Publications by authors named "Hugo Neels"

160 Publications

Stability of phosphatidylethanol 16:0/18:1 in authentic and spiked whole blood.

Drug Test Anal 2021 Jun 12;13(6):1219-1222. Epub 2021 Jan 12.

Toxicological Centre, University of Antwerp, Antwerp, Belgium.

Phosphatidylethanol 16:0/18:1 (PEth) is the most abundant homologue of the phosphatidylethanol group of phospholipids. Formed only in the presence of ethanol, PEth is used as a biomarker in whole blood to provide information about the consumption of alcohol. As information on the storage life of PEth is essential for its beneficial use as a biomarker, this study investigated the stability of PEth in spiked and authentic whole blood samples stored at 4°C. Human whole blood samples (n = 23) and spiked whole blood samples (n = 7) with a concentration range between 5 and 2000 ng/ml were analysed at specific time intervals, up to 90 days. Differences were evident between the stability of authentic and spiked samples. PEth was stable at 4°C for 60 days (concentrations within 15% of initial concentration) in authentic samples, whereas spiked samples were stable for up to 30 days. This study emphasizes the importance of including authentic samples in stability experiments.
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http://dx.doi.org/10.1002/dta.2995DOI Listing
June 2021

Diagnostic Accuracy of Biomarkers of Alcohol Use in Patients With Liver Disease: A Systematic Review.

Alcohol Clin Exp Res 2021 01 25;45(1):25-37. Epub 2020 Dec 25.

Department of Gastroenterology and Hepatology, (FN, JV), University Hospitals KU Leuven, Leuven, Belgium.

Background And Aims: Alcohol-related liver disease is the most frequent cause of cirrhosis and a major indication for liver transplantation. Several alcohol use biomarkers have been developed in recent years and are already in use in several centers. However, in patients with liver disease their diagnostic performance might be influenced by altered biomarker formation by hepatic damage, altered excretion by kidney dysfunction and diuretics use, and altered deposition in hair and nails. We systematically reviewed studies on the diagnostic accuracy of biomarkers of alcohol use in patients with liver disease and performed a detailed study quality assessment.

Methods: A structured search in PubMed/Medline/Embase databases was performed for relevant studies, published until April 28, 2019. The risk of bias and applicability concerns was assessed according to the adapted quality assessment of diagnostic accuracy studies-2 (QUADAS-2) checklist.

Results: Twelve out of 6,449 studies met inclusion criteria. Urinary ethyl glucuronide and urinary ethyl sulfate showed high sensitivity (70 to 89 and 73 to 82%, respectively) and specificity (93 to 99 and 86 to 89%, respectively) for assessing any amount of alcohol use in the past days. Serum carbohydrate-deficient transferrin showed low sensitivity but higher specificity (40 to 79 and 57 to 99%, respectively) to detect excessive alcohol use in the past weeks. Whole blood phosphatidylethanol showed high sensitivity and specificity (73 to 100 and 90 to 96%, respectively) to detect any amount of alcohol use in the previous weeks. Scalp hair ethyl glucuronide showed high sensitivity (85 to 100%) and specificity (97 to 100%) for detecting chronic excessive alcohol use in the past 3 to 6 months. Main limitations of the current evidence are the lack of an absolute gold standard to assess alcohol use, heterogeneous study populations, and the paucity of studies.

Conclusions: Urinary and scalp hair ethyl glucuronide are currently the most validated alcohol use biomarkers in patients with liver disease with good diagnostic accuracies. Phosphatidylethanol is a highly promising alcohol use biomarker, but so far less validated in liver patients. Alcohol use biomarkers can complement each other regarding diagnostic time window. More validation studies on alcohol use biomarkers in patients with liver disease are needed.
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http://dx.doi.org/10.1111/acer.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898850PMC
January 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

Human exposure pathways to organophosphate flame retardants: Associations between human biomonitoring and external exposure.

Environ Int 2019 06 9;127:462-472. Epub 2019 Apr 9.

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

Organophosphate flame retardants (PFRs) have largely replaced the market of polybrominated diphenyl ethers (PBDEs). Concerns about PFR contamination and its impact on human health have consequently increased. A comprehensive investigation on the human exposure pathways to PFRs is to be endeavoured. This study investigated the occurrence of PFR metabolites in human urine, serum and hair, correlating them with external exposure data that was presented in our previous studies. Participants from Oslo (n = 61) provided a set of samples, including dust, air, handwipes, food, urine, serum and hair. Associations between PFR metabolites analyzed in the biological samples and the PFRs in environmental samples were explored. Different sampling strategies for dosimeters (e.g. floor/surface dust, personal/stationary air) were also compared to understand which is better for predicting human exposure to PFRs. Seven out of the eleven target PFR metabolites, including diphenyl phosphate (DPHP) and bis(1-chloro-2-propyl)-1-hydroxy-2-propyl phosphate (BCIPHIPP), were frequently detected (DF > 30%) in urine. DPHP was the most frequently detected metabolite in both serum and hair. Several PFR metabolites had higher levels in morning urine than in afternoon urine. Floor dust appeared to be a better proxy for estimating PFR internal exposure than surface dust, air, and handwipes. Some PFRs in handwipes and air were also correlated with their metabolites in urine and hair. Age, beverage consumption and food consumption were negatively associated with DPHP levels in urine. Discrepancies observed between the external and internal exposure for some PFRs call for further investigation on PFR bioaccessibility and clearance.
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http://dx.doi.org/10.1016/j.envint.2019.03.053DOI Listing
June 2019

Therapeutic Drug Monitoring of Second-Generation Antipsychotics for the Estimation of Early Drug Effect in First-Episode Psychosis.

Ther Drug Monit 2019 04;41(2):252-253

Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medical and Health Sciences, University of Antwerp, Belgium.

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http://dx.doi.org/10.1097/FTD.0000000000000588DOI Listing
April 2019

How to Interpret Hair EtG Concentrations in Individuals with High Body Mass Index? Brief Commentary on: Influence of Body Mass Index on Hair Ethyl Glucuronide Concentrations.

Alcohol Alcohol 2019 Mar;54(2):188-189

Toxicological Center, Antwerp University, Antwerp, Belgium.

Body mass index (BMI) is a variable that complicates the interpretation of the alcohol metabolite ethyl glucuronide (EtG) in hair. However, direction on how EtG should currently be interpreted within individuals consuming moderate and excessive daily amounts of alcohol related to their BMI is lacking. In light of interpretation of EtG in individuals with high BMI, we present post hoc analysis of earlier data regarding the effect of BMI on hair EtG concentrations.
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http://dx.doi.org/10.1093/alcalc/agz006DOI Listing
March 2019

Everolimus depletes plaque macrophages, abolishes intraplaque neovascularization and improves survival in mice with advanced atherosclerosis.

Vascul Pharmacol 2019 Feb 24;113:70-76. Epub 2018 Dec 24.

Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

Background And Aims: Inhibition of the mechanistic target of rapamycin (mTOR) is a promising approach to halt atherogenesis in different animal models. This study evaluated whether the mTOR inhibitor everolimus can stabilize pre-existing plaques, prevent cardiovascular complications and improve survival in a mouse model of advanced atherosclerosis.

Methods: ApoEFbn1 mice (n = 24) were fed a Western diet (WD) for 12 weeks. Subsequently, mice were treated with everolimus (1.5 mg/kg daily) or vehicle for another 12 weeks while the WD continued.

Results: Despite hypercholesterolemia, everolimus treatment was associated with a reduction in circulating Ly6C monocytes (15 vs. 28% of total leukocytes, p = 0.046), a depletion of plaque macrophages (2.1 vs. 4.1%, p = 0.040) and an abolishment of intraplaque neovascularization, which are all indicative of a more stable plaque phenotype. Moreover, everolimus reduced hypoxic brain damage and improved cardiac function, which led to increased survival (100 vs. 67% of animals, p = 0.038).

Conclusions: Everolimus enhances features of plaque stability and counters cardiovascular complications in ApoEFbn1 mice, even when administered at a later stage of the disease.
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http://dx.doi.org/10.1016/j.vph.2018.12.004DOI Listing
February 2019

Evaluation of vilazodone for the treatment of depressive and anxiety disorders.

Expert Opin Pharmacother 2019 Feb 26;20(3):251-260. Epub 2018 Nov 26.

a Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences , University of Antwerp, Belgium; University Psychiatric Hospital Duffel , Duffel , Belgium.

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD. Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library. Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug's dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.
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http://dx.doi.org/10.1080/14656566.2018.1549542DOI Listing
February 2019

Gammahydroxybutyrate in hair of non-GHB and repeated GHB users: A new and optimized method.

Forensic Sci Int 2018 Oct 30;291:193-198. Epub 2018 Aug 30.

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

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid used recreationally as a drug of abuse due its strong suppressive effect on the central nervous system. The detection window of GHB in blood and urine is very narrow (t1/2=30min) but can be substantially prolonged using alternative matrices such as hair. We here present a newly developed and limited validated method with a solid phase extraction (SPE) using GC-MS/MS to determine concentrations of GHB in hair samples. The soft extraction technique (water and 90min ultrasonic bath) preserves GHB with a high yield and clean extracts. In addition, endogenous GHB can be detected in hair of non-GHB users. However, little is known about GHB concentrations in hair of abstinent, frequent and chronic GHB users. Therefore, we present data from hair samples of healthy volunteers to evaluate the proposed endogenous GHB ranges, and from GHB-dependent patients to address GHB concentrations in hair with GHB intake. In 20 non-GHB users, a mean endogenous concentration of 1.1±0.6ng/mg hair (range of 0.3-2ng/mg) was found. In GHB-dependent patients, concentrations between 6.3-239.6ng/mg hair were found, with no correlation between concentrations in hair and dose of GHB intake. In summary, we present a new and limited validated method, adequately sensitive for the detection of GHB in hair, as well as first-time measurements of GHB concentrations in dependent patients in order to better understand the relationship between the frequency of use/dose and concentrations observed in hair samples.
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http://dx.doi.org/10.1016/j.forsciint.2018.08.025DOI Listing
October 2018

Pharmacokinetic evaluation of the aripiprazole (once-monthly) injection for the treatment of bipolar disorder.

Expert Opin Drug Metab Toxicol 2018 Oct 7;14(10):999-1005. Epub 2018 Sep 7.

a Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medical and Health Sciences , University of Antwerp , Antwerpen , Belgium.

Introduction: Bipolar disorder is a severe, chronic psychiatric disorder with a need for long-term treatment. Patient nonadherence is frequent and poses a major problem in maintenance therapy. Aripiprazole once-monthly long-acting injectable (AOM LAI) is a recently US Food and Drug Administration-approved treatment option for maintenance therapy that could be of great value. Areas covered: This paper reviews the pharmacokinetic, efficacy and safety data for AOM LAI in bipolar disorder. Expert opinion: AOM LAI is a safe and efficacious treatment option in the maintenance therapy of bipolar I disorder. However, further research is still needed to determine the position of AOM LAI relative to other available treatment options.
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http://dx.doi.org/10.1080/17425255.2018.1515911DOI Listing
October 2018

Pharmacotherapy and nutritional supplements for seasonal affective disorders: a systematic review.

Expert Opin Pharmacother 2018 Aug 26;19(11):1221-1233. Epub 2018 Jul 26.

a Collaborative Antwerp Psychiatric Research Institute (CAPRI), Faculty of Medicine and Health Sciences , University of Antwerp. Campus Drie Eiken , Antwerpen , Belgium.

Introduction: A seasonal affective disorder (SAD) is a subtype of unipolar and bipolar major depressive disorders. It is characterized by its annual recurrence of depressive episodes at a particular season, mostly seen in winter and is responsible for 10-20% of the prevalence of major depressive disorders. Some pathophysiological hypotheses, such as the phase delay and the monoamine depletion hypotheses, have been postulated but the exact cause has not been fully unraveled yet. Studies on treatment for SAD in the last decade are lacking. To tackle this chronic disease, attention needs to be drawn to the gaps in this research field.

Areas Covered: In this systematic review, the authors give a broad overview of the pharmacological therapy available for SAD. Also, nutritional substances fitting well with the postulated hypotheses are reviewed for the treatment and prevention of SAD. There is a specific focus on the quality of the currently performed studies.

Expert Opinion: Light therapy and fluoxetine are the only proven and effective acute treatment options for SAD, while bupropion is the only registered drug for prevention of SAD. This area of research is in dire need of valid large-scale and sufficiently reproducible randomized control trials.
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http://dx.doi.org/10.1080/14656566.2018.1501359DOI Listing
August 2018

Assessment of ethyl sulphate in hair as a marker for alcohol consumption using liquid chromatography-tandem mass spectrometry.

Drug Test Anal 2018 Oct 19;10(10):1566-1572. Epub 2018 Jun 19.

Toxicological Centre, University of Antwerp, Belgium.

Ethyl glucuronide (EtG) and ethyl sulphate (EtS) are 2 non-oxidative and direct metabolites of ethanol. EtG is known to accumulate in hair and has proved to be a reliable biomarker for detection of chronic alcohol consumption. EtS has been analysed in blood and urine but has never been reported in hair. This article presents the first analytical assay based on liquid chromatography coupled to tandem mass spectrometry for the quantification of EtS in hair. Sample preparation, chromatographic, and mass spectrometric parameters, such as solid-phase extraction, column type, and transitions were optimised. The method was validated according to the guidelines of the European Medicine Agency, fulfilling the requirements for limit of quantification (LOQ), linearity, accuracy, precision, carry-over, matrix effects, and recovery. Linearity ranged from 5 to 500 pg mg and the LOQ was achieved at 5 pg mg . The novel method was successfully applied to hair samples (n = 40) from patients treated for alcohol use disorders. EtS concentrations in hair ranged from 24 to 1776 pg mg , while EtG concentrations in hair ranged from 1 to 1149 pg mg . Hair concentrations of EtS and EtG were compared to assess the relationship between both biomarkers. There was a significant and positive correlation between EtS and EtG in hair, suggesting that EtS can be used as a biomarker for alcohol consumption. Relatively high basal EtS levels were observed in alcohol-abstinent persons, comparable to what has been reported for EtG. The developed analytical procedure offers an alternative method to prove alcohol consumption using hair analysis.
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http://dx.doi.org/10.1002/dta.2410DOI Listing
October 2018

Carbohydrate Deficient Transferrin in Patients with Cirrhosis: A Tale of Bridges.

Alcohol Alcohol 2018 05;53(3):350-351

Department of Gastroenterology & Hepatology, University Hospitals KU Leuven, Herestraat 49, 3000 Leuven, Belgium.

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http://dx.doi.org/10.1093/alcalc/agy008DOI Listing
May 2018

Lower Limbic Metabotropic Glutamate Receptor 5 Availability in Alcohol Dependence.

J Nucl Med 2018 04 18;59(4):682-690. Epub 2018 Jan 18.

Division of Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium.

Animal studies suggest an important role for the metabotropic glutamate receptor subtype 5 (mGlu5) in the pathophysiology of alcohol dependence, but direct human evidence is lacking. The goal of this study was to investigate cerebral mGlu5 availability in alcohol-dependent subjects versus controls using F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile (F-FPEB) PET. Dynamic 90-min F-FPEB scans combined with arterial blood sampling were acquired for 16 recently abstinent alcohol-dependent subjects and 32 age-matched controls. Regional mGlu5 availability was quantified by the F-FPEB total distribution volume using both a voxel-by-voxel and a volume-of-interest analysis with partial-volume effect correction. Alcohol consumption within the last 3 mo was assessed by questionnaires and by hair ethyl glucuronide analysis. Craving was assessed using the Desire for Alcohol Questionnaire. mGlu5 availability was lower in mainly limbic regions of alcohol-dependent subjects than in controls ( < 0.05, familywise error-corrected), ranging from 14% in the posterior cingulate cortex to 36% in the caudate nucleus. Lower mGlu5 availability was associated with higher hair ethyl glucuronide levels for most regions and was related to a lower level of craving specifically in the middle frontal gyrus, cingulate cortex, and inferolateral temporal lobe. These findings provide human in vivo evidence that limbic mGlu5 has a role in the pathophysiology of alcohol dependence, possibly involved in a compensatory mechanism helping to reduce craving during abstinence.
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http://dx.doi.org/10.2967/jnumed.117.199422DOI Listing
April 2018

Keratinous matrices for the assessment of drugs of abuse consumption: A correlation study between hair and nails.

Drug Test Anal 2018 Jan 5. Epub 2018 Jan 5.

Toxicological Centre, University of Antwerp, Belgium.

Keratinous matrices - hair and nails - accumulate substances over time and allow retrospective investigation of past consumption. Analysis of these matrices can provide information complementary to blood and urine analysis or can be used as standalone. So far, research has primarily focused on the detection of substances in hair, while studies in nails are scarce. In this study, we assessed concentrations of drugs of abuse and their metabolites in hair, fingernails, and toenails collected from the same individuals to evaluate differences and correlations between matrices. A total of 26 hair, 24 fingernail, and 18 toenail samples were collected. Samples were analysed by a validated liquid chromatography-tandem mass spectrometry method able to simultaneously detect the following compounds: amphetamine (AMP), methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine, morphine (MOR), codeine (COD), 6-monoacetylmorphine (6-MAM), methadone (MTD), 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), cocaine (COC), benzoylecgonine (BE), and ecgonine methyl ester (EME). Strong positive correlations between hair, fingernails, and toenails were present for COC, BE, EME, AMP and MDMA. MOR, COD, 6-MAM, MTD and EDDP showed positive trends. Concentrations were generally higher in nails compared to hair. Ratios between parent compounds and their metabolites were assessed for 6-MAM/MOR, EDDP/MTD, BE/COC and EME/COC. Preliminary cut-off concentrations for COC, BE, EME and AMP in fingernails and toenails were proposed. In light of these results, nails can be considered as a useful alternative to hair for monitoring of long-term drug consumption. However, care should be taken regarding the variability in the accumulation of compounds between the matrices.
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http://dx.doi.org/10.1002/dta.2356DOI Listing
January 2018

Ethyl glucuronide in keratinous matrices as biomarker of alcohol use: A correlation study between hair and nails.

Forensic Sci Int 2017 Oct 26;279:187-191. Epub 2017 Aug 26.

Toxicological Center, University of Antwerp, Universiteitsplein 1, B2610 Antwerp, Belgium. Electronic address:

To quantify alcohol use, objective, specific and sensitive long-term alcohol markers are necessary. Ethyl glucuronide (EtG), a direct metabolite of alcohol, accumulates in keratinous matrices such as hair and nails, and is a specific and sensitive long-term biomarker for the detection of chronic alcohol consumption. So far, research has primarily focused on the detection of EtG in hair, and studies on its measurement in nails are scarce. In this article, we assessed EtG concentrations in hair, finger- and toenails from the same individuals in order to evaluate the direct correlation between the matrices. To this end, a total amount of 45 hair, 41 fingernail, and 13 toenail samples were collected from patients treated for alcohol use disorders at two psychiatric centers in Belgium. Samples were analyzed by gas chromatography-tandem mass spectrometry. Hair EtG concentrations ranged from 123pg/mg for chronic excessive alcohol consumption, 59-123pg/mg for moderate alcohol consumption, and <59pg/mg for alcohol abstinence. In light of these results, nails may be a useful alternative to hair samples for monitoring of long-term alcohol consumption, e.g., in cases where hair is not available. Further studies are needed to establish cut-off values for EtG levels in nails.
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http://dx.doi.org/10.1016/j.forsciint.2017.08.022DOI Listing
October 2017

Assessment of dietary exposure to organohalogen contaminants, legacy and emerging flame retardants in a Norwegian cohort.

Environ Int 2017 May 20;102:236-243. Epub 2017 Mar 20.

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address:

Polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), polybrominated diphenyl ethers (PBDEs), emerging halogenated flame retardants (EHFRs) and organophosphate flame retardants (PFRs) were detected in 24h duplicate diet samples from a Norwegian cohort (n=61), with concentrations ranging from
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http://dx.doi.org/10.1016/j.envint.2017.03.009DOI Listing
May 2017

A straightforward, validated liquid chromatography coupled to tandem mass spectrometry method for the simultaneous detection of nine drugs of abuse and their metabolites in hair and nails.

Anal Chim Acta 2017 Apr 25;960:101-109. Epub 2017 Jan 25.

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

Hair and nails allow for a stable accumulation of compounds over time and retrospective investigation of past exposure and/or consumption. Owing to their long window of detection (weeks to months), analysis of these matrices can provide information complementary to blood and urine analysis or can be used in standalone when e.g. elimination from the body has already occurred. Drugs of abuse are often used together and, therefore, multi-analyte methods capable of detecting several substances and their metabolites in a single run are of importance. This paper presents the development and validation of a method based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for the simultaneous detection of nine drugs of abuse and their metabolites in hair and nails. We focused on a simple and straightforward sample preparation to reduce costs, and allow application in routine laboratory practice. Chromatographic and mass spectrometric parameters, such as column type, mobile phase, and multiple reaction monitoring transitions were optimized. The method was validated according to the European Medicine Agency guidelines with an assessment of specificity, limit of quantification (LOQ), linearity, accuracy, precision, carry-over, matrix effects, recovery, and process efficiency. Linearity ranged from 25 to 20 000 pg mg hair and from 50 to 20 000 pg mg nails, and the lowest calibration point achieved the requirements for the LOQ (25 pg mg for hair and 50 pg mg for nails). Although it was not the main focus of the article, the reliability of the method was proven through successful participation in a proficiency test, and by investigation of authentic hair and nail samples from self-reported drug users. In the future, the method should allow comparison between the two matrices to acquire an in-depth knowledge of nail analysis and to define cutoff levels for nail analysis, as they exist for hair.
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http://dx.doi.org/10.1016/j.aca.2017.01.022DOI Listing
April 2017

Hair ethyl glucuronide concentrations in teetotalers: Should we re-evaluate the lower cut-off?

Forensic Sci Int 2017 May 14;274:107-108. Epub 2016 Nov 14.

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

Aims: Ethyl glucuronide in hair (hEtG) can be used to assess the retrospective consumption of alcohol. A lower cut-off of 7pg/mg hair in the 0-3cm proximal scalp hair segment has been used for repeated alcohol consumption in the previous three months. While a concentration below this cut-off is stated not to contradict self reported abstinence, it is often used to assess whether an individual has remained abstinent in the period prior to hair sampling. Here, we address hEtG concentrations in alcohol consuming individuals and critically evaluate this cut-off value.

Methods: Ten individuals remained abstinent from alcohol for 12 weeks. A lock of hair was cut before the start of the study, and the regrown hairs were cut after twelve weeks of abstinence. Hair EtG concentrations were measured both at baseline and after 12 weeks of abstinence. Study compliance was assessed by urine analysis every 2-3 days by liquid chromatography-tandem mass spectrometry with a lower limit of quantification (LLOQ) of 0.1μg/mL. HEtG concentrations were assessed in the first 3cm hair using gas chromatography-tandem mass spectrometry with an LLOQ of 0.2pg/mg.

Results: At the beginning of the study, participants had hEtG concentrations ranging between
Discussion: In participants consuming no alcohol, all but one had low, but measurable hEtG concentrations (up to 4.5pg/mg hair), which was in the participant with the highest pre-study alcohol consumption. As only regrown hairs were cut, it is not likely that this was due to residual EtG from the pre-study period.

Conclusions: Although the number of specimens was low, this study reports measurable hEtG concentrations following total abstinence, although not exceeding the current 7pg/mg cut-off for hair. A suitable sensitive method (GC-MS/MS) is preferred when assessing alcohol abstinence. We propose that the current cut-off of 7pg/mg should be discussed further, and, in view of the small study sample, evaluated using a larger sample size.
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http://dx.doi.org/10.1016/j.forsciint.2016.11.008DOI Listing
May 2017

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

Continuous administration of the mTORC1 inhibitor everolimus induces tolerance and decreases autophagy in mice.

Br J Pharmacol 2016 12 23;173(23):3359-3371. Epub 2016 Oct 23.

Laboratory of Physiopharmacology, Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium.

Background And Purpose: Everolimus is an allosteric inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) widely known for its potent autophagy stimulating properties. Because everolimus shows poor solubility and stability in aqueous solutions, long-term in vivo administration in preclinical models is challenging. The aim of the present study was to evaluate the effects of short-term and long-term everolimus administration on mTORC1 inhibition and autophagy induction in mice.

Experimental Approach: We developed a vehicle in which everolimus was solubilized and stable at 37°C for at least 1 month. Using osmotic minipumps, GFP microtubule-associated protein light chain 3 transgenic mice were treated continuously either with vehicle or everolimus (1.5 mg·kg per day) for 3 or 28 days. Alternatively, a regimen consisting of intermittent everolimus administration (every other day) for 56 days by oral gavage was used. Autophagy markers and mTORC1 activation status were investigated in the liver.

Key Results: As expected, everolimus inhibited mTORC1 and stimulated autophagy in the liver after 3 days of treatment. However, continuous administration for 28 days resulted in hyperactivation of the Akt1-mTORC1 pathway accompanied by a remarkable decrease in autophagy markers. Everolimus given intermittently for 56 days partially rescued mTORC1 sensitivity to the drug but without inducing autophagy. The failure to induce autophagy following long-term everolimus administration was due to uncoupling of the mTORC1 substrate unc-51 like autophagy activating kinase 1.

Conclusions And Implications: Our data encourage the use of intermittent everolimus regimens to prevent tolerance and to extend its activity.
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http://dx.doi.org/10.1111/bph.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738667PMC
December 2016

Does Biotransformation of Aryl Phosphate Flame Retardants in Blood Cast a New Perspective on Their Debated Biomarkers?

Environ Sci Technol 2016 11 4;50(22):12439-12445. Epub 2016 Nov 4.

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

Aryl phosphate flame retardants (aryl-PFRs), such as triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPHP), are emerging contaminants that can exhibit toxic properties, including severe aquatic toxicity and endocrine disruptive effects. Monitoring exposure to aryl-PFRs through specific biomarkers is necessary to assess the health risk associated with chronic exposure. Hydrolytic serum enzymes could play an important role in the formation of the hydrolysis product diphenyl phosphate (DPHP), the seemingly most abundant in vivo biomarker of TPHP in urine. Here, we assess whether serum enzymes have an impact on the toxicokinetics of TPHP and EHDPHP and on the contribution of both aryl-PFRs to in vivo DPHP levels. TPHP and EHDPHP were incubated separately with pooled human serum to measure the formation of hydrolysis products DPHP and 2-ethylhexyl phenyl phosphate (EHPHP) by liquid chromatography-tandem mass spectrometry. Clearance of TPHP and EHDPHP was 70 and 8.6 mL/min/L serum (as measured by formation of DPHP and EHPHP, respectively). No discernible amount of DPHP was produced from EHDPHP by serum hydrolases. Our results suggest that serum hydrolases can significantly contribute to the in vivo levels of DPHP formed from TPHP and can play an important role in the toxicokinetics, toxicity, and selection of biomarkers for aryl-PFRs.
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http://dx.doi.org/10.1021/acs.est.6b03214DOI Listing
November 2016

Comprehensive Study of Human External Exposure to Organophosphate Flame Retardants via Air, Dust, and Hand Wipes: The Importance of Sampling and Assessment Strategy.

Environ Sci Technol 2016 07 11;50(14):7752-60. Epub 2016 Jul 11.

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

We compared the human exposure to organophosphate flame retardants (PFRs) via inhalation, dust ingestion, and dermal absorption using different sampling and assessment strategies. Air (indoor stationary air and personal ambient air), dust (floor dust and surface dust), and hand wipes were sampled from 61 participants and their houses. We found that stationary air contains higher levels of ΣPFRs (median = 163 ng/m(3), IQR = 161 ng/m(3)) than personal air (median = 44 ng/m(3), IQR = 55 ng/m(3)), suggesting that the stationary air sample could generate a larger bias for inhalation exposure assessment. Tris(chloropropyl) phosphate isomers (ΣTCPP) accounted for over 80% of ΣPFRs in both stationary and personal air. PFRs were frequently detected in both surface dust (ΣPFRs median = 33 100 ng/g, IQR = 62 300 ng/g) and floor dust (ΣPFRs median = 20 500 ng/g, IQR = 30 300 ng/g). Tris(2-butoxylethyl) phosphate (TBOEP) accounted for 40% and 60% of ΣPFRs in surface and floor dust, respectively, followed by ΣTCPP (30% and 20%, respectively). TBOEP (median = 46 ng, IQR = 69 ng) and ΣTCPP (median = 37 ng, IQR = 49 ng) were also frequently detected in hand wipe samples. For the first time, a comprehensive assessment of human exposure to PFRs via inhalation, dust ingestion, and dermal absorption was conducted with individual personal data rather than reference factors of the general population. Inhalation seems to be the major exposure pathway for ΣTCPP and tris(2-chloroethyl) phosphate (TCEP), while participants had higher exposure to TBOEP and triphenyl phosphate (TPHP) via dust ingestion. Estimated exposure to ΣPFRs was the highest with stationary air inhalation (median =34 ng·kg bw(-1)·day(-1), IQR = 38 ng·kg bw(-1)·day(-1)), followed by surface dust ingestion (median = 13 ng·kg bw(-1)·day(-1), IQR = 28 ng·kg bw(-1)·day(-1)), floor dust ingestion and personal air inhalation. The median dermal exposure on hand wipes was 0.32 ng·kg bw(-1)·day(-1) (IQR = 0.58 ng·kg bw(-1)·day(-1)) for ΣTCPP. The selection of sampling and assessment strategies could significantly affect the results of exposure assessment.
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http://dx.doi.org/10.1021/acs.est.6b00246DOI Listing
July 2016

Biotransformation of three phosphate flame retardants and plasticizers in primary human hepatocytes: untargeted metabolite screening and quantitative assessment.

J Appl Toxicol 2016 11 18;36(11):1401-8. Epub 2016 Feb 18.

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

Tris(2-butoxyethyl) phosphate (TBOEP), triphenyl phosphate (TPHP) and tris(1-chloro-2-propyl) phosphate (TCIPP) are current high-volume organophosphate flame retardants/plasticizers (PFRs) and are abundant in the indoor environment. While recent in vitro research has indicated potential toxic effects in the endocrine system, biotransformation of these compounds is still underexplored. In this study, we aimed to characterize the metabolite formation for three PFRs in primary human hepatocytes, an in vitro system that mimics in vivo liver metabolism more closely than hepatic subcellular fractions or cell lines. Cryopreserved human hepatocytes were thawed and suspended in media with 50 μm TBOEP or TCIPP, or 20 μm TPHP up to 2 h. Extracts were analyzed by liquid chromatography-quadrupole-time-of-flight-mass spectrometry. Quantification of biotransformation products in hepatocytes exposed for 2 h revealed that bis(1-chloro-2-propyl) phosphate and diphenyl phosphate corresponded to less than half of the depletion of TCIPP and TPHP, respectively, while bis(2-butoxyethyl) 2-hydroxyethyl phosphate compared to 40-66% of the depletion of TBOEP. Other metabolite structures of these PFRs were produced at 4- to 10-fold lower rates. These findings help interpret biological levels of the major metabolites and relate it to levels of their parent PFR. Percentage of substrate depletion was largest for TBOEP followed by comparable values for TPHP and TCIPP, indicating that hepatic clearance of TPHP and TCIPP would be slower than that of TBOEP. The resulting higher levels and longer presence of TPHP in the circulation after exposure, would allow TPHP a larger time window to exert its suspected adverse effects compared to TBOEP. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/jat.3293DOI Listing
November 2016

Hair ethyl glucuronide and serum carbohydrate deficient transferrin for the assessment of relapse in alcohol-dependent patients.

Clin Biochem 2016 May 3;49(7-8):554-9. Epub 2016 Feb 3.

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

Objectives: Ethyl glucuronide in hair (hEtG) and serum carbohydrate deficient transferrin (%CDT) are valuable markers for alcohol abuse, but their diagnostic accuracy to monitor abstinence and relapse is unclear. Here, we investigate to what extent repeated measurements of hEtG and %CDT can be used to monitor relapse in alcohol-dependent patients during abstinence treatment.

Design And Methods: HEtG and %CDT were measured in individuals starting treatment for alcohol dependence both at treatment entry and 3months later. Alcohol consumption and relapse episodes were recorded using the Time Line Follow Back and by alcohol breath and urine tests, and correlated with hEtG and %CDT measurements.

Results: Fifteen patients completed the study, of which nine had one or more relapses. Hair EtG and serum %CDT identified whether a relapse occurred in 78% and 57% of cases, respectively. Only hEtG correlated with the amount of alcohol consumed before treatment entry (Pearson r=0.92; p<0.001). The specificity of %CDT to assess abstinence during treatment was 100%. HEtG had a specificity of only 17%; however, in all patients who remained abstinent, hEtG decreased with >85% from initial values. Mean hEtG, but not %CDT, differed significantly between patients who relapsed and patients who remained abstinent (p=0.034).

Conclusions: HEtG was more sensitive than serum %CDT to assess relapse in alcohol-dependent patients and was positively correlated with the amounts of alcohol consumed. In contrast, serum %CDT was more specific for assessing abstinence. We highlight the benefit of repeated measurements of hEtG and serum %CDT for monitoring abstinence during treatment.
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http://dx.doi.org/10.1016/j.clinbiochem.2015.11.023DOI Listing
May 2016

Spatial and temporal trends in alcohol consumption in Belgian cities: A wastewater-based approach.

Drug Alcohol Depend 2016 Mar 14;160:170-6. Epub 2016 Jan 14.

Toxicological Centre, Department of Pharmaceutical Sciences, University of Antwerp (UA), Universiteitsplein 1, 2610 Antwerp, Belgium. Electronic address:

Background: In recent years, scientific evidence has emerged that wastewater-based epidemiology can deliver complementary information concerning the use of different substances of abuse. In this study, the potential of wastewater-based epidemiology in monitoring spatial and temporal trends in alcohol consumption in different populations in Belgium has been examined.

Methods: Concentrations of ethyl sulphate, a minor Phase-II metabolite of ethanol, in 163 influent wastewater samples from eight wastewater treatment plants in Belgium in the period 2013-2015 were measured with liquid chromatography coupled to tandem mass spectrometry and used to estimate alcohol consumption.

Results: The highest levels of alcohol consumption were detected in the metropoles Antwerp and Brussels compared to smaller villages. Annual variations were detected, with a higher alcohol consumption measured in 2013 compared with 2014. The weekly pattern showed a clear week and weekend difference in alcohol use, with intermediate levels on Monday and Friday. The results were extrapolated and a use of 5.6L pure alcohol per year per inhabitant aged 15+ has been estimated in Belgium. The comparison with available information on drinking habits of the Belgian population further demonstrated the usefulness of the wastewater-based epidemiology approach.

Conclusions: This is the largest wastewater-based epidemiology study monitoring alcohol consumption to date, demonstrating that objective and quick information on spatio-temporal trends in alcohol consumption on a local and (inter)national scale can be obtained.
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http://dx.doi.org/10.1016/j.drugalcdep.2016.01.002DOI Listing
March 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
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