Publications by authors named "Kristof Maudens"

38 Publications

Multi-analyte LC-MS/MS quantification of 38 antipsychotics and metabolites in plasma: Method validation & application to routine analyses.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Aug 21;1179:122867. Epub 2021 Jul 21.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

The past decades have seen a rise in the prescription of antipsychotic drugs in the European population, despite the risk of extra-pyramidal, metabolic and cardiac side effects. A multi-analyte liquid chromatography - triple quadrupole mass spectrometry method was developed for the quantification of 38 antipsychotic drugs in plasma. Samples were extracted by a straightforward liquid-liquid extraction with methyl-tertiary-butyl-ether and the compounds of interest were chromatographically separated within 6 min. Calibration curves covered the recommended therapeutic range for all compounds, in addition to sub- and supratherapeutic concentrations for most. The method was successfully validated according to the European Medicines Agency guidelines on bioanalytical method validation. Analysis of medico-legal samples confirmed the relatively common use of the second generation antipsychotics quetiapine and olanzapine, as well as the continued presence of the first generation antipsychotic haloperidol.
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http://dx.doi.org/10.1016/j.jchromb.2021.122867DOI Listing
August 2021

Quantification of 54 Benzodiazepines and Z-Drugs, Including 20 Designer Ones, in Plasma.

J Anal Toxicol 2021 Feb;45(2):141-153

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Benzodiazepines are widely used in the treatment of sleep and anxiety disorders, as well as epileptic seizures and alcohol withdrawal because of their broad therapeutic index and low cost. Due to their central nervous system depressant effects they are also often implicated in traffic accidents and drug-related intoxications. With an increasing number of designer benzodiazepines used in a recreational setting, there is a need for analytical methods to be able to quantify both the prescribed and designer benzodiazepines. A liquid chromatography-triple quadrupole mass spectrometry method was developed for the quantification of 34 prescribed and 20 designer benzodiazepines in plasma. Different sample preparation strategies, including protein precipitation, liquid-liquid extraction, solid-phase extraction and mini-QuEChERS, were tested. The best recoveries for all compounds of interest were obtained with a liquid-liquid extraction using methyl-tertiary-butyl-ether and 500 μL plasma. The method was fully validated according to the European Medicines Agency guidelines for all compounds, except pivoxazepam, which is included for qualitative purposes only. In-sample stability issues were observed for cloxazolam, both at ambient temperature and during long-term storage at -20°C. Due to the large number of compounds included, the simple and time-efficient sample preparation and the relatively inexpensive instrumentation used, the presented method can be readily implemented in both therapeutic drug monitoring and forensic analyses.
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http://dx.doi.org/10.1093/jat/bkaa059DOI Listing
February 2021

When clozapine appears at a dance event….

Acta Clin Belg 2020 Dec 14;75(6):416-420. Epub 2019 Jun 14.

Emergency Department, Maria Middelares General Hospital , Ghent, Belgium.

: The content of substances sold and consumed as party drugs is often unknown. They may contain inactive, contaminated or unexpected ingredients, and the dosage of the active components may vary considerably. Obviously, these phenomena increase the chances of a wrong or delayed therapy. To illustrate this point, we report 3 cases of clozapine intoxication at a dance event where most likely clozapine tablets were sold as party drugs.: The three cases were part of a prospective toxicology study at a nocturnal indoor dance event.: One patient had to be intubated after obstructive breathing with desaturation and bradycardia, while the 2 other patients presented with syncope and altered mental status. All patients recovered after 20 minutes to 8 hours. Systematic toxicological analysis of the blood samples revealed the presence of clozapine (73-244 ng/ml) and its metabolite norclozapine (9-59 ng/ml). A pill, found in a pocket of one patient, was identified as Leponex® 100 mg (clozapine). This neuroleptic drug is mainly prescribed for treatment-resistant schizophrenia. In clozapine-naive subjects, orthostatic hypotension, bradycardia and syncope have been reported with a single 25 mg oral dose. Serum clozapine concentrations of the 3 cases were below the defined therapeutic range (350-600ng/ml) and the clozapine:norclozapine ratios were suggestive for recent drug intake.: Routine drug screening may be unable to detect the toxic agent(s) involved. Whenever unusual symptoms are observed in an intoxicated patient, blood and urine samples should be sent to a reference toxicology laboratory.
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http://dx.doi.org/10.1080/17843286.2019.1630068DOI Listing
December 2020

Lessons to be learned from toxicological analyses in intoxicated patients and seized materials at an electronic music dance festival.

Forensic Sci Int 2019 Jun 6;299:174-179. Epub 2019 Apr 6.

Belgian Early Warning System Drugs, Sciensano, Brussels, Belgium.

Medical problems related to illicit drug use are frequently encountered at electronic dance music (EDM) events. In this prospective study, the medical problems and toxicological analyses on intoxicated persons and seized materials are described jointly. The aim of this study is to find out to what extent these efforts may assist in developing prevention strategies and organising on-site care at EDM events. The most frequently encountered clinical presentation in the 121 included patients was: agitation/aggression (26%), drunkenness (25%), depressed level of consciousness (24%) and hallucinations (9%). Only five patients were transported by ambulance to a hospital. In 100 of the 121 included patients (83%) an ethanolemia of at least 0.50 g/L was measured (with ethanol as the only drug found in 47 cases). 3,4-methylenedioxymethamphetamine (MDMA) was detected in 54% of the blood samples, cocaine in 11%, gamma-hydroxybutyric acid (GHB) in 11%, amphetamine in 7%, ketamine in 6% and a new psychoactive substance (NPS) in 4%. Except for 8 MDMA-users poly drug use was found in all these cases. The 178 seized samples most frequently contained MDMA (31%), cannabis (28%) or no active substance (15%). In 11 samples (6%) an NPS was detected. Of particular interest was a tablet containing 4-chloromethamphetamine (a previously unknown neurotoxic NPS), 4-chloroamphetamine, para-methoxyamphetamine, para-methoxymethamphetamine and ethylone. Our data show that at EDM events ethanol and MDMA are still the party drugs causing most health hazards and that NPS only play a minor role. Regarding the toxicological efforts, we recommend to analyse all seized materials from an EDM event, but only blood samples from the most severely intoxicated patients.
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http://dx.doi.org/10.1016/j.forsciint.2019.03.047DOI Listing
June 2019

Suspect and non-target screening workflows to investigate the in vitro and in vivo metabolism of the synthetic cannabinoid 5Cl-THJ-018.

Drug Test Anal 2019 Mar 23;11(3):479-491. Epub 2018 Oct 23.

Toxicological Centre, University of Antwerp, Antwerp, Belgium.

The use of synthetic cannabinoids causes similar effects as Δ -tetrahydrocannabinol and long-term (ab)use can lead to health hazards and fatal intoxications. As most investigated synthetic cannabinoids undergo extensive biotransformation, almost no parent compound can be detected in urine, which hampers forensic investigations. Limited information about the biotransformation products of new synthetic cannabinoids makes the detection of these drugs in various biological matrices challenging. This study aimed to identify the main in vitro biotransformation pathways of 5Cl-THJ-018 and to compare these findings with an authentic urine sample of a 5Cl-THJ-018 user. The synthetic cannabinoid was incubated with pooled human liver microsomes and cytosol to simulate phase I and phase II biotransformations. Resulting extracts were analyzed with liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Three different data analysis workflows were applied to identify biotransformation products. A suspect screening workflow used an in-house database built from literature data and in silico biotransformation predictions. Two non-target screening workflows used a commercially available software and an open-source software for mass spectrometry data processing. A total of 23 in vitro biotransformation products were identified, with hydroxylation, oxidative dechlorination, and dihydrodiol formation pathways as the main phase I reactions. Additionally, five glucuronidated and three sulfated phase II conjugates were identified. The predominant in vivo pathway was through oxidative dechlorination and in total six metabolites of 5Cl-THJ-018 were identified. Biotransformation products both in vitro and in vivo were successfully identified using complementary suspect and non-target screening workflows.
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http://dx.doi.org/10.1002/dta.2508DOI Listing
March 2019

Validation of a simple, fast liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of 40 antidepressant drugs or their metabolites in plasma.

Clin Chim Acta 2018 Oct 13;485:243-257. Epub 2018 Jul 13.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium. Electronic address:

Introduction: Antidepressant (AD) use has increased significantly over the last decades. Therapeutic drug monitoring is recommended for compliance, toxicity and treatment efficiency. ADs also show a high prevalence in forensic cases. Few methods have been developed that combine a fast, easy sample clean-up with a quantification based on liquid chromatography-triple quadrupole mass spectrometry (LC-QQQ).

Methodology: A liquid-liquid extraction (LLE) was performed using 200 μL of plasma. The evaporated and reconstituted upper fraction was injected on a LC-QQQ system monitoring 3 transitions per compound. The method was fully validated according to international guidelines.

Results & Discussion: The chromatographic run time was under 12 min. The LLE was successful in removing interferences with minimal sensitivity loss. Calibration curves ranged from sub-therapeutic to toxic concentrations. Quality control samples showed high accuracy (81%-119%) and precision (≤14%) within and between batches. Stability was tested at ambient temperature and -20 °C. The method was successfully applied to external quality control and case samples.

Conclusion: The presented method successfully quantifies 40 compounds of interest. Because of a simple sample clean-up, a relatively short chromatographic run and a wide calibration range this method can be implemented in therapeutic drug monitoring, forensic research and related fields.
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http://dx.doi.org/10.1016/j.cca.2018.06.047DOI Listing
October 2018

In vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

J Pharm Biomed Anal 2018 May 21;153:158-167. Epub 2018 Feb 21.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium.

Designer benzodiazepines have recently emerged as a class of new psychoactive substances. These substances are used in recreational settings and as alternatives to prescription benzodiazepines as self-medication for patients suffering from anxiety or other mental disorders. Due to the limited information available on the metabolic fate of these new substances, it is challenging to reliably detect their usage in bioanalytical (e.g. clinical and forensic) settings. The objective of this study was to investigate the in vitro Phase I and Phase II metabolism of the new designer benzodiazepine cloniprazepam and identify potential biomarkers for its detection in human biological fluids. Cloniprazepam was incubated with human liver microsomes and cytosolic fractions to generate both Phase I and II metabolites. The extracts were analysed using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Identification of the metabolites was performed using two complementary workflows, including a suspect screening based on in silico predictions and a non-targeted screening. A total of nine metabolites were identified, eight Phase I metabolites and one Phase II metabolite, of which five were specific for cloniprazepam. Clonazepam was the major metabolite of cloniprazepam. Hydroxy-cloniprazepam, dihydroxy-cloniprazepam, 3-keto-cloniprazepam, 7-amino-cloniprazepam, hydroxy-clonazepam, 7-amino-clonazepam and 3-hydroxy-7-amino-clonazepam were formed through oxidation, hydroxylation, and/or reduction of the nitro-group. Glucuronidated hydroxy-cloniprazepam was the only Phase II metabolite detected. Five metabolites were specific for cloniprazepam. This study provided a set of human in vitro biotransformation products which can assist specific detection of cloniprazepam consumption in future studies.
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http://dx.doi.org/10.1016/j.jpba.2018.02.032DOI Listing
May 2018

Medical Emergencies Related to Ethanol and Illicit Drugs at an Annual, Nocturnal, Indoor, Electronic Dance Music Event.

Prehosp Disaster Med 2018 Feb 29;33(1):71-76. Epub 2017 Dec 29.

10Belgian Early Warning System on Drugs,Scientific Institute of Public Health,Brussels,Belgium.

Introduction Medical problems are frequently encountered during electronic dance music (EDM) events. Problem There are uncertainties about the frequencies and severity of intoxications with different types of recreational drugs: ethanol, "classical" illicit party drugs, and new psychoactive substances (NPS).

Methods: Statistical data on the medical problems encountered during two editions of an indoor electronic dance event with around 30,000 attendants were retrieved from the Belgian Red Cross (Mechelen, Belgium) database. Data on drug use were prospectively collected from the patient (or a bystander), the clinical presentation, and/or toxicological screening.

Results: In the on-site medical station, 487 patients were treated (265 in 2013 and 222 in 2014). The most frequent reasons were trauma (n=171), headache (n=36), gastro-intestinal problems (n=44), and intoxication (n=160). Sixty-nine patients were transferred to a hospital, including 53 with severe drug-related symptoms. Analysis of blood samples from 106 intoxicated patients detected ethanol in 91.5%, 3,4-methylenedioxymethamphetamine (MDMA) in 34.0%, cannabis in 30.2%, cocaine in 7.5%, amphetamine in 2.8%, and gamma-hydroxybutyric acid (GHB) in 0.9% of patients (alone or in combination). In only six of the MDMA-positive cases, MDMA was the sole substance found. In 2014, the neuroleptic drug clozapine was found in three cases and ketamine in one. Additional analyses for NPS were performed in 20 cases. Only in one agitated patient, the psychedelic phenethylamines 25B-NBOMe and 25C-NBOMe were found.

Conclusions: At this particular event, recreational drug abuse necessitated on-site medical treatment in one out of 350 attendants and a hospital transfer in one out of 1,000. Ethanol remains the most frequently abused (legal) drug, yet classical illicit recreational drugs are also frequently (co-) ingested. The most worrying observation was high-risk poly-drug use, especially among MDMA users. Regarding NPS, the number of cases was low and the clinical presentations were rather mild. It should be stressed that these observations only apply to this particular event and cannot be generalized to other EDM events. Calle P , Sundahl N , Maudens K , Wille SMR , Van Sassenbroeck D , De Graeve K , Gogaert S , De Paepe P , Devriese D , Arno G , Blanckaert P . Medical emergencies related to ethanol and illicit drugs at an annual, nocturnal, indoor, electronic dance music event. Prehosp Disaster Med. 2018;33(1):71-76.
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http://dx.doi.org/10.1017/S1049023X17007099DOI Listing
February 2018

Influence of Body Mass Index on Hair Ethyl Glucuronide Concentrations.

Alcohol Alcohol 2017 Jan 20;52(1):19-23. Epub 2016 Oct 20.

Laboratoire National de Santé, Service de Toxicologie, Dudelange, Luxembourg.

Aim: Analysis of ethyl glucuronide (EtG) concentrations in hair is increasingly used to estimate the consumption of alcohol of the prior months. Linear correlations between the amount of alcohol consumed and the concentration of EtG in hair have been reported, and several variables that may influence this correlation have been investigated: e.g. cosmetic hair treatments, gender influences or hair color. Here, we investigate the influence of body mass index (BMI) on this correlation.

Methods: A post hoc analysis on the influence of BMI on the relation between amounts of alcohol consumed and the measured EtG concentrations in hair in 199 participants.

Results: Our data show higher EtG concentrations in participants with high BMI (≥25) compared to participants with low BMI (<25) (P = 0.001) across a wide range of amounts of alcohol consumed.

Conclusions: We conclude that BMI should be taken into account when interpreting hair EtG concentrations.

Short Summary: Ethyl glucuronide concentrations in hair (hEtG) can be used to estimate the consumption of alcohol of the prior months. Body mass index (BMI) influences this relation and BMI should be taken into account when interpreting hEtG concentrations in participants with high BMI (≥25) compared to participants with low BMI (<25).
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http://dx.doi.org/10.1093/alcalc/agw079DOI Listing
January 2017

Identification of in vitro and in vivo human metabolites of the new psychoactive substance nitracaine by liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

Anal Bioanal Chem 2016 Jul 16;408(19):5221-9. Epub 2016 May 16.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

The purpose of this work was to investigate the in vitro metabolism of nitracaine, a new psychoactive substance, using human liver microsome incubations, to evaluate the cytochrome P450 (CYP) enzyme isoforms responsible for the phase-I metabolism and to compare the information from the in vitro experiments with data resulting from an authentic user's urine sample. Accurate mass spectra of metabolites were obtained using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and were used in the structural identification of metabolites. Two major and three minor phase-I metabolites were identified from the in vitro experiments. The observed phase-I metabolites were formed through N-deethylation, N,N-deethylation, N-hydroxylation, and de-esterification, with CYP2B6 and CYP2C19 being the main enzymes catalyzing their formation. One glucuronidated product was identified in the phase-II metabolism experiments. All of these metabolites are reported for the first time in this study except the N-deethylation product. All the in vitro metabolites except the minor N,N-deethylation product were also present in the human urine sample, thus demonstrating the reliability of the in vitro experiments in the prediction of the in vivo metabolism of nitracaine. In addition to the metabolites, three transformation products (p-nitrobenzoic acid, p-aminobenzoic acid, and 3-(diethylamino)-2,2-dimethylpropan-1-ol) were identified, as well as several glucuronides and glutamine derived of them.
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http://dx.doi.org/10.1007/s00216-016-9616-7DOI Listing
July 2016

Ethyl glucuronide concentrations in hair: a controlled alcohol-dosing study in healthy volunteers.

Anal Bioanal Chem 2016 Mar 9;408(8):2019-25. Epub 2015 Nov 9.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Campus Drie Eiken, Universiteitsplein 1, 2610, Antwerp, Wilrijk, Belgium.

Ethyl glucuronide (EtG) is a minor phase II metabolite of alcohol that accumulates in hair. It has been established as a sensitive marker to assess the retrospective consumption of alcohol over recent months using a cut-off of ≥7 pg/mg hair to assess repeated alcohol consumption. The primary aim was to assess whether amounts of alcohol consumed correlated with EtG concentrations in hair. Additionally, we investigated whether the current applied cut-off value of 7 pg/mg hair was adequate to assess the regular consumption of low-to-moderate amounts of alcohol. A prospective controlled alcohol-dosing study in 30 healthy individuals matched on age and gender. Individuals were instructed to drink no alcohol (N = 10), 100 g alcohol per week (N = 10) or 150 g alcohol per week (N = 10) for 12 consecutive weeks, before and after which hair was collected. Throughout the study, compliance to daily alcohol consumption was assessed by analyzing urine EtG three times weekly. Participants in the non-drinking group had median EtG concentrations of 0.5 pg/mg hair (interquartile range (IQR) 1.7 pg/mg; range < 0.21-4.5 pg/mg). Participants consuming 100 and 150 g alcohol per week showed median EtG concentrations of 5.6 pg/mg hair (IQR 4.7 pg/mg; range 2.0-9.8 pg/mg) and 11.3 pg/mg hair (IQR 5.0 pg/mg; range 7.7-38.9 pg/mg), respectively. Hair EtG concentrations between the three study groups differed significantly from one another (p < 0.001). Hair EtG concentrations can be used to differentiate between repeated (low-to-moderate) amounts of alcohol consumed over a long time period. For the assessment of repeated alcohol use, we propose that the current cut-off of 7 pg/mg could be re-evaluated.
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http://dx.doi.org/10.1007/s00216-015-9117-0DOI Listing
March 2016

Genotype and co-medication dependent CYP2D6 metabolic activity: effects on serum concentrations of aripiprazole, haloperidol, risperidone, paliperidone and zuclopenthixol.

Eur J Clin Pharmacol 2016 Feb 30;72(2):175-84. Epub 2015 Oct 30.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.

Purpose: Therapeutic drug monitoring (TDM) of antipsychotics can aid in therapy optimization, explaining adverse effects or non-response. One reason for therapeutic failure or adverse effects is caused by genetic variations in the cytochrome P450 drug-metabolizing genes. The aim of this study was to evaluate the impact of CYP2D6 polymorphisms on steady-state serum concentrations of antipsychotics metabolized by CYP2D6, taking into account the co-medication with CYP2D6 inhibitors.

Methods: Serum and EDTA samples were collected from 82 psychiatric patients. After a liquid-liquid extraction, serum samples were analyzed using an ultra-high performance liquid chromatography-tandem mass spectrometric (UHPLC-MS/MS) method for quantification of the antipsychotics. CYP2D6 genotyping was performed using the Luminex xTAG® CYP2D6 Kit v3 (Luminex Corporation). Patients were divided into five phenotype subgroups by calculation of the activity score (AS): poor metabolizers (PM; AS 0), intermediate metabolizers (IM; AS 0.5-1), extensive metabolizers with slow activity (EM-s; AS 1-1.5), extensive metabolizers with fast activity (EM-f; AS 2), and ultra-rapid metabolizers (UM; AS >2). The influence of the phenotypes on the concentration-to-dose and metabolite-to-parent ratios was evaluated.

Results: Overall, 6.1 % UM (n = 5), 25.6 % EM-f (n = 21), 46.3 % EM-s (n = 38), 1.2 % EM-s/EM-f (n = 1), 6.1 % IM (n = 5), and 14.6 % PM (n = 12) were found, taking co-administration of strong and moderate CYP2D6 inhibitors into account (phenoconversion). It was demonstrated that CYP2D6 polymorphisms affect the serum concentrations of aripiprazole (n = 18), haloperidol (n = 11), risperidone (n = 20), and zuclopenthixol (n = 6), while no influence was seen on the paliperidone serum concentrations (n = 31).

Conclusions: Even with a small number of patients per antipsychotic, the importance of CYP2D6 genotyping was still clearly stated. This study illustrates the high potential of combining TDM and CYP2D6 genotyping in clinical practice.
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http://dx.doi.org/10.1007/s00228-015-1965-1DOI Listing
February 2016

Determination of Common Antipsychotics in Quantisal-Collected Oral Fluid by UHPLC-MS/MS: Method Validation and Applicability for Therapeutic Drug Monitoring.

Ther Drug Monit 2016 Feb;38(1):87-97

*Toxicological Centre, University of Antwerp; †Laboratory for TDM and Toxicology, ZNA Stuivenberg; ‡Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine, University of Antwerp; §Psychiatric Hospital Broeders Alexianen, Boechout; and ¶Psychiatric Centre Sint-Norbertushuis, Duffel, Belgium.

Background: Oral fluid (OF) is an interesting alternative for conventional blood testing in therapeutic drug monitoring. OF can be used for screening but its value for quantification has to be established.

Methods: To evaluate the value of OF for quantification of 11 commonly used antipsychotics (APs) and 5 metabolites, an ultra-high performance liquid chromatography-tandem mass spectrometric method was validated. OF was obtained from psychiatric patients using a Quantisal collection device. OF to serum concentration ratios were determined, taking into account the exact volume of collected OF.

Results: Linearity was evaluated at 7 or 8 calibration levels. Accuracy criteria were fulfilled, except for pipamperone (PIP) at quality control (QC) low. The intraday precision ranged 0.88%-14.73% and interday precision ranged 1.92%-16.17%. The mean recovery from the collection pad was 37.1% at QC low and 40.3% at QC high for 1 mL of collected OF; for 0.5 mL collected OF mean recovery was 35.0% at QC low and 37.3% at QC high. When 0.1 mL OF was collected, recovery data were unreliable. Mean absolute matrix effect was 101.1% (82.0%-120.0%). OF patient samples (n = 89) containing 269 APs and metabolites were acquired and the mean volume of collected OF was 0.562 mL (0.057-1.232 mL). The OF to serum ratios were above 1 for all APs (1.54-28.50), except for aripiprazole (0.21) and zuclopenthixol (0.66). A broad range of calculated ratios for all APs was obtained.

Conclusions: This validated ultra-high performance liquid chromatography-tandem mass spectrometric method can be used to reliably quantify APs in OF, even when recovery is low. Because the correlation between OF and serum concentrations was low and in addition results were highly variable, it can only be concluded that OF is a potentially interesting matrix, particularly for screening for noncompliance.
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http://dx.doi.org/10.1097/FTD.0000000000000242DOI Listing
February 2016

Are capillary DBS applicable for therapeutic drug monitoring of common antipsychotics? A proof of concept.

Bioanalysis 2015 ;7(16):2119-30

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Aim: DBS sampling has been proposed as an alternative for venous blood collection in therapeutic drug monitoring (TDM) of antipsychotics. For implementation in routine practice, a comparison between capillary and venous blood concentrations is mandatory.

Results: A DBS method for quantification of antipsychotics was clinically validated. First, whole blood therapeutic ranges were calculated using the blood:serum ratio. Calculation of DBS:blood ratios and Passing-Bablok regression analysis demonstrated that concentrations obtained by DBS analysis were highly comparable to those obtained by conventional whole blood analysis. Clinical interpretation of serum, whole blood and DBS concentrations were highly identical (sensitivity 91.6-97.6%).

Conclusion: This is the first clinical study demonstrating the value of DBS sampling in TDM of antipsychotics.
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http://dx.doi.org/10.4155/bio.15.100DOI Listing
June 2016

Are capillary DBS applicable for therapeutic drug monitoring of common antipsychotics? A proof of concept.

Bioanalysis 2015 ;7(16):2119-30

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.

Aim: DBS sampling has been proposed as an alternative for venous blood collection in therapeutic drug monitoring (TDM) of antipsychotics. For implementation in routine practice, a comparison between capillary and venous blood concentrations is mandatory.

Results: A DBS method for quantification of antipsychotics was clinically validated. First, whole blood therapeutic ranges were calculated using the blood:serum ratio. Calculation of DBS:blood ratios and Passing-Bablok regression analysis demonstrated that concentrations obtained by DBS analysis were highly comparable to those obtained by conventional whole blood analysis. Clinical interpretation of serum, whole blood and DBS concentrations were highly identical (sensitivity 91.6-97.6%).

Conclusion: This is the first clinical study demonstrating the value of DBS sampling in TDM of antipsychotics.
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http://dx.doi.org/10.4155/bio.15.100DOI Listing
June 2016

In vitro and in vivo human metabolism of the synthetic cannabinoid AB-CHMINACA.

Drug Test Anal 2015 Oct 12;7(10):866-76. Epub 2015 Apr 12.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide (AB-CHMINACA) is a recently introduced synthetic cannabinoid. At present, no information is available about in vitro or in vivo human metabolism of AB-CHMINACA. Therefore, biomonitoring studies to screen AB-CHMINACA consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated the in vitro metabolism of AB-CHMINACA using human liver microsomes (HLMs). Formation of AB-CHMINACA metabolites was monitored using liquid chromatography coupled to time-of-flight mass spectrometry. Twenty-six metabolites of AB-CHMINACA were detected including seven mono-hydroxylated and six di-hydroxylated metabolites and a metabolite resulting from N-dealkylation of AB-CHMINACA, all produced by cytochrome P450 (CYP) enzymes. Two carboxylated metabolites, likely produced by amidase enzymes, and five glucuronidated metabolites were also formed. Five mono-hydroxylated and one carboxylated metabolite were likely the major metabolites detected. The involvement of individual CYPs in the formation of AB-CHMINACA metabolites was tested using a panel of seven human recombinant CYPs (rCYPs). All the hydroxylated AB-CHMINACA metabolites produced by HLMs were also produced by the rCYPs tested, among which rCYP3A4 was the most active enzyme. Most of the in vitro metabolites of AB-CHMINACA were also present in urine obtained from an AB-CHMINACA user, therefore showing the reliability of the results obtained using the in vitro metabolism experiments conducted to predict AB-CHMINACA in vivo metabolism. The AB-CHMINACA metabolites to target in biomonitoring studies using urine samples are now reliably identified and can be used for routine analysis.
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http://dx.doi.org/10.1002/dta.1796DOI Listing
October 2015

Influence of repeated permanent coloring and bleaching on ethyl glucuronide concentrations in hair from alcohol-dependent patients.

Forensic Sci Int 2015 Feb 9;247:18-22. Epub 2014 Dec 9.

Toxicological Center, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium; Toxicology Laboratory, ZNA Stuivenberg, Antwerp, Belgium.

Background: Ethyl glucuronide (EtG), a minor metabolite of alcohol, is used as a sensitive marker in hair to detect the retrospective consumption of alcohol. The proximal 0-3 cm hair segment is often used for analysis, providing information on alcohol consumption over the past 3 months. Using more distal segments would allow the detection of alcohol consumption over longer time periods, thereby addressing the chronicity of the consumption. In view of this, permanent coloring and bleaching were shown in vitro to alter EtG concentrations in hair, but no in vivo studies are available to prove or disprove this.

Aims: To investigate the influence of repeated bleaching and permanent coloring on EtG concentrations in vivo and to assess the stability of EtG concentrations in distal compared to proximal hair segments.

Methods: Hair samples from alcohol-dependent patients with uncolored/unbleached (N=4), permanent coloration (N=5) and bleached hair (N=5) were analyzed in two to six 3 cm long segments for EtG concentrations, and alcohol consumption and hair cosmetic treatments were assessed.

Results: We observed that hair bleaching and permanent coloring reduces EtG concentrations by 82±11% and 65±24%, respectively, with correlations between the number of cosmetic treatments and the decrease in EtG concentrations. EtG remained stable in untreated hair samples up to 18 cm.

Conclusions: EtG is a sensitive marker to assess chronic alcohol consumption up to 18 months in alcohol-dependent patients with no cosmetic hair treatments. However, in alcohol-dependent patients who color or bleach their hair, care should be taken when interpreting EtG measurements.
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http://dx.doi.org/10.1016/j.forsciint.2014.11.023DOI Listing
February 2015

Advances in detection of antipsychotics in biological matrices.

Clin Chim Acta 2015 Feb 12;441:11-22. Epub 2014 Dec 12.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerp, Belgium.

Measuring antipsychotic concentrations in human matrices is important for both therapeutic drug monitoring and forensic toxicology. This review provides a critical overview of the analytical methods for detection and quantification of antipsychotics published in the last four years. Focus lies on advances in sample preparation, analytical techniques and alternative matrices. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is used most often for quantification of antipsychotics. This sensitive technique makes it possible to determine low concentrations not only in serum, plasma or whole blood, but also in alternative matrices like oral fluid, dried blood spots, hair, nails and other body tissues. Current literature on analytical techniques for alternative matrices is still limited and often requires a more thorough validation including a comparison between conventional and alternative results to determine their actual value. Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) makes it possible to quantify a high amount of compounds within a shorter run time. This technique is widely used for multi-analyte methods. Only recently, high-resolution mass spectrometry has gained importance when a combination of screening of (un)known metabolites, and quantification is required.
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http://dx.doi.org/10.1016/j.cca.2014.12.008DOI Listing
February 2015

Retrospective evaluation of therapeutic drug monitoring of clozapine and norclozapine in Belgium using a multidrug UHPLC-MS/MS method.

Clin Biochem 2014 Dec 5;47(18):336-9. Epub 2014 Oct 5.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.

Objective: Clozapine is an atypical antipsychotic with a narrow therapeutic range and serious toxic side effects. According to AGNP-TDM consensus guidelines, therapeutic drug monitoring (TDM) of clozapine and its metabolite norclozapine is strongly recommended. 330 serum samples, sent to the toxicological laboratory of Ziekenhuis Netwerk Antwerpen for monitoring of clozapine, were tested with a new ultra-high performance liquid chromatography-tandem mass spectrometric method (UHPLC-MS/MS). The aim of this research was to evaluate this method for TDM of clozapine and norclozapine, but also to determine other antipsychotics present in these serum samples.

Design And Methods: Serum samples were taken just prior to the morning dose of the antipsychotic (trough concentration). All samples were, after a simple liquid-liquid extraction with methyl t-butylether, analyzed using a fully validated UHPLC-MS/MS method which is able to quantitate 16 different antipsychotics and 8 of their major metabolites. Serum concentrations were compared with the therapeutic ranges as defined by the AGNP-TDM guidelines.

Results: For clozapine, only 22.3% of the serum concentrations were within the therapeutic range of 350-600 ng/mL, while 67.9% of the concentrations were below 350 ng/mL. For norclozapine, 68.2% of the serum samples were within the therapeutic range of 100-600 ng/mL. The mean clozapine:norclozapine ratio was 1.7 (SD 0.8). 218 of the 330 serum samples contained other antipsychotics than clozapine. Only 52.5% of these concentrations were within the proposed range.

Conclusion: This retrospective study highlights the importance of TDM for clozapine and other APs, since many patients show suboptimal serum concentrations.
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http://dx.doi.org/10.1016/j.clinbiochem.2014.09.021DOI Listing
December 2014

The use of dried blood spots for quantification of 15 antipsychotics and 7 metabolites with ultra-high performance liquid chromatography - tandem mass spectrometry.

Drug Test Anal 2015 Jun 31;7(6):502-11. Epub 2014 Jul 31.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610, Antwerp, Belgium.

Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25 μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10 μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5 mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1 month at room temperature, 4 °C and -18 °C. Lurasidone was unstable when the extract was stored for 12 h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine.
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http://dx.doi.org/10.1002/dta.1698DOI Listing
June 2015

Hair ethyl glucuronide as a biomarker of alcohol consumption in alcohol-dependent patients: role of gender differences.

Drug Alcohol Depend 2014 Aug 2;141:163-6. Epub 2014 Jun 2.

Toxicological Center, University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium; Toxicology Laboratory, ZNA Stuivenberg, Lange Beeldekenstraat 267, B2060 Antwerp, Belgium. Electronic address:

Background: Ethyl glucuronide (EtG) is a minor alcohol metabolite that accumulates in hair and is proposed as a stable marker for the detection of chronic and excessive alcohol consumption above a cut-off level of 30pg/mg hair. A correlation between drinking behavior and EtG hair concentrations is observed, but large variability exists.

Aims: To investigate the correlation between alcohol consumption and hair EtG concentrations in alcohol dependent patients, and the effect of gender differences as a factor for the variability on this correlation.

Methods: EtG was measured by gas chromatography coupled to mass spectrometry in the hairs (first 3cm) of 36 alcohol dependent patients (25 males/11 females) starting and alcohol detoxification program. Factors that possibly influence EtG content in hair (except age and gender) were excluded. Detailed retrospective alcohol consumption was obtained over the last 3 months using the Timeline Follow Back interview.

Results: Median total alcohol consumption over 3 months was 13,050g pure alcohol (range 60-650g/day). Hair EtG concentrations varied between 32 and 662pg/mg. There was a statistically significant linear and positive correlation between hair EtG and amounts of alcohol consumed (Pearson r=0.83; p<0.001), in both males (Pearson r=0.83; p<0.001) and females (Pearson r=0.76; p=0.007).

Conclusions: There is a linear correlation, with no significant effect of gender, between hair EtG concentrations and amounts of alcohol consumed in alcohol-dependent individuals. Analysis of EtG in hair can be applied to estimate retrospective alcohol consumption in both male and female alcohol dependent subjects using the same cut-off.
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http://dx.doi.org/10.1016/j.drugalcdep.2014.05.014DOI Listing
August 2014

The influence of the body mass index (BMI) on the volume of distribution of ethanol.

Forensic Sci Int 2014 Oct 6;243:74-8. Epub 2014 May 6.

University of Antwerp, Toxicological Centre, Universiteitsplein 1, Wilrijk B-2610, Belgium; ZNA Stuivenberg, Laboratory for TDM and Toxicology, Lange Beeldekensstraat 267, Antwerp B-2060, Belgium. Electronic address:

The volume of distribution of ethanol was already established in 1930s by Widmark. However, since then the average body composition has changed considerably. The effect of the body mass index (BMI) on the volume of distribution of ethanol was evaluated in this study. Fifty healthy volunteers (23 men and 27 women), with BMI-values between 16.0 and 36.0kg/m(2), were asked to drink a dose of 0.4g ethanol per kilogram body weight after an overnight fast. The ethanol content was measured by a fully validated headspace-GC-FID method. The volume of distribution of ethanol varied between 0.40 and 0.68L/kg for women, and between 0.43 and 0.73L/kg for men. For both sexes, the volume of distribution decreased with increasing BMI. Regression analysis resulted in the following equations: volume of distribution=0.8202-0.0090×BMI for men (r=0.66), and 0.7772-0.0099×BMI for women (r=0.78). Population probability prediction interval limits were also calculated. In view of the current study, fixed values for the volume of distribution of 0.7L/kg and 0.6L/kg for men and women, respectively, often applied in legal blood alcohol calculations, are mainly suited to judge underweight or normal weight people, but not obese persons.
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http://dx.doi.org/10.1016/j.forsciint.2014.04.036DOI Listing
October 2014

High throughput identification and quantification of 16 antipsychotics and 8 major metabolites in serum using ultra-high performance liquid chromatography-tandem mass spectrometry.

Clin Chim Acta 2014 Feb 28;429:51-8. Epub 2013 Nov 28.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Laboratory for TDM and Toxicology, ZNA Stuivenberg, Lange Beeldekensstraat 267, B-2060 Antwerpen, Belgium.

Background: Therapeutic drug monitoring of antipsychotics is important for optimizing therapy, explaining adverse effects, non-response or poor compliance. We developed a UHPLC-MS/MS method for quantification of 16 commonly used and recently marketed antipsychotics and 8 metabolites in serum.

Methods: After liquid-liquid extraction using methyl tert-butyl ether, analysis was performed on an Agilent Technologies 1290 Infinity LC system coupled with an Agilent Technologies 6460 Triple Quadrupole MS. Separation with a C18 column and gradient elution at 0.5 mL/min resulted in a 6-min run-time. Detection was performed in dynamic MRM, monitoring 3 ion transitions per compound. Isotope labeled internal standards were used for every compound, except for bromperidol and levosulpiride.

Results: Mean recovery was 86.8%. Matrix effects were -18.4 to +9.1%. Accuracy ranged between 91.3 and 107.0% at low, medium and high concentrations and between 76.2 and 113.9% at LLOQ. Within-run precision was <15% (CV), except for asenapine and hydroxy-iloperidone. Between-run precision was aberrant only for 7-hydroxy-N-desalkylquetiapine, asenapine and reduced haloperidol. No interferences were found. No problems of instability were observed, even for olanzapine. The method was successfully applied on patient samples.

Conclusions: The liquid-liquid extraction and UHPLC-MS/MS technique allows robust target screening and quantification of 23 antipsychotics and metabolites.
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http://dx.doi.org/10.1016/j.cca.2013.11.024DOI Listing
February 2014

Hair ethyl glucuronide levels as a marker for alcohol use and abuse: a review of the current state of the art.

Drug Alcohol Depend 2014 Jan 30;134:1-11. Epub 2013 Oct 30.

Toxicological Centre, University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium; Toxicology Laboratory, ZNA Stuivenberg, Lange Beeldekenstraat 267, B2060 Antwerp, Belgium.

Background: Ethyl glucuronide (EtG) is a minor alcohol metabolite that has been proposed as a stable marker in hair to detect and quantify alcohol consumption over long time periods.

Methods: We provide an outline of currently available techniques for EtG hair sample analysis and highlight the pitfalls related to data interpretation. The literature of EtG analysis has been reviewed from January 1980 up to August 2013. In addition, we present an overview of the clinical and forensic studies which have used EtG quantification in hair as a marker for alcohol consumption/abstinence and we provide suggestions for future research.

Results: EtG is a stable marker in hair that can be used to detect and quantify alcohol consumption over long time periods. This alcohol metabolite remains in hair after complete elimination of alcohol. Currently, there are three main analytical techniques used to quantify EtG in hair: gas chromatography-mass spectrometry (GC-MS), gas chromatography-tandem mass spectrometry (GC-MS/MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS). No standardized protocols are yet available for the analysis of EtG levels in hair samples, and the current protocols vary in sample preparation and extraction procedures. Variables such as hair length, cosmetic treatment, gender, and pathophysiological conditions influence the final results and should be taken into account.

Conclusions: EtG quantification in hair is a useful tool for the objective detection of alcohol consumption over extended time periods, but care should be taken when interpreting the results.
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http://dx.doi.org/10.1016/j.drugalcdep.2013.10.008DOI Listing
January 2014

Optimization, validation, and the application of liquid chromatography-tandem mass spectrometry for the analysis of new drugs of abuse in wastewater.

Drug Test Anal 2014 Jul-Aug;6(7-8):861-7. Epub 2013 Feb 19.

Toxicological Center, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.

Recently it was demonstrated that the analysis of drugs of abuse (DOA) in wastewater can be used to track their use in communities. This paper presents the optimization, validation, and application of an analytical procedure based on solid-phase extraction (SPE) and liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the determination of some emerging drugs in influent wastewater. The compounds of interest were the cathinone derivatives methylenedioxypyrovalerone (MDPV) and 4-methylmethcathinone (mephedrone (MEPH)), ketamine (KET) and its metabolites norketamine (NK) and dehydronorketamine (DHNK), as well as the major metabolite of cannabis, 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH). Except for DHNK, deuterated analogues were used as internal standards for quantification. The use of a short C18 column (50 mm x 2 mm, 3 µm) allowed a good separation for the compounds analyzed in positive ionization mode (KET, NK, DHNK, MDPV, and MEPH) and for THC-COOH, which was analyzed in negative ionization mode, with a total run time of 13 min. Sample preparation using SPE was optimized by comparing Oasis HLB and Oasis MCX sorbents. The method was validated for each compound by assessing the following parameters: linearity, accuracy, precision, recovery, and relative process efficiency. The lowest calibration level was considered as the lower limit of quantification (LLOQ) and was 5 ng/l for KET, NK, DHNK, MDPV, and MEPH and 20 ng/l for THC-COOH. KET, and THC-COOH could be quantified in the majority of wastewater samples from three large wastewater treatment plants in Belgium. The other compounds were below the LLOQ or could not be detected.
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http://dx.doi.org/10.1002/dta.1460DOI Listing
March 2015

Therapeutic drug monitoring of common antipsychotics.

Ther Drug Monit 2012 Dec;34(6):629-51

Toxicological Centre, University of Antwerp, Universiteitsplein 1, Antwerp, Belgium.

The aim of this review is to provide information for interpreting outcome results from monitoring of antipsychotics in biological samples. A brief overview of the working mechanisms, pharmacological effects, drug interactions, and analytical methods of classical and atypical antipsychotics is given. Nineteen antipsychotics were selected based on their importance in the worldwide market as follows: amisulpride, aripiprazole, asenapine, bromperidol, clozapine, flupenthixol, haloperidol, iloperidone, lurasidone, olanzapine, paliperidone, perphenazine, pimozide, pipamperone, quetiapine, risperidone, sertindole, sulpiride, and zuclopenthixol. A straightforward relationship between administered dose, plasma or serum concentration, clinical outcome, or adverse effects is often lacking. Nowadays, focus lies on therapeutic drug monitoring and individualized therapy to find adequate treatment, to explain treatment failure or nonresponse, and to check patient compliance. However, extensive research in this field is still mandatory.
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http://dx.doi.org/10.1097/FTD.0b013e3182708ec5.DOI Listing
December 2012

Pharmacokinetic evaluation of armodafinil for the treatment of bipolar depression.

Expert Opin Drug Metab Toxicol 2012 Sep 18;8(9):1189-97. Epub 2012 Jul 18.

Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium.

Introduction: Bipolar disorder is a psychiatric illness with recurring episodes of mania and depression. Armodafinil , the R-enantiomer of modafinil, approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder, is possibly effective as an adjunctive treatment for bipolar depression.

Areas Covered: This review covers the pharmacokinetics of armodafinil, with an emphasis on its use in bipolar depression. Its clinical efficacy in the treatment of bipolar depression is evaluated, along with current data regarding its safety and tolerability.

Expert Opinion: One placebo-controlled trial is available, in which armodafinil was efficacious as an adjunctive treatment in bipolar depression. Armodafinil shows a linear pharmacokinetic profile over a broad dose range of 50 - 400 mg (maximal plasma concentration and area under concentration-time curve). Compared with modafinil, an equivalent dose of armodafinil attains higher blood concentrations 4 - 6 h post-dose. The possibility of drug interactions is generally low, although interactions have been shown with some drugs used in bipolar disorder, through mild CYP3A4-induction and CYP2C19-inhibition. Armodafinil is well tolerated and presents a possible new treatment option for bipolar depression. However, further investigation is still needed in order to confirm its efficacy and to clarify its role in the treatment of bipolar depression.
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http://dx.doi.org/10.1517/17425255.2012.708338DOI Listing
September 2012

Dancing on coke: smuggling cocaine dispersed in polyvinyl alcohol.

J Forensic Sci 2012 Jan 31;57(1):234-8. Epub 2011 Oct 31.

Toxicological Centre, University of Antwerp, Antwerp, Belgium.

Recent trends suggest that cocaine smugglers have become more and more inventive to avoid seizures of large amounts of cocaine transported between countries. We report a case of a mail parcel containing a dance pad which was seized at the Customs Department of Brussels Airport, Belgium. After investigation, the inside of the dance pad was found to contain a thick polymer, which tested positive for cocaine. Analysis was performed using a routine colorimetric swipe test, gas chromatography coupled with mass spectrometry and nuclear magnetic resonance spectroscopy. The polymer was identified as polyvinyl alcohol (PVA) and contained 18% cocaine, corresponding to a street value of € 20,000. Laboratory experiments showed that cocaine could be easily extracted from the PVA matrix. This case report reveals a new smuggling technique for the transportation of large amounts of cocaine from one country to another.
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http://dx.doi.org/10.1111/j.1556-4029.2011.01947.xDOI Listing
January 2012
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