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Background: Several studies have indicated that commonly used piperacillin-tazobactam (TZP) and meropenem (MEM) dosing regimens lead to suboptimal plasma concentrations for a range of pharmacokinetic/pharmacodynamic (PK/PD) targets in intensive care unit (ICU) patients. These targets are often based on a hypothetical worst-case scenario, possibly overestimating the percentage of suboptimal concentrations. We aimed to evaluate the pathogen-based clinically relevant target attainment (CRTA) and therapeutic range attainment (TRA) of optimized continuous infusion dosing regimens of TZP and MEM in surgical ICU patients. Methods: A single center prospective observational study was conducted between March 2016 and April 2019. Free plasma concentrations were calculated by correcting total plasma concentrations, determined on remnants of blood gas samples by ultra-performance liquid chromatography with tandem mass spectrometry, for their protein binding. Break points (BP) of identified pathogens were derived from epidemiological cut-off values. CRTA was defined as a corrected measured total serum concentration above the BP and calculated for increasing BP multiplications up to 6 × BP. The upper limit of the therapeutic range was set at 157.2 mg/L for TZP and 45 mg/L for MEM. As a worst-case scenario, a BP of 16 mg/L for TZP and 2 mg/L for MEM was used. Results: 781 unique patients were included with 1036 distinctive beta-lactam antimicrobial prescriptions (731 TZP, 305 MEM) for 1003 unique infections/prophylactic regimens (750 TZP, 323 MEM). 2810 samples were available (1892 TZP, 918 MEM). The median corrected plasma concentration for TZP was 86.4 mg/L [IQR 56.2–148] and 16.2 mg/L [10.2–25.5] for MEM. CRTA and TRA was consistently higher for the pathogen-based scenario than for the worst-case scenario, but nonetheless, a substantial proportion of samples did not attain commonly used PK/PD targets. Conclusion: Despite these pathogen-based data demonstrating that CRTA and TRA is higher than in the often-used theoretical worst-case scenario, a substantial proportion of samples did not attain commonly used PK/PD targets when using optimised continuous infusion dosing regimens. Therefore, more dosing optimization research seems warranted. At the same time, a 'pathogen-based analysis' approach might prove to be more sensible than a worst-case scenario approach when evaluating target attainment and linked clinical outcomes. [ABSTRACT FROM AUTHOR]

Etazene (or etodesnitazene) is a novel and highly active synthetic opioid belonging to the rapidly evolving and emerging group of "nitazenes." Etazene metabolites were identified through analysis of a human urine sample. The sample was obtained from a 25‐year‐old man who attempted suicide by taking a new psychoactive substances (NPS) cocktail purchased online and was analyzed by ultrahigh performance liquid chromatography‐high‐resolution mass spectrometry (UHPLC‐HRMS). Etazene metabolites were predicted with BioTransformer 3.0, and the exact masses were added to the inclusion list. Eight possible metabolites were identified in the urine sample. N‐ and O‐deethylation were identified as the predominant metabolism routes, resulting in M1 (O‐deethylated etazene; most abundant metabolite based on the peak area), M2 (N‐deethylated etazene), and M3 (N,O‐dideethylated etazene) metabolites. Less abundant hydroxylated products of these deethylated metabolites and etazene were also found. Additionally, in the analysis without β‐glucuronidase treatment, M1‐ and M3‐glucuronide phase II metabolites were found. As N‐ and O‐deethylated products seem to be the predominant urinary metabolites, the detection of these metabolites in urine can be useful to demonstrate etazene exposure. [ABSTRACT FROM AUTHOR]

Background: Beta-lactam antimicrobial concentrations are frequently suboptimal in critically ill patients. Population pharmacokinetic (PopPK) modeling is the golden standard to predict drug concentrations. However, currently available PopPK models often lack predictive accuracy, making them less suited to guide dosing regimen adaptations. Furthermore, many currently developed models for clinical applications often lack uncertainty quantification. We, therefore, aimed to develop machine learning (ML) models for the prediction of piperacillin plasma concentrations while also providing uncertainty quantification with the aim of clinical practice.Methods: Blood samples for piperacillin analysis were prospectively collected from critically ill patients receiving continuous infusion of piperacillin/tazobactam. Interpretable ML models for the prediction of piperacillin concentrations were designed using CatBoost and Gaussian processes. Distribution-based Uncertainty Quantification was added to the CatBoost model using a proposed Quantile Ensemble method, useable for any model optimizing a quantile function. These models are subsequently evaluated using the distribution coverage error, a proposed interpretable uncertainty quantification calibration metric. Development and internal evaluation of the ML models were performed on the Ghent University Hospital database (752 piperacillin concentrations from 282 patients). Ensuing, ML models were compared with a published PopPK model on a database from the University Medical Centre of Groningen where a different dosing regimen is used (46 piperacillin concentrations from 15 patients.).Results: The best performing model was the Catboost model with an RMSE and [Formula: see text] of 31.94-0.64 and 33.53-0.60 for internal evaluation with and without previous concentration. Furthermore, the results prove the added value of the proposed Quantile Ensemble model in providing clinically useful individualized uncertainty predictions and show the limits of homoscedastic methods like Gaussian Processes in clinical applications.Conclusions: Our results show that ML models can consistently estimate piperacillin concentrations with acceptable and high predictive accuracy when identical dosing regimens as in the training data are used while providing highly relevant uncertainty predictions. However, generalization capabilities to other dosing schemes are limited. Notwithstanding, incorporating ML models in therapeutic drug monitoring programs seems definitely promising and the current work provides a basis for validating the model in clinical practice. [ABSTRACT FROM AUTHOR]

Fast and reliable ethanol assays analysis are used in a clinical context for patients suspected of ethanol intoxication. Mostly, automated systems using an enzymatic reaction based on ethanol dehydrogenase are used. The manuscript focusses on the evaluation of the performance of these assays. Data included 30 serum samples used in the Belgian EQA scheme from 2019 to 2021 and concentrations ranged from 0.13 to 3.70 g/L. A regression line between target concentrations and reported values was calculated to evaluate outliers, bias, variability and measurement uncertainty. A total of 1,611 results were taken into account. Bias was the highest for Alinity c over the whole concentration range and the lowest for Vitros for low concentrations and Cobas 8000 using the c702 module for high concentrations. The Architect and Cobas c501/c502 systems showed the lowest variability over the whole concentration range. Highest variability was observed for Cobas 8000 using the 702 module, Thermo Scientific and Alinity c. Cobas 8000 using the c702 module showed the highest measurement uncertainty for lower concentrations. For higher concentrations, Alinity c, Thermo Scientific and Vitros were the methods with the highest measurement uncertainty. The bias of the enzymatic techniques is nearly negligible for all methods except Alinity c. Variability differs strongly between measurement procedures. This study shows that the Alinity c has a worse measurement uncertainty than other systems for concentrations above 0.5 g/L. Overall, we found the differences in measurement uncertainty to be mainly influenced by the differences in variability. [ABSTRACT FROM AUTHOR]

N-Piperidinyl etonitazene ('etonitazepipne') represents a recent addition to the rapidly expanding class of 2-benzylbenzimidazole 'nitazene' opioids. Following its first identification in an online-sourced powder and in biological samples from a patient seeking help for detoxification, this report details its in-depth chemical analysis and pharmacological characterization. Analysis of the powder via different techniques (LC-HRMS, GC–MS, UHPLC-DAD, FT-IR) led to the unequivocal identification of N-piperidinyl etonitazene. Furthermore, we report the first activity-based detection and analytical identification of N-piperidinyl etonitazene in authentic samples. LC-HRMS analysis revealed concentrations of 1.21 ng/mL in serum and 0.51 ng/mL in urine, whereas molecular networking enabled the tentative identification of various (potentially active) urinary metabolites. In addition, we determined that the extent of opioid activity present in the patient's serum was equivalent to the in vitro opioid activity exerted by 2.5–10 ng/mL fentanyl or 10–25 ng/mL hydromorphone in serum. Radioligand binding assays in rat brain tissue revealed that the drug binds with high affinity (Ki = 14.3 nM) to the µ-opioid receptor (MOR). Using a MOR-β-arrestin2 activation assay, we found that N-piperidinyl etonitazene is highly potent (EC50 = 2.49 nM) and efficacious (Emax = 183% versus hydromorphone) in vitro. Pharmacodynamic evaluation in male Sprague Dawley rats showed that N-piperidinyl etonitazene induces opioid-like antinociceptive, cataleptic, and thermic effects, its potency in the hot plate assay (ED50 = 0.0205 mg/kg) being comparable to that of fentanyl (ED50 = 0.0209 mg/kg), and > 190 times higher than that of morphine (ED50 = 3.940 mg/kg). Taken together, our findings indicate that N-piperidinyl etonitazene is a potent opioid with the potential to cause harm in users. [ABSTRACT FROM AUTHOR]

Therapeutic drug monitoring (TDM) of tyrosine kinase inhibitors (TKIs) is not yet performed routinely in the standard care of oncology patients, although it offers a high potential to improve treatment outcome and minimize toxicity. TKIs are perfect candidates for TDM as they show a relatively small therapeutic window, a wide inter-patient variability in pharmacokinetics and a correlation between drug concentration and effect. Moreover, most of the available TKIs are susceptible to various drug-drug interactions and medication adherence can be checked by performing TDM. Plasma, obtained via traditional venous blood sampling, is the standard matrix for TDM of TKIs. However, the use of plasma poses some challenges related to sampling and stability. The use of dried blood microsamples can overcome these limitations. Collection of samples via finger-prick is minimally invasive and considered convenient and simple, enabling sampling by the patients themselves in their home-setting. The collection of small sample volumes is especially relevant for use in pediatric populations or in pharmacokinetic studies. Additionally, working with dried matrices improves compound stability, resulting in convenient and cost-effective transport and storage of the samples. In this review we focus on the different dried blood microsample-based methods that were used for the quantification of TKIs. Despite the many advantages associated with dried blood microsampling, quantitative analyses are also associated with some specific difficulties. Different methodological aspects of microsampling-based methods are discussed and applied to TDM of TKIs. We focus on sample preparation, analytics, internal standards, dilution of samples, external quality controls, dried blood spot specific validation parameters, stability and blood-to-plasma conversion methods. The various impacts of deviating hematocrit values on quantitative results are discussed in a separate section as this is a key issue and undoubtedly the most widely discussed issue in the analysis of dried blood microsamples. Lastly, the applicability and feasibility of performing TDM using microsamples in a real-life home-sampling context is discussed. [ABSTRACT FROM AUTHOR]

An ultra‐high pressure liquid chromatography high‐resolution mass spectrometric (UHPLC–HRMS) method was developed for the simultaneous and sensitive quantification of 10 β‐lactam antibiotics (cefepime, meropenem, amoxicillin, cefazolin, benzylpenicillin, ceftazidime, piperacillin, flucloxacillin, cefuroxime and aztreonam), linezolid and β‐lactamase inhibitors tazobactam and clavulanic acid in human plasma. Validation according to the EMA guidelines showed excellent within‐ and between‐run accuracy and precision (i.e. between 1.1 and 8.5%) and high sensitivity (i.e. lower limit of quantification between 0.25 and 1 mg/L). The UHPLC–HRMS method enables a short turnaround time and high sensitivity and needs only a small amount of plasma, allowing appropriate routine therapeutic drug monitoring. The short turnaround time is obtained by speeding up the protocol on multiple levels, i.e. fast and workload‐efficient sample preparation (i.e. protein precipitation and dilution), short (4 min) instrument run time, simultaneous measurement of all relevant β‐lactam antibiotics used in the intensive care unit and the use of the same instrument, column and mobile phases as for the other routine methods in our laboratory. [ABSTRACT FROM AUTHOR]

Cyclosporine A, immunoassay, immunosuppressant drugs, liquid chromatography-tandem mass spectrometry (LC-MS/MS), therapeutic drug monitoring Recently, the CsA immunoassay was reformulated (ref: LN 3R30) to improve assay imprecision of the previous on-market assay (ref: LK 1L75). Keywords: cyclosporine A; immunoassay; immunosuppressant drugs; liquid chromatography-tandem mass spectrometry (LC-MS/MS); therapeutic drug monitoring EN cyclosporine A immunoassay immunosuppressant drugs liquid chromatography-tandem mass spectrometry (LC-MS/MS) therapeutic drug monitoring e209 e212 4 04/12/21 20210501 NES 210501 To the Editor, Cyclosporine A (CsA) is an immunosuppressant drug (ISD) used to prevent transplant rejection after organ transplantation. Assay imprecision (within-run, between-run and total imprecision) was evaluated, both for the immunoassays as for the LC-MS/MS method, following the Clinical and Laboratory Standards Institute protocol EP5-A3 and using three Lyphocheck Whole Blood Immunosuppressant Controls, level 1, 2 and 3 (Bio-Rad Laboratories, Hercules, CA; LOT: 26270, EXP: 09/2021) [[10]]. [Extracted from the article]

Summary: Objective: One third of epilepsy patients do not become seizure‐free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long‐term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. Methods: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno‐associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell‐specific promotor targeting excitatory neurons. The effect of clozapine‐mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long‐term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. Results: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD‐expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long‐term treatment with clozapine and olanzapine both resulted in significant seizure‐suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. Significance: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure‐suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

New psychoactive substances continue to appear on the drug market. Until recently, new synthetic opioids, which are among the most dangerous new psychoactive substances, primarily encompassed analogs of the potent analgesic fentanyl. Lately, also other new synthetic opioids have increasingly started to surface. This is the first report on the identification and full chemical characterization of brorphine, a novel potent synthetic opioid with a piperidine benzimidazolone structure. A powder, identified as brorphine, was obtained from a patient seeking medical help for detoxification. Brorphine was also found in a serum sample of the patient. Liquid chromatography–high-resolution mass spectrometry (LC–HRMS) identified an exact mass of m/z 400.1020 and 402.1005 for the compound, corresponding to both bromine isotopes. Further chemical characterization was performed by gas chromatography–mass spectrometry, liquid chromatography–diode array detection and Fourier-transform infrared spectroscopy analyses. Finally, the structure was confirmed by performing 1H-NMR and 13C-NMR spectroscopy. In vitro biological activity of brorphine was determined by a cell-based µ-opioid receptor activation assay, resulting in an EC 50 of 30.9 nM (13.5 ng/mL) and an E max of 209% relative to hydromorphone, confirming the high potency and efficacy of this compound. In a serum sample of the patient, brorphine and a hydroxy-metabolite were found using the LC–HRMS screening method. The presence of opioid activity in the serum was also confirmed via the activity-based opioid screening assay. The occurrence of brorphine is yet another example of how the illicit drug market is continuously evolving in an attempt to escape international legislation. Its high potency poses a serious and imminent health threat for any user. [ABSTRACT FROM AUTHOR]

The aim of this study is to assess the results of inspections in the last three years of drug abuse testing in medical laboratories according to the latest regulations in Turkey. The on‐site inspections of medical laboratories for drugs abuse testing performed in Alcohol and Drug Addiction Treatment Centers during 2014–2016 are described, and laboratory processes and performance evaluated. The performance of 35 laboratories in 2014, 62 laboratories in 2015, and 94 laboratories in 2016 were scored as the sum of the scores for all answers on the inspection form. An inspected laboratory was considered to have an unconformity if the total score was less than 2/3 of maximum score. The total scores of inspections and the number of laboratories with between years were compared using one‐way analysis of variance and slope Chi‐square for trend test, respectively. Total scores increased statistically significantly from 35.9 ± 16.2 in 2014, to 43.5 ± 16.3 in 2015 and 49.1 ± 1.3 in 2016 (p < 0.001). The laboratories with unconformities decreased statistically significantly from 57% in 2014 to 37% in 2015 and 22% in 2016 (p < 0.001). The published legislation and the inspections contributed to national standardization and improved quality of service in medical laboratories for drug abuse testing. Drug treatment centers for probation service in Turkey have increased approximately four‐fold in two years, also laboratory services about drug abuse testing. This report assessed the recent status of drug of abuse testing performed by medical laboratories in Turkey. Total scores increased statistically and the laboratories with unconformities decreased statistically according to on‐site inspections (detail in Table). The published legislation and the inspections contributed to national standardization and improved quality of service in medical laboratories for drug abuse testing. [ABSTRACT FROM AUTHOR]

Background: Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem concentrations in an independent validation dataset when meropenem is infused continuously.Patients and methods: A PopPK model was developed with concentration-time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted.Results: A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ± 3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from -8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L.Conclusions: Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing. [ABSTRACT FROM AUTHOR]

Background Several population pharmacokinetic (PopPK) models for meropenem dosing in ICU patients are available. It is not known to what extent these models can predict meropenem concentrations in an independent validation dataset when meropenem is infused continuously. Patients and methods A PopPK model was developed with concentration–time data collected from routine care of 21 ICU patients (38 samples) receiving continuous infusion meropenem. The predictability of this model and seven other published PopPK models was studied using an independent dataset that consisted of 47 ICU patients (161 samples) receiving continuous infusion meropenem. A statistical comparison of imprecision (mean square prediction error) and bias (mean prediction error) was conducted. Results A one-compartment model with linear elimination and creatinine clearance as a covariate of clearance best described our data. The mean ± SD parameter estimate for CL was 9.89 ± 3.71 L/h. The estimated volume of distribution was 48.1 L. The different PopPK models showed a bias in predicting serum concentrations from the validation dataset that ranged from −8.76 to 7.06 mg/L. Imprecision ranged from 9.90 to 42.1 mg/L. Conclusions Published PopPK models for meropenem vary considerably in their predictive performance when validated in an external dataset of ICU patients receiving continuous infusion meropenem. It is necessary to validate PopPK models in a target population before implementing them in a therapeutic drug monitoring program aimed at optimizing meropenem dosing. [ABSTRACT FROM AUTHOR]

Background: Harmonization of units is an important step to improve the comparability of clinical chemistry results, but few examples exist of successful harmonization efforts. We present the results of a pragmatic approach that was implemented in Belgium from 2012. Methods: After a large consultation and information of stakeholders, preferred units were proposed for 140 assays, including the 23 immunoassays discussed in more detail here. The change occurred in two phases, first involving assays for which there was no change in the numerical result, then changes involving a change in numerical results. Laboratories were invited to participate in this harmonization on a voluntary basis. The project was based on a bottom-up approach, large consultation and the pragmatic choice of the proposed units, including conventional and SI units. Results: The large heterogeneity of units was drastically reduced; adoption of the preferred units increased from 3% (insulin) – 45% (HCG) to 70% (insulin) – 96% (LH and FSH). Adoption of the preferred units was higher if it involved no change in numerical values (90%) than when there was a change (76%). Conclusions: We believe that the harmonization effort has reached its goals. Without aiming at implementing SI units for all parameters, our strategy was successful with a large majority of the laboratories switching to the proposed units. Moreover, the harmonization program is still progressing, with additional laboratories converting to the consensus units. [ABSTRACT FROM AUTHOR]

Objectives: Antibiotic therapy is of vital importance for the control of infectious exacerbations in cystic fibrosis (CF) patients. However, very little is known regarding the fraction of systemically administered antibiotics reaching the lower respiratory tract secretions. We developed and validated a method to measure the concentrations of piperacillin, ceftazidime, meropenem and aztreonam in CF sputum, and present the validation data.Methods: Ultra-performance LC coupled to tandem MS was used. A single sample can be measured in 2.5 min with multiple reaction monitoring in positive electrospray ionization mode. Deuterated internal standards were used and a concentration range of 0.7-160 mg/L was covered. The method was validated according to the EMA guideline on analytical method validation.Results: The boundaries within which a reliable measurement in CF sputum can be performed were determined. A few constraints are linked to the instability of the antibiotics in sputum. Piperacillin showed limited stability at room temperature and during freeze-thaw cycles. Autosampler instability was observed after 15 h for aztreonam at low concentrations.Conclusions: The method allows a reliable measurement of the selected antibiotics, if precautions are taken regarding the limited stability of piperacillin at room temperature. Due to freeze-thaw instability, piperacillin should always be analysed on the day of sampling. Quick review of the analytical data and reanalysis are needed as low concentrations of aztreonam are not stable in the autosampler. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the population pharmacokinetics of piperacillin and tazobactam in critically ill infants and children, in order to develop an evidence-based dosing regimen.Patients and methods: This pharmacokinetic study enrolled patients admitted to the paediatric ICU for whom intravenous piperacillin/tazobactam (8:1 ratio) was indicated (75 mg/kg every 6 h based on piperacillin). Piperacillin/tazobactam concentrations were measured by an LC-MS/MS method. Pharmacokinetic data were analysed using non-linear mixed effects modelling.Results: Piperacillin and tazobactam blood samples were collected from 47 patients (median age 2.83 years; range 2 months to 15 years). Piperacillin and tazobactam disposition was best described by a two-compartment model that included allometric scaling and a maturation function to account for the effect of growth and age. Mean clearance estimates for piperacillin and tazobactam were 4.00 and 3.01 L/h for a child of 14 kg. Monte Carlo simulations showed that an intermittent infusion of 75 mg/kg (based on piperacillin) every 4 h over 2 h, 100 mg/kg every 4 h given over 1 h or a loading dose of 75 mg/kg followed by a continuous infusion of 300 mg/kg/24 h were the minimal requirements to achieve the therapeutic targets for piperacillin (60% f T >MIC >16 mg/L).Conclusions: Standard intermittent dosing regimens do not ensure optimal piperacillin/tazobactam exposure in critically ill patients, thereby risking treatment failure. The use of a loading dose followed by a continuous infusion is recommended for treatment of severe infections in children >2 months of age. [ABSTRACT FROM AUTHOR]

For many drugs, there is a poor correlation between the plasma and oral fluid (OF) concentrations, due to differences in OF pH, oral contamination, stimulation of OF flow and variability of the volume of sample taken. The aim of this study was to evaluate the OF/plasma ratio and variability in drug concentration in OF sampled by two commercially available collection systems: Saliva Collection System (SCS) and Quantisal. Blood and OF samples were collected from 12 volunteers after intake of 19.5 mg codeine phosphate. Six persons were sampled by SCS first, followed by Quantisal; six other participants used Quantisal before SCS. The OF content of SCS tubes was measured spectrophotometrically. The Quantisal devices were weighed to correct for the effectively obtained OF volume. Codeine was measured by gas chromatography-mass spectrometry. The mean codeine concentration at 1 h was 29.8 ± 18.8 µg/L in plasma, 72.8 ± 63.9 µg/L in SCS OF and 85.3 ± 72.6 µg/L in Quantisal OF. The mean OF/plasma ratio was 2.30 ± 0.77 (SCS) and 2.69 ± 1.94 (Quantisal). Pearson's correlation coefficient between OF and plasma codeine concentrations was statistically significantly (P = 0.005) higher for SCS (R² = 0.745) than for Quantisal (R² = 0.403). The variability in ratios with Quantisal wasmarkedly reduced when used after SCS. Codeine concentrationsmeasured in OF taken with SCS correlate better with plasma concentrations than in OF obtained with Quantisal, particularly when Quantisal was used first. [ABSTRACT FROM AUTHOR]

ContextCyanide poisoning may be caused by acetonitrile, a common industrial organic solvent and laboratory agent.ObjectiveTo describe the potential use of disulfiram in treating acetonitrile poisoning in a human clinical case and to further study its effect in human liver microsomesin vitro.Case detailsA 30-year-old man initially presented with a cholinergic toxic syndrome following ingestion of aldicarb. Toxicological analysis revealed coingestion of ethanol. He subsequently developed severe metabolic acidosis caused by the cyanogenic compound acetonitrile which was erroneously interpreted as acetone in the chromatogram. After three treatments with hydroxocobalamin (5 g i.v.) and sodium thiosulfate (12.5 g i.v.) on days 2, 3, and 5, he had transient improvement but recurrent lactic acidosis. Treatment with disulfiram was associated on day 7 with resolution of metabolic acidosis and slowing of the decrease in acetonitrile concentration. He recovered from acetonitrile toxicity completely. The time course of acetonitrile, thiocyanate, and cyanide concentrations suggested that disulfiram inhibited cyanide formation.ResultsIn vitro experiments with human liver microsomes showed the cyanide concentration was significantly lower after incubation with acetonitrile and disulfiram than acetonitrile alone (a mean 60% reduction in cyanide level).DiscussionAlthough disulfiram was given late in the course of the poisoning it is possible that it contributed to the recovery. [ABSTRACT FROM AUTHOR]

Background: In problem-based learning, a tutor, the quality of the problems and group functioning play a central role in stimulating student learning. This study is conducted in a hybrid medical curriculum where problem-based learning is one of the pedagogical approaches. The aim of this study was to examine which tutor tasks are the most important during the tutorial sessions and thus should be promoted in hybrid (and in maybe all) problem-based learning curricula in higher education. Methods: A student (N = 333) questionnaire was used to obtain data about the problem-based learning process, combined with the achievement score of the students on a multiple-choice exam. Structural equation modeling was used to test the fit of different models (two existing models and a new simplified model) representing the factors of interest and their relationships, in order to determine which tutor characteristics are the most important in the present study. Results: A new simplified model is presented, which demonstrates that stimulation of active and self-directed learning by tutors enhances the perceived case quality and the perceived group functioning. There was no significant effect between the stimulation of collaborative learning and perceived group functioning. In addition, group functioning was not a significant predictor for achievement. Conclusions: We found that stimulating active and self-directed learning are perceived as tutors' most important tasks with regard to perceived case quality and group functioning. It is necessary to train and teach tutors how they can stimulate active and self-directed learning by students. [ABSTRACT FROM AUTHOR]

The article discusses a study which evaluated the efficacy of voriconazole (VRC) in treating fungal infections. Topics covered include the major determinants of variability of VRC plasma concentrations such as oral bioavailability and VRC pharmacokinetics, an overview of the analytical methods for measuring VRC in plasma including bioassays, and the linearity of the VRC assay.

Objectives To investigate the population pharmacokinetics of cefuroxime in critically ill patients. Methods In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous cefuroxime. Blood samples were analysed using a validated ultra HPLC tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. Results One hundred and sixty blood samples were collected from 20 patients. CLCR ranged between 10 and 304 mL/min. A two-compartment model with between-subject variability on CL, V of the central compartment and V of the peripheral compartment described the data adequately. Twenty-four hour urinary CLCR was supported as a descriptor of drug CL. The population model for CL was CL = θ1 × CLCR/100, where θ1 is the typical cefuroxime CL in the population, which is 9.0 L/h. The mean V was 22.5 L. Dosing simulations showed failure to achieve the pharmacokinetic/pharmacodynamic target of 65% fT>MIC for an MIC of 8 mg/L with standard dosing regimens for patients with CLCR ≥50 mL/min. Conclusions Administration of standard doses by intermittent bolus is likely to result in underdosing for many critically ill patients. Continuous infusion of higher than normal doses after a loading dose is more likely to achieve pharmacokinetic/pharmacodynamic targets. However, even continuous infusion of high doses (up to 9 g per day) does not guarantee adequate levels for all patients with a CLCR of ≥300 mL/min if the MIC is 8 mg/L. [ABSTRACT FROM PUBLISHER]

The relationship of drug concentrations between oral fluid and whole blood was evaluated by studying the linear correlation of concentrations and calculating the oral fluid to blood concentration ratios (OF/B) for different substances. Paired oral fluid and whole blood samples were collected from volunteers and persons suspected of drug use in four European countries. Oral fluid samples were collected with the Saliva∙Sampler™ device. All samples were analyzed for drugs of abuse and psychoactive medicines with validated gas and liquid chromatography-mass spectrometric methods. The median OF/B ratios were, for amphetamines 19-22, for opioids 1.8-11, for cocaine and metabolites 1.7-17, for tetrahydrocannabinol (THC) 14, for benzodiazepines 0.035-0.33, and for other psychoactive medicines 0.24-3.7. Most of the these results were close to theoretical values based on the physicochemical properties of the drugs and to values presented earlier, but there was a lot of inter-individual variation in the OF/B ratios. For all substances, except for lorazepam (R2 = 0.031) and THC (R2 = 0.030), a correlation between the oral fluid and whole blood concentrations was observed. Due to large variation seen here, drug findings in oral fluid should not be used to estimate the corresponding concentrations in whole blood (or vice versa). However, detection of drugs in oral fluid is a sign of recent drug use and oral fluid can be used for qualitative detection of several drugs, e.g. in epidemiological prevalence studies. By optimizing the sampling and the analytical cut-offs, the potential of oral fluid as a confirmation matrix could be enhanced. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Oral fluid is an easily available specimen for studying drug use in a cohort or population. The prevalence of drugs in samples of oral fluid is the same as the prevalence in blood if using equivalent cutoff concentrations. The cutoffs in oral fluid may be higher or lower than that in blood in accordance with the median oral fluid-to-blood (OF/B) concentration ratio, but it is also influenced by the skewness of the distribution of OF/B ratios. The aim of this study was to determine formulae for the estimation of equivalent cutoff concentrations in oral fluid and blood for 12 commonly used illegal and medicinal psychoactive drugs when oral fluid was collected with Statsure Saliva·SamplerTM. Paired samples from 4,080 persons were collected and analyzed with chromatographic methods and mass spectroscopic detection. Regression formulae for the concentrations corresponding to selected percentiles in oral fluid versus the same concentration percentiles in blood were determined. The accuracy when multiplying the cutoff thresholds in blood with the average and median OF/B ratios to estimate equivalent cutoffs in oral fluid was also investigated. Prevalence regression gave the most accurate results. The regression formulae can be used to estimate equivalent cutoff concentrations in oral fluid and blood. [ABSTRACT FROM AUTHOR]

The article examines the analytical characteristics of the ARK methotrexate (MTX) immunoassay for the quantitative examination of MTX in human plasma on automated clinical chemistry analyzers. Topics discussed include the purpose of the antifolate MTX, results of the accuracy evaluation of the immunoassay and functional sensitivity and linearity of the ARK MTX immunoassay. Also discussed is the potential of the ARK Assay as an alternative to fluorescence polarization immunoassay (FPIA).

The objective of this study was to compare the number of drivers who self-reported cannabis use by questionnaires to the results of toxicological analysis. During roadside surveys, 2957 respondents driving a personal car or van completed a questionnaire to report their use of drugs and medicines during the previous two weeks and to indicate the time of their last intake. Cannabis was analyzed in oral fluid by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), in blood by gas chromatography-mass spectrometry (GC-MS). Frequencies in the time categories were calculated and compared with toxicological results. Diagnostic values were calculated for the time categories in which positive findings were to be expected (<4 h and <2 4h, respectively for tetrahydrocannabinol (THC) and delta9-tetrahydrocannabinol (THCCOOH) in blood, <12 h for THC in oral fluid). Most self-reported cannabis use was more than 12 h before driving. The sensitivity of the questionnaire was low, while the specificity and accuracy were high. Kappa statistics revealed a fair agreement between self-report and positive findings for THC in oral fluid and blood and moderate agreement with THCCOOH in blood. Self-report largely underestimates driving under the influence of cannabis, particularly recent cannabis use; therefore analysis of biological samples is necessary. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: Variation in thyroid hormone (TH) concentrations between subjects is greater than in a single subject over a prolonged period of time, suggesting an individual set point for thyroid function. We have previously shown that TH levels within normal range are associated with clinical indices such as bone mass, BMI, and heart rate. The aim of this study on young men was therefore to gain insight into the determinants of variation in TH levels among healthy subjects. Methods: Healthy male siblings (n=941, 25-45 years) were recruited in a cross-sectional, populationbased study; a history or treatment of thyroid disease and thyroid auto-immunity were exclusion criteria. A complete assessment of TH status was performed (TSH, free thyroxine (FT4), free triiodothyronine (FT3), thyroperoxidase, and thyroglobulin antibodies, reverse T3 (rT3), thyroidbinding globulin (TBG), and urinary iodine levels). Genotyping was performed by TaqMan and KASP (KBiosciences) genotyping assays. Results: (F)T4, rT3, and TBG had heritability estimates between 80 and 90%. Estimates were lower for (F)T3 (60%) and lowest for TSH (49%). Significant associations were observed between different single-nucleotide polymorphisms (SNPs) in the thyroid pathway and TSH, FT4, ratio FT3:FT4, and rT3. Nevertheless, these SNPs only explain a limited part of the heredity. As to age and lifestyle-related factors, (F)T3 was negatively related to age and education level, positively to smoking and BMI (all P<0.0001) but not substantially to urinary iodine concentrations. Smoking was also negatively related to TSH and positively to FT4. Conclusion: Both genetic and lifestyle-related factors play a role in determining between-subject variation in TH levels in euthyroid young men, although genetic factors seem most important. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to investigate the population pharmacokinetics and pharmacodynamics of amoxicillin and clavulanic acid in critically ill patients. Methods In this observational pharmacokinetic study, multiple blood samples were taken over one dosing interval of intravenous amoxicillin/clavulanic acid (1000/200 mg). Blood samples were analysed using a validated ultra HPLC–tandem mass spectrometry technique. Population pharmacokinetic analysis and dosing simulations were performed using non-linear mixed-effects modelling. Results One-hundred-and-four blood samples were collected from 13 patients. For both amoxicillin and clavulanic acid, a two-compartment model with between-subject variability for both the clearance and the volume of distribution of the central compartment described the data adequately. For both compounds, 24 h urinary creatinine clearance was supported as a descriptor of drug clearance. The mean clearance of amoxicillin was 10.0 L/h and the mean volume of distribution was 27.4 L. For clavulanic acid, the mean clearance was 6.8 L/h and the mean volume of distribution was 19.2 L. Dosing simulations for amoxicillin supported the use of standard dosing regimens (30 min infusion of 1 g four-times daily or 2 g three-times daily) for most patients when using a target MIC of 8 mg/L and a pharmacodynamic target of 50% fT>MIC, except for those with a creatinine clearance >190 mL/min. Dosing simulations for clavulanic acid showed little accumulation when high doses were administered to patients with high creatinine clearance. Conclusions Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance. [ABSTRACT FROM PUBLISHER]

The objective of this paper is to compare concentrations of alcohol, illicit, and medicinal drugs in seriously injured drivers and drivers selected randomly at the roadside. Blood samples were analyzed for alcohol, 17 medicinal drugs and 8 illicit psychoactive substances and/or their metabolites by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography mass spectrometry (GC-MS) in injured drivers admitted to the emergency departments of five hospitals in Belgium between January 2008 and May 2010 and in drivers randomly selected between January 2008 and September 2009. Three hundred and seventy-seven seriously injured drivers and 2750 roadside respondents were selected. In the roadside survey, out of the 203 concentrations above DRUID (Driving Under the Influence of Drugs, Alcohol and Medicines) cut-offs for medicinal drugs, 51% were in the therapeutic range, 46% infratherapeutic, and 2.5% supratherapeutic. In the seriously injured drivers, out of the 78 concentrations above DRUID cut-offs for medicinal drugs, these percentages were respectively 63%, 33%, and 4%. Significant differences were found in the distribution of concentrations for opioids, benzodiazepines, and Z-drugs. For the latter, while in the seriously injured drivers study most concentrations were therapeutic, in the roadside survey most were infratherapeutic. The opposite was observed for the opioids. Eight and 41% of the roadside respondents and injured drivers, respectively, had an alcohol concentration above 0.1 g/L, with higher concentrations found in the injured drivers. For illicit drugs, significant differences were found for amphetamine and cocaine, for which respectively lower and higher concentrations were observed in the blood samples taken in the roadside survey. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The objective of this study was to determine the presence of alcohol and drugs in drivers severely injured in traffic crashes in six European countries. Data were collected from 2492 seriously injured drivers of cars and vans in Belgium, Denmark, Finland, Italy, Lithuania, and the Netherlands, between 2007 and 2010. Toxicological analysis was performed with chromatographic techniques on whole blood for 23 substances. The percentage of drivers positive for at least one psychoactive substance ranged between 28% (Lithuania) and 53% (Belgium). Alcohol (≥0.1 g/L) was the most common finding with the highest percentage in Belgium (42.5%). Among the alcohol-positive drivers, 90.5% had a blood alcohol count (BAC) ≥0.5 g/L and 65.7% had a BAC ≥1.3 g/L. Benzodiazepines (0.0-10.2%) and medicinal opioids (0.5-7.8%) were the most prevailing medicinal drugs, but half of the concentrations were lower than therapeutic. Cannabis (0.5-7.6%) was the most prevailing illicit drug. Alcohol was found in combination with drugs in 2.3-13.2% of the drivers. Drug combinations were found in 0.5-4.3% of the drivers. This study confirms the high prevalence of psychoactive substances in injured drivers, but we observed large differences between the participating countries. Alcohol was the most common finding, followed by cannabis and benzodiazepines. Notable are the many drivers having a BAC ≥ 1.3 g/L. The majority of the substances were found in combination with another psychoactive substance, mostly alcohol. The high prevalence of high BACs and combinations (compared to roadside surveys) suggest that those drivers are most at risk and that preventive actions should target them preferentially. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Rational: An increasing number of fatal road-accidents have been reported in which ecstasy was found in the blood of drivers. Although, ecstasy is frequently found to have been used in combination with alcohol, studies on the acute effects of ecstasy co-administered with alcohol on driving performance are relatively rare. Objective: The present study was designed to establish the extent of driver impairment as a consequence of ecstasy or combined ecstasy and alcohol use as compared to driving under the influence of 0.3‰, 0.5‰ and 0.8‰ alcohol. Furthermore, subjective performance was also assessed. Results: Alcohol and ecstasy mainly influenced automated driving performance such as lateral and speed control. However, small to no effects of the substances were found on more complex driving behaviour. Overall, variance within the different driving measures was high especially when participants were treated with 3.4-methylenedioxy-methamphetamine (MDMA) and alcohol. Furthermore, equivalence testing showed that combined use may lead to impaired driving for some, but not all, drivers. Participants rated their own performance to be slightly worse than normal in both studies. Since driving was actually seriously deteriorated, this was a falsely positive assessment of their condition. Conclusions: The dissociation between subjective perceptions and objective performance decrements are important notions for traffic safety since this may affect a driver's judgement of whether or not it is safe to drive. For example, an intoxicated individual might decide to drive because the feelings of alertness caused by MDMA cloud the impairing effects of other drugs such as alcohol, thereby creating a potentially serious risk for traffic safety. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to assess the risk of having a traffic accident after using alcohol, single drugs, or a combination, and to determine the concentrations at which this risk is significantly increased. Methods: A population-based case-control study was carried out, collecting whole blood samples of both cases and controls, in which a number of drugs were detected. The risk of having an accident when under the influence of drugs was estimated using logistic regression adjusting for gender, age and time period of accident (cases)/sampling (controls). The main outcome measures were odds ratio (OR) for accident risk associated with single and multiple drug use. In total, 337 cases (negative: 176; positive: 161) and 2726 controls (negative: 2425; positive: 301) were included in the study. Results: Main findings were that 1) alcohol in general (all the concentrations together) caused an elevated crash risk; 2) cannabis in general also caused an increase in accident risk; at a cut- off of 2 ng/mL THC the risk of having an accident was four times the risk associated with the lowest THC concentrations; 3) when ranking the adjusted OR from lowest to highest risk, alcohol alone or in combination with other drugs was related to a very elevated crash risk, with the highest risk for stimulants combined with sedatives. Conclusion: The study demonstrated a concentration- dependent crash risk for THC positive drivers. Alcohol and alcohol-drug combinations are by far the most prevalent substances in drivers and subsequently pose the largest risk in traffic, both in terms of risk and scope. [ABSTRACT FROM AUTHOR]

Background The consumption of some psychotropic medicines has a negative effect on the fitness to drive. Pharmacists are expected to give useful advice to patients on their participation in traffic. However, almost no information is available on this topic. Objective To assess the effect of training and implementation of new dispensing guidelines with regard to driving-impairing medicines, in two types of dispensing support tools. User acceptance was measured as well as the effect on pharmacists' attitudes & awareness, self-reported behaviour and knowledge. Setting Pharmacists from East Flanders in Belgium. Methods Two intervention groups and a control group participated. The intervention groups followed a training and were provided with a dispensing support tool containing information on the effect of medicines on driving ability, which was either stand-alone (USB stick) or integrated into the daily used software (ViaNova). The three groups filled out a questionnaire prior to and after the intervention period. Main outcome measure Answers to a pre/post-questionnaire on attitudes and awareness, self-reported behaviour, knowledge and user acceptance. Results Many pharmacists were already strongly interested in the topic at the beginning of the study. Positive changes in attitude, self-reported behaviour and knowledge were measured mostly in the group of pharmacists for which the information was integrated in their daily used software. These pharmacists asked significantly more about the patients' driving experience, informed them more about driving-related risk and gave more detailed information on impairing effects of medicines. The knowledge of the participating pharmacists on the topic 'medicines and driving' remained generally low. The participants acknowledge the importance of being aware of the topic medicines and driving but they report a lack of information or education. They strongly prefer a tool that integrates the information in their daily used software. Conclusion Dispensing support tools with information on the potential impairing effect of a medicine on the fitness to drive increases awareness, reported risk communication behaviour as well as knowledge of pharmacists on this topic. Computerised dispensing support tools are most effective when the information is integrated into the daily used dispensing software. [ABSTRACT FROM AUTHOR]

In Europe, authorities frequently ask forensic laboratories to analyze seized cannabis plants to prove that cultivation was illegal (drug type and not fiber type). This is generally done with mature and flowering plants. However, authorities are often confronted with very young specimens. The aim of our study was to evaluate when the chemotype of cannabis plantlets can be surely determined through analysis of eight major cannabinoids content during growth. Drug-type seedlings and cuttings were cultivated, sampled each week, and analyzed by high-performance liquid chromatography with diode array detection. The chemotype of clones was recognizable at any developmental stage because of high total Δ9-tetrahydrocannabinol (THC) concentrations even at the start of the cultivation. Conversely, right after germination seedlings contained a low total THC content, but it increased quickly with plant age up, allowing chemotype determination after 3 weeks. In conclusion, it is not necessary to wait for plants' flowering to identify drug-type cannabis generally cultivated in Europe. [ABSTRACT FROM AUTHOR]