Publications by authors named "Olav Spigset"

253 Publications

Genetic variants associated with cardiometabolic abnormalities during treatment with selective serotonin reuptake inhibitors: a genome-wide association study.

Pharmacogenomics J 2021 Apr 6. Epub 2021 Apr 6.

NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.
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http://dx.doi.org/10.1038/s41397-021-00234-8DOI Listing
April 2021

Legemiddelavvik hos pasienter innlagt i sykehus.

Tidsskr Nor Laegeforen 2021 Mar 16;141(5). Epub 2021 Mar 16.

Background: Errors in the use and administration of medicinal drugs are not uncommon. There is little up-to-date information available on medication errors in Norwegian hospitals.

Material And Method: It is compulsory to report all adverse events internally at St Olav's Hospital via an electronic form. For the three-year period 2015-2017 we have reviewed all medication errors in the database where the reports are stored and compared them with figures from a similar study conducted in the period 2002-2006.

Results: Altogether 1604 medication errors were registered, distributed among 1587 reports. Dosing errors were most common (n=1070; 67 %), followed by administration of another drug than prescribed (n=175; 11 %). Most errors were of an insignificant or low degree of severity. There was a preponderance of reporting among the youngest and the oldest patients. 79 % of the errors were reported by nurses. Inattention/forgetfulness (15 %), stress/high workload (12 %), sloppy documentation in drug charts (10 %) and erroneous/unclear prescribing (10 %) were reported as the most frequent causes.

Interpretation: The number of reports of medication errors is increasing, but the extent of underreporting is uncertain. The types of errors and their distribution are similar to previous studies. The underlying causes are also well known; the challenge is to prevent these situations from arising.
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http://dx.doi.org/10.4045/tidsskr.20.0664DOI Listing
March 2021

Transfer of triptans into human breast milk and estimation of infant drug exposure through breastfeeding.

Basic Clin Pharmacol Toxicol 2021 Mar 17. Epub 2021 Mar 17.

Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.

Clinical data on the transfer of triptans into human breast milk remain scarce. In a lactation study including 19 breastfeeding women with migraine, we examined the excretion of six different triptans into milk. Following intake of a single dose, each participant collected seven breast milk samples at predefined intervals up to 24 hours after dose. Triptan concentrations in milk were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Infant drug exposure was estimated by calculating the relative infant dose (RID). Twenty-two breast milk sample sets were obtained for sumatriptan (n = 8), rizatriptan (n = 5), zolmitriptan (n = 4), eletriptan (n = 3), almotriptan (n = 1) and naratriptan (n = 1). Based on the average concentration in milk throughout the day, estimated mean RIDs (with range in parenthesis) were as follows: eletriptan 0.6% (0.3%-0.8%), sumatriptan 0.7% (0.2%-1.8%), rizatriptan 0.9% (0.3%-1.4%), almotriptan 1.8% (-), zolmitriptan 2.1% (0.7%-5.3%) and naratriptan 5.0% (-). Infant drug exposure through breastfeeding appears to be low and indicates that use of the triptans in this study is compatible with breastfeeding. Naratriptan may not be first choice in breastfeeding mothers initiating triptans during the neonatal period.
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http://dx.doi.org/10.1111/bcpt.13579DOI Listing
March 2021

Phosphatidylethanol as Blood Biomarker of Alcohol Consumption in Early Pregnancy: An Observational Study in 4,067 Pregnant Women.

Alcohol Clin Exp Res 2021 Feb 15. Epub 2021 Feb 15.

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology - NTNU, Trondheim, Norway.

Background: The teratogenic effects of alcohol are well documented, but there is a lack of screening methods to detect alcohol use during pregnancy. Phosphatidylethanol 16:0/18:1 (PEth) is a specific and sensitive biomarker reflecting alcohol intake up to several weeks after consumption. The aim of this study was to investigate the prevalence of positive PEth values as an indicator of early prenatal alcohol exposure in a general population of pregnant women.

Methods: Rhesus typing is routinely performed in Norway in all pregnancies around gestational week 12. Rhesus-negative women have an additional test taken around week 24. Blood samples submitted to St. Olav University Hospital in Trøndelag, Norway, for Rhesus typing during the period September 2017 to October 2018 were collected. A total of 4,533 whole blood samples from 4,067 women were analyzed for PEth (limit of quantification of 0.003 µM).

Results: Fifty-eight women had a positive PEth sample. Of these, 50 women were positive around gestational week 12, 3 women were positive around week 24, and in 5 cases, the timing was unknown. There were no significant differences in proportions of women with positive PEth values related to age, or rural versus urban residency.

Conclusion: In an unselected pregnant population in Norway, 1.4% had a positive PEth sample around gestational week 12, whereas 0.4% had a positive sample around week 24. The use of PEth as an alcohol biomarker should be further investigated as a diagnostic tool in the antenatal setting.
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http://dx.doi.org/10.1111/acer.14577DOI Listing
February 2021

Antidepressant transfer into amniotic fluid, umbilical cord blood & breast milk: A systematic review & combined analysis.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Apr 2;107:110228. Epub 2021 Jan 2.

Department of Clinical Pharmacology, St Olav University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Objective: Data regarding the ability of antidepressants to enter fetal, newborn and infant fluids have become gradually available, but mechanisms of antidepressant transfer remain poorly understood. Here we calculated penetration ratios in an array of matrices from combined samples of pregnant/breastfeeding women taking antidepressants.

Method: We performed a systematic literature search of PubMed and EMBASE to identify studies with concentrations of antidepressants from maternal blood, amniotic fluid, umbilical cord blood and/or breast milk. Penetration ratios were calculated by dividing the concentrations in amniotic fluid, umbilical cord plasma or breast milk by the maternal plasma concentration. When data from multiple studies were available, we calculated combined penetration ratios, weighting the study mean by study size.

Results: Eighty-five eligible studies were identified. For amniotic fluid, the highest penetration ratios were estimated for venlafaxine (mean 2.77, range 0.43-4.70 for the active moiety) and citalopram (mean 2.03, range 0.35-6.97), while the lowest ratios were for fluvoxamine (mean 0.10) and fluoxetine (mean 0.11, range 0.02-0.20 for the active moiety). For umbilical cord plasma, nortriptyline had the highest ratio (mean 2.97, range 0.25-26.43) followed by bupropion (mean 1.14, range 0.3-5.08). For breast milk, the highest ratios were observed for venlafaxine (mean 2.59, range 0.85-4.85), mianserin (mean 2.22, range 0.80-3.64) and escitalopram (mean 2.19, range 1.68-3.00).

Conclusion: We observed considerable variability across antidepressants regarding their ability to enter fetal, newborn and infant fluids. Measuring antidepressant concentrations in a maternal blood sample can provide a reliable estimate of fetal/infant exposure, although further evidence for concentration-dependent effects is required.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882033PMC
April 2021

Efficacy of Self-Administered Intranasal Oxytocin on Alcohol Use and Craving After Detoxification in Patients With Alcohol Dependence. A Double-Blind Placebo-Controlled Trial.

Alcohol Alcohol 2020 Dec 23. Epub 2020 Dec 23.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology - NTNU, Trondheim, Norway.

Aims: The aim of this study was to assess the efficacy of self-administered intranasal oxytocin on alcohol dependence after detoxification.

Methods: In a double-blind, randomized, placebo-controlled trial, 38 patients fulfilling the criteria for ICD-10 diagnosis of alcohol dependence received either 8 IU oxytocin or placebo at their own discretion up to thrice daily for 4 weeks, after completing detoxification. Primary outcome was alcohol intake specified as the amount of alcohol consumed, the number of days to relapse into alcohol use and the proportion of subjects relapsing. Secondary outcomes were self-reported symptoms of craving, sleep and mental distress.

Results: There were no significant differences between the oxytocin group and the placebo group in daily alcohol intake in total (mean 1.3 ± 2.9 vs. 2.0 ± 5.0 units; P = 0.63) or on drinking days (mean 8.4 ± 2.7 vs. 7.7 ± 6.0 units; P = 0.76), in the number of days until relapse (P = 0.91) or in the proportion of subjects relapsing (37.5 vs. 41.2%; P = 0.84). Neither were there any statistically significant differences in any other outcomes, except a larger decrease in self-reported nervousness in the oxytocin group (P = 0.022).

Conclusion: The results were inconclusive as to whether intranasal oxytocin reduced the time to relapse, degree of craving or total amount of alcohol consumed after detoxification. However, the oxytocin group had a larger decrease in self-reported nervousness.
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http://dx.doi.org/10.1093/alcalc/agaa133DOI Listing
December 2020

The relationship between oxytocin blood concentrations and antidepressants over pregnancy and the postpartum.

Prog Neuropsychopharmacol Biol Psychiatry 2020 Dec 18;109:110218. Epub 2020 Dec 18.

Psychology, Murdoch University, Australia.

Antidepressant treatment of perinatal depression is increasingly common and accepted in clinical guidelines. It has been suggested that serotonergic antidepressants may effect changes in the oxytocinergic system, including oxytocin levels, and that this may be one of the beneficial mechanisms of action for these drugs. Furthermore, oxytocin has been associated with the quality of the parent-child relationship, which may be important in treatment of perinatal depression. This study will explore if there is a relationship between antidepressant use over the perinatal period and oxytocin levels. Data from a pregnancy cohort study are used from 279 women across three groups: women taking antidepressants in pregnancy (n = 48), women with untreated depression (n = 31) and healthy control women (n = 200). Data included antidepressant use, maternal depression and oxytocin plasma concentrations in pregnancy and up to 12 months postpartum. We found that concurrent oxytocin blood concentrations were not associated with perinatal antidepressant use. However, oxytocin blood concentrations increased more steeply in those on antidepressants across the perinatal period compared to control women. A steeper increase for Selective Serotonergic Reuptake Inhibitors was observed, however, this effect was on the boarder of statistical significance. In conclusion, although antidepressant use and oxytocin was not associated at any time point, women taking antidepressants during pregnancy had larger increases in oxytocin over the perinatal period. Future research could examine specific agents and class of antidepressant and the relationship to parenting.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110218DOI Listing
December 2020

Antidepressant exposure in pregnancy and child sensorimotor and visuospatial development.

J Psychiatr Res 2020 Nov 25. Epub 2020 Nov 25.

Psychology, Murdoch University, Australia.

Motor development underlies many aspects of education and learning. There has been uncertainty about the impact of exposure of antidepressant medication in pregnancy on child motor outcomes. This paper examines whether exposure to antidepressants in utero increases the risk of poorer motor development in two areas: sensorimotor and visuospatial processing. Data were obtained from 195 women and children across 3 groups: women with untreated depression in pregnancy, women treated with antidepressants and control women. Data were collected across pregnancy, postpartum and until 4 years for mother and child. Maternal depression was established at baseline with the Structured Clinical Interview for DSM-IV. Antidepressant exposure, including type, dose and timing, was measured through repeated self-report across pregnancy and the postpartum, medical records at delivery and in cord blood samples collected at delivery. Child sensorimotor and visuospatial outcomes were assessed at 4 years of age with four subtests from the NEPSY-II. Our study found for sensorimotor development, visuomotor precision completion time was associated with better performance for antidepressant-exposed children compared to those with mothers with untreated depression. Yet another measure of sensorimotor development, motor manual sequences, was poorer in those exposed to antidepressants. One subtest for visuospatial processing, block construction, was associated with poorer performance in antidepressant-exposed children who had poor neonatal adaptation and those exposed to a higher dose of antidepressant. These findings suggest an inconsistent association between sensorimotor development and antidepressant use in pregnancy. However, the findings for visuospatial processing would support further exploration of antidepressant associated poor neonatal adaption and later motor development.
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http://dx.doi.org/10.1016/j.jpsychires.2020.11.035DOI Listing
November 2020

Effect of Sleeve Gastrectomy on Buprenorphine Pharmacokinetics: A Planned Case Observation.

Clin Ther 2020 11 25;42(11):2232-2237. Epub 2020 Sep 25.

Department of Clinical Pharmacology, Clinic of Laboratory Medicine, St. Olav University Hospital, Trondheim, Norway; Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.

Purpose: Bariatric surgery may affect the absorption and metabolism of drugs by various mechanisms. We present a planned case observation of a patient treated with sublingual buprenorphine in an opioid maintenance treatment program, and the observed changes in buprenorphine pharmacokinetics following gastric sleeve surgery.

Methods: Serial blood samples during a dose interval of 24 hours were obtained approximately 1 year preoperatively as well as 1 week, 1 month and 12 months postoperatively and key pharmacokinetic variables were calculated.

Findings: The systemic exposure of buprenorphine (AUC) was relatively stable from the preoperative sampling to 1 week postoperatively (-6.3%), but declined markedly at 1 month (-43%) and 12 months (-42%) postoperatively. The maximum concentration of buprenorphine almost doubled at 1 week postoperatively before returning to baseline values 1 month and 12 months postoperatively.

Implications: This case observation indicates that after sleeve gastrectomy, the systemic exposure of sublingual buprenorphine can decrease. Clinicians should be aware of the possibility of loss of effect and emerging abstinence symptoms following sleeve gastrectomy. We recommend monitoring the patient closely for abstinence symptoms postoperatively and considering measuring serum concentrations of buprenorphine pre- and postoperatively.
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http://dx.doi.org/10.1016/j.clinthera.2020.08.016DOI Listing
November 2020

Stability of Phosphatidylethanol 16:0/18:1 in Freshly Drawn, Authentic Samples from Healthy Volunteers.

J Anal Toxicol 2021 Apr;45(4):417-421

Department of Clinical Pharmacology, St. Olavs Hospital, 7006 Trondheim, Norway.

Due to its specificity, phosphatidylethanol (PEth) 16:0/18:1 has gained increased popularity as a marker for high alcohol consumption in recent years. As conflicting results regarding the stability of PEth 16:0/18:1 in whole blood have been published, there are still uncertainties related to optimum handling, transport and storage of blood samples for the analysis of PEth 16:0/18:1. A stability study where whole blood samples were drawn from healthy volunteers, who had ingested alcohol, is presented. The samples were collected in tubes with ethylenediamine tetraacetic acid (EDTA) and heparin as additives and stored under standardized conditions within 1 h of blood sampling. Storage times were 28 days in ambient temperature and at 4-8°C, and 90 days at -20°C and -80°C. All samples were analyzed regularly during the storage periods. PEth 16:0/18:1 concentrations were stable (defined as < 15% decrease compared with baseline values) at all temperatures up to 28 days, independent of additive. After 90 days of storage at -20°C, the mean concentrations had decreased by 18.8% in EDTA tubes and by 13.8% in heparin tubes. At -80°C, the concentrations were stable throughout the 90-day period. The present study shows that in samples containing PEth formed in vivo, PEth 16:0/18:1 is stable for 28 days irrespective of storage temperature. During long-term storage, samples should be stored at -80°C.
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http://dx.doi.org/10.1093/jat/bkaa082DOI Listing
April 2021

Correction to: Learning the effects of psychotropic drugs during pregnancy using real‑world safety data: a paradigm shift toward modern pharmacovigilance.

Int J Clin Pharm 2021 Feb;43(1):280

PharmacoEpidemiology and Drug Safety Research Group, School of Pharmacy, and PharmaTox Strategic Research Initiative, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.

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http://dx.doi.org/10.1007/s11096-020-01104-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878202PMC
February 2021

Enantiomeric separation and quantification of R/S-amphetamine in serum using semi-automated liquid-liquid extraction and ultra-high performance supercritical fluid chromatography-tandem mass spectrometry.

Drug Test Anal 2020 Sep 16;12(9):1344-1353. Epub 2020 Jul 16.

Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.

The amphetamine molecule contains a chiral center and its enantiomers exhibit differences in pharmacological effects, with the S-enantiomer mediating most of the central nervous system stimulating activity. The majority of prescribed amphetamine consists of the pure S-enantiomer, but therapeutic formulations containing the R-enantiomer in various proportions are also available. Illegal amphetamine remains available mainly as a racemic mixture of the R- and S-enantiomers. To distinguish between legal and illegal consumption of amphetamine a method for enantiomeric separation and quantification of R/S-amphetamine in serum was developed and validated using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS). Sample preparation prior to UHPSFC-MS/MS analysis was performed by a semi-automated liquid-liquid extraction method. The UHPSFC-MS/MS method used a Chiralpak AD-3 column with a mobile phase consisting of CO and 0.1% ammonium hydroxide in 2-propanol/methanol (50/50, v/v). The injection volume was 2 μL and run time was 4 minutes. MS/MS detection was performed with positive electrospray ionization and two multiple reaction monitoring transitions (m/z 136.1 > 119.0 and m/z 136.1 > 91.0). The calibration range was 12.5-1,000 nM for each analyte. The between-assay relative standard deviations were in the range of 1.3-3.0%. Recovery was 73% and matrix effects ranged from 95 to 100% when corrected with internal standard. After development and validation, the method has been successfully implemented in our laboratory for both separation and quantification of R/S-amphetamine and has proved to be a reliable and useful tool for distinguishing intake of R- and S-amphetamine in authentic patient samples.
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http://dx.doi.org/10.1002/dta.2879DOI Listing
September 2020

Association between low body weight and cytochrome P-450 enzyme activity in patients with anorexia nervosa.

Pharmacol Res Perspect 2020 06;8(3):e00615

Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.

Very little is known to which extent severe underweight could affect cytochrome P-450 (CYP) enzyme activity. In this study, 24 patients with anorexia nervosa at two occasions ingested single oral doses of five test drugs known to be metabolized by CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. A mixed model analysis was used to evaluate the effect of changes in body mass index (BMI) on the metabolic activities of these enzymes. The primary end point was the change in drug/metabolite ratio of each of the test drugs per kg/m change in BMI. With increasing BMI, the metabolic activity of CYP3A4 decreased (change in the CYP3A4 drug/metabolite ratio per unit change in BMI = 0.056; 95% confidence interval [CI] 0.011 to 0.102; P = .017). For CYP1A2, increasing BMI increased the metabolic activity with borderline significance (change in the CYP1A2 drug/metabolite ratio per unit change in BMI = -0.107; CI -0.220 to 0.005; P = .059). For CYP2C9, CYP2C19, and CYP2D6, no significant changes were seen. The clinical impact of these findings for drug treatment in patients with anorexia nervosa and other severely underweight patients needs to be further studied by examining the pharmacokinetics of specific drugs. This might be particularly relevant for drugs metabolized by CYP1A2 and/or CYP3A4.
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http://dx.doi.org/10.1002/prp2.615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290083PMC
June 2020

Retrospective screening of synthetic cannabinoids, synthetic opioids and designer benzodiazepines in data files from forensic post mortem samples analysed by UHPLC-QTOF-MS from 2014 to 2018.

Forensic Sci Int 2020 Jun 3;311:110274. Epub 2020 Apr 3.

Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden; National Forensic Centre, Drug Unit, Linköping, Sweden.

The introduction of new psychoactive substances (NPS) on the illicit drug market has led to major challenges for the analytical laboratories. Keeping screening methods up to date with all relevant drugs is hard to achieve and the risk of missing important findings in biological samples is a matter of concern. Aiming for an extended retrospective data analysis, diagnostic fragment ions from synthetic cannabinoids (n=251), synthetic opioids (n=88) and designer benzodiazepines (n=26) not included in our original analytical method were obtained from the crowdsourced database HighResNPS.com and converted to a personalized library in a format compatible with the analytical instrumentation. Data files from the analysis of 1314 forensic post mortem samples with an Agilent 6540 ultra high pressure liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) performed in our laboratory from January 2014 to December 2018 were retrieved and retrospectively processed with the new personalized library. Potentially positive findings were grouped in two: The most confident findings contained MS/MS data for library match (category 1) whereas the less confident findings lacked such data (category 2). Five new category 1 findings were identified: Flubromazepam in two data files from 2015 and 2016, respectively, phenibut (4-amino-3-phenylbutyric acid) in one data file from 2015, fluorofentanyl in one data file from 2016 and cyclopropylfentanyl in one data file from 2018. Retention time matches with reference standards further strengthened these findings. A list of 35 presumably positive category 2 findings was generated. Of these, only one finding of phenibut was considered plausible after checking retention times and signal-to-noise ratios. This study shows that new compounds can be detected retrospectively in data files from QTOF-MS using an updated library containing diagnostic fragment ions. Automatic screening procedures can be useful, but a manual re-evaluation of positive findings will always be necessary.
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http://dx.doi.org/10.1016/j.forsciint.2020.110274DOI Listing
June 2020

The impact of pregnancy on the pharmacokinetics of antidepressants: a systematic critical review and meta-analysis.

Expert Opin Drug Metab Toxicol 2020 May 10;16(5):431-440. Epub 2020 Apr 10.

Department of Clinical Pharmacology, St Olav University Hospital, Trondheim, Norway.

: Pregnancy-related physiological changes exert a crucial impact on the pharmacokinetics of antidepressants; however, the current evidence presents inconsistencies. A clearer understanding of pregnancy-related effects on antidepressant disposition may facilitate the development of guidelines for appropriate dose adjustments during the course of pregnancy based on therapeutic drug monitoring.: We systematically reviewed studies comparing antidepressant levels in the same individuals during pregnant and non-pregnant states. Using dose-adjusted plasma concentration measurements, we estimated alteration ratios between the 3rd trimester and baseline (before or after pregnancy). Additionally, we performed a meta-analysis for changes in dose-adjusted concentrations to estimate mean differences.: Data for several antidepressants display clear alteration patterns during pregnancy. On the basis of the alteration ratios trimipramine, fluvoxamine, and nortriptyline show a prominent decrease in dose-adjusted levels, especially in the 3rd trimester. Clomipramine, imipramine, citalopram, and paroxetine show smaller decreases in dose-adjusted concentrations in the third trimester. For escitalopram, venlafaxine and fluoxetine, changes are considered negligible. For sertraline, there was a tendency toward increased dose-adjusted concentrations in pregnancy. Available evidence suffers from major limitations and factors affecting pharmacokinetics have been insufficiently addressed. Further research is required to promote knowledge on pregnancy effects on antidepressant pharmacokinetics.
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http://dx.doi.org/10.1080/17425255.2020.1750598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323120PMC
May 2020

Actigraphy assessment of motor activity and sleep in patients with alcohol withdrawal syndrome and the effects of intranasal oxytocin.

PLoS One 2020 13;15(2):e0228700. Epub 2020 Feb 13.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology-NTNU, Trondheim, Norway.

Background And Aims: The alcohol withdrawal syndrome increases autonomic activation and stress in patients during detoxification, leading to alterations in motor activity and sleep irregularities. Intranasal oxytocin has been proposed as a possible treatment of acute alcohol withdrawal. The aim of the present study was to explore whether actigraphy could be used as a tool to register symptoms during alcohol detoxification, whether oxytocin affected actigraphy variables related to motor activity and sleep compared to placebo during detoxification, and whether actigraphy-recorded motor function during detoxification was different from that in healthy controls.

Methods: This study was a part of a randomized, double blind, placebo-controlled trial in which 40 patients with alcohol use disorder admitted for acute detoxification were included. Of these, 20 received insufflations with intranasal oxytocin and 20 received placebo. Outcomes were actigraphy-recorded motor activity during 5-hour sequences following the insufflations and a full 24-hour period, as well as actigraphy-recorded sleep. Results were related to clinical variables of alcohol intake and withdrawal, including self-reported sleep. Finally, the actigraphy results were compared to those in a group of 34 healthy individuals.

Results: There were no significant differences between the oxytocin group and the placebo group for any of actigraphy variables registered. Neither were there any correlations between actigraphy-recorded motor function and clinical symptoms of alcohol withdrawal, but there was a significant association between self-reported and actigraphy-recorded sleep. Compared to healthy controls, motor activity during alcohol withdrawal was lower in the evenings and showed increased variability.

Conclusion: Intranasal oxytocin did not affect actigraphy-recorded motor activity nor sleep in patients with acute alcohol withdrawal. There were no findings indicating that actigraphy can be used to evaluate the degree of withdrawal symptoms during detoxification. However, patients undergoing acute alcohol withdrawal had a motor activity pattern different from than in healthy controls.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228700PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018062PMC
May 2020

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study.

Eur J Clin Pharmacol 2020 May 15;76(5):673-683. Epub 2020 Jan 15.

Department of Internal Medicine, Diakonhjemmet Hospital, PO BOX 23, Vinderen, N-0319, Oslo, Norway.

Purpose: The β-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI).

Methods: We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200 mg/day within 2 months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up.

Results: According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p < 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p < 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2 bpm, p < 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups.

Conclusion: Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.
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http://dx.doi.org/10.1007/s00228-020-02832-0DOI Listing
May 2020

The effect of antenatal depression and antidepressant treatment on placental tissue: a protein-validated gene expression study.

BMC Pregnancy Childbirth 2019 Dec 5;19(1):479. Epub 2019 Dec 5.

Department of Women's and Children's Health, Uppsala University, 751 85, Uppsala, Sweden.

Background: Antenatal depression affects 10-20% of pregnant women. Around 2-4% of European pregnant women use antidepressant treatment, most commonly selective serotonin reuptake inhibitors (SSRIs). Poor pregnancy outcomes, such as preterm birth and low birth weight, have been described in women with antenatal depression and in pregnant women on SSRI treatment. However, the effects of antenatal depression and antidepressant treatment on the placenta are largely unknown. The aim of this work was to compare placental gene and protein expression in healthy women, women with untreated antenatal depression and women on antidepressant treatment during pregnancy.

Methods: Placental samples from 47 controls, 25 depressed and 45 SSRI-treated women were analysed by means of qPCR using custom-designed TaqMan low-density arrays (TLDAs) for 44 genes previously known to be involved in the pathophysiology of depression, and expressed in the placenta. Moreover, placental protein expression was determined by means of immunohistochemistry in 37 healthy controls, 13 women with untreated depression and 21 women on antidepressant treatment. Statistical comparisons between groups were performed by one-way ANOVA or the Kruskal-Wallis test.

Results: Nominally significant findings were noted for HTR1A and NPY2R, where women with untreated depression displayed higher gene expression than healthy controls (p < 0.05), whereas women on antidepressant treatment had similar expression as healthy controls. The protein expression analyses revealed higher expression of HTR1A in placentas from women on antidepressant treatment, than in placentas from healthy controls (p < 0.05).

Conclusion: The differentially expressed HTR1A, both at the gene and the protein level that was revealed in this study, suggests the involvement of HTR1A in the effect of antenatal depression on biological mechanisms in the placenta. More research is needed to elucidate the role of depression and antidepressant treatment on the placenta, and, further, the effect on the fetus.
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http://dx.doi.org/10.1186/s12884-019-2586-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896358PMC
December 2019

Metabolite Profiling of Ortho-, Meta- and Para-Fluorofentanyl by Hepatocytes and High-Resolution Mass Spectrometry.

J Anal Toxicol 2020 Mar;44(2):140-148

Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.

New psychoactive substances are emerging on the illegal drug market. Synthetic opioids including fentanyl analogues are of special concern due to their high potency. This indicates the possibility of low drug concentrations in vivo and calls for sensitive analytical methods and identification of the most appropriate analytical targets. In this study the in vitro metabolism of ortho-, meta- and para-fluorofentanyl, three fluorinated derivatives of fentanyl, has been investigated using human hepatocytes and compared to the results from an authentic human urine sample. Based on knowledge on the metabolism of similar fentanyl analogues N-dealkylation and hydroxylation was hypothesized to be the most central pathways. The three fluorofentanyl isomers were incubated with pooled human hepatocytes at 1, 3 and 5 h. Liquid chromatography quadrupole time of flight mass spectrometry operating in data-dependent mode was used to analyse the hepatocyte samples, as well as the hydrolysed and non-hydrolysed authentic urine sample. Data were analysed by a targeted approach with a database of potential metabolites. The major metabolite formed in vitro was the N-dealkylation product norfluorofentanyl. In addition various hydroxylated metabolites, a N-oxide, dihydrodiol metabolites and a hydroxymethoxy metabolite were found. In total, 14 different metabolites were identified for each fluorofentanyl isomer. In the authentic urine sample, three metabolites were detected in addition to the ortho-fluorofentanyl parent compound, with hydroxymethoxy metabolite having the highest abundance followed by norfluorofentanyl and a metabolite hydroxylated on the ethylphenyl ring. This in vitro study showed that the metabolic pattern for ortho-, meta-, and para-fluorofentanyl was close to those previously reported for other fentanyl analogues. We suggest that the hydroxymethoxy metabolite and the metabolite hydroxylated on the ethylphenyl ring should be the metabolites primarily investigated in further studies to determine the most appropriate marker for intake of fluorofentanyl derivatives in urine drug screening for human subjects.
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http://dx.doi.org/10.1093/jat/bkz081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238673PMC
March 2020

Safety with use of long-acting β₂-selective agonists for asthma.

Tidsskr Nor Laegeforen 2019 Nov 18;139(17). Epub 2019 Nov 18.

Background: Since their introduction more than 50 years ago, use of β-agonists for inhalation has been associated with increased mortality. Since the turn of the century, particular concern has been voiced regarding long-acting β2-selective agonists. Our purpose was to investigate the evidence from recently published randomised trials of possible increased risks of death and serious adverse events related to exposure to these drugs.

Material And Method: A PubMed search identified ten clinical trials which fulfilled predefined inclusion criteria.

Results: The ten trials encompassed 66 664 patients. A total of 16 asthma-related deaths after exposure to long-acting β2-selective agonists were recorded among 33 043 actively treated patients, whereas four such deaths were recorded among the 33 621 patients in the control groups. A single, large, pragmatic trial accounts for a majority of these fatalities.

Interpretation: Exposure to long-acting β2-selective agonists is associated with a small increase in mortality. Whether concomitant use of inhalation steroids fully reverses this effect is not clear.
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http://dx.doi.org/10.4045/tidsskr.19.0032DOI Listing
November 2019

Stability of 21 Antihypertensive Drugs in Serum Collected in Standard (Nongel) Serum Tubes Versus Tubes Containing a Gel Separator.

Ther Drug Monit 2020 04;42(2):335-340

Department of Clinical Pharmacology, St. Olav University Hospital; and.

Background: Therapeutic drug monitoring of antihypertensive drugs is being increasingly used to optimize treatment and to assess nonadherence. Separator gels are often used in blood collection tubes to facilitate serum or plasma separation from other blood constituents before analyses. Drug adsorption into the separator gel presents a possible pre-analytical cause of falsely low concentrations or false negative results.

Methods: Drug-free blood from blood donors was spiked with therapeutic concentrations of 21 antihypertensive drugs, transferred to serum tubes with and without separator gel (Vacuette gel plastic tubes and plain serum plastic tubes, respectively), and centrifuged. Serum was collected immediately after centrifugation and after 24 and 72 hours of room temperature storage, samples were analyzed in triplicates using liquid chromatography-mass spectrometry.

Results: Serum samples collected immediately after centrifugation or 24 hours later, had the same drug concentrations in the gel and nongel tubes. After 72 hours of room temperature storage, verapamil and lercanidipine serum concentrations were 43% and 29%, respectively, lower in gel tubes than nongel tubes. Canrenone, diltiazem, and bendroflumethiazide showed between 10% and 20% concentration loss in gel tubes, compared with nongel tubes, with the 2 latter observed as unstable also in nongel tubes.

Conclusions: Except for verapamil, lercanidipine, and canrenone, which showed substantial concentration loss in gel tubes, gel tubes may be used for therapeutic drug monitoring purposes for the most commonly used antihypertensive drugs. Transferring serum to gel-free containers immediately after centrifugation minimizes concentration loss; however, bendroflumethiazide and diltiazem are generally unstable at room temperature.
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http://dx.doi.org/10.1097/FTD.0000000000000708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077963PMC
April 2020

Academic detailing as a method of continuing medical education.

Adv Med Educ Pract 2019 30;10:717-725. Epub 2019 Aug 30.

Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.

Introduction: Academic detailing is an interactive educational outreach to prescribers to present unbiased, non-commercial, evidence-based information, mostly about medications, with the goal of improving patient care. Academic detailing in Norway is an approach for providing continuing medical education to general practitioners (GPs). The basis of academic detailing is a one-to-one discussion between a trained health professional (the academic detailer) and the GP at the GP's workplace.

Method: Our first campaign was named "Better use of non-steroidal anti-inflammatory drugs (NSAIDs), which aim was to reduce the use of diclofenac due to the risk of serious cardiovascular adverse events. At the same time we advised the GPs to use naproxen as the drug of choice if an NSAID was needed. We did a one-to-one intervention in two cities, where a trained academic detailer met the GP during office hours. A total of 247 GPs were invited to participate and 213 visits (86%) were completed. This article reviews the theoretical framework underlying the method and describes the development and implementation of academic detailing to GPs in Norway.

Results: More than 90% the participating GPs considered academic detailing a suitable method for providing up-to-date evidence-based, manufacturer-independent information, and nearly all would most likely or probably welcome another visit. After the intervention there was a reduction of diclofenac prescribing of 16% and 18%, respectively, in the two cities.

Conclusion: We consider that academic detailing is a suitable method to bring the best available evidence to the point at which care is delivered, to achieve the best for the patients. According to the Norwegian GPs' evaluation, it is a key supplement to other methods of continuing medical education. To have maximum impact, it is important that academic detailing is practiced according to the consensus that has evolved in the USA and Australia.
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http://dx.doi.org/10.2147/AMEP.S206073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719842PMC
August 2019

Excretion of Antipsychotics Into the Amniotic Fluid, Umbilical Cord Blood, and Breast Milk: A Systematic Critical Review and Combined Analysis.

Ther Drug Monit 2020 04;42(2):245-254

Alexianer Hospital Aachen, Aachen; and.

Background: Antipsychotics are being increasingly prescribed during pregnancy and in the postpartum period. However, knowledge regarding the ability of antipsychotics to enter the fetal, newborn, and infant circulation presents inconsistencies. Evidence for penetration ratios in an array of matrices will contribute to further studies examining the mechanistic pathway from antipsychotic use to adverse events.

Methods: A systematic literature search of PubMed and EMBASE was performed to identify studies assessing the concentrations of antipsychotics in maternal blood (serum or plasma), amniotic fluid, umbilical cord blood, and/or breast milk. The penetration ratios were estimated by dividing the antipsychotic concentrations in the target matrix (ie, amniotic fluid, umbilical cord blood or breast milk) by the maternal concentration. Data are provided in means with ranges or SD depending on data availability.

Results: Forty-nine eligible studies were identified. For amniotic fluid, the penetration ratios were estimated for quetiapine, clozapine, and flupentixol, with quetiapine displaying the highest ratio (mean 0.59, range 0.09-1.70 versus 0.56, range 0.31-0.82 for clozapine and 0.24, range 0.23-0.24 for flupentixol). For umbilical cord blood, olanzapine had the highest ratio (mean 0.71 ± 0.42) followed by haloperidol (mean 0.66 ± 0.40) and paliperidone (mean 0.53, range 0.50-0.58). In case of breast milk, the highest ratio was observed for amisulpride (mean 14.42, range 11.86-19.50) followed by clozapine (mean 3.19, range 2.79-4.32) and haloperidol (mean 3.11, range 0.59-6.67).

Conclusions: The ability of antipsychotics to enter the fetal, newborn, and infant circulation varies considerably among antipsychotics. Given sampling constraints of other matrices, measuring antipsychotic concentrations in maternal blood may represent the least expensive, most readily available, and reliable estimate of fetal/infant exposure.
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http://dx.doi.org/10.1097/FTD.0000000000000692DOI Listing
April 2020

Adverse events with fatal outcome associated with alemtuzumab treatment in multiple sclerosis.

BMC Res Notes 2019 Aug 12;12(1):497. Epub 2019 Aug 12.

Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Post Office Box 1400, 5021, Bergen, Norway.

Objective: Sporadic fatal adverse events have been reported during treatment of multiple sclerosis with alemtuzumab. To provide a systematic overview, we searched the centralized European Medicines Agency database of suspected adverse reactions related to medicinal products (EudraVigilance) for fatal adverse events associated with treatment with alemtuzumab (Lemtrada®) for multiple sclerosis. Four independent reviewers with expertise on MS, clinical immunology, infectious diseases and clinical pharmacology reviewed the reports, and scored the likelihood for causality.

Results: We identified nine cases with a probable and one case with a possible causal relationship between alemtuzumab treatment and a fatal adverse event. Six of these patients died within one month after treatment; one from intracerebral hemorrhage, two from acute multiple organ failure and septic shock, one from listeriosis, one from pneumonia and one from agranulocytosis. Four patients died several months after administration of alemtuzumab from either autoimmune hepatitis, immune-mediated thrombocytopenia, autoimmune hemolytic anemia or agranulocytosis. Four of the 10 cases had been published previously in case reports or congress abstracts. Fatal adverse events related to treatment with alemtuzumab occur more frequently than previously published in the literature. A significant proportion occurs in the first month after treatment.
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http://dx.doi.org/10.1186/s13104-019-4507-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689881PMC
August 2019

Use and validity of child neurodevelopment outcome measures in studies on prenatal exposure to psychotropic and analgesic medications - A systematic review.

PLoS One 2019 11;14(7):e0219778. Epub 2019 Jul 11.

PharmacoEpidemiology and Drug Safety Research Group, Department of Pharmacy, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.

In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or "other". We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child's daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies. Review registration number: CRD42018086101 in the PROSPERO database.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219778PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6622545PMC
February 2020

Methadone serum concentrations and influencing factors: A naturalistic observational study.

Psychopharmacology (Berl) 2019 Nov 28;236(11):3159-3167. Epub 2019 May 28.

Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway.

Rationale: Although methadone maintenance treatment (MMT) has long been used for opioid addiction, our knowledge on its pharmacokinetics is still limited.

Objectives: We aimed to investigate effects of age, gender, and various co-medications on methadone serum concentration-to-dose ratio (CDR) in a naturalistic setting.

Methods: In total, 4425 routine serum methadone concentrations obtained from 1691 MMT patients in the period October 1999 to July 2017 were included. Information about doses, age, gender, and concurrent medications was available in the laboratory database at the Department of Clinical Pharmacology at St. Olav University Hospital in Trondheim, Norway. A log-linear mixed model was used when analyzing the data.

Results: Mean age was 38.4 (range, 21-78) years and 70% were men. Mean CDR was 332 (range, 7-1776) (ng/mL)/(100 mg/d). Concomitant medication with at least one out of totally 170 drugs was recorded in 26% of the samples. CDRs were significantly lower in women (- 9%; confidence interval (CI), - 13%, - 4%; p = 0.001) and with concurrent use of CYP inducers (- 36%; CI, - 44%, - 28%; p < 0.001), but higher using CYP3A4 inhibitors as co-medications (+ 36%; CI, + 10%, + 68%; p = 0.005).

Conclusions: Our results warrant taking into consideration gender differences in methadone metabolism as well as the impact of potential drug-drug interactions to obtain an optimal therapeutic effect and avoid adverse effects in MMT. Although the clinical implications of the altered drug levels require further study, our results call for close clinical monitoring of all patients undergoing MMT, preferably along with laboratory measurements of methadone serum concentrations.
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http://dx.doi.org/10.1007/s00213-019-05277-1DOI Listing
November 2019

Serum Concentrations and Pharmacokinetics of Tranexamic Acid after Two Means of Topical Administration in Massive Weight Loss Skin-Reducing Surgery.

Plast Reconstr Surg 2019 06;143(6):1169e-1178e

From the Section for Plastic and Reconstructive Surgery, Clinic of Surgery, the Clinic of Anesthesia and Intensive Care, and the Department of Clinical Pharmacology, St. Olav's University Hospital; the Departments of Circulation and Medical Imaging and Clinical and Molecular Medicine, Norwegian University of Science and Technology; and the Section for Plastic Surgery, Aleris Medical Center.

Background: Topical administration of tranexamic acid to reduce bleeding is receiving increasing attention, as it is inexpensive, simple, and possibly beneficial in most surgery. Concerns regarding potential systemic adverse effects such as thromboembolic events and seizures may prevent general use of tranexamic acid. Although serum concentrations after topical application are assumed to be low, proper pharmacokinetic studies of tranexamic acid after topical application are lacking.

Methods: The authors have investigated systemic absorption of tranexamic acid after two means of topical administration in patients undergoing abdominoplasty after massive weight loss: a bolus of 200 ml of 5 mg/ml into the wound cavity versus moistening the wound surface with 20 ml of 25 mg/ml. Twelve patients were recruited in each group. Serum concentrations achieved were compared with those after administration of 1 g as an intravenous bolus to arthroplasty patients. Serial blood samples for tranexamic acid analysis were obtained for up to 24 hours.

Results: After intravenous administration, the peak serum concentration was 66.1 ± 13.0 µg/ml after 6 ± 2 minutes. Peak serum concentration after topical moistening was 5.2 ± 2.6 µg/ml after 80 ± 33 minutes, and in the topical bolus group, it was 4.9 ± 1.8 µg/ml after 359 ± 70 minutes. Topical moistening resulted in homogenous and predictable absorption across the individuals included, whereas topical bolus administration caused variable and unpredictable serum concentrations.

Conclusion: Topical administration of tranexamic acid in patients undergoing abdominoplasty results in low serum concentrations, which are highly unlikely to cause systemic effects.
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http://dx.doi.org/10.1097/PRS.0000000000005620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553511PMC
June 2019

A Compilation of Serum Concentrations of 12 Antipsychotic Drugs in a Therapeutic Drug Monitoring Setting.

Ther Drug Monit 2019 06;41(3):348-356

Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping.

Background: No comprehensive collection of routine therapeutic drug monitoring data for antipsychotic drugs has been published.

Methods: In this compilation, data on 12 antipsychotics are presented. The drugs included are amisulpride (n = 506), aripiprazole (n = 1610), clozapine (n = 1189), flupentixol (n = 215), haloperidol (n = 390), olanzapine (n = 10,268), perphenazine (n = 1065), quetiapine (n = 5853), risperidone (n = 3255), sertindole (n = 111), ziprasidone (n = 1235), and zuclopenthixol (n = 691). Because only one sample per patient is included, the number of patients equals the number of samples. For each drug, median serum concentrations as well as that of the 10th and 90th percentiles are given for a range of daily doses. Comparisons are made between males and females, between patients younger than 65 years and 65 years and older, and between those treated with a low and a high dose of each drug. The concentration-to-dose (C/D) ratio is the primary variable used in these comparisons. Coefficients of variation (CVs) for the serum concentrations of each drug within and between subjects are presented.

Results: In general, the C/D ratios were higher in females than in males, higher in those 65 years and older than in younger subjects, and lower in those treated with higher doses than in those treated with lower doses. CVs between individuals were larger than within subjects, and the CVs were highest for the drugs with short elimination half-lives.

Conclusions: For each antipsychotic drug, the results presented can serve as a reference tool for pharmacokinetic interpretation of the individual patient's serum drug level. The compiled serum concentrations and the C/D ratios can support the physician's decision when individualizing dosing and determining treatment strategies for a specific patient.
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http://dx.doi.org/10.1097/FTD.0000000000000585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553956PMC
June 2019

Mucosal 5-aminosalicylic acid concentration, drug formulation and mucosal microbiome in patients with quiescent ulcerative colitis.

Aliment Pharmacol Ther 2019 05 20;49(10):1301-1313. Epub 2019 Mar 20.

Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology, Trondheim, Norway.

Background: 5-aminosalicylic acid (5-ASA) is the first-line therapy for ulcerative colitis (UC). 5-ASA acts locally in the colonic mucosa by numerous proposed mechanisms, and is metabolised by N-acetyltransferase (NAT). Large variations in mucosal 5-ASA concentrations have been reported, but the underlying mechanisms are not understood.

Aim: To study the relationship between 5-ASA concentration, 5-ASA formulation, NAT genotype and bacterial microbiome in patients with UC.

Methods: Patients with quiescent UC, using monotherapy of Mezavant (n = 18), Asacol (n = 14) or Pentasa (n = 10), 4.0-4.8 g/day were included. 5-ASA was measured in colonic mucosal biopsies and serum by ultra-high performance liquid chromatography. NAT genotypes were determined by Sanger sequencing. Bacterial microbiome was sequenced from faeces and mucosa by 16S rRNA sequencing using Illumina Miseq.

Results: Mezavant provided the highest mucosal 5-ASA levels (geometric mean 2.39 ng/mg), followed by Asacol (1.60 ng/mg, 33% lower, P = 0.50) and Pentasa (0.57 ng/mg, 76% lower, P = 0.033). Mucosal 5-ASA concentration was not associated with NAT genotype, but serum 5-ASA concentration and NAT1 genotype was associated (P = 0.044). Mucosal 5-ASA concentration was positively associated with mucosal bacterial diversity (P = 0.0005) and bacterial composition. High mucosal 5-ASA concentration was related to reduced abundance of pathogenic bacteria such as Proteobacteria, and increased abundance of several favourable bacteria such as Faecalibacterium.

Conclusions: Mucosal 5-ASA concentration is positively associated with bacterial diversity and a mucosal bacterial composition that are perceived favourable in UC. Mezavant yielded higher mucosal 5-ASA concentrations than Pentasa. 5-ASA may have beneficial effects on the mucosal microbiome, and high concentrations possibly amend dysbiosis in UC.
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http://dx.doi.org/10.1111/apt.15227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593792PMC
May 2019