55 research outputs found
Mortality and QTc prolongation in opioid maintenance treatment
Dødelighet og helseproblemer knyttet til legemiddelassistert rehabilitering (LAR) er utilstrekkelig forsket pü. I det første studiet undersøkte vi dødelighet knyttet til perioden før, under og etter LAR behandling. Et norsk LAR register ble etablert og inneholdt informasjon om alle som hadde søkt LAR i Norge over en syv ürs periode, fra januar 1997 til desember 2003. Ved bruk av personnummer ble dette registeret krysset med det norske dødsürsaksregisteret til Statistisk sentralbyrü (SSB). Kun hoveddødsürsak ble benyttet.
En signifikant totalreduksjon i dødelighet ble funnet under behandling, sammenlignet med før LAR. Pü totalgruppenivü var det ingen dødelighetsforskjell mellom før- og etter-LAR gruppene, mens en tendens til kjønnsforskjell ble funnet. Etter avsluttet behandling hadde menn en signifikant økt dødelighet sammenlignet med før LAR, mens kvinner hadde en ikke-signifikant tendens til lavere dødelighet. En signifikant nedgang i dødelighet ble funnet mellom før-LAR og intensjon-om-ü-behandle-gruppene. Risiko for overdosedød ble redusert med LAR, büde for de i behandling og for intensjon-om-ü-behandle-gruppen.
Vi undersøkte ogsü forekomsten av korrigert QT (QTc) forlengelse i LAR. Mange studier har vist til en sammenheng mellom metadon og QTc forlengelse. Dette tilknyttes en type hjertearytmi kjent som torsades des pointes (TdP), som kan lede til synkope og i verste fall brü død. Vürt mül var ü undersøke forekomsten av QTc forlengelse over 500 millisekunder (ofte antatt ü vÌre terskel for TdP utvikling),
ü sammenligne metadon og buprenorfin, undersøke en potensiell dose-avhengighet, samt ü kartlegge risikofaktorer for forlenget QTc intervall.
I vür tverrsnittsstudie tok vi elektrokardiografi (EKG) av 200 LAR pasienter i Oslo. 173 av disse sto pü metadon, resten pü buprenorfin. EKG'ene ble tolket av en kardiolog, uvitende om alle pasientdetaljer. Av de 173 metadonpasientene ble ütte identifisert med QTc forlengelse over 500 millisekunder. Alle disse hadde metadondose pü 120 mg eller mer per dag. Ingen av buprenorfin-pasientene hadde QTc forlengelse. Et dose-avhengig forhold ble funnet mellom metadondose og lengden av QTc intervallet. Det ble ikke funnet noen sammenheng mellom alder, kjønn eller tid i LAR og lengden pü QTc intervallet.
Den kliniske relevansen av QTc forlengelse og hvorvidt dødsfall i LAR potensielt kunne tilskrives QTc forlengelse og ventrikulÌr arytmi ble undersøkt. Data fra det foregüende kryss-registerstudiet ble nøye gjennomgütt og dødsürsakene for pasienter i behandling analysert. 90 dødsfall hadde forekommet blant de 2382 LAR pasientene med til sammen 6450 ür i LAR. Kun fire av disse kunne muligens tilskrives ventrikulÌr arytmi. Den maksimale dødeligheten som potentielt kunne tilskrives QTc forlengelse var 0.06 dødsfall per 100 personür i LAR. Av 3850 oppstarter i LAR forekom det kun ett dødsfall under den første behandlingsmüneden.
De ütte pasientene med QTc forlengelse over 500 millisekunder i tverrsnittsstudiet ble tilbudt videre hjerteutredning og behandling. Undersøkelsene inkluderte et nytt hvileEKG, belastningsEKG, 24 timers EKG (Holter) og genetisk test for de fem mest vanlige lang QT syndrom (LQTS) mutasjonene. Syv pasienter ønsket genetisk testing. En av disse droppet etterpü ut av LAR. Seks pasienter deltok i videre hjerteutredning. Alle hadde store døgnvariasjoner i QTc intervallet og ogsü under belastning. To pasienter var heterozygote bÌrere av LQTS mutasjoner, henholdsvis i LQTS1 og LQTS2 gener. Begge hadde i anamnesen tidligere opplevd hjertesymptomer, men de hadde ikke blitt utredet for dette før deltagelse i studiet. En av dem hadde allerede byttet fra metadon til buprenorfin og startet under studiet pü en beskyttende beta-blokker. Ingen av de resterende fem pasientene, inkludert kvinnen med LQTS2 mutasjon, ønsket overgang til buprenorfin eller andre hjertebeskyttende tiltak. Trygg hjertebehandling av metadonpasienter med QTc forlengelse viste seg svÌrt utfordrende
Effects of marine mixtures of persistent organic pollutants on steroidogenesis on LH-stimulated primary Leydig cells
The ability of POPs (persistent organic pollutants) to act as endocrine disruptors and their
potential role in negative trends in male reproductive health have caused increased concern
over the last few decades. There has been an increased focus on the endocrine disrupting
capacity of environmental mixtures of pollutants, compared to earlier focus on single
compound exposure studies.
While Norwegian health authorities strongly recommend a higher consumption of fish and
fish liver oil dietary supplements because of their beneficial health effects, they have been put
forward as considerable sources of human intake of POPs.
Leydig cells are responsible for the biosynthesis of testosterone, which is essential for male
developmental and reproductive function. The predominant steroid biosynthesis Î5 pathway is
similar in pig and human. Thus, the porcine Leydig cell provides a useful model for
investigating human testicular steroidogenesis.
The aim of this study was to investigate the effects of POPs in three marine mixtures (âCodâ,
âWasteâ and âTranâ), representing different steps in the refinement process of cod liver oil
used as a dietary supplement, on steroidogenesis in LH-stimulated primary porcine Leydig
cells. The investigation of effects was performed through a holistic approach, including
exploration of hormone production and regulation of genes involved in steroidogenesis,
epigenetic and anti-oxidative mechanisms. In addition to the aspect of achieving a better
understanding of the effect of POPs in mixtures on steroidogenesis, we also compared effects
of the three mixtures. The mixtures gave three different exposure scenarios; exposure to
âCodâ mixture (POPs extracted from crude cod liver oil), âWasteâ mixture (POPs extracted
from waste from the refinement process, containing mainly non-dioxin-like POPs) and âTranâ
mixture (POPs extracted from finished cod liver oil dietary supplement).
Environmentally relevant doses of the marine mixtures of POPs had a disrupting effect on
steroidogenesis in primary LH-stimulated porcine Leydig cells. The âCodâ, âWasteâ and
âTranâ mixtures had a generally inhibitory effect on testosterone and 17β-estradiol
production. The expression pattern of genes involved in steroidogenesis was decreased
expression after exposure to all three mixtures. The decrease in gene expression could explain
5
the altered hormone production in exposed cells. There was a trend towards decreased
expression aof genes involved in epigenetics and anti-oxidative mechanisms after exposure to
the âTranâ mixture.
The fact that endocrine disrupting effects were observed also with the âTranâ mixture,
representing pollutants extracted from purified cod liver oil for human consumption, gives
reason for concern. The beneficial effects of fish consumption and intake of cod liver oil
supplements should be balanced against the increased exposure to POPs and their potential
ability to exert negative health effects. Further investigation should be carried out to elucidate
wether the endocrine disruption after âTranâ mixture exposure also occurs in vivo.Master i biomedisi
Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society
Effects of marine mixtures of persistent organic pollutants on steroidogenesis on LH-stimulated primary Leydig cells
The ability of POPs (persistent organic pollutants) to act as endocrine disruptors and their
potential role in negative trends in male reproductive health have caused increased concern
over the last few decades. There has been an increased focus on the endocrine disrupting
capacity of environmental mixtures of pollutants, compared to earlier focus on single
compound exposure studies.
While Norwegian health authorities strongly recommend a higher consumption of fish and
fish liver oil dietary supplements because of their beneficial health effects, they have been put
forward as considerable sources of human intake of POPs.
Leydig cells are responsible for the biosynthesis of testosterone, which is essential for male
developmental and reproductive function. The predominant steroid biosynthesis Î5 pathway is
similar in pig and human. Thus, the porcine Leydig cell provides a useful model for
investigating human testicular steroidogenesis.
The aim of this study was to investigate the effects of POPs in three marine mixtures (âCodâ,
âWasteâ and âTranâ), representing different steps in the refinement process of cod liver oil
used as a dietary supplement, on steroidogenesis in LH-stimulated primary porcine Leydig
cells. The investigation of effects was performed through a holistic approach, including
exploration of hormone production and regulation of genes involved in steroidogenesis,
epigenetic and anti-oxidative mechanisms. In addition to the aspect of achieving a better
understanding of the effect of POPs in mixtures on steroidogenesis, we also compared effects
of the three mixtures. The mixtures gave three different exposure scenarios; exposure to
âCodâ mixture (POPs extracted from crude cod liver oil), âWasteâ mixture (POPs extracted
from waste from the refinement process, containing mainly non-dioxin-like POPs) and âTranâ
mixture (POPs extracted from finished cod liver oil dietary supplement).
Environmentally relevant doses of the marine mixtures of POPs had a disrupting effect on
steroidogenesis in primary LH-stimulated porcine Leydig cells. The âCodâ, âWasteâ and
âTranâ mixtures had a generally inhibitory effect on testosterone and 17β-estradiol
production. The expression pattern of genes involved in steroidogenesis was decreased
expression after exposure to all three mixtures. The decrease in gene expression could explain
5
the altered hormone production in exposed cells. There was a trend towards decreased
expression aof genes involved in epigenetics and anti-oxidative mechanisms after exposure to
the âTranâ mixture.
The fact that endocrine disrupting effects were observed also with the âTranâ mixture,
representing pollutants extracted from purified cod liver oil for human consumption, gives
reason for concern. The beneficial effects of fish consumption and intake of cod liver oil
supplements should be balanced against the increased exposure to POPs and their potential
ability to exert negative health effects. Further investigation should be carried out to elucidate
wether the endocrine disruption after âTranâ mixture exposure also occurs in vivo
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