Relationship between alcohol intake based on daily smartphone-reported consumption and PEth concentrations in healthy volunteers.

AIMS: To investigate the association between alcohol consumption registered daily with a digital smartphone-based diary and concentration of phosphatidylethanol (PEth) 16:0/18:1 in a population without a known alcohol use disorder (AUD), and evaluate whether prospective registration of alcohol consumption is better than retrospective registration and if the association between alcohol intake and PEth was affected by sex or body mass index (BMI). METHODS: A total of 41 women and 21 men without AUD-diagnosis registered their alcohol consumption prospectively with a digital diary for 14 days, and retrospectively with the Timeline Followback method in the same time interval. PEth was measured before and after the registration period. RESULTS: The correlation between alcohol consumption and PEth varied from 0.65 to 0.87. It did not depend significantly on the reporting method, and was not influenced by sex or BMI. Based on the regression coefficient, a reduction of alcohol consumption by two alcohol units (26 g of pure ethanol) per day would lead to a reduction of the PEth concentration of about 0.1 µmol/l, and vice versa. CONCLUSIONS: There was a good correlation between PEth concentration and alcohol consumption, both when alcohol consumption was reported prospectively and retrospectively. The preferred cut-off for PEth should be adjusted to the level of alcohol consumption considered harmful and a purposeful trade-off between sensitivity and specificity. In order to identify persons with a daily alcohol consumption of more than two or three units of alcohol with a sensitivity of 80% or 90%, we suggest a cut-off of around 0.1 µmol/l.

Pharmacokinetics of propofol in severely obese surgical patients.

BACKGROUND: Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from normal-weight up to, and including, a high number of very obese patients. METHODS: Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time-concentration data were analysed by population PK modelling using non-linear mixed-effects modelling. RESULTS: Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19-60 years with a BMI 21.6-67.3 kg/m2. Twenty one patients had a BMI above 50 kg/m2. A 3-compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post-hoc performance evaluation. CONCLUSION: We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI.

Effects of Sleeve Gastrectomy and Roux-en-Y Gastric Bypass on Escitalopram Pharmacokinetics: A Cohort Study.

BACKGROUND: Changes in the gastrointestinal physiology after bariatric surgery may affect the pharmacokinetics of medications. Data on the impact of different surgical techniques on the pharmacokinetics of commonly prescribed antidepressants such as escitalopram are limited. METHODS: This case-only prospective study investigated escitalopram-treated patients who underwent bariatric surgery at hospitals in Central Norway. Escitalopram concentrations were assessed using serial blood samples obtained during a dose interval of 24 hours preoperatively and at 1, 6, and 12 months, postoperatively. The primary outcomes were changes in the area under the time-concentration curve (AUC 0-24 ) with secondary outcomes, including full pharmacokinetic profiling. We performed repeated-measures analysis of variance for the AUC 0-24 and secondary outcomes. RESULTS: Escitalopram-treated obese patients who underwent sleeve gastrectomy (n = 5) and Roux-en-Y gastric bypass (n = 4) were included. Compared with preoperative baseline, dose-adjusted AUC 0-24 values were within ±20% at all time points, postoperatively in the sleeve gastrectomy and oux-en-Y gastric bypass groups, with the largest changes occurring 1 month postoperatively (+14.5 and +17.2%, respectively). No statistically significant changes in any pharmacokinetic variables over time were reported; however, there was a trend toward increased maximum concentrations after surgery ( P = 0.069). CONCLUSIONS: Our findings suggest that bariatric surgery has no systematic effect on the pharmacokinetics of escitalopram. However, because of the substantial interindividual variation, therapeutic drug monitoring can be considered to guide postoperative dose adjustments.

Quantifying Alcohol Consumption in the General Population by Analysing Phosphatidylethanol Concentrations in Whole Blood: Results from 24,574 Subjects Included in the HUNT4 Study.

AIMS: To evaluate the association between self-reported alcohol consumption and phosphatidylethanol (PEth) concentrations in blood in a large general population study, and discuss optimal cut-off PEth concentrations for defined levels of alcohol consumption. METHODS: Population based, longitudinal cohort study including 24,574 adults from The Trøndelag Health Study 4 (HUNT4) conducted in Trøndelag County, Norway. Data included PEth concentration, self-reported alcohol consumption and CAGE score. RESULTS: PEth levels in whole blood increased with the number of alcohol units consumed, the frequency of alcohol consumption, the frequency of binge drinking and the CAGE score (lifetime, i.e. 'have you ever'). The cut-off concentrations with highest combined sensitivity and specificity were 0.057 µmol/l (40 ng/ml) for identification of those consuming >1 alcohol unit per day (sensitivity 86%, specificity 76%), 0.087 µmol/l (61 ng/ml) for consuming >2 units per day (sensitivity 87%, specificity 81%) and 0.122 µmol/l (86 ng/ml) for consuming >3 alcohol units per day (sensitivity 80%, specificity 86%). By defining a CAGE score ≥ 2 as potentially harmful consumption, a cut-off of 0.100 µmol/l (70 ng/ml) identified 52% of all those subjects. CONCLUSIONS: Cut-off limits of PEth concentrations should take into account the indication for sampling. Using cut-offs for the PEth concentrations of about 0.05 µmol/l (35 ng/ml) and 0.08 µmol/l (56 ng/ml) would identify about 90% of the subjects consuming more than 1 and 2 alcohol units per day, respectively. Concentrations above these cut-offs should lead to a more detailed interview related to alcohol use.

Extrapleural infusion of levobupivacaine versus levobupivacaine-sufentanil-adrenaline after video-assisted thoracoscopic surgery (VATS): A randomised controlled trial.

BACKGROUND: Peripheral blocks are increasingly used for analgesia after video-assisted thoracic surgery (VATS). We hypothesised that addition of sufentanil and adrenaline to levobupivacaine would improve the analgesic effect of a continuous extrapleural block. METHODS: We randomised 60 patients undergoing VATS to a 5-mL h-1 extrapleural infusion of levobupivacaine at 2.7 mg mL-1 (LB group) or levobupivacaine at 1.25 mg mL-1 , sufentanil at 0.5 µg mL-1 , and adrenaline at 2 µg mL-1 (LBSA group). The primary outcome was the cumulative morphine dose administered as patient-controlled analgesia (PCA-morphine) at 48 and 72 h. The secondary outcomes were pain according to numerical rating scale (NRS) at rest and after two deep breaths twice daily, peak expiratory flow (PEF) daily, quality of recovery (QoR)-15 score at 1 day and 3 weeks postoperatively, serum levobupivacaine concentrations at 1 h after the start and at the end of the intervention, and adverse events. RESULTS: At 48 h, the median cumulative PCA-morphine dose for the LB group was 6 mg (IQR, 2-10 mg) and for the LBSA group 7 mg (IQR, 3-13.5 mg; p = .378). At 72 h, morphine doses were 10 mg (IQR, 3-22 mg) and 12.5 mg (IQR, 4-21 mg; p = .738), respectively. Median NRS score at rest and after two deep breaths was 3 or lower at all time points for both treatment groups. PEF did not differ between groups. Three weeks postoperatively, only the LB group returned to baseline QoR-15 score. The LB group had higher, but well below toxic, levobupivacaine concentrations at 48 and 72 h. The incidence of nausea, dizziness, pruritus and headache was equally low overall. CONCLUSION: For a continuous extrapleural block, and compared to plain levobupivacaine at 13.5 mg h-1 , levobupivacaine at 6.25 mg h-1 with addition of sufentanil and adrenaline did not decrease postoperative morphine consumption. The levobupivacaine serum concentrations after 48 and 72 h of infusion were well below toxic levels, therefore our findings support the use of the maximally recommended dose of levobupivacaine for a 2- to 3-day continuous extrapleural block.

Depression and antidepressant treatment in the development of hypertensive disorders of pregnancy: Results from a prospective cohort study.

BACKGROUND: Hypertensive disorders of pregnancy are associated with longer term cardiovascular risk. Understanding if depression or antidepressant use in pregnancy is associated with HDP is important in identifying those potentially vulnerable to poorer health in later life. This study examines if depression and antidepressants are associated with HDP. METHODS: In all, 815 pregnant women were recruited within an Australian pregnancy cohort study at less than 20 weeks of pregnancy, all undertook the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and were assigned to four groups for this paper: those with unmedicated depression meeting criteria for current depression (n = 97), those taking selective serotonin reuptake inhibitors in early pregnancy (n = 101), those taking serotonin and noradrenaline reuptake inhibitors in early pregnancy (n = 31), and those without depression or taking antidepressant medication (control; n = 586). Women were then assessed again following birth. Hypertensive disorders of pregnancy were diagnosed according to the Society of Obstetric Medicine in Australia and New Zealand Guidelines. RESULTS: Use of serotonin and noradrenaline reuptake inhibitors (SNRIs) (adjusted risk ratio = 9.10, 95% confidence interval = [3.82, 21.67]) and unmedicated depression (adjusted risk ratio = 3.11, 95% confidence interval = [1.32, 7.35]) were independently associated with significantly higher risk for developing hypertensive disorders of pregnancy compared to controls. Selective serotonin reuptake inhibitors (SSRIs) use did not confer any increased risk. Higher doses of SNRIs, but not selective serotonin reuptake inhibitors, were associated with significantly higher risk for developing HDP (adjusted risk ratio = 4.83, 95% confidence interval = [1.50, 15.58]). CONCLUSIONS: Our findings suggest that those with depression in pregnancy and/or on an serotonin and noradrenaline reuptake inhibitor should have closer surveillance for the development of hypertensive disorders of pregnancy. These findings support treatment of depression in pregnancy, however, also the consideration of class of antidepressant.

Academic detailing as a method to improve general practitioners' drug prescribing in type 2 diabetes: evaluation of changes in prescribing.

OBJECTIVE: To investigate the effect of an academic detailing intervention on the utilisation of type 2 diabetes medication among general practitioners. DESIGN: We developed an academic detailing campaign based on the revised national treatment guideline for diabetes and the best available evidence. General practitioners were offered a 20-minute one-to-one visit by a trained academic detailer. SETTING AND SUBJECTS: A total of 371 general practitioners received a visit and represented the intervention group. The control group consisted of 1282 general practitioners not receiving a visit. MAIN OUTCOME MEASURES: Changes in prescribing from 12 months before to 12 months after the intervention. The primary endpoint was a change in metformin. Secondary endpoints were changes in other groups of Type 2 diabetes medication and of these drugs in total. RESULTS: Prescribing of metformin increased by 7.4% in the intervention group and 5.2% in the control group (p = .043). Sodium-glucose cotransporter-2 inhibitors increased by 27.6% in the intervention group and 33.8% in the control group (p = .019). For sulfonylureas there was a decrease of 3.6% in the intervention group vs. 8.9% in the control group (p = .026). The total amount of prescribed medications for type 2 diabetes increased by 9.1% in the intervention group and 7.3% in the control group (p = .08). CONCLUSION: Academic detailing initiated a small but statistically significant increase in the prescription of metformin. For a complex subject like type 2 diabetes, we recommend reserving more time in the visit than the 20 min our campaign aimed for.

Academic detailing is a validated method for facilitating changes in prescribing, via interactive one-to-one meetings with a trained academic detailer.General practitioners who received a 20-minute visit on the treatment of type 2 diabetes prescribed more metformin, compared to the control group.For a complex interventions like the present, we recommend setting aside more than 20 minutes, to ensure sufficient time for discussion and reflection.Academic detailing can impact prescribing, even for a complex subject like the treatment of Type 2 Diabetes.

The effect of intranasal oxytocin on processing emotional stimuli during alcohol withdrawal: A randomized placebo-controlled double-blind clinical trial.

Alcohol dependence is associated with difficulties in processing emotional stimuli, which can lead to interpersonal problems. The neuropeptide oxytocin has been shown to modulate the processing of emotional stimuli, however, oxytocin treatment has not yet been examined in patients with withdrawal symptoms during alcohol detoxification. The aim of the present study was to investigate the effect of oxytocin on the reading the mind in the eyes test (RMET), which indexes theory of mind ability, during a three-day period of alcohol detoxification at an addiction treatment centre in Norway. We performed a randomized, double-blind, placebo-controlled trial in 39 patients fulfilling criteria for ICD-10 diagnosis of alcohol dependence admitted for alcohol detoxification and withdrawal treatment. Participants were randomized to receive either intranasal oxytocin (24 IU) or placebo, twice daily for three days. We evaluated RMET performance on day 2 and day 3 of detoxification and differences in RMET scores between day 2 and day 3 of detoxification. Frequentist and Bayesian statistical inference suggested that oxytocin administration during alcohol withdrawal in alcohol-dependent patients did not improve RMET performance. However, exploratory analyses provided preliminary evidence that oxytocin might improve performance on the RMET negative emotion subscale (uncorrected p value = 0.038), and that oxytocin treatment might show the most promise for those with high levels of alcohol consumption (i.e., ≥20 alcohol units per day; uncorrected p value = 0.023). Moreover, alcohol consumption levels significantly predicted RMET performance on day 2, but not on day 3, of withdrawal.

Stability of Direct Oral Anticoagulants and Antiarrhythmic Drugs in Serum Collected in Standard (Nongel) Serum Tubes Versus Tubes Containing Gel Separators.

BACKGROUND: Separation gels are often used in collection tubes, but adsorption of drugs onto the gel may cause falsely low concentrations in therapeutic drug monitoring. In this study, the stability of apixaban, edoxaban, rivaroxaban, flecainide, amiodarone, and desethylamiodarone was assessed in tubes, with and without gel separators. METHODS: Drug-free blood was spiked and stored for up to 7 days in nongel tubes and gel tubes from 2 manufacturers (Vacuette and Vacutainer). The samples were analyzed in triplicates using ultra-high-pressure liquid chromatography-tandem mass spectrometry. RESULTS: At ambient temperature conditions, the serum concentrations of apixaban, edoxaban, and rivaroxaban in a tube with acrylic-based gel had already decreased at baseline, whereas it took 6 hours to observe the same result in a tube with olefin-based gel. At 4°C, the reduction in serum concentration was considerably slower. For flecainide, the gel tube concentrations were stable at ambient temperature for 3 days, but decreased after 7 days in acrylic-based gel tubes. Amiodarone and desethylamiodarone stored in gel tubes at 4°C showed decrease in concentrations after 24 hours and 6 hours, respectively. CONCLUSIONS: Acrylic-based gel tubes should not be used for any of the tested drugs. Although olefin-based gel tubes may be used for anticoagulants and flecainide, it is advisable to prefer nongel tubes as a general precaution.

Serum or Plasma for Quantification of Direct Oral Anticoagulants?

BACKGROUND: Direct oral anticoagulants are increasingly replacing vitamin K antagonists for prevention of stroke in patients with atrial fibrillation, partly owing to the lack of a need for routine monitoring. Therapeutic drug monitoring may still be warranted under certain circumstances. It is generally assumed that serum and plasma can be interchangeably used for this purpose. The aim of this study was to investigate possible differences between the serum, citrate-plasma, and ethylenediaminetetraacetic acid (EDTA)-plasma concentrations of apixaban and rivaroxaban in a larger patient group and their relation to factor X measurements. METHODS: Plasma and serum samples were drawn during the same venipuncture from patients treated with apixaban or rivaroxaban. Drug levels were measured using ultrahigh-performance liquid chromatography combined with tandem mass spectrometry. Three sample matrices were obtained from 8 healthy volunteers for measurement of factor X antigen and activity. RESULTS: Mean concentrations of apixaban and rivaroxaban were 16.8% and 36.6% higher in serum than in citrate-plasma, respectively (both P < 0.001). The corresponding differences in serum versus EDTA-plasma were 4.5% for apixaban and 13.1% for rivaroxaban (both P < 0.001). Factor X antigen measurements in citrate-plasma, EDTA-plasma, serum with clot activator, and serum without additives yielded comparable results, and factor X activity was significantly higher in serum than in plasma. CONCLUSIONS: Apixaban and rivaroxaban concentrations were significantly higher in serum than in plasma. The difference was more pronounced with rivaroxaban and was larger between serum and citrate-plasma than between serum and EDTA-plasma. Higher factor X activity in serum may explain the observed concentration differences. The choice of matrix is, thus, important when interpreting therapeutic drug monitoring results and in research involving analyses of direct oral anticoagulants. The authors recommend citrate-plasma as the preferred matrix.

Co-prescription of metoprolol and CYP2D6-inhibiting antidepressants before and after implementation of an optimized drug interaction database in Norway.

PURPOSE: To compare the co-prescription of metoprolol and potent CYP2D6-inhibiting antidepressants before and during a 10-year period after implementation of an optimized drug interaction database into clinical decision support systems in Norway. METHODS: The study was a retrospective, cross-sequential nationwide analysis of drug-dispensing data retrieved from the Norwegian Prescription Database over a 1-year period before (2007) and two 1-year periods after (2012 and 2017) implementation of a drug interaction database providing recommendations on non-interacting alternative medications. Primary outcome was changes in co-prescription rates of metoprolol and the potent CYP2D6-inhibiting antidepressants fluoxetine, paroxetine, or bupropion relative to alternative antidepressants with no or limited CYP2D6 inhibitory potential. To control for potential secular trend bias, a comparison group consisting of atenolol/bisoprolol users was included. RESULTS: The co-prescription rate of metoprolol with potent CYP2D6 inhibitors declined following implementation of the optimized database, by 21% (P < 0.001) after 5 years and by 40% (P < 0.001) after 10 years. Compared with atenolol/bisoprolol users, patients treated with metoprolol had significantly reduced likelihood of being prescribed a CYP2D6-inhibiting antidepressant in the two post-implementation periods (OR 0.61 (95% CI 0.54-0.69) and OR 0.45 (95% CI 0.40-0.51), respectively, versus OR 0.84 (95% CI 0.74-0.94) prior to implementation). Small and mostly insignificant differences in average daily metoprolol dosage were found between patients treated with the various antidepressants. CONCLUSION: The present study suggests that implementation of a drug interaction database providing recommendations on non-interacting drug alternatives contributes to reduced co-prescribing of drug combinations associated with potentially serious adverse effects.

Identification of unhealthy alcohol use by self-report and phosphatidylethanol (PEth) blood concentrations in an acute psychiatric department.

BACKGROUND: The use of standard screening methods could improve the detection rate of unhealthy alcohol use in patients admitted to psychiatric acute and emergency departments. The aim of the present study was to investigate the ability of the alcohol biomarker phosphatidylethanol (PEth) to identify patients with high levels of alcohol consumption prior to admission. METHODS: The data were prospectively collected at admittance to an acute psychiatric department in the period January 2016 to June 2017. A blood sample for the analysis of PEth was available from 177 patients. We compared the PEth concentrations with the Alcohol Use Disorders Identification Test (AUDIT) scores during the hospital stay, and psychiatric diagnoses at discharge. RESULTS: A total of 45.8% of the patients had a PEth concentration ≥ 0.03 µmol/L, indicating significant alcohol consumption. AUDIT scores consistent with unhealthy alcohol use were present in 51.7%. There was a significant positive correlation between PEth concentrations and AUDIT scores (r = 0.631, p < 0.001). PEth was above the detection limit of 0.03 µmol/L in 19% of those reporting an average daily intake of zero alcohol units per day during the last week before admission. PEth concentrations were significantly higher among those with an alcohol diagnosis than among those without such a diagnosis (0.82 µmol/L vs. 0.09 µmol/L, p = 0.001). CONCLUSION: PEth provides supplementary information on recent alcohol consumption in a psychiatric population and would be particularly helpful in patients unable or unwilling to give such information at admission.

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

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.

Vitamin B status and association with antiseizure medication in pregnant women with epilepsy.

OBJECTIVE: Antiseizure medication (ASM) use interacts with vitamin B status in nonpregnant epilepsy populations. We aimed to examine the association between ASM and vitamin B status in pregnant women with epilepsy. METHODS: We performed a cross-sectional study of pregnancies in women with epilepsy enrolled in the Norwegian Mother, Father and Child Cohort Study from 1999 to 2008. Data on ASM and vitamin supplement use were collected from questionnaires. We analyzed maternal plasma concentrations of ASM and metabolites of folate, including unmetabolized folic acid (UMFA), riboflavin (vitamin B2), pyridoxine (vitamin B6), and niacin (vitamin B3) during gestational weeks 17-19. RESULTS: We included 227 singleton pregnancies exposed to ASM with available plasma samples (median maternal age 29 years, range 18 to 41 years). From the preconception period to gestational week 20, any supplement of folic acid was reported in 208 of pregnancies (94%), riboflavin in 72 (33%), pyridoxine in 77 (35%), and niacin in 45 (20%). High ASM concentrations correlated with high concentrations of UMFA and inactive folate metabolites, and with low concentrations of riboflavin and metabolically active pyridoxine. There was no association between ASM and niacin status. SIGNIFICANCE: ASM concentrations during pregnancy were associated with vitamin B status in pregnant women with epilepsy. Additional studies are needed to determine the clinical impact of these findings, and to define the optimal vitamin doses that should be recommended to improve pregnancy outcomes.

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

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.

Prenatal exposure to non-steroidal anti-inflammatory drugs and risk of attention-deficit/hyperactivity disorder: A follow-up study in the Norwegian mother, father and child cohort.

PURPOSE: To estimate the association between Attention-Deficit/Hyperactivity Disorder (ADHD) in children in preschool and primary school, and prenatal exposure to non-steroidal anti-inflammatory drugs (NSAIDs) by timing and duration. METHODS: This study was based on the Norwegian Mother, Father and Child Cohort Study linked to the Medical Birth Registry of Norway, the Norwegian Patient Registry (NPR) and the Norwegian Prescription Database (NorPD). NSAID exposure was identified by maternal self-report in pregnancy. Child diagnosis of ADHD was obtained from NPR and NorPD. Symptoms of ADHD at age 5 years were measured using Conners' Parent Rating Scale-Revised, where higher scores correspond to more symptoms. To account for time-varying exposure and confounders, marginal structural models were fitted to estimate hazard ratios and mean difference in z-scores. RESULTS: The analyses on ADHD diagnosis and ADHD symptoms included 56 340 and 34 961 children respectively. Children exposed to NSAIDs prenatally had no increased risk of ADHD diagnosis (first trimester: HR 1.12, 95% CI 0.86;1.45, second trimester: HR 0.98, 95% CI 0.69;1.38, third trimester: HR 0.68, 95% CI 0.31; 1.46) or ADHD symptoms (first trimester: standardized mean difference 0.03, 95% CI -0.03;0.09, second trimester: standardized mean difference 0.03, 95% CI -0.04;0.11, third trimester: standardized mean difference 0.11, 95% CI -0.03; 0.25). There was no duration-response relationship for either outcome. CONCLUSION: Though non-differential misclassification of the exposure may have attenuated results, these findings are reassuring and suggest no substantially increased risk of ADHD diagnosis or symptoms in children prenatally exposed to NSAIDs, regardless of timing or duration.

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

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.

Medication errors in hospitalised patients. / Legemiddelavvik hos pasienter innlagt i sykehus.

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.

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

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.

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

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.