandin E₂-induced enhancement of the mitogenic response to Side 54 av 70 epidermal growth factor in cultured hepatocytes. Biochem Biophys Res Commun 421:25560, 2012 2011 Afzal F, Aronsen JM, Moltzau LR, Sjaastad I, Levy FO, Skomedal T, Osnes J-B, Qvigstad E. Differential regulation of β2-adrenoceptor-mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non-failing rat cardiac ventricle. Br J Pharmacol 162:54-71, 2011 Afzal F, Qvigstad E, Aronsen JM, Moltzau LR, Sjaastad I, Skomedal T, Osnes J-B, Levy FO: Agents increasing cyclic GMP amplify 5-HT4-elicited positive inotropic response in failing rat cardiac ventricle. Naunyn-Schmiedeberg’s Arch. Pharmacol. 384:543-53, 2011 Berrade L, Aisa B, Ramirez MJ, Galiano S, Guccione S, Moltzau LR, Levy FO, Nicoletti F, Battaglia G, Molinaro G, Aldana I, Monge A, Perez-Silanes S. Novel benzo[b]thiophene derivatives as new potential antidepressants with rapid onset of action. J Med Chem 54:3086-90, 2011 Brattelid T, Levy FO. Quantification of GPCR mRNA using Real-Time RT-PCR. Methods Mol Biol 746:165-93, 2011 Dehnes Y, Hemmersbach P. Effect of single doses of methoxypolyethylene glycolepoetin beta (CERA, MiceraTM) and epoetin delta (DynepoTM) on isoelectric erythropoietin profiles and haematological parameters. Drug Test Anal 3(5):291-5, 2011 Elers J, Pedersen L, Henninge J, Hemmersbach P, Dalhoff K, Backer V. Urine concentrations of repetitive doses of inhaled salbutamol. Int. J. Sports Med. 32:574-9, 2011 Evang JA, Berg JP, Casar-Borota O, Lekva T, Kringen MK, Ramm-Pettersen J, Bollerslev J. Reduced levels of E-cadherin correlate with progression of corticotroph pituitary tumours. Clin Endocrinol 75:811-8, 2011 Grundtvig M, Hagen T, Amrud E, Reikvam Å. Mortality after myocardial infarction: impact of gender and smoking status. Eur J Epidemiol 26:385-93, 2011 Haug JB, Berild D, Walberg M, Reikvam Å. Increased antibiotic use in Norwegian hospitals despite a low antibiotic resistance rate. J Antimicrob Chemother 66:2643-6, 2011 Haug JB, Myhr R, Reikvam Å. Pharmacy sales data versus ward stock counting for the surveillance of broad-spectrum antibiotic use in hospitals. BMC Med Res Methodol 11:166, 2011 Hemmersbach P. Compounds enhancing oxygen delivery. Endocrine Abstracts 25: p.S).2, 2011 Hemmerbach P. The 29th Manfred Donike Workshop on Doping Analysis – Editorial manuscript. Drug Test. Analysis 3, 755, 2011 Hemmersbach P, Drange M, Rabin O, Botrè, Dehnes Y. Doping analysis on solid ground. Tidsskr Nor Lægefor (in press) Hemmersbach P, Drange M, Rabin O, Botrè, Dehnes Y. Dpinganalyse på trygg grunn. Tidsskr Nor Lægefor (in press) Hovda KE, Julsrud J, Øvrebø S, Brørs O, Jacobsen D. Studies on ethylene glycol poisoning: one patient – 154 admissions. Clin Toxicol 49(6): 478-84, 2011 Hussain RI, Afzal F, Mørk HK, Aronsen JM, Sjaastad I, Osnes J-B, Skomedal T, Levy FO, Krobert KA. Cyclic AMP-dependent inotropic effects are differentially regulated by Side 55 av 70 muscarinic Gi-dependent constitutive inhibition of adenylyl cyclase in failing rat ventricle. Br J Pharmacol 162:908-16, 2011 Johannessen Landmark C, Fossmark H, Larsson, PG, Rytter E, Johannessen SI. Prescription patterns of antiepileptic drugs in patients with epilepsy in a nation-wide population. Epilepsy Res 95:51-59, 2011 Johannessen Landmark C, Johannessen SI. Drug safety aspects of antiepileptic drugs- focus on pharmacovigilance. Pharmacoepidemiol Drug Saf, Epub Nov 8, 2011 Johannessen Landmark C, Johannessen SI, Tomson T. Host factors affecting antiepileptic drug delivery - Pharmacokinetic variability. Adv Drug Deliv Rev Oct 21, 2011 [Epub ahead of print] Johannessen Landmark C, Larsson PG, Rytter E, Johannessen SI. Oppklarende om pregabalin og Reseptregisteret [Elucidating pregabalin and The Norwegian Prescription Database]. Tidsskr Nor Laegefor 131:800-801, 2011 (In Norwegian) Johannessen Landmark C, Fossmark H, Larsson PG, Rytter E, Johannessen SI. Reseptregisteret og misbruk av pregabalin [The Norwegian Prescription Database and abuse of pregabalin]. Tidsskr Nor Laegefor 131:223, 2011 (In Norwegian) Johansen JS, Westergren T, Lingaas E. Profylaktisk behandling etter varicellaeksponering. Tidsskr Nor Legeforen 2011;131:1645-8. Klemp M, Tvete IF, Skomedal T, Gaasemyr J, Natvig B, Aursnes I. A review and bayesian meta-analysis of clinical efficacy and adverse effects of 4 atypical neuroleptic drugs compared with haloperidol and placebo. J Clin Psychopharmacol 31:698-704, 2011 Kringen MK, Haug KB, Grimholt RM, Stormo C, Narum S, Opdal MS, Fosen JT, Piehler AP, Johansen PW, Seljeflot I, Berg JP, Brørs O. Genetic variation of VKORC1 and CYP4F2 genes related to warfarin maintenance dose in patients with myocardial infarction. J Biomed Biotechnol 739-51, 2011 Kringen MK, Narum S, Lygren I, Seljeflot I, Sandset PM, Trøseid AM, Johansen PW, Brørs O, Holthe MR. Reduced platelet function and role of drugs in acute gastrointestinal bleeding. Basic Clin Pharmacol Toxicol 108:194-201, 2011 Landmark K, Aursnes I, Kvan E, Reikvam Å. RAS inhibitors and size of infarct. Tidsskr Nor Lægeforen 131:441-2, 2011 Midtvedt K, Jenssen T, Hartmann A, Vethe NT, Bergan S, Havnes K, Asberg A. No change in insulin sensitivity in renal transplant recipients converted from standard to once-daily prolonged release tacrolimus. Nephrol Dial Transplant 26:3767-72, 2011 Myhr K. BigPharma and unethical marketing of medicinal products. Southern Med Review 4(2):1, 2011 Myhr K. Tilgang til og pris på legemidler globalt. Tidsskr Nor Legeforen 131:2019-21, 2011 (In Norwegian) Müller KM, Tveteraas IH, Aasrum M, Ødegård J, Dawood M, Dajani O, Christoffersen T, Sandnes DL. Role of protein kinase C and epidermal growth factor receptor signalling in growth stimulation by neurotensin in colon carcinoma cells. BMC Cancer 11:421, 2011 Narum S, Solhaug V, Myhr K, Johansen PW, Brørs O, Kringen MK. Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. Br J Clin Pharmacol 71:254-62, 2011 Opdal MS. Syk av sykdom, rus eller medikament. Tidsskr Nor Lægefor 132:52, 2011 (In Norwegian) Reikvam Å, Hagen T. Changes in myocardial infarction mortality. Tidsskr Nor Lægeforen 131:468-70, 2011 Side 56 av 70 Sæves I, Vethe NT, Bergan S. Quantification of 6 glucocorticoids in human plasma by liquid chromatography tandem mass spectrometry: method development, validation, and assessment of matrix effects. Ther Drug Monit 33:402-10, 2011 Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sørbye H, Pyrhonen S, Sigurdsson F, Kure E, Ikdahl T, Skovlund E, Fokstuen T, Hansen F, Hofsli E, Birkemeyer E, Johnsson A, Starkhammar H, Yilmaz MK, Keldsen N, Erdal AB, Dajani O, Dahl O, Christoffersen T: Phase III trial of cetuximab with continuous intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: The Nordic-VII study. J Clin Oncol 2011, accepted Vethe NT, Midtvedt K, Asberg A, Amundsen R, Bergan S. [Drug interactions and immunosuppression in organ transplant recipients]. Tidsskr Nor Lægeforen 131:2000-3, 2011 (In Norwegian) Årdal C, Iversen JH, Myhr K. Nye modeller for utvikling av legemidler for fattige land. Tidsskr Nor Legeforen 131:2016-8, 2011 2010 Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS. Progress report on new antiepileptic drugs: A summary of the Ninth Eilat Conference (EILAT X). Epilepsy Res 92:189-124, 2010. Blix HS, Viktil KK, Moger TA, Reikvam Å. Drugs with narrow therapeutic index as indicators in the risk management of hospitalised patients. Pharmacy Practice 8:50-55, 2010 Brattelid T, Winer LH, Levy FO, Liestol K, Sejersted OM, Andersson KB. Reference gene alternatives to Gapdh in rodent and human heart failure gene expression studies. BMC Mol Biol 11:22, 2010 Brudeli B, Moltzau LR, Andressen KW, Krobert KA, Klaveness J, Levy FO: Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor ligands. Bioorg Med Chem 18:8600-13, 2010 Brusevold IJ, Søland TM, Khuu C, Christoffersen T, Bryne M. Nuclear and cytoplasmic expression of Met in oral squamous cell carcinoma and in an organotypic oral cancer model. Eur J Oral Sci 118:342-49, 2010 Dehnes Y, Lamon S, Lönnberg M. Erythropoietin (EPO) immunoaffinity columns - A powerful tool for purifying EPO and its recombinant analogues. J Pharm Biomed Anal 53:1028-32, 2010 Edvardsen H, Brunsvig PF, Solvang H, Tsalenko A, Andersen A, Syvanen AC, Yakhini Z, Børresen-Dale AL, Olsen H, Aamdal S, Kristensen VN. SNPs in genes coding for ROS metabolism and signalling in association to docetaxel clearance. Pharmacogenomics J 10:513-23, 2010 Elers J, Pedersen L, Henninge J, Lund TK, Hemmersbach P, Dalhoff K, Backer V. Blood and urinary concentrations of salbutamol in asthmatic subjects. Med Sci Sports Exerc 42:24449, 2010 Hagen TP, Anthun KS, Reikvam Å. [Acute myocardial infarctions in Norway 1. Tidsskr Nor Laegeforen 130:820-824, 2010 Johannessen SI and Johannessen Landmark C. Clinically important interactions with antiepileptic drugs. Curr Neuropharm 8:254-67, 2010 Karouni M, Arulthas S, Larsson PG, Rytter E, Johannessen SI, Johannessen Landmark C. Psychiatric comorbidity in patients with epilepsy: A population-based study. Eur J Clin Pharmacol 66:1151-60, 2010 Side 57 av 70 Kongsgaard UE, Andersen A, Øien M, Oswald IAY, Bruun LI. Experience of unpleasant sensations in the mouth after injection of saline from prefilled syringes. BMC Nursing 9:1, 2010 Lund T, Korsgren O, Aursnes IA, Scholz H, Foss A. Sustained reversal of diabetes following islet transplantation to striated musculature in the rat. J Surg Res 160:145-54, 2010 Osnes JB, Skomedal T: Time for reclassification of digitalis? Hjerteforum, Suppl. 2: 87-91, 2010 Qvigstad E, Moltzau LR, Aronsen JM, Nguyen CH, Hougen K, Sjaastad I, Levy FO, Skomedal T, Osnes JB. Natriuretic peptides increase beta1-adrenoceptor signalling in failing hearts through phosphodiesterase 3 inhibition. Cardiovasc Res 85:763-72, 2010 Reikvam Å. [Changed digitalis dosing]. Tidsskr Nor Laegeforen 130:1324, 2010 Reine PA, Kongsgaard UE, Andersen A, Thøgersen AK, Olsen H. Infusions of albumin increase the free fraction of naproxen in healthy volunteers: a randomized crossover study. Acta Anaesthesiol Scand 54:430-434, 2010 Sandnes D, Müller KM, Akhtar K, Johansen EJ, Christoffersen T, Thoresen GH. Induction of LRF-1/ATF3 by vasopressin in hepatocytes: role of MAP kinases. Cell Physiol Biochem 25:523-32, 2010 Selmer R, Blix HS, Landmark K, Reikvam Aa: Prescribing patterns of antihypertensive drugs in 78000 incident users. Pharmacoepidemiology and Drug Safety 19 (suppl 1): 33-4, 2010 Sørensen O, Andersen A, Olsen H, Ekstrøm PO, Kristian A, Giercksky KE, Flatmark K. Validation and use of microdialysis for determination of pharmacokinetic properties of the chemotherapeutic agent mitomycin C - an experimental study. BMC Cancer 10:469, 2010 Vethe NT, Gjerdalen LC, Bergan S. Determination of cyclosporine, tacrolimus, sirolimus and everolimus by liquid chromatography coupled to electrospray ionization and tandem mass spectrometry: assessment of matrix effects and assay performance. Scand J Clin Lab Invest 70:583-591, 2010 Åsberg A, Bergan S. Kliniske studier på organtransplanterte pasienter - eksempler på utprøverinitiert forskning. Norsk Farmaceutisk Tidsskrift. 118:20-23, 2010 (In Norwegian) 9.2 Book chapters 2013 Andersen, GØ, Levy FO: Legemidler ved hjerte- og karsykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1059-11143 (In Norwegian) Berg TJ, Eriksen EF, Johansen PW, Jørgensen AP, Løvås K, Norheim I, Rishaug U: Endokrine sykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 135-170 (In Norwegian) Berg TJ, Eriksen EF, Johansen PW, Jørgensen AP, Løvås K, Moen MH, Norheim I. Legemidler i endokrinologien. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-8290732-11-5. pp 839-907 (In Norwegian) Side 58 av 70 Brustugun OT, Dajani O, Lehne G, Thoresen GH: Legemidler i behandlingen av kreftsykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 785-838 (In Norwegian) Johansen PW. Legemiddelbruk og –dosering ved nedsatt nyrefunksjon. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1363-1382 (In Norwegian) Johansen PW. Doping. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1429 (In Norwegian) Johansen PW, Opdal MS. Legemiddelanalyser og rusmiddelanalyser. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1431 (In Norwegian) Myhr, K. Bivirkninger og legemiddelovervåking. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1405 (In Norwegian) Nordeng H, Sandnes DL: Amming og legemidler. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1419-1421 (In Norwegian) Sandnes DL, Nordeng H, Stray-Pedersen B: Graviditet og legemidler. In: Norsk legemiddelhåndbok for helsepersonell 2013. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2013. ISBN 978-82-90732-11-5. pp 1415-1417 (In Norwegian) 2011 Hemmersbach P, Helle C. Kosttilskudd. In: Idrettsernæring. Garthe I, Helle C (eds). Gyldendal, Oslo 2011 pp 204-224 (In Norwegian) Henninge J, Hullstein I, Hemmersbach P. Unknown peptide preparations analysed in 2010: An overview. In: Recent Advances in Doping Analysis. Schänzer W, Geyer H, Gotzman A, Marek U (eds), Vol 19, Sportsverlag Strauß, Cologne, 2011, p. 231 Ringerike T, Hamidi V, Hagen G, Reikvam Å, Gjertsen MK. Thromboprophylactic treatment with rivaroxaban or dabigatran compared with enoxaparin or dalteparin in patients undergoing elective hip- or knee replacement surgery. Nasjonalt kunnskapssenter for helsetjenesten 2011 (ISBN 978-82-8121-414-9) 92 s. Trulsen LN, Øverøyen AW, Dehnes Y. Colostrum and acute effect on serum IGF-1 levels – a pilot study. In: Recent Advances in Doping Analysis. Schänzer W, Geyer H, Gotzman A, Marek U (eds), Vol 19, Sportsverlag Strauß, Cologne, 2011, p. 247 2010 Birkeland KI, Christoffersen T, Eriksen EF, Johansen PW, Jørgensen AP, Løvås K, Norheim I: Endokrine sykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-8290732-10-8. pp 129-165 (In Norwegian) Birkeland KI, Christoffersen T, Eriksen EF, Johansen PW, Jørgensen AP, Løvås K, Moen MH, Norheim I. Legemidler i endokrinologien. In: Norsk legemiddelhåndbok for Side 59 av 70 helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 742-814 (In Norwegian) Hemmersbach P, Grosse J. Nandrolone: A multi-faceted doping agent. Handb Exp Pharmacol 127-54, 2010 Dahl O, Iversen PO, Kolmannskog S, Lehne G, Sandset PM, Christoffersen T: Kreftsykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 103-127 (In Norwegian) Johannessen Landmark C, Johannessen SI. Antiepileptic drugs: Pregabalin. In: Atlas of epilepsies. Panayiotopoulos C (ed). Springer 2010, ch. 57. Johannessen Landmark C, Johannessen SI, Chung S. Antiepileptic drugs: New AEDs in development. In: Atlas of epilepsies. Panayiotopoulos C (ed). Springer 2010, ch. 53 Johannessen Landmark C, Johannessen SI. Antiepileptic drugs: Eslicarbazepine acetate. In: Atlas of epilepsies. Panayiotopoulos C (ed). Springer 2010, ch.73 Johannessen Landmark C, Johannessen SI. New antiepileptic drugs in Neuropsychiatric disorders. Basic and clinical pharmacology. In: Brain Protection in Schizophrenia, Mood and Cognitive disorders. Ritsner M (ed). Springer 2010, ch.16, pp 485-504 Johannessen SI. Kapittel 11. Medikamentell behandling av epilepsi. In: Fokus på epilepsi, 2. utgave, Nakken KO, Cappelen, Oslo, 2010 (In Norwegian). Johannessen SI. Kapittel 12. De enkelte antiepileptika. In: Fokus på epilepsi, 2. utgave, Nakken KO, Cappelen, Oslo, 2010 (In Norwegian) Johannessen SI, Johannessen Landmark C. Therapeutic monitoring of AEDs. In: Handbook of Drug targeting and monitoring: Developments, Challenges and Applications. (Nova Science publ.) Andreev B and Egorov V (Eds.) Chapter 13, pp. 1-9, 2010 Johansen PW. Dosage of drugs in renal disease (Legemiddelbruk og -dosering ved nedsatt nyrefunksjon). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1397-1418 (In Norwegian) Johansen PW. Use of medicines and dosing in relation to reduced renal function (Legemiddelbruk og –dosering ved nedsatt nyrefunksjon). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1397-1418 (In Norwegian) Johansen PW. Doping in sports (Doping). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1915-1925 (In Norwegian) Johansen PW, Christoffersen T. Substances with androgen effect (Midler med androgen effekt). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 868-872 (In Norwegian) Johansen PW, Christoffersen T. Male gonadal dysfunction (Mannlige gonadefunksjonsforstyrrelser). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 97882-90732-10-8. pp 160-161 (In Norwegian) Johansen PW, Opdal MS. Laboratory analyses of medical drugs and drugs of abuse (Legemiddelanalyser og rusmiddelanalyser). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk Legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1931-1942 (In Norwegian) Side 60 av 70 Johansen PW, Opdal MS: Drug and drugs-of-abuse analysis (Legemiddelanalyser og rusmiddelanalyser). In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1931-1942 (In Norwegian) Myhr K. Global farmasi. Granås AG, Bakken K, red. Samfunnsfarmasi – legemiddelbruk og farmasøytisk profesjonsutøvelse. Fagbokforlaget, Bergen, Norway 2010. pp 272-289 (In Norwegian) Nordeng HME, Sandnes DL, Nylander G: Amming og legemidler. In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1481-1534 (In Norwegian) Sandnes DL, Christoffersen T, Stray-Pedersen B: Graviditet og legemidler. In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 1723-1779 (In Norwegian) Thoresen GH, Dahl O, Christoffersen T: Legemidler i behandlingen av kreftsykdommer. In: Norsk legemiddelhåndbok for helsepersonell 2010. Foreningen for utgivelse av Norsk legemiddelhåndbok, Oslo, Norway, 2010. ISBN 978-82-90732-10-8. pp 821-902 (In Norwegian) 9.3 Books Nikanorova M, Genton P, Johannessen Landmark C, Johannessen SI (Eds.). The orphan drugs in epilepsy. "Topics in Epilepsy" vol. 4, John Libbey Eurotext, Escher, UK, 2011 Reikvam Å, Sandset PM (eds.): Warfarinbehandling i praksis: tryggere antikoagulasjon, 2. utg. Den norske legeforening (Skriftserie for leger: Utdanning og kvalitetsutvikling), Oslo, Norway. ISBN 978-82-8070-083-4 (h.) 72 pages, 2010 (In Norwegian) Thieme D, Hemmersbach P (eds.) Doping in Sports. Handbook of Experimental Pharmacology, Vol. 195, Springer, Heidelberg 2010 Dahl O, Lehne G, Baksaas I, Kvaløy SO, Christoffersen T. (eds.) Medikamentell kreftbehandling. Farmakologisk institutt, Det medisinske fakultet, Universitetet i Oslo, Oslo, Norway. ISBN 978-82993312-5. 495 pages, 2009 (In Norwegian) Reikvam Å, Sandset PM (eds.) Warfarinbehandling i praksis: tryggere antikoagulasjon. Den norske lægeforening (Skriftserie for leger: Utdanning og kvalitetsutvikling), Oslo, Norway. ISBN 82-8070-031-5 (h.) 56 pages, 2005 (In Norwegian) 9.4 Publikasjoner i norske tidsskrifter 2014 Fjeld H, Raknes G: Er det virkelig farlig å kombinere metronidazol og alkohol? Tidsskrift for Den norske legeforening 134:1661-63, 2014 Husøy MAR, Brinch L, Tjønnfjord GE, Gedde-Dahl T Jr., Heldal D, Holme PA, Dybedal I, Kolstad A, Akkøk CA, Rollag H, Gaustad P, Bergan S, Egeland T, Josefsen D, Kvalheim G, Fløisand Y: Allogen stamcelletransplantasjon hos voksne 1985-2012. Tidsskrift for Den norske legeforening 134:1569-75, 2014 Side 61 av 70 Landmark K.; Hva er galt med karakterer? Tidsskr Nor Legeforen 134: 10-1, 2014 Landmark K.; Rødt kjøtt og kardiovaskulære sykdommer. Indremedisineren 1: 15, 2014 Landmark K.; Tvilsom effekt av atenolol ved kardiovaskulære sykdommer. Indremedisineren, 3: 14-5, 2014 2013 Bjørner T, Tvete IF, Aursnes I, Skomedal T: [Dispensing of benzodiazepines and Z drugs by Norwegian pharmacies 2004-2011]. Tidsskr Nor Laegeforen 133:2149-53, 2013 Bogsrud MP, Reikvam A, Retterstøl K: [Treatment with statins]. Tidsskr Nor Laegeforen 133:1316-9, 2013 Landmark K: Kan fisk og omega-3-fettsyrer redusere størrelsen på et hjerteinfarkt? Indremedisineren 1:18-9, 2013 Landmark K, Alm CS: Har omega-3-fettsyrer effekt mot kardiovaskulær sykdom? Tidsskr Nor Laegeforen 133:269, 2013 Skomedal T, Hanem S, Dybvik T, Ilner SO: Long-acting injectable olanzapine can give rise to a condition consistent with central anticholinergic syndrome. Tidsskr Nor Laegeforen 133:2238-9, 2013 2012 Blix HS, Landmark K, Selmer R, Reikvam A: [Patterns in the prescription of antihypertensive drugs in Norway, 1975-2010]. Tidsskr Nor Laegeforen 132:1224-8, 2012 Gjersvik P, Helsing P, Holdaas H, Bergan S: [Immunosuppressive drugs and the development of skin cancer after organ transplantation]. Tidsskr Nor Laegeforen 132:2064-8, 2012 Hemmersbach P, Drange M, Rabin O, Botre F, Dehnes Y: Doping analysis on solid ground. Tidsskr Nor Laegeforen 132:130, 2012 Landmark K: Et uvanlig svangerskap. Michael quarterly 9/3: 296-300, 2012 Landmark K, Alm CS: Fisk og omega-3-fettsyrer ved hjertesvikt. Tidsskr Nor Laegeforen 132:2281-4, 2013 Reikvam A: Is the warfarin era over? Tidsskr Nor Laegeforen 132:2583, 2012 2011 Holager T, Solhaug V, Bergman J. Allergibehandling av gravide og ammende. Nor Farmaceut Tidsskr 119(5):18-9, 2011 Johansen JS, Nordmo E. Tamoksifen og nikotintyggegummi. Nor Farmaceut Tidsskr 119(9):4, 2011 Landmark K, Alm CS: Alkohol, omega-3-fettsyrer og kardiovaskulær sykdom. Indremedisineren 1:23-5, 2011 Landmark K, Aursnes I, Kvan E, Reikvam Å: RAS-hemmere og infarktstørrelse. Tidsskr Nor Laegeforen 131:441-2, 2011 Landmark K, Landmark K jr Haarr H: Omega-3-fettsyrer, telomerer, telomerase og kradiovaskulær sykdom. Hjerteforum, 24:64-7, 2011 Side 62 av 70 Larsen BM, Myhr K. Starte opp og slutte med et antidepressivum – like lett? Nor Farmaceut Tidsskr 119(3):18-9, 2011 Myhr R, Westergren T. Linicin og hodelus. Nor Farmaceut Tidsskr 119(10):18-9, 2011 Mørch-Johnsen GH, Myhr R. Vitamin B12 og metforminbehandling. Utposten 7:44-5, 2011 Nergård CS. Laktoseintoleranse og legemidler med laktose. Nor Farmaceut Tidsskr 119(2):4, 2011 Schultz Johansen J, Holager T. Prevensjon og bruk av lamotrigin. Utposten 4: 38-9, 2011 Solhaug V, Myhr K. Acetylsalisylsyre -"pillen mot nesten alt"? Utposten 2: 36, 2011 Søberg OØ, Linnsund JM, Dyvesveen A, Johansen PW, Kristoffersen N, Platou H, Storbakken B. Tryggere håndtering av medisiner. Sykepleien 2: 50-53, 2011 2010 Eriksen AK, Forsberg KL, Høyland HK, Roland PDH, Westergren T, Larsen BM. RELIS fremstår i ny drakt. Nor Farmaceut Tidsskr 118(4):2, 2010 Holager T, Stenberg-Nilsen H. Behandling av spedbarnskolikk. Nor Farmaceut Tidsskr 118(1):4, 2010 Landmark K: How in vitro animal experiments can contribute to solve a clinical problem. Mode of action of phenothiazine derivatives. Hjerteforum, Suppl 2:75-80, 2010 Landmark K, Høiegge A: Urinsyre som kardiovaskulær risikofaktor. Har medikamenter effekt? Hjerteforum 23:45-8, 2010 Larsen BM. Ketoprofen gel og effekt på smerter ved bløtdelsskader. Nor Farmaceut Tidsskr 118(3): 21-2, 2010 Myhr K. Benzodiazepiner og graviditet. Nor Farmaceut Tidsskr 118(2):15, 2010 Myhr K. Tilgang til essensielle legemidler - kan nye initiativ hjelpe? Nor Farmaceut Tidsskr118(2):10-1, 2010 Myhr R, Johansen JS, Solhaug V. Triptaner under graviditet og amming. Utposten 39(4):46-7, 2010 Nergård CS, Mysen TH. Redusert effekt av levotyroksin (Levaxin) ved samtidig bruk av soyatilskudd. Nor Farmaceut Tidsskr 118(9): 28-9, 2010 Solhaug V, Nergård CS. Interaksjoner mellom warfarin og naturmidler. Tidsskr Nor Legeforen 130(12):1252-4, 2010 Stenberg-Nilsen H. Slimhinneavsvellende nesedråper/nesespray til små barn. Nor Farmaceut Tidsskr 118(12):4, 2010 Stenberg-Nilsen H, Holager T. Melatonin og avhengighet. Nor Farmaceut Tidsskr 118(6):4, 2010 Westergren T. Elektronisk legemiddelinformasjon: Økt pasientsikkerhet eller falsk trygghet? Norsk Farmaceut Tidsskr 118(2):16-7, 2010 Westergren T, Johansen JS. Gir kombinasjon av SSRI med platehemmere eller NSAID økt frekvens av blødninger? Utposten 39(6):44-5, 2010 Westergren T, Widnes SF, Giverhaug T, Nordmo EN. Tilskudd av folsyre og kreftrisiko. Utposten 39(2): 42-3, 2010 Side 63 av 70 9.5 Doctoral theses 1970-2014 Ingun Heiene Tveteraas, MD, PhD: The role of epidermal growth factor receptor transactivation in the effects of G-protein-coupled receptor-mediated signalling in gastrointestinal and oral carcinoma cells. Faculty of Medicine, University of Oslo, 2014 Jon Birger Haug, MD, PhD: Hospital antibiotic use in Norway. Epidemiology and surveillance methodology. Faculty of Medicine, University of Oslo, 2014 Ingjerd Sæves, PhD: Pharmacokinetics, pharmacodynamics and pharmacogenetics of immunosuppressants in liver transplant recipients. School of Pharmacy, University of Oslo, 2013 Morten Grundtvig, MD, PhD: Acute myocardial infarction in men and women – Different impact of smoking in the two genders. Analyses of a cohort study of 2281 patients admitted to hospital. Faculty of Medicine, University of Oslo, 2012 Lise Román Moltzau, PhD: Effects of natriuretic peptides on contractility and cGMP compartmentation in failing rat myocardium. Faculty of Medicine, University of Oslo, 2012 Jon Riise, MD, PhD: Inotropic effects of prostaglandins in ventricular myocardium. Faculty of Medicine, University of Oslo, 2012 Ingvild Brusevold, PhD: Oral cancer – hepatocyte growth factor receptor in patient prognosis and cell migration. In vivo and in vitro studies. Faculty of Dentistry, University of Oslo 2011 Kristin Meisdalen Müller, PhD: Stimulation of cell proliferation by agonists activating G protein-coupled receptors: signalling mechanisms involved and interaction with receptor tyrosine kinases. Faculty of Medicine, University of Oslo, 2011 Faraz Afzal, MD, PhD: Phosphodiesterases and regulation of contractile function through βadrenoceptors and 5-HT4 receptors in the failing heart. Faculty of Medicine, University of Oslo, 2010 Sara Bremer, PhD: Inosine monophosphate dehydrogenase: The molecular target of mycophenolate. Faculty of Medicine, University of Oslo, 2009 Hilde Eikemo, PhD: Regulation of myosin light chain 2 phosphorylation in cardiac muscle and its possible role in contractile responses. Faculty of Medicine, University of Oslo, 2009 Annike Irene Totlandsdal, PhD: Ultrafine carbon black-induced cytokine responses of lung and heart cells. Faculty of Medicine, University of Oslo, 2009 Nils Tore Vethe, PhD: Molecular pharmacodynamics of the immunosuppressant mycophenolic acid: A basis for monitoring and individual treatment. Faculty of Medicine, University of Oslo 2009 Kjetil Wessel Andressen, PhD: The 5-HT7 serotonin receptor: G protein preassociation and functional selectivity. Faculty of Medicine, University of Oslo, 2008 Randeep Mandla, PhD: Mycophenolic acid in renal allograft recipients; pharmacokinetic challenges and pharmacodynamic opportunities. Faculty of Medicine, University of Oslo, 2008 Kjell I. Pettersen, MD, PhD: Health-related quality of life after myocardial infarction: methods for assessment and determinants. Faculty of Medicine, University of Oslo, 2008 Hege Salvesen Blix, PhD: Drug-related problems in hospitalized patients. A prospective bedside study of an issue needing particular attention. Faculty of Medicine, University of Oslo, 2007 Kirsten Viktil, PhD: Drug-related problems in hospitalized patients. A major challenge in current medicine. Faculty of Medicine, University of Oslo, 2007 Side 64 av 70 Trond Brattelid, PhD: Characterisation and function of a novel serotonin receptor and the role of serotonin receptors in heart failure. Faculty of Medicine, University of Oslo, 2006 Elena Kvan, MD, PhD: Studies on drug therapy in myocardial infarction. The infarction and pharmacotherapy (INPHARM) study. Faculty of Medicine, University of Oslo, 2006 Jens Henrik Norum, PhD: Mechanisms of ERK activation through Gs -coupled serotonin receptors. Faculty of Medicine, University of Oslo, 2005 Hedvig Nordeng, PhD: Drug use in pregnancy and after deilvery. Faculty of Medicine, University of Oslo, 2005 Ingebjørg Buajordet, PhD: Investigation of adverse drug events in different patient populations. Faculty of Medicine, University of Oslo, 2004 Eirik Qvigstad, MD, PhD: Adrenergic and serotonergic receptor function in the failing heart. Faculty of Medicine, University of Oslo, 2004 Laila Sortvik Nilssen, PhD: Signaling mechanisms involved in the growth-stimulatory effects of G protein-coupled receptor agonists in hepatocytes. Faculty of Medicine, University of Oslo, 2003 Tormod Kyrre Guren, MD, PhD: Signal transduction pathways from the epidermal growth factor receptor in hepatocytes. Faculty of Medicine, University of Oslo, 2002 Mohammad Nouri Sharikabad, PhD: Calcium and reactive oxygen species during reoxygenation of hypoxic cardiomyocytes and effects of increased extracellular magnesium: Studies with a model for ischemia-reperfusion injury. Faculty of Medicine, University of Oslo, 2002 Frode Willoch, MD, PhD: PET studies on pain and analgesia: brain activity changes & opioidergic mechanisms. Faculty of Medicine, University of Oslo, 2001 Kjell Borthne, MD, PhD: The role of α1- and β-adrenoceptors in sympathetic inotropic myocardial control. Faculty of Medicine, University of Oslo, 2001 Olav Dajani, MD, PhD: The role of phospholipid signaling in regulation of hepatocyte growth. Faculty of Medicine, University of Oslo, 2001 Per Lagerløv, MD, PhD: Improving drug treatment in primary care. An educational interaction. Faculty of Medicine, University of Oslo, 2001 Toril Rabben, PhD: Studies on experimental and neuropathic orofacial pain, and low-dose ketamine as a probe for NMDA receptor function. Faculty of Medicine, University of Oslo, 2000 Øyvind Melien, MD, PhD: G proteins and signal transduction in hepatocytes with particular reference to mechanisms of activation of extracellular-signal regulated kinases. Faculty of Medicine, University of Oslo, 2000 Gustav Lehne, MD, PhD: P-glycoprotein – a target for circumvention of multidrug resistance in cancer. Faculty of Medicine, University of Oslo, 1999 Geir Øystein Andersen, MD, PhD: α1-adrenoceptor mediated effects on potassium efflux from rat myocardium. Faculty of Medicine, University of Oslo, 1998 Stein Bergan, PhD: Azathioprine monitoring in renal transplantation. Faculty of Medicine, University of Oslo, 1998 Olav Hustveit, MD, PhD: Studies on the receptor specificity of strong analgesic drugs with particular reference to the possible role of muscarinic cholinergic receptors in the side effects of fentanyl and ketamine. Faculty of Medicine, University of Oslo, 1997 Håvard Viko, MD, PhD: Myocardial potassium uptake and IP3 response after α1- and βadrenoceptor stimulation; receptor subtypes and mechanisms involved, and a possible Side 65 av 70 interaction between the two receptor systems. Faculty of Medicine, University of Oslo, 1997 Mimi Stokke, MD, PhD: Modulation of cardiac Ca2+ antagonist binding by drugs, nucleotides, divalent cations and ischemia. Faculty of Medicine, University of Oslo, 1996 Sigrid Hanem, MD, PhD: Some aspects of mechanisms involved in alpha-1-adrenoceptor stimulation of rat myocardium. Faculty of Medicine, University of Oslo, 1995 Øyvind Hundal,PhD: Studies on the possible relationship between levels of piroxicam and naproxen in biological fluids from patients with osteoarthritis as well as reactive arthritis, and clinical events. Faculty of Medicine, University of Oslo, 1994 G. Hege Thoresen, MD, PhD: Positive and negative hormonal regulation of hepatocyte growth: Effects of cyclic AMP and transforming growth factor β. Faculty of Medicine, University of Oslo, 1993 Ingrid Matheson, PhD: Epidemiological and pharmacokinetic studies on drugs and breastfeeding. Faculty of Medicine, University of Oslo, 1991 Kirsten Sundby-Hall, MD, PhD: Contributions to the treatment of primary liver cancer. Faculty of Medicine, University of Oslo, 1991 Ivar P. Gladhaug, MD, PhD: Epidermal growth factor receptors in hepatocytes. Faculty of Medicine, University of Oslo, 1990 Halfdan Aass, MD, PhD: α- and β-adrenergic regulation of cardiac contraction and relaxation – some physiological and pharmacological aspects. Faculty of Medicine, University of Oslo, 1989 Gunnar O. Brønstad, MD, PhD: Cyclic AMP and liver cell growth. Faculty of Medicine, University of Oslo, 1988 Dag Fremstad, MD, PhD: Pharmacokinetics of quinidine in rat and man, with special emphasis on the influence of plasma protein binding, blood and tissue distribution. Faculty of Medicine, University of Oslo, 1988 Magne Refsnes, PhD: Mechanisms regulating hepatic β-adrenoceptor-linked adenylate cyclase. Faculty of Medicine, University of Oslo, 1988 Tor-Erik Sand, MD, PhD: Hormonal regulation of liver growth. Studies on primary cultures of adult rat hepatocytes. Faculty of Medicine, University of Oslo, 1988 Dagny Sandnes, PhD: Beta-adrenoceptors on rat hepatocytes and human mononuclear leucocytes – with special reference to quantitation and regulation. Faculty of Medicine, University of Oslo, 1987 Jan Erik Bredesen, PhD: Therapeutic drug monitoring of disopyramide. Analytical, pharmacokinetic and pathophysiological variables. Faculty of Medicine, University of Oslo, 1986 Eva Flovold Pike, PhD: The role of lipoproteins, albumin and orosomucoid for serum (plasma) binding of different drugs: Deficient sera versus isolated proteins. Faculty of Medicine, University of Oslo, 1986 Georg Sager jr., MD, PhD: Some aspects of beta-adrenergic drug binding in human blood, with special reference to the binding of propranolol, dihydroalprenolol and isoproterenol. Faculty of Medicine, University of Oslo, 1986 Liv Endresen, PhD: Metallothionein - Experimental studies on its protective function against certain anticancer agents. Faculty of Medicine, University of Oslo, 1985 Tor Skomedal, MD, PhD: Some aspects of α- and β-adrenergic receptors and mechanical effects in rat myocardium. Faculty of Medicine, University of Oslo, 1984 Side 66 av 70 Harald Bergrem, MD, PhD: Prednisolone pharmacokinetics in man. Faculty of Medicine, University of Oslo, 1983 Kirsten Selvig, PhD: Proxyphylline and theophylline - a comparative pharmacological study on their use in obstructive lung disease. Faculty of Medicine, University of Oslo, 1983 Odd Brørs, MD, PhD: Pharmacological studies on hydroflumethiazide in man: The pharmacokinetics and its relationship to the natriuretic and kaliuretic effects. Faculty of Medicine, University of Oslo, 1982 Svein Ivar Johannessen, PhD: Therapeutic drug monitoring of antiepileptic drugs - clinical pharmacokinetic aspects of carbamazepine and sodium valproate and their interaction with other antiepileptic drugs. Faculty of Medicine, University of Oslo, 1982 Ingebjørg Baksaas, PhD: Drug utilization studies - at overall, prescription and patient levels. Faculty of Medicine, University of Oslo, 1980 Odd Georg Nilsen, PhD: The binding of quinidine to proteins in human serum. Faculty of Medicine, University of Oslo, 1978 Jan-Bjørn Osnes, MD, PhD: Cyclic AMP dependent and independent inotropic effects of adrenergic amines. Faculty of Medicine, University of Oslo, 1978 Svein G. Dahl, MD, PhD: Clinical pharmacology of chlorpromazine and levomepromazine. Pharmacokinetics in man and effects of metabolites on isolated rat atria. Faculty of Medicine, University of Oslo, 1977 Helge Refsum, MD, PhD: Electrophysiological and mechanical effects of calcium on isolated rat cardiac muscle. Faculty of Medicine, University of Oslo, 1976 Thoralf Christoffersen, MD, PhD: Cyclic AMP metabolism in rat liver during normal and neoplastic development. Faculty of Medicine, University of Oslo, 1975 Erik Dybing, MD, PhD: Effects of some drugs on glucuronidation and certain cellular transport mechanisms. With special reference to the action of the so-called membrane stabilizers. Faculty of Medicine, University of Oslo, 1974 Jørg Mørland, MD, PhD: Effects of ethanol on rat liver metabolism with special reference to protein synthesis. Faculty of Medicine, University of Oslo, 1974 Britt-Ingjerd Nesheim, MD, PhD: Adrenergic receptors in the rabbit uterus. Faculty of Medicine, University of Oslo, 1974 Jon FW Haffner, MD, PhD: The excitatory adrenergic response in gastric smooth muscle. Faculty of Medicine, University of Oslo, 1973 Knud Landmark, MD, PhD: The mode of action of promazine and thioridazine in isolated rat cardiac muscle. Faculty of Medicine, University of Oslo, 1972 Asbjørn Langslet, MD, PhD: Effects of chlorpromazine and related compounds in the isolated rat heart. Faculty of Medicine, University of Oslo, 1971 Side 67 av 70 10 Ansatte pr 31.12.2014 Avdelingsledelse Muan, Berit Larsen, Marianne Spalder Cand.pharm., Dr.scient. Avdelingsleder [email protected] Lederassistent [email protected] Klinisk farmakologi - Medisinsk fagligseksjon Gustavsen, Ingebjørg Dr.med. Seksjonsleder/overlege Brørs, Odd Dr. med. Professor emeritus Burns, Margrete Larsen Cand.med. Overlege Gadeholt, Gaut Dr.med. Overlege Opdal, Mimi Stokke Dr.med. Overlege/1. amanuensis Krabseth, Hege-Merete Cand.med. LiS Nordal, Kristin Cand.med. LiS Rognstad, Stine Cand.med. LiS Tveteraas, Ingun Heiene Dr.med. LiS [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Klinisk farmakologi - Seksjon for utvikling Bergan, Stein Cand.pharm., PhD Seksjonsleder/professor II Andersen, Anders Mikal Ingeniør Avdelingsingeniør Clasen, Per-Erik Cand.scient Overingeniør Føreid, Siri Cand.scient. Overingeniør Johannessen, Svein I Cand.real., PhD Emeritus Gottås, André Cand scient PhD Overingeniør Klaasen, Rolf Cand. pharm. Stipendiat (vikar) Kringen, Marianne K. Cand.scient., PhD Forsker Muller, Lill Dannevig Cand.real., PhD Overingeniør Rudberg, Nina Cand.scient. Overingeniør Thorstensen, Christian W Cand. scient., PhD Overingeniør Vethe Nils Tore Cand.pharm., PhD Forsker [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Klinisk farmakologi - Driftsseksjon Heesch, Bente Bioingeniør Seksjonsleder [email protected] Enhet Rikshospitalet Skogseth, Torunn Abraham, Semhar Ekholt, Karin Godager, Borghild Gryvill, Anne Randi Hotvedt, Siv-Anne Overgaard, Mette Istad Quiogue, Antonio Manuel Skrøvseth, Lisa Youssefi, Asrin Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Enhetsleder Bioingeniør Bioingeniør Bioingeniør Bioingeniør Spesialbioingeniør Bioingeniør Spesialbioingeniør Bioingeniør Bioingeniør [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Bioingeniør Bioingeniør Bioingeniør Enhetsleder Bioingeniør Bioingeniør Helsesekretær Bioingeniør [email protected] [email protected] [email protected] [email protected] [email protected] Enhet SSE Schmidt, Marianne Lund Alfstad, Else Kristin Melvik Hella, Gerd Karin Høgseth, Berit Khoshnamak, Kvestan Bioingeniør Side 68 av 70 Listhaug, Cecilie Myran, Farzad Bioingeniør Bioingeniør Bioingeniør Bioingeniør Enhet Ullevål Johansen, Hanne Britt Ahmed, Shukri Bakke, Hege Gilbø Brenna, Inger Helen Elhami, Farasat Farahi, Eva Julie Haldsrud, Renate Helstrøm, Trine Mamen, Marte M. Mannivannan, Kumuthini Mongstad, Trude Tornes, Hilde Bioingeniør Bioingeniør Ingeniør Ingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Bioingeniør Enhetsleder Bioingeniør Ingeniør Ingeniør Fagbioingeniør Fagbioingeniør Bioingeniør Bioingeniør II Bioingeniør Bioingeniør Bioingeniør II Bioingeniør [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Seksjonsleder Studiesykepleier/koordinator Studiesykepleier/koordinator Studiesykepleier [email protected] [email protected] Seksjonsleder/ overlege Spesialrådgiver Provisorfarmasøyt [email protected] Seksjon Klinisk forskningspost Khiabani, Hassan Zarè Dr.med. Boezelijn, Gro Sykepleier Halstensen, Anne Marie Raad, Line Samuelsen Spesialutd. sykepleier Sykepleier Seksjon legemiddelkomité og –sikkerhet Johansen, Per Wiik Dr.med. Bruun, Laila Irene Timenes, Anne Marie Cand.pharm Cand.pharm Seksjon Regionalt legemiddelinformasjonssenter Sør-Øst Westergren, Tone Cand.pharm. Seksjonsleder Eek, Anne Katrine Cand. pharm. Rådgiver Fjell, Hilde Cand. pharm. Rådgiver Grønstad, Anne Cand.pharm. Rådgiver Havnen, Gro Cecilie Cand.pharm. Rådgiver Holager, Tanja Margrete Cand.pharm. Spesialrådgiver Lindland-Tjønn, Helle Cand.pharm. Rådgiver Myhr, Randi Gerd Cand.pharm. Spesialrådgiver Myhr, Kirsten Cand.pharm. Spesialrådgiver Nielsen, Ingunn Marie R Cand.med. Rådgiver Nordén, Hilde Sekretær Reiter, Lillian Cand.pharm. Rådgiver, PhD Solhaug, Vigdis Cand.pharm. Spesialrådgiver Stenberg-Nilsen, Hanne Cand.pharm. Spesialrådgiver Seksjon Norges laboratorium for dopinganalyse Hemmersbach, Peter Dr.rer.nat. Seksjonsleder/prof II Amlie, Lise-Marit Bioing/Master of Enhetsleder Management Andersen, Astrid Kjemiingeniør Ingeniør Broderstad, Lillian Lorenzo Bioingeniør Avdelingsingeniør Dehnes, Yvette Cand.scient. Faglig ansvarlig Hagen, Linn Camilla H Kjemiingeniør Ingeniør Side 69 av 70 [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Helle, Kjersti Marie E. Holthe, Anne Lise Hullstein, Ingunn Riise Jensen, Aase-Brith E. Lund, Kari Malerød-Fjeld, Helle Rzeppa, Sebastian Simmack, Catherine D. Sletten, Camilla Johanne Zandy, Essa Aarsand, Randi Bioingeniør Cand.scient. Bioingeniør Kjemiingeniør Cand.scient., PhD PhD Kjemiingeniør Kjemiingeniør Seksjon Farmakologisk institutt Levy, Finn Olav Dr.med. Andresen, Henriette Andressen, Kjetil Wessel Bach, Trond Bjørnerem, Marianne Brusevold, Ingvild Johnsen Christoffersen, Thoralf Dahl, Marie Dugstad, Kari S. Henjum, Kristi Hiis, Halvard Gautefall Hussain, Rizwan I. Jendresen, Charlotte Klemp, Marianne Krobert, Kurt Landmark, Knud Magnussen, Eva Østby Manfra, Ornella Meier, Silja Melsom, Caroline Bull Moltzau, Lise Román Nilsson, Lars Osnes, Jan-Bjørn Patel, Renukaben Reikvam, Åsmund Sandnes, Dagny Student Cand.pharm., PhD PhD Student Cand.odont., PhD Dr.med. MSc Stud.med. Cand.pharm Stud.med Cand.med. Cand.scient. Dr.med. PhD Dr.med. Bioing. MSc MSc Cand.scient. Cand.pharm. PhD Dr.med. BSc Dr.med. Cand.pharm./ Dr.philos Schiander Iwona Gutowska MSc Skomedal, Tor Sollie, Selene Julie Thoresen, Hege Tjomsland, Vegard Tveteraas, Ingun Heiene Tømmerdal, Heidi Ulsund, Andrea H. Ørstavik, Øivind Årskog, Vibeke Aasrum, Monica Dr.med. Cand.scient. Dr.med. PhD Cand.med. Cand.scient. Cand.med. Msc Cand.scient. Cand.scient. Avdelingsingeniør Helsesekretær Faglig ansvarlig Ingeniør Avdelingsingeniør Faglig ansvarlig Faglig ansvarlig Sekretær Ingeniør Ingeniør Avdelingsingeniør [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Seksjonsleder/ Professor/ Forskningsleder Mastergradstudent Forsker Postdoc Mastergradstudent Postdoc Professor emeritus Avdelingsingeniør Forskerlinjestudent Doktorgradsstipendiat Forskerlinjestudent Doktorgradsstipendiat Doktorgradsstipendiat 1. amanuensis 20 % Forsker, 1.aman.vikar Professor emeritus Senioringeniør Doktorgradsstipendiat Doktorgradsstipendiat Doktorgradsstipendiat Doktorgradsstipendiat Professor Professor emeritus Avdelingsingeniør Professor emeritus Professor [email protected] Overingeniør [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Professor Doktorgradsstipendiat Professor Postdoc Doktorgradsstipendiat Førstekonsulent Doktorgradsstipendiat Doktorgradstipendiat Overingeniør Overingeniør Side 70 av 70 [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] [email protected] Møklegaard Print Shop 69 35 49 99 - www.mprint.no

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