1. No category

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
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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.
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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
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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
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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..
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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,
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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
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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.
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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,
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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).
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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
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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.
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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.
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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.
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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
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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
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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:
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Asberg A, Midtvedt K, van GM, Storset E, Bremer S, Bergan S, Jelliffe R, Hartmann A, Neely
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Haug JB, Reikvam A: WHO defined daily doses versus hospital-adjusted defined daily doses:
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Riise J, Ørstavik Ø, Qvigstad E, Dahl CP, Osnes JB, Skomedal S, Levy FO, Krobert KA:
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Selmer R, Blix HS, Landmark K, Reikvam Å: Choice of initial antihypertensive drugs and
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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
bermua@ous-hf.no
Lederassistent
mlarsen@ous-hf.no
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
igusta@ous-hf.no
odbroe@ous-hf.no
margrl@ous-hf.no
ggadehol@ous-hf.no
uxmist@ous-hf.no
hegkra@ous-hf.no
knorda@ous-hf.no
stirog@ous-hf.no
inhetv@ous-hf.no
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
sbergan@ous-hf.no
aan@ous-hf.no
peclas@ous-hf.no
sirifo@ous-hf.no
sveinj@ous-hf.no
amgott@ous-hf.no
rolkla@ous-hf.no
uxkrmj@ous-hf.no
uxmuil@ous-hf.no
uxniud@ous-hf.no
uxthcb@ous-hf.no
nvethe@ous-hf.no
Klinisk farmakologi - Driftsseksjon
Heesch, Bente
Bioingeniør
Seksjonsleder
uxhebc@ous-hf.no
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
tskogset@ous-hf.no
uxabse@ous-hf.no
karekh@ous-hf.no
borgod@ous-hf.no
agryvil@ous-hf.no
shotvedt@ous-hf.no
uxetis@ous-hf.no
aquiogue@ous-hf.no
lisskr@ous-hf.no
uxyoas@ous-hf.no
Bioingeniør
Bioingeniør
Bioingeniør
Enhetsleder
Bioingeniør
Bioingeniør
Helsesekretær
Bioingeniør
malusc@ous-hf.no
ekl@ous-hf.no
gerrin@ous-hf.no
beritho@ous-hf.no
kkhosh@ous-hf.no
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
uxhaoh@ous-hf.no
sukosm@ous-hf.no
hege.gilbo.bakke@ous-hf.no
inhbre@ous-hf.no
uxfael@ous-hf.no
uxevhi@ous-hf.no
renaha@ous-hf.no
uxtrls@ous-hf.no
uxskrm@ous-hf.no
uxmkum@ous-hf.no
uxtron@ous-hf.no
uxilor@ous-hf.no
Seksjonsleder
Studiesykepleier/koordinator
Studiesykepleier/koordinator
Studiesykepleier
haskhi@ous-hf.no
groboe@ous-hf.no
Seksjonsleder/
overlege
Spesialrådgiver
Provisorfarmasøyt
pewjoh@ous-hf.no
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
ceclis@ous-hf.no
uxfmyr@ous-hf.no
ahalsten@ous-hf.no
uxlsam@ous-hf.no
lbr@ous-hf.no
antime@ous-hf.no
twesterg@ous-hf.no
ankeek@ous-hf.no
hildeth@ous-hf.no
agroen@ous-hf.no
grohav@ous-hf.no
tholager@ous-hf.no
hlindl@ous-hf.no
randimy@ous-hf.no
uxkiyh@ous-hf.no
inielsen@ous-hf.no
hilde.norden@ous-hf.no
lillian.reiter@ous-hf.no
uxsolv@ous-hf.no
hstenber@ous-hf.no
p.j.hemmersbach@farmasi.uio.no
limaam@ous-hf.no
andeas@ous-hf.no
lilbro@ous-hf.no
yvedeh@ous-hf.no
licaha@ous-hf.no
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
kjmhel@ous-hf.no
hoanne@ous-hf.no
inghul@ous-hf.no
aabrje@ous-hf.no
lundka@ous-hf.no
hemale@ous-hf.no
serzep@ous-hf.no
cadesi@ous-hf.no
camsle@ous-hf.no
esszan@ous-hf.no
rahiaa@ous-hf.no
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
f.o.levy@medisin.uio.no
Overingeniør
iwona.gutowskaschiander@medisin.uio.no
tor.skomedal@medisin.uio.no
s.j.sollie@medisin.uio.no
hege.thoresen@medisin.uio.no
vegard.tjomsland@medisin.uio.no
i.h.tveteraas@medisin.uio.no
heidi.tommerdal@medisin.uio.no
andreahu@studmed.uio.no
oivind.orstavik@medisin.uio.no
v.h.arskog@medisin.uio.no
monica.aasrum@medisin.uio.no
Professor
Doktorgradsstipendiat
Professor
Postdoc
Doktorgradsstipendiat
Førstekonsulent
Doktorgradsstipendiat
Doktorgradstipendiat
Overingeniør
Overingeniør
Side 70 av 70
henriean@student.farmasi.uio.no
k.w.andressen@medisin.uio.no
trond.bach@medisin.uio.no
MBJO@IBV.uio.no
i.j.brusevold@medisin.uio.no
thoralf.christoffersen@medisin.uio.no
marie.dahl@medisin.uio.no
k.s.dugstad@studmed.uio.no
Kristi.henjum@medisin.uio.no
h.g.hiis@studmed.uio.no
Hussain.rizwan@medisin.uio.no
c.b.jendresen@medisin.uio.no
m.k.gjertsen@medisin.uio.no
k.a.krobert@medisin.uio.no
k.h.landmark@labmed.uio.no
e.o.magnussen@medisin.uio.no
ornella.manfra@medisin.uio.no
silja.meier@medisin.uio.no
caroline.melsom@medisin.uio.no
l.r.moltzau@medisin.uio.no
lars.nilsson@medisin.uio.no
j.b.osnes@medisin.uio.no
renukaben.patel@medisin.uio.no
asmund.reikvam@medisin.uio.no
d.l.sandnes@medisin.uio.no
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