Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

Quantitative determination of R/S-methadone in human serum using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry: A method for routine use.

Methadone has two enantiomers, which exhibit differences in pharmacological effects, with R-methadone being the active and S-methadone the inactive enantiomer. A robust, simple and rapid method for chiral separation of the two enantiomers in serum samples using ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MSMS) has been developed and validated. Enantiomeric separation was achieved using a Chiralpak IH-3 column with a mobile phase consisting of CO2 and 30mM ammonium acetate in methanol/water (98/2, v/v). Runtime was 4 minutes. Sample preparation was semi-automated using a Hamilton ML Star robot with protein precipitation, and phospholipid removal was carried out using a Waters OSTRO™ 96-well plate. The calibration range was 50.0-1,500 nM for each enantiomer. The between-assay relative standard deviations were in the range of 1.2-3.6%. Matrix effects ranged from 99% to 115% corrected with internal standard. The method has been implemented in our laboratory and has proven to be a robust and reliable method for determining the ratio of R/S-methadone in authentic patient samples.

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.

Direct oral anticoagulant concentrations and adherence in stroke patients.

No therapeutic ranges linking drug concentrations of apixaban and rivaroxaban to clinical outcomes have been defined. We investigated whether direct oral anticoagulant (DOAC) concentrations among patients admitted to hospital with symptoms of stroke differed between those later verified to suffer an ischaemic cerebrovascular event (stroke or transient ischaemic attack) and those having other diagnoses (control group). Serum concentrations in 102 patients on DOAC for atrial fibrillation (84%) and thromboembolic disease (16%) were measured within 24 h of the acute event, employing ultra-high performance liquid chromatography with tandem mass spectrometry. We converted all concentrations to standardized trough levels. DOAC concentrations were lower in the 64 patients with verified ischaemic cerebrovascular event than in the 30 controls, 255 ± 155 versus 329 ± 144 nmol/L (p = 0.029), despite no statistically significant difference in self-reported adherence and daily dosages. Calculated concentrations were 5.4-596 nmol/L (median = 229 nmol/L) in the ischaemic stroke group and 41-602 nmol/L (median = 316 nmol/L) in controls. CHA2 DS2 -VASc score was significantly higher in the ischaemic stroke group than in controls (4.9 ± 1.6 versus 4.1 ± 1.7; p = 0.007). These results may suggest that patients with high cerebrovascular risk might benefit from higher DOAC levels than those with a lower risk.

Transfer of cetirizine/levocetirizine into human breast milk and estimation of drug exposure to infants through breastfeeding: A human lactation study from the ConcePTION project.

Data on drug transfer into human breast milk are sparse. This study aimed to quantify concentrations of cetirizine and levocetirizine in breast milk and to estimate drug exposure to infants. Breastfeeding women at least 8 weeks postpartum and using cetirizine or its pure (R)-enantiomer levocetirizine were eligible to participate. Breast milk samples were collected at six predefined times during a dose interval (0, 2, 4, 8, 12 and 24 h after drug intake) at steady state. Infant drug exposure was estimated by calculating the absolute infant dose (AID) and the weight-adjusted relative infant dose (RID). In total, 32 women were eligible for final inclusion, 31 women using cetirizine and one woman using levocetirizine. Means of the individual maximum and average cetirizine milk concentrations were 41.0 and 16.8 µg/L, respectively. Maximum concentrations occurred on average 2.4 h after intake, and the mean half-life in milk was 7.0 h. Estimated AID and RID for cetirizine in a day were 2.5 µg/kg and 1.9%, respectively. The corresponding values for levocetirizine were 1.1 µg/kg and 1.9%. No severe adverse events were reported. Our findings demonstrate that the transfer of cetirizine and levocetirizine into breast milk is low and compatible with breastfeeding.

Methadone pharmacokinetics in opioid agonist treatment: Influencing factors and clinical implications.

BACKGROUND: A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood. OBJECTIVES: We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings. METHODS: We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses. FINDINGS: A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations. CONCLUSIONS: This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes.

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.

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.

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.

Transfer of anticonvulsants and lithium into amniotic fluid, umbilical cord blood & breast milk: A systematic review & combined analysis.

OBJECTIVE: Data on the ability of anticonvulsants and lithium to enter fetal and newborn circulation has become increasingly available; here we estimated penetration ratios in a series of matrices from combined samples of pregnant/breastfeeding women treated with anticonvulsants or lithium. METHODS: We conducted a systematic literature search in PubMed/EMBASE for studies with concentrations of anticonvulsants/lithium 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 concentrations. When data from multiple studies were available, we calculated combined penetration ratios, weighting studies' mean by study size. RESULTS: Ninety-one eligible studies for brivaracetam, carbamazepine, clonazepam, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, lithium, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproate, vigabatrin and zonisamide were identified. For amniotic fluid, the highest penetration ratios were estimated for levetiracetam (mean 3.56, range 1.27-5.85, n = 2) and lowest for valproate (mean 0.11, range 0.02-1.02, n = 57). For umbilical cord plasma, oxcarbazepine had the highest ratio (mean 1.59, range 0.11-4.33, n = 12) with clonazepam having the lowest (mean 0.55, range 0.52-0.59, n = 2). For breast milk, the highest ratios were observed for oxcarbazepine (mean 3.75, range 0.5-7.0, n = 2), whereas the lowest were observed for valproate (mean 0.04, range 0.01-0.22, n = 121). DISCUSSION: We observed substantial variability between anticonvulsants and lithium regarding their ability to enter fetal/newborn circulation. Assessing concentrations of anticonvulsants and lithium in maternal samples can provide a surrogate of fetal/infant exposure, although patterns of concentration-dependent effects for maternal/neonatal safety are lacking.

Topical tranexamic acid for prophylaxis of bleeding. / Lokal bruk av traneksamsyre som blødningsprofylakse.

Uncertainty surrounding possible thromboembolic events may prevent widespread use of tranexamic acid in surgery. Topical application may be an alternative.

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.

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.

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.