Codeine-containing medication is commonly used for pain after c-section. In most people, 10% of codeine is biotransformed into morphine by the Cytochrome P450 enzyme 2D6 (CYP2D6). Individuals who convert up to 50 fold more codeine into morphine, ultrarapid metaboizers, are at a greater risk for adverse effects. Conversely poor metabolizers, individuals who convert almost no codeine into morphine, are at risk for untreated pain. The pharmacodynamic relationship between codeine-analgesia and CYP2D6 genotype is studied for possible development of a titration model. To minimize these treatment risks, alternatives to opioids are sought. Reiki, an ancient Japanese form of healing used to treat pain and depression, has not been systematically reviewed for its efficacy in treating pain. My systematic review of Reiki literature (n=12) showed that while most trials yielded a positive result on primary outcomes, all existing Reiki studies lacked in one of the three key areas of proper patient allocation concealment, randomization or blinding which can lead to the introduction of bias. We designed a randomized controlled trial using distant Reiki for postpartum pain, taking careful steps to control for each of those three key areas. Eighty pregnant women scheduled for an elective c-section where recruited and randomly allocated to one of the two arms (n=40 Reiki and n=40 control). Women were monitored in hospital for up to three days. Visual Analogue Scores (VAS) for pain were recorded 4 times per day; and all pain medication, adverse effects and milestone recovery rates after c-section were recorded. Blood samples were taken to determine CYP2D6 genotype. We determined that distant Reiki did not reduce women’s pain; neither the measured pain nor the cumulative dose of pain medication differed between groups. Moreover, rates of recovery after c-section were also not different between the two groups. This led to the conclusion that distant Reiki was not suitable as a primary method of controlling pain after c-section. Our second study (n=45) looked for correlation between CYP2D6 genotype and effectiveness of codeine analgesia. Only a small sample of the women were genetic extremes (n=2 poor metabolizers and n=3 ultrarapid metabolizers), while most were, as expected, extensive or intermediate metabolizers. An individual examination of each of these cases provided valuable insight into patients where CYP2D6 polymorphism is clinically relevant. Two of the three ultrarapid metabolizers stopped opioid analgesia due to adverse effects, while both poor metabolizers complained that the codeine-containing medication was not providing analgesia (i.e. ineffective pain treatment). Healthcare providers need to be aware of patient response to pharmacotherapy and use this information to individualize postpartum opioid analgesia.

Codeine-containing medication is commonly used for pain after c-section. In most people, 10% of codeine is biotransformed into morphine by the Cytochrome P450 enzyme 2D6 (CYP2D6). Individuals who convert up to 50 fold more codeine into morphine, ultrarapid metaboizers, are at a greater risk for adverse effects. Conversely poor metabolizers, individuals who convert almost no codeine into morphine, are at risk for untreated pain. The pharmacodynamic relationship between codeine-analgesia and CYP2D6 genotype is studied for possible development of a titration model. To minimize these treatment risks, alternatives to opioids are sought. Reiki, an ancient Japanese form of healing used to treat pain and depression, has not been systematically reviewed for its efficacy in treating pain. My systematic review of Reiki literature (n=12) showed that while most trials yielded a positive result on primary outcomes, all existing Reiki studies lacked in one of the three key areas of proper patient allocation concealment, randomization or blinding which can lead to the introduction of bias. We designed a randomized controlled trial using distant Reiki for postpartum pain, taking careful steps to control for each of those three key areas. Eighty pregnant women scheduled for an elective c-section where recruited and randomly allocated to one of the two arms (n=40 Reiki and n=40 control). Women were monitored in hospital for up to three days. Visual Analogue Scores (VAS) for pain were recorded 4 times per day; and all pain medication, adverse effects and milestone recovery rates after c-section were recorded. Blood samples were taken to determine CYP2D6 genotype. We determined that distant Reiki did not reduce women’s pain; neither the measured pain nor the cumulative dose of pain medication differed between groups. Moreover, rates of recovery after c-section were also not different between the two groups. This led to the conclusion that distant Reiki was not suitable as a primary method of controlling pain after c-section. Our second study (n=45) looked for correlation between CYP2D6 genotype and effectiveness of codeine analgesia. Only a small sample of the women were genetic extremes (n=2 poor metabolizers and n=3 ultrarapid metabolizers), while most were, as expected, extensive or intermediate metabolizers. An individual examination of each of these cases provided valuable insight into patients where CYP2D6 polymorphism is clinically relevant. Two of the three ultrarapid metabolizers stopped opioid analgesia due to adverse effects, while both poor metabolizers complained that the codeine-containing medication was not providing analgesia (i.e. ineffective pain treatment). Healthcare providers need to be aware of patient response to pharmacotherapy and use this information to individualize postpartum opioid analgesia.

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

Postoperative Übelkeit und/oder Erbrechen (PONV: postoperative nausea and/or vomiting) stellen mit einer Inzidenz von etwa 30-80% eine häufige und für den Patienten unangenehme Nebenwirkung von Narkosen dar, die zu schweren postoperativen Komplikationen führen können und nicht unerhebliche Kosten für das Gesundheitssystem verursachen. Zur medikamentösen PONV-Prophylaxe werden u.a. die vom sog. CYP2D6-Enzym metabolisierten 5HT3A-Antagonisten verwendet. Das CYP2D6 ist ein hochpolymorphes Enzym aus der Cytochrom-P450 Familie. Mittlerweile sind ca. 80 Allele bekannt, die unterschiedliche Enzymaktivitäten repräsentieren. Man unterscheidet eine hohe Enzymaktivität beim Extensive Metabolizer (EM) vom Poor Metabolizer (PM) mit fehlender Enzymaktivität. Der Intermediate Metabolizer (IM) besitzt eine niedrige Enzymaktivität und der Ultrarapid Metabolizer (UM) hat eine sehr hohe Enzymaktivität. Ziel der vorliegenden Arbeit war die CYP2D6-Genotypisierung von PONV-Patienten, die abhängig von ihrer PONV-Risikostratifizierung eine Emesisprophylaxe erhielten oder nicht. Zur Genotypisierung wurde bei 97 Patienten das komplette CYP2D6-Gen sequenziert. Bei der Suche nach genetischen Varianten wurden auch nicht-kodierende Intronbereiche eingeschlossen. Zusätzlich wurden PCR-Assays zur Prüfung auf eventuelle CYP2D6-Duplikationen und –Deletionen angewandt. Nachfolgend wurden die ermittelten Genotypen durch ein Punktwertsystem einem Phänotyp zugeordnet. Bezüglich der Fragestellung der Wirksamkeit einer applizierten PONV-Prophylaxe in Abhängigkeit der vom Genotyp abgeleiteten individuellen Metabolisierungskapazität erfolgten statistische Gruppenanalysen nach Auftreten oder Nicht-Auftreten von PONV. Hierbei sollten ergänzende Informationen zur praktischen Anwendung im anästhesiologischen Sektor und mögliche Prädiktoren für PONV herausgearbeitet werden.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 9 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2000. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2000. / Härtill 6 uppsatser.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.

The enzyme CYP2D6 can metabolize many centrally acting drugs and endogenous neural compounds (e.g. catecholamines); it can also inactivate neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1,2,3,4-tetrahydroisoquinoline (TIQ) and β-carbolines that have been associated with Parkinson’s disease (PD). CYP2D6 is ideally situated in the brain to inactivate these neurotoxins. The CYP2D6 gene is also highly polymorphic, which leads to large variation in substrate metabolism. Furthermore, CYP2D6 genetically poor metabolizers are known to be at higher risk for developing PD, a risk that increases with exposure to pesticides. Conversely, smokers have a reduced risk for PD and smokers are suggested to have higher brain CYP2D6 levels. Our studies furthered the characterization and involvement of CYP2D6 in neuroprotection against PD. METHODS: We investigated the effects of CYP2D6 inhibition on MPP+-induced cell death in SH-SHY5Y human neuroblastoma cells. We compared levels of brain CYP2D6, measured by western blotting, between human smokers and non-smokers, between African Green monkeys treated with saline or nicotine, and between PD cases and controls. In addition, we assessed changes in human brain CYP2D6 expression with age. RESULTS: Blocking CYP2D6 activity in SH-SY5Y cells with four diverse inhibitors significantly increased MPP+-induced neurotoxicity. Smokers have higher brain CYP2D6 compared to non-smokers. In monkeys, basal expression of CYP2D6 varied across brain regions and was increased by chronic nicotine treatment in select regions (notably the basal ganglia) and specific cell types. Expression of human brain CYP2D6 increased from fetal to 80 years of age in the frontal cortex; the influence of age on CYP2D6 expression was brain region specific. Compared to age-matched controls, PD cases had ~40% lower CYP2D6 levels in the frontal cortex, cerebellum and hippocampus consistent with lower CYP2D6 increasing the risk for PD. In the caudate and substantia nigra, CYP2D6 levels were similar between PD case and controls using Western blotting. This is likely due to the increase in CYP2D6-expressing astrocytes and much higher cellular CYP2D6 in PD affected areas as observed with immunocytochemical staining. CONCLUSIONS: Brain CYP2D6 can meaningfully inactivate neurotoxins, and it can be increased by nicotine in brain regions of interest to PD. These findings support the contention that higher brain CYP2D6 is protective and lower levels may contribute to increased risk for PD.