Publications by authors named "Nicolas Fabresse"

18 Publications

  • Page 1 of 1

Analysis of pharmaceutical products and dietary supplements seized from the black market among bodybuilders.

Forensic Sci Int 2021 May 30;322:110771. Epub 2021 Mar 30.

Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, FHU Sepsis, AP-HP, 104 boulevard Raymond Poincaré, 92380 Garches, France; Plateforme de Spectrométrie de Masse MassSpecLab, INSERM UMR 1173, UFR des Sciences de la Santé Simone Veil, Université Paris-Saclay (Versailles Saint-Quentin-en-Yvelines), 2 avenue de la source de la Bièvre, 78180 Montigny-le-Bretonneux, France. Electronic address:

Substandard/counterfeit drugs are a growing global problem. According to the World Health Organisation, counterfeit medicines are medicines that are mislabelled deliberately and fraudulently regarding their identity and/or source. In high income countries, drugs seized are mainly represented by performance and image enhancing drugs (PIEDs). The aim of this study was to present the qualitative and quantitative results of toxicological analyses of pharmaceutical and dietary supplements seized from the black market among bodybuilders in France. All dietary supplements and pharmaceuticals seized from the black market and addressed to the laboratory for a qualitative and quantitative analysis between January 2016 and December 2019 were included in the study. A screening was carried out by gas chromatography-mass spectrometry and liquid chromatography-high resolution mass spectrometry. Identified compounds were quantified by liquid chromatography-tandem mass spectrometry. One hundred and ten products were seized and submitted to the laboratory for identification of active compounds and quantification: 75 pharmaceuticals and 35 dietary supplements. This included 39 oily and 3 aqueous solutions for intramuscular injection, 34 tablets, 13 capsules, 14 powders, 4 liquids and 3 lyophilizates. Among the pharmaceuticals, 25/75 (33%) were substandard (dosage not on the acceptable range defined for original products), 24/75 (32%) were counterfeit (qualitative formulation does not match the label) and 14/75 (19%) were original (qualitative formulation and levels of active ingredients fully matches the declared formulation. The analysis of the 12 remaining products revealed a correct qualitative content for 11/75 (15%), but quantitation could not be carried out because of the lack of reference standards at the time of the analysis. Fifty-four pharmaceuticals contained anabolic-androgenic steroids (AAS). Four out of 54 (7.4%) AAS were found as original, 8/54 (15%) could not be quantified (one with wrong active ingredient), corresponding to 43/54 (80%) AAS being non-original. In contrast, only 1/35 dietary supplement (3%) was adulterated, with a doping substance (1,3-dimethylbutylamine, DMBA). This work allows to show that France is not spared by the trafficking of PIEDs. The use of counterfeit drugs in mainstream population is an underestimated public health issue.
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http://dx.doi.org/10.1016/j.forsciint.2021.110771DOI Listing
May 2021

Molecular adsorbent recirculating system (MARS) and continuous veno-venous hemodiafiltration (CVVHDF) for diltiazem removal: An in vitro study.

Int J Artif Organs 2020 Dec 1:391398820975041. Epub 2020 Dec 1.

MassSpecLab, Plateforme de Spectrométrie de Masse, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Montigny le Bretonneux, France.

The objective of the present study was to evaluate the efficacy of the molecular adsorbent recirculating system (MARS) vs continuous veno-venous hemodiafiltration (CVVHDF). Diltiazem poisoning was simulated in a central compartment consisting in a 5L dialysis solute spiked with diltiazem at two different toxic concentrations: 750 and 5000 µg/L. For CVVHDF, mean extraction coefficients (EC = (in concentration - out concentration)/in concentration) were concentration-dependent with a decrease all along the dialysis. At the end of the sessions the mean amounts remaining in the central compartment were 8% and 7% of the initial dose at 750 and 5000 µg/L, respectively. The mean cumulative amounts found in the effluent were 60% and 75% of the initial dose, respectively. The missing amounts accounted for 32% and 18% of the initial dose, respectively, corresponding to an adsorption to the dialysis membrane. In contrast, the different compartments of the MARS resulted in undetectable output concentration earlier that the end of the session. The mean concentrations of diltiazem remaining in the central compartment were <1 µg/L at the end of the sessions. Global ECs were around 50% all along the experiment at both concentrations, and the average charcoal cartridge ECs was 80% throughout the experiments.CVVHDF system in the developed model was efficient for diltiazem removal, mainly by diffusion, convection and to a lesser extent by adsorption to the dialysis membrane. In MARS system, resin cartridge and hemodialysis components are ineffective, charcoal cartridge is responsible for almost all drug removal.
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http://dx.doi.org/10.1177/0391398820975041DOI Listing
December 2020

Quantification of free and protein bound uremic toxins in human serum by LC-MS/MS: Comparison of rapid equilibrium dialysis and ultrafiltration.

Clin Chim Acta 2020 Aug 3;507:228-235. Epub 2020 May 3.

Laboratory of Pharmacology and Toxicology, CHU Raymond Poincare, Garches, France; INSERM U-1173, UFR des Sciences de la Santé Simone Veil, Université Paris-Saclay (Versailles-Saint-Quentin-en-Yvelines), Montigny le Bretonneux, France. Electronic address:

The objectives of this study were (1) to develop a method for the determination of 10 uremic toxins (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid, kynurenine, p-cresyl glucuronide, p-cresyl sulfate, phenylacetylglutamine and trimethylamine N-oxide (TMAO)), and 3 precursors (tyrosine, phenylalanine, tryptophan) in serum and (2) to compare two separation methods to determine the free serum fraction: rapid equilibrium dialysis (RED) and ultrafiltration (UF). The method was developed on a liquid chromatography system coupled to a tandem mass spectrometer. Fifty µL of serum sample were precipitated with methanol after addition of internal standard. The two separation methods were compared using serum samples from patients suffering from renal impairment (n = 30). The method has been validated according to the European Medicines Agency (EMA) guidelines. Calibration curves were linear from 1 to 50 ng/mL up to 10,000-50,000 ng/mL according to the compounds. The comparison between the two separation methods produced similar results for all compounds except kynurenine, tryptophan (around 30% more with UF) and indole-3-acetic acid (around 30% more with RED). This study has allowed the development and validation of a sensitive and robust assay for the quantification of free and total concentrations of 10 uremic toxins and 3 precursors in human serum.
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http://dx.doi.org/10.1016/j.cca.2020.04.032DOI Listing
August 2020

Does the Administration of Sevelamer or Nicotinamide Modify Uremic Toxins or Endotoxemia in Chronic Hemodialysis Patients?

Drugs 2019 Jun;79(8):855-862

Inserm U-1018 Centre de Recherche en Epidémiologie et Santé des Populations (CESP), Equipe 5, Villejuif, France.

Background: Hyperphosphatemia control is a major issue in hemodialysis patients. Both sevelamer and nicotinamide are prescribed for this purpose. In addition, they exert pleiotropic effects such as an improvement of inflammatory status and potentially enhanced clearance of uremic toxins. In the present secondary analysis of the NICOREN trial, we investigated the impact of sevelamer and nicotinamide on uremic toxins, toxin precursors, and endotoxemia in chronic hemodialysis patients.

Methods: Circulating uremic toxins (including phenylacetylglutamine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, kynurenine, hippuric acid, indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid, kynurenic acid, and p-cresyl glucuronide) and precursors were measured by ultra-performance liquid chromatography-tandem mass spectrometry, and urea, uric acid, phosphate, C-reactive protein, and intact parathyroid hormone by routine biochemistry methods. Serum endotoxin (evaluated by lipopolysaccharide levels) and C-terminal fibroblast growth factor-23 levels were measured using enzyme-linked immunosorbent assay kits.

Results: One hundred hemodialysis patients were randomized to receive either nicotinamide or sevelamer treatment. Among them, 63% were male, mean (± standard deviation) age was 65 ± 14 years, 47% had diabetes mellitus, and 51% had a history of cardiovascular disease. In the sevelamer group, but not the nicotinamide group, serum levels of urea, uric acid, and fibroblast growth factor-23 were significantly reduced after 6 months of treatment. The other circulating uremic toxins and toxin precursors remained unchanged in response to either phosphate-lowering agent. Sevelamer treatment led to a marked decrease in serum lipopolysaccharide (p < 0.001) whereas nicotinamide treatment induced an only modest decrease of borderline significance (p = 0.057). There was no change in C-reactive protein levels.

Conclusion: In contrast to sevelamer, nicotinamide did not reduce circulating levels of low-molecular-weight uremic toxins other than phosphate, and neither agent reduced circulating uremic toxins of high-molecular-weight or protein-bound toxins. Sevelamer, but not nicotinamide, reduced serum endotoxin levels. Despite no change in serum C-reactive protein, the endotoxin-lowering effect of sevelamer may help to attenuate the inflammatory status of patients with chronic kidney disease.
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http://dx.doi.org/10.1007/s40265-019-01118-9DOI Listing
June 2019

Validation according to European and American regulatory agencies guidelines of an LC-MS/MS method for the quantification of free and total ropivacaine in human plasma.

Clin Chem Lab Med 2020 04;58(5):701-708

Plateforme de spectrométrie de masse MasSpecLab, INSERM UMR 1173, UFR Simone Veil - Santé, Université Versailles Saint Quentin, Université Paris Saclay, Montigny le Bretonneux, France.

Background Ropivacaine is a widely used local anaesthetic drug, highly bound to plasma proteins with a free plasma fraction of about 5%. Therefore, the monitoring of free drug concentration is most relevant to perform pharmacokinetic studies and to understand the drug pharmacokinetic/pharmacodynamic (PK/PD) relationship. Methods A high-sensitivity liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using reverse-phase LC and electrospray ionisation mass spectrometry with multiple reaction monitoring (MRM) is described for the quantitation of both free and total ropivacaine in human plasma. Ropivacaine-d7 was used as an internal standard (IS). Results The method was validated in the range 0.5-3000 ng/mL, with five levels of QC samples and according to the European Medicine Agency and Food and Drug Administration guidelines. The performance of the method was excellent with a precision in the range 6.2%-14.7%, an accuracy between 93.6% and 113.7% and a coefficient of variation (CV) of the IS-normalised matrix factor below 15%. This suitability of the method for the quantification of free and total ropivacaine in clinical samples was demonstrated with the analysis of samples from patients undergoing knee arthroplasty and receiving a local ropivacaine infiltration. Conclusions A method was developed and validated for the quantification of free and total ropivacaine in human plasma and was shown suitable for the analysis of clinical samples.
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http://dx.doi.org/10.1515/cclm-2018-1298DOI Listing
April 2020

Development and validation of a liquid chromatography-tandem mass spectrometry method for simultaneous detection of 10 illicit drugs in oral fluid collected with FLOQSwabs™ and application to real samples.

Drug Test Anal 2019 Jun 17;11(6):824-832. Epub 2019 Jan 17.

Plateforme MasSpecLab, U-INSERM 1173, UFR Simone Veil, Université de Versailles Saint-Quentin, 2 avenue de la source de la Bièvre, 78180, Montigny le Bretonneux, France.

According to French law, the roadside testing for drugs of abuse (DOA) should be performed in oral fluid (OF) using an immunological screening kit. If the screening is positive, confirmation has to be done in OF collected by a special swab, called the FLOQSwab™ (FS). Unlike other sampling kits, this device was not designed to collect OF since it does not contain an elution buffer. An analytical method was developed for the simultaneous detection of 10 DOA under control in France: tetrahydrocannabinol (THC) at 1 ng/mL, and cocaine, benzoylecgonine (BZE), morphine, 6-monoacetylmorphine (6-MAM), amphetamine, methamphetamine, 3,4-methylenedioxy-N-ethylamphetamine (MDEA), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxy-N-methylamphetamine (MDMA) at 10 ng/mL. Samples were eluted using the Quantisal buffer and extracted by liquid-liquid extraction for THC and by solid-phase extraction for the remaining analytes. Analyses were performed by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The validated method made it possible to detect the concentrations required by law and was successfully applied to samples from drivers who screened positive. The main limitations of this kit are the large variability of the collected OF volume and the poor stability of DOA in OF, requiring the use of a conservation buffer.
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http://dx.doi.org/10.1002/dta.2563DOI Listing
June 2019

Development of a sensitive untargeted liquid chromatography-high resolution mass spectrometry screening devoted to hair analysis through a shared MS2 spectra database: A step toward early detection of new psychoactive substances.

Drug Test Anal 2019 May 25;11(5):697-708. Epub 2018 Nov 25.

Plateforme de Spectrométrie de Masse MassSpecLab, INSERM UMR 1173, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, Montigny le Bretonneux, France.

Untargeted liquid chromatography-high resolution mass spectrometry (LC-HRMS) techniques have become indispensable tools for systematic toxicological analysis. They allow the research of an almost unlimited number of drugs within a single analytical cycle, but shared mass spectra libraries are still missing to identify newly marketed compounds, along with defined analytical procedures. This article describes the optimization, validation, and application of an untargeted screening method devoted to hair analysis using data-dependent analysis (DDA) and a shared HRMS database. This method used an ultra-high performance liquid chromatography coupled to a benchtop Orbitrap. Raw MS data were processed with Compound Discoverer software coupled to the mzCloud™ library. Optimizations were performed on blank hair spiked with 19 analytes having different physical and chemical properties. To validate the effectiveness of a shared spectra database, 20 compounds spectra were added and then retrospectively screened. Sensitivity and reliability were evaluated on 317 compounds of interest in toxicology. The method was then applied to 11 hair samples. The matrix effect range by ion suppression/enhancement was 40%-110%. The method allows the detection of 284 among the 317 screened compounds, including 72 new psychoactive substances (NPS). Lower limit of identification (LLOI) and lower limit of detection (LLOD) were 1 to 1000 pg/mg and 1 to 500 pg/mg, respectively. The method was successfully applied to 11 clinical cases and 144 compounds were identified including 24 NPS including AKB48-5F for the first time in hair. We developed and validated an LC-HRMS untargeted screening of 284 compounds and successfully applied it to 11 real hair samples.
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http://dx.doi.org/10.1002/dta.2535DOI Listing
May 2019

Drug-facilitated sexual assault (DFSA) involving 4-methylethcathinone (4-MEC), 3,4-Methylenedioxypyrovalerone (MDPV), and doxylamine highlighted by hair analysis.

Drug Test Anal 2018 Mar 10. Epub 2018 Mar 10.

Laboratory of Pharmacology-Toxicology, AP-HP, Raymond Poincaré University Hospital, Versailles Saint-Quentin-en-Yvelines University, Garches, France.

Recently, the emergence of new psychoactive substances (NPS) has led to their wide use among clubbers and men who have sex with men (MSM) for their stimulant effects. However, their use in drug-facilitated sexual assault (DFSA) has rarely been described. Herein we report a case of a 44-year-old man who was assaulted after a party. Due to late reporting of the offense, only hair (black) was sampled 15 days later and a segmental analysis was achieved to look for most DFSA agents and NPS. Twenty mg of each segment (A: 0-1 cm, B: 1-3 cm, and C: 3-5 cm) were incubated in phosphate buffer pH 5.0. After alkaline liquid extraction and chromatographic separation on 1.9 μm Hypersil GOLD PFP column, compounds were detected by a TSQ Vantage mass spectrometer with electrospray ionization in positive mode with multiple reaction monitoring (MRM) acquisition. 4-methylethcathinone (4-MEC), methylenedioxypyrovalerone (MDPV) and doxylamine were found in proximal segment at very low concentrations (3, 5, and 9 pg/mg, respectively) which is in agreement with a single exposure in the previous month corresponding to the alleged facts. These substances were not detected in segments B and C showing a lack of repetitive exposure before the alleged event. Thus, the results do not contradict the patient's claim of being assaulted. Doxylamine has already been encountered in such cases but no publications referring to 4-MEC or MDPV use have ever been documented. Our case reports the unusual administration of cathinones to achieve a sexual assault and stresses the interest of looking for designer drugs when dealing with DFSA cases.
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http://dx.doi.org/10.1002/dta.2377DOI Listing
March 2018

Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study.

Clin Toxicol (Phila) 2018 08 15;56(8):773-781. Epub 2018 Jan 15.

c Laboratoire de Pharmacologie - Toxicologie , Centre Hospitalier Universitaire Raymond Poincaré, AP-HP et MassSpecLab, Plateforme de Spectrométrie de Masse, Inserm U-1173, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin , Garches , France.

Background: Colchicine poisoning is commonly lethal. Colchicine-specific Fab fragments increase rat urinary colchicine clearance and have been associated with a good outcome in one patient. We aimed to develop a porcine model of colchicine toxicity to study the pharmacokinetics and efficacy of ovine Fab.

Methods: A Göttingen minipig critical care model was established and serial blood samples taken for colchicine and Fab pharmacokinetics, clinical chemistry, and haematology. Animals were euthanised when the mean arterial pressure fell below 45 mmHg without response to vasopressor, or at study completion.

Results: Initial studies indicated that oral dosing produced variable pharmacokinetics and time-to-euthanasia. By contrast, intravenous infusion of 0.25 mg/kg colchicine over 1 h produced reproducible pharmacokinetics (AUC 343 [SD = 21] µg/L/h), acute multi-organ injury, and cardiotoxicity requiring euthanasia a mean of 22.5 (SD = 3.2) h after dosing. A full-neutralising equimolar Fab dose given 6 h after the infusion (50% first hour, 50% next 6 h [to reduce renal-loss of unbound Fab]) produced a 7.35-fold increase in plasma colchicine (AUC 2,522 [SD = 14] µg/L/h), and removed all free plasma colchicine, but did not prevent toxicity (euthanasia at 29.1 [SD = 3.4] h). Earlier administration over 1 h of the full-neutralising dose, 1 or 3 h after the colchicine, produced a 12.9-fold (AUC 4,433 [SD = 607] µg/L/h) and 6.0-fold (AUC 2,047 [SD = 51] µg/L/h) increase in plasma colchicine, respectively, absence of free plasma colchicine until 20 h, and survival to study end without marked cardiotoxicity.

Conclusions: Colchicine-specific Fab given early, in equimolar dose, bound colchicine, eliciting its movement into the blood, and preventing severe toxicity. Clinical studies are now needed to determine how soon this antidote must be given to work in human poisoning.
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http://dx.doi.org/10.1080/15563650.2017.1422510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021765PMC
August 2018

Common Neurotransmission Recruited in (R,S)-Ketamine and (2R,6R)-Hydroxynorketamine-Induced Sustained Antidepressant-like Effects.

Biol Psychiatry 2018 07 26;84(1):e3-e6. Epub 2017 Oct 26.

CESP/UMR-S 1178, Université Paris-Sud, Faculté de Pharmacie, INSERM, Université Paris-Saclay, Châtenay Malabry, France. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2017.10.020DOI Listing
July 2018

Plasma 7-Hydroxymethotrexate Levels Versus Methotrexate to Predict Delayed Elimination in Children Receiving High-Dose Methotrexate.

Ther Drug Monit 2018 02;40(1):76-83

INSERM U911-CRO2 SMARTc, Aix-Marseille Univ, Marseille, France.

Background: The aim of this study was to investigate the correlation between 7-hydroxymethotrexate (7-OHMTX) and creatinine and to evaluate the predictive value of 7-OHMTX levels on delayed elimination at 24 and 48 hours. In addition, differences in methotrexate (MTX), 7-OHMTX levels, and MTX metabolism using the ratio MTX/7-OHMTX were determined according to age.

Methods: The authors included a total of 106 cycles, corresponding to 33 patients (mean age: 9.8 years, range: 2-18 years) suffering from acute lymphoblastic leukemia, non-Hodgkin lymphoma and osteosarcoma and receiving high-dose MTX (HD-MTX). Plasma MTX, 7-OHMTX, and creatinine at T24 and T48 hours were measured.

Results: Children older than 14 years had significantly higher MTX levels at T48 hours (1.25 versus 0.5 μmol/L, P < 0.05) and a higher MTX/7-OHMTX ratio (0.63 versus 0.20, P < 0.05) than children younger than 6 years. Plasma 7-OHMTX at T24 and T48 hours was positively correlated with serum creatinine and creatinine ratio at T24 and T48 hours. MTX levels provided a better specificity and sensitivity at both 24 and 48 hours than 7-OHMTX to predict delayed MTX elimination. A MTX threshold close to 0.83 μmol/L at T48 hours improved specificity from 58% to 82% and keeps sensitivity at 100%. The authors identified a cut-off at 65 μmol/L for MTX at T24 hours with a good sensitivity (75%) and specificity above 50%.

Conclusions: These results confirm the concentration-dependent nephrotoxicity of 7-OHMTX. Children older than 14 years old had a higher MTX levels at 48 hours and a higher MTX/7-OHMTX ratio, suggesting a faster metabolism in younger children. This study identified a higher and more specific MTX threshold at T48 hours compared to those currently used, and a new threshold at T24 hours.
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http://dx.doi.org/10.1097/FTD.0000000000000445DOI Listing
February 2018

Hair analysis does not allow to discriminate between acute and chronic administrations of a drug in young children.

Int J Legal Med 2018 Jan 18;132(1):165-172. Epub 2017 Oct 18.

Laboratory of Pharmacology-Toxicology, AP-HP, INSERM U-1173, Raymond Poincaré University Hospital, Versailles Saint Quentin-en-Yvelines University, 104 Boulevard Raymond Poincaré, 92380, Garches, France.

There are many differences between the hair from children and that of adult subjects, the hair being thinner, more porous with a different growth rate from the usual 1 cm/month observed in adults. In order to determine whether hair analysis could discriminate between chronic use and acute administration of a drug in children like in adults, we analyzed hair from 18 children aged between 1 day and 15 years in whom the administration of different drugs was known (single therapeutic administration or acute intoxication). A strand of hair was sampled within 1 to 45 days after treatment or intoxication. Analysis was conducted using LC/MS/MS. In the 10 youngest children, aged between 1 day and 29 months, the compounds administered in hospital or responsible for intoxication (lidocaine, ropivacaine, diazepam, midazolam, levetiracetam, morphine, ketamine, methadone, buprenorphine, THC, MDMA) were found in all segments of the hair independently of the time of sampling (1-45 days after ingestion). The concentrations detected were similar along the hair shaft, showing a radial diffusion and incorporation of the analytes in the hair of young children from the sebum. Concentrations could be very high when sampled shortly after administration (72 ng/mg for methadone, 75 ng/mg for MDMA after 3 days) and lower when sampling later (1.2 ng/mg for MDMA after 45 days). In these cases, hair analysis allowed to highlight the compounds responsible for intoxication even when they had disappeared from the blood or urine but should not be used to discriminate long-term exposure to a drug. In the eight remaining children aged from 34 months to 15 years, the drugs used in hospital (lidocaine, diazepam, morphine) or responsible for intoxication (THC, codeine, buprenorphine) were not found in any analyzed segments sampled 1 to 5 days after administration of the drugs, in agreement with the non-incorporation of the drugs from the sebum into the hair. For those children aged over 34 months, hair analysis allows to determine the chronic administration of a drug, like in adults.
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http://dx.doi.org/10.1007/s00414-017-1720-5DOI Listing
January 2018

Prevalence and Surveillance of Synthetic Cathinones Use by Hair Analysis: An Update Review.

Curr Pharm Des 2017 01;23(36):5487-5495

Department of Pharmacology and Toxicology, Versailles Saint-Quentin-en-Yvelines University, Inserm U-1173, Raymond Poincare hospital, AP-HP, Garches, France.

New psychoactive substances (NPS) have emerged in a threatening way in the last decades. They are sold via the internet or head shops with several names (bath salts, Research chemical, RCs, Legal Highs) and forms (pills, tablets, powder...etc.), and are labelled ambiguously to escape governmental legislation. Designer drugs belong to different chemical classes, but cathinones derivatives presented the most prevalent group. In 2013, this group accounted for 30% of NPS seizures in Europe with more than 450 different compounds, including 101 new molecules reported for the first time in 2014. The increased number of NPS as being sold in parallel market has led several countries to adopt different strategies either on individual surveillance of new emerging drugs or more efficiently on generic control regrouping a wide number of isomers and structurally similar compounds. The identification of these substances is a challenge for toxicologists, which requires sensitive and specific analytical methods based on LC-MS/MS or GC-MS. The usefulness of hair as an alternative matrix for prevalence studies was proved since it offers an overview on drug exposure with a large detection window over weeks or even months and years according to the length of the hair strand. However, as for many drugs of abuse, prevalence studies on cathinones derivatives use are still scarce. Self-reported use or case reports provide most of the available data. The aim of this paper is to provide an update review on prevalence and surveillance of synthetic cathinones use conducted by hair analysis, excluding case report.
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http://dx.doi.org/10.2174/1381612823666170704124156DOI Listing
January 2017

LC-MS/MS quantification of free and Fab-bound colchicine in plasma, urine and organs following colchicine administration and colchicine-specific Fab fragments treatment in Göttingen minipigs.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Aug 20;1060:400-406. Epub 2017 Jun 20.

MassSpecLab, Plateforme de Spectrométrie de Masse, Inserm U-1173, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, 2 Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France; Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, 104 Boulevard R. Poincaré, 92380 Garches, France. Electronic address:

Clinical evaluation of a colchicine specific antigen-binding fragment (Fab) in order to treat colchicine poisoning required the development of an accurate method allowing quantification of free and Fab-bound colchicine in plasma and urine, and free colchicine in tissues, to measure colchicine redistribution after Fab administration. Three methods have been developed for this purpose, and validated in plasma, urine and liver: total colchicine was determined after denaturation of Fab by dilution in water and heating; free colchicine was separated from Fab-bound colchicine by filtration with 30KDa micro-filters; tissues were homogenized in a tissue mixer. Deuterated colchicine was used as internal standard. Samples were extracted by liquid-liquid extraction and analyzed with a LC-MS/MS. LOQ were 0.5ng/mL in plasma and urine for free and total colchicine and 5pg/mg in tissues. The methods were linear in the 0.5-100ng/mL range in plasma and urine, and 5-300pg/mg in tissues with determination coefficients>0.99. Precision and accuracy of QC samples presented a CV<9.4%. The methods require only 200μL of sample and allow a high throughput due to short analytical run (2min). These methods were successfully applied to a pig intoxicated with colchicine and treated with colchicine specific Fab fragments.
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http://dx.doi.org/10.1016/j.jchromb.2017.06.034DOI Listing
August 2017

LC-MS/MS determination of tranexamic acid in human plasma after phospholipid clean-up.

J Pharm Biomed Anal 2017 Jul 19;141:149-156. Epub 2017 Apr 19.

Plateforme de spectrométrie de masse MasSpecLab, INSERM UMR 1173, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint Quentin, Université Paris Saclay, Montigny le Bretonneux, France; Département des maladies respiratoires, Hôpital Foch, Suresnes, France. Electronic address:

Tranexamic acid is a widely used antifibrinolytic drug but its pharmacology and pharmacokinetics remains poorly understood. Owing to the recent knowledge on phospholipid-induced matrix effects during human plasma analysis, our aim was to develop a liquid chromatography-mass spectrometry method for the quantitation of tranexamic acid after efficient sample clean-up. Sample preparation consisted in phospholipid removal and protein precipitation. Hydrophilic interaction liquid chromatography was used and the detection was achieved with multiple reaction monitoring. The method was validated according to the European Medicine Agency guideline in the range 1.0-1000.0μg/mL. The performance of the method was excellent with a precision in the range 1.2-3.0%, an accuracy between 88.4 and 96.6% and a coefficient of variation of the internal standard-normalized matrix factor below 6.7%. This method is suitable for the quantification of tranexamic acid in the wide range of concentrations observed during clinical studies, with all the advantages related to phospholipid removal.
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http://dx.doi.org/10.1016/j.jpba.2017.04.024DOI Listing
July 2017

Detection and quantification of 12 anabolic steroids and analogs in human whole blood and 20 in hair using LC-HRMS/MS: application to real cases.

Int J Legal Med 2017 Jul 24;131(4):989-999. Epub 2017 Feb 24.

MassSpecLab, Plateforme de Spectrométrie de Masse, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin, 2 Avenue de la Source de la Bièvre, 78180, Montigny le Bretonneux, France.

We developed and validated a method to detect and quantify 12 anabolic steroids in blood (androstenedione, dihydrotestosterone, boldenone, epitestosterone, mesterolone, methandienone, nandrolone, stanozolol, norandrostenedione, tamoxifene, testosterone, trenbolone) and eight more in hair samples (nandrolone phenylpropionate, nandrolone decanoate, testosterone propionate, testosterone benzoate, testosterone cypionate, testosterone decanoate, testosterone phenylpropionate, testosterone undecanoate) using liquid chromatography coupled to high-resolution mass spectrometry. This method used a benchtop Orbitrap mass spectrometer operating with an APCI probe under positive ionization mode. Analysis was realized in full scan experiment with a nominal resolving power of 140,000. After addition of the internal standard (testosterone-D3) and incubation in phosphate buffer pH = 5 for hair, 200 μL of blood and 30 mg of hair samples were extracted with heptane. LOQ and LOD were determined at 5 and 1 ng mL in whole blood and 10 to 100 pg mg and 2 to 20 pg mg in hair according to the compounds, respectively. The method was linear in the 5-1000 ng mL range in whole blood and between 10 or 100 pg mg and 1000 pg mg in hair with correlation coefficients >0.99, and intra- and inter-day accuracy and precision were <14.8% for all compounds except for some esters in hairs (<19.9%) probably due to an important matrix effect for these compounds. This sensitive and specific method to detect anabolic steroids has been successfully applied to two real cases, for which various anabolic steroids in whole blood, urine, and hair were identified and quantified.
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http://dx.doi.org/10.1007/s00414-017-1552-3DOI Listing
July 2017

Identification and quantification of 4-methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV) in hair by LC-MS/MS after chronic administration.

Forensic Sci Int 2017 Jan 24;270:39-45. Epub 2016 Nov 24.

Laboratory of Pharmacology-Toxicology, AP-HP, Raymond Poincaré Universitary Hospital, Versailles Saint-Quentin-en-Yvelines University, Inserm U-1173, 92380 Garches, France.

4-Methylethcathinone (4-MEC) and 3,4-methylenedioxypyrovalerone (MDPV) are synthetic cathinones. The objective of this study was to develop a method in order to measure these compounds in hair of a patient. After decontamination, 20mg of hair were grinded and incubated in phosphate buffer pH 5.0 in presence of 100ng of MDMA-d5 used as internal standard. Double basic liquid-liquid extraction was performed. Samples were separated on a 1.9μm Hypersil GOLD PFP column (100×2.1mm) using gradient elution. Compounds were detected by a LCQ TSQ Vantage XP triple-quadrupole mass spectrometer. SRM transitions m/z 192.1→146.1 and 174.2, m/z 276.1→175.0 and 205.1 and m/z 199.1→165.1 were used for 4-MEC, MDPV and IS, respectively. The assay was accurate and precise over the range 0.001 (lower limit of quantification) to 1ng/mg in hair. No matrix effect was observed. The method has been applied to a 30-year-old man who usually consumed cathinones for 6 months administered intravenously and was admitted to a general hospital for delirious and tachycardia after absorption of 10g of a powder sold as 4-MEC and 5g of MDPV. Both 4-MEC (30ng/mg) and MDPV (1ng/mg) were identified in the hair at high concentrations showing a regular consumption of these drugs. Many others compounds were also identified (mephedrone, MDMA, MDA, cocaine and metabolites, tramadol, hydroxyzine, aripiprazole, haloperidol). Few data are available on concentration of these new designer drugs in hair however important in order to determine the acute or chronic consumption of these drugs.
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http://dx.doi.org/10.1016/j.forsciint.2016.11.028DOI Listing
January 2017

A case of drug-facilitated sexual assault involving 3,4-methylenedioxy-methylamphetamine.

J Psychoactive Drugs 2013 Jan-Mar;45(1):94-7

Centre for Evaluation and Information on Pharmacodependence, Addictovigilance, Medical Pharmacology and Toxicology Department, University Hospital of Montpellier, France.

Typical scenarios of drug-facilitated sexual assaults usually involve victims having ingested a drink after which they had little, partial or no recollection of events for a period of time. We were surprised by the case of a woman who was sexually assaulted and described a state of amazement, leading to an incapacity to resist physically or verbally to her aggressor, and who remembered everything. Alcohol was first suspected but toxicological analysis revealed the presence of 3,4-methylene-dioxy-methylamphetamine (MDMA, Ecstasy). In the literature review, a few cases of sexual assault involving involuntarily MDMA intake are described.
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http://dx.doi.org/10.1080/02791072.2013.763573DOI Listing
June 2013