Mortality and QTc prolongation in opioid maintenance treatment

Dødelighet og helseproblemer knyttet til legemiddelassistert rehabilitering (LAR) er utilstrekkelig forsket på. 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 års periode, fra januar 1997 til desember 2003. Ved bruk av personnummer ble dette registeret krysset med det norske dødsårsaksregisteret til Statistisk sentralbyrå (SSB). Kun hoveddødsårsak ble benyttet. En signifikant totalreduksjon i dødelighet ble funnet under behandling, sammenlignet med før LAR. På totalgruppenivå 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-å-behandle-gruppene. Risiko for overdosedød ble redusert med LAR, både for de i behandling og for intensjon-om-å-behandle-gruppen. Vi undersøkte også 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 brå død. Vårt mål var å undersøke forekomsten av QTc forlengelse over 500 millisekunder (ofte antatt å være terskel for TdP utvikling), å sammenligne metadon og buprenorfin, undersøke en potensiell dose-avhengighet, samt å kartlegge risikofaktorer for forlenget QTc intervall. I vår tverrsnittsstudie tok vi elektrokardiografi (EKG) av 200 LAR pasienter i Oslo. 173 av disse sto på metadon, resten på buprenorfin. EKG'ene ble tolket av en kardiolog, uvitende om alle pasientdetaljer. Av de 173 metadonpasientene ble åtte identifisert med QTc forlengelse over 500 millisekunder. Alle disse hadde metadondose på 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 på QTc intervallet. Den kliniske relevansen av QTc forlengelse og hvorvidt dødsfall i LAR potensielt kunne tilskrives QTc forlengelse og ventrikulær arytmi ble undersøkt. Data fra det foregående kryss-registerstudiet ble nøye gjennomgått og dødsårsakene for pasienter i behandling analysert. 90 dødsfall hadde forekommet blant de 2382 LAR pasientene med til sammen 6450 år i LAR. Kun fire av disse kunne muligens tilskrives ventrikulær arytmi. Den maksimale dødeligheten som potentielt kunne tilskrives QTc forlengelse var 0.06 dødsfall per 100 personår i LAR. Av 3850 oppstarter i LAR forekom det kun ett dødsfall under den første behandlingsmåneden. De åtte 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 etterpå ut av LAR. Seks pasienter deltok i videre hjerteutredning. Alle hadde store døgnvariasjoner i QTc intervallet og også under belastning. To pasienter var heterozygote bærere 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 på 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 svært 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 Δ5 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 (“Cod”, “Waste” and “Tran”), 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 “Cod” mixture (POPs extracted from crude cod liver oil), “Waste” mixture (POPs extracted from waste from the refinement process, containing mainly non-dioxin-like POPs) and “Tran” 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 “Cod”, “Waste” and “Tran” 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 “Tran” mixture. The fact that endocrine disrupting effects were observed also with the “Tran” 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 “Tran” mixture exposure also occurs in vivo.Master i biomedisi

2 kirja J. J. Mascov`ile, Hafnia

http://tartu.ester.ee/record=b1885810~S1*es

Norske retspsykiatriske erklæringer 1930-53

See abstract in article

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 Δ5 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 (“Cod”, “Waste” and “Tran”), 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 “Cod” mixture (POPs extracted from crude cod liver oil), “Waste” mixture (POPs extracted from waste from the refinement process, containing mainly non-dioxin-like POPs) and “Tran” 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 “Cod”, “Waste” and “Tran” 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 “Tran” mixture. The fact that endocrine disrupting effects were observed also with the “Tran” 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 “Tran” mixture exposure also occurs in vivo