Publications by authors named "Islam Amine Larabi"

21 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

Metabolic profiling of deschloro-N-ethyl-ketamine and identification of new target metabolites in urine and hair using human liver microsomes and high-resolution accurate mass spectrometry.

Drug Test Anal 2021 Feb 3. Epub 2021 Feb 3.

Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-En-Yvelines University), Garches, France.

The aim of this study was to identify new markers of deschloro-N-ethyl-ketamine (O-PCE), a ketamine analogue that has been involved in acute intoxications with severe outcomes including death and whose metabolism has never been studied before. In vitro study after 2-h incubation with pooled human liver microsomes (HLMs) cross-checked by the analysis of urine and hair from a 43-year-old O-PCE user (male) were performed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). Acquired data were processed by the Compound Discoverer® software, and a full metabolic profile of O-PCE was proposed. In total, 15 metabolites were identified, 10 were detected in vitro (HLMs) and confirmed in vivo (urine and/or hair), two were present only in HLMs, and the remaining three metabolites were identified only in biological specimens. While O-PCE was no longer detected in urine, nine metabolites were identified allowing to increase its detection window. In descending order of metabolites abundance, we suggest using 2-en-PCA-N-Glu (34%, first), M3 (16%, second), O-PCA-N-Glu (15.4%, third), OH-O-PCE (15%, fourth) and OH-PCE (11.9%, fifth) as target metabolites to increase the detection window of O-PCE in urine. In hair, nine metabolites were identified. OH-PCA was the major compound (78%) with a relevant metabolite to parent drug ratio (=6) showing its good integration into hair and making it the best marker for long-term monitoring of O-PCE exposure.
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http://dx.doi.org/10.1002/dta.3007DOI Listing
February 2021

Atropine-induced toxicity after off-label sublingual administration of eyedrop for sialorrhoea treatment in neurological disabled patients.

Br J Clin Pharmacol 2021 Feb 1. Epub 2021 Feb 1.

Unité de Soins de Rééducation Post-Réanimation, Hôpital Raymond Poincaré, APHP. Université Paris-Saclay, Garches, France.

Sialorrhea is a troublesome and disabling symptom defined by the unintentional loss of saliva from the mouth, usually associated with swallowing disorders. Today there is no consensus about the management of sialorrhoea, but off-label use of ophthalmic atropine eyedrop administered sublingually may offer benefits, despite limited safety data. We report 2 cases of atropine overdose after sublingual administration illustrating that atropine can expose to severe adverse effects when administered sublingually. The noncompartmental pharmacokinetic study of atropine performed in 1 patient highlighted that systemic absorption of sublingual atropine was effective (C [1 h] = 2.2 ng mL ; approximately) after a single dose of 1 mg.
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http://dx.doi.org/10.1111/bcp.14757DOI Listing
February 2021

Evaluation of Drug Abuse by Hair Analysis and Self-Reported Use Among MSM Under PrEP: Results From a French Substudy of the ANRS-IPERGAY Trial.

J Acquir Immune Defic Syndr 2021 04;86(5):552-561

Département de Pharmacologie-Toxicologie, Hôpital Raymond Poincaré, AP-HP, et MassSpecLab, Plateforme de Spectrométrie de Masse, Inserm U-1173, UFR des Sciences de la Santé Simone Veil, Université Paris-Saclay (Versailles Saint-Quentin-en-Yvelines), Garches, France.

Background: We used the Agence nationale de Recherches sur le sida et les hépatites virales (ANRS)-IPERGAY trial to qualitatively and quantitatively measure drug use among men who have sex with men under preexposure prophylaxis using 2 different methods, to better understand and collectively respond to risky practices.

Method: We included 69 volunteers of the ANRS-IPERGAY trial. We measured drug use by 2 methods: (1) drug detection by hair analysis and (2) reported drug use by self-reported drug consumption.

Results: New psychoactive substances (NPS) and conventional drugs were detected in 53 of the 69 (77%) volunteers by hair analysis and in 39 of the 69 (57%) volunteers by questionnaires. On the 219 hair segments analyzed, the most commonly used drugs were cocaine in 47 of the 69 (68%), 3,4-methylenedioxymethamphetamine/ecstasy in 31 of the 69 (45%), and NPS in 27 of the 69 (39%). On the 1061 collected questionnaires, the most commonly used drugs were cocaine in 31 of the 69 (45%), 3,4-methylenedioxymethamphetamine/ecstasy in 29 of the 69 (42%), and NPS in 16 of the 69 (23%). Hair analysis detects more conventional drugs and/or NPS use (P < 0.05). Drug use identified by hair was significantly associated with a higher number of sexual partners in the past 2 months (P ≤ 0.001), more often casual partners (P ≤ 0.001), condomless anal sex (P ≤ 0.005), hardcore sexual practices (P ≤ 0.001), a higher number of sexually transmitted infections, and chemsex (P ≤ 0.05).

Conclusions: Self-report drug use by questionnaires remains the reference tool for harm reduction at the individual level because of its feasibility and low cost. However, hair analysis is more sensitive, objectively assessing consumption, and interesting to understand uses and to be able to collectively respond to risky practices with adapted messages.
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http://dx.doi.org/10.1097/QAI.0000000000002610DOI Listing
April 2021

Population pharmacokinetic model of blood THC and its metabolites in chronic and occasional cannabis users and relationship with on-site oral fluid testing.

Br J Clin Pharmacol 2021 Jan 2. Epub 2021 Jan 2.

APHM, INSERM, IRD, SESSTIM, Hôpital Sainte Marguerite Pharmacologie Clinique CAP-TV, Aix Marseille Univ, Marseille, France.

Aims: To develop a population pharmacokinetic (PP) model of delta-9-tetrahydrocannabinol (THC) and its metabolites in blood and to determine the relationship between blood THC pharmacokinetics and results of on-site oral fluid (OF) testing in chronic (CC) and occasional (OC) cannabis users.

Methods: Fifteen CC (1-2 joints/day) and 15 OC (1-2 joints/week) aged 18-34 years were included, genotyped for their CYP2C9 polymorphisms. Twelve measurements of blood THC, 11-OH-THC and THC-COOH were carried out during the 24-hour period after controlled cross-over random inhalation of placebo, 10 mg or 30 mg of THC. OF tests (DrugWipe® 5S) were performed up to 6 hours and then stopped after two successive negative results. The blood concentrations and their relationship to OF testing results were analysed using a PP approach with NONMEM® and R.

Results: A three-compartment model described the pharmacokinetics of THC, with zero-order absorption, and a two-compartment model the metabolites. The fraction of THC converted to 11-OH-THC was 0.27 and the fraction of 11-OH-THC to THC-COOH was 0.86. Smoking 30 mg of THC decreased the THC bioavailability to 0.68 compared to 10 mg. CC showed a 2.41 greater bioavailability than OC, leading to higher C and AUC for the three compounds for the same dose. The best model describing the probability of a positive OF test included THC blood concentration and the group as covariate: for a similar THC blood concentration, a CC was less likely to be positive than an OC.

Conclusion: OC are more likely to screen positive than CC for a similar blood concentration.
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http://dx.doi.org/10.1111/bcp.14724DOI Listing
January 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

Population pharmacokinetics of lopinavir/ritonavir in Covid-19 patients.

Eur J Clin Pharmacol 2021 Mar 13;77(3):389-397. Epub 2020 Oct 13.

APHM, INSERM, IRD, SESSTIM, Hop Sainte Marguerite, Service de Pharmacologie clinique, CAP-TV, Aix-Marseille University, Marseille, France.

Objective: To develop a population pharmacokinetic model for lopinavir boosted by ritonavir in coronavirus disease 2019 (Covid-19) patients.

Methods: Concentrations of lopinavir/ritonavir were assayed by an accredited LC-MS/MS method. The population pharmacokinetics of lopinavir was described using non-linear mixed-effects modeling (NONMEM version 7.4). After determination of the base model that better described the data set, the influence of covariates (age, body weight, height, body mass index (BMI), gender, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C reactive protein (CRP), and trough ritonavir concentrations) was tested on the model.

Results: From 13 hospitalized patients (4 females, 9 males, age = 64 ± 16 years), 70 lopinavir/ritonavir plasma concentrations were available for analysis. The data were best described by a one-compartment model with a first-order input (KA). Among the covariates tested on the PK parameters, only the ritonavir trough concentrations had a significant effect on CL/F and improved the fit. Model-based simulations with the final parameter estimates under a regimen lopinavir/ritonavir 400/100 mg b.i.d. showed a high variability with median concentration between 20 and 30 mg/L (C/C) and the 90% prediction intervals within the range 1-100 mg/L.

Conclusion: According to the estimated 50% effective concentration of lopinavir against SARS-CoV-2 virus in Vero E6 cells (16.7 mg/L), our model showed that at steady state, a dose of 400 mg b.i.d. led to 40% of patients below the minimum effective concentration while a dose of 1200 mg b.i.d. will reduce this proportion to 22%.
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http://dx.doi.org/10.1007/s00228-020-03020-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552959PMC
March 2021

A strange New Year's Eve: triggers in Kleine-Levin syndrome.

J Clin Sleep Med 2021 Feb;17(2):329-332

National Reference Center for Kleine-Levin Syndrome, Paris, France.

None: Kleine-Levin syndrome is a rare neurological disease of unknown cause beginning typically during adolescence, characterized by remittent-relapsing episodes of severe hypersomnia associated with cognitive and behavioral disturbances. Triggering factors at Kleine-Levin syndrome onset include infection, sleep deprivation, as well as alcohol, drug, and substance intake. A young woman had 6 episodes over 2 years, including hypersomnia, confusion, derealization, cognitive impairment, anxiety, feeling of being scrutinized, anorexia (and sweet craving once) but no hypersexuality. The first episode started after a party where she experienced a complete, 4-hour-long blackout despite moderate alcohol intake. The patient suspected having been poisoned. Twenty-five months after the party, when Kleine-Levin syndrome was eventually diagnosed, her long hair was analyzed and exogenous γ-hydroxybutyrate was found in the tips (corresponding to the party time). This case illustrates the interest of looking for γ-hydroxybutyrate in the hair when Kleine-Levin syndrome starts after a party.
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http://dx.doi.org/10.5664/jcsm.8858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853233PMC
February 2021

Correction to: Suspected paracetamol overdose in Monrovia, Liberia: a matched case-control Study.

BMC Pediatr 2020 Aug 14;20(1):383. Epub 2020 Aug 14.

Médecins sans Frontières - Operational Center Paris, Paris, France.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s12887-020-02250-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427277PMC
August 2020

Quantification of plasma remdesivir and its metabolite GS-441524 using liquid chromatography coupled to tandem mass spectrometry. Application to a Covid-19 treated patient.

Clin Chem Lab Med 2020 08 22;58(9):1461-1468. Epub 2020 Jun 22.

Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines), Inserm U-1173, Raymond Poincaré Hospital, AP-HP, Garches, France.

Objectives: A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524.

Methods: A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 → m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 → m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 → m/z 206.0 for remdesivir-13C6.

Results: Calibration curves were linear in the 1-5000 μg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 μg/L and limit of quantification at 1 and 5 μg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 μg/L for remdesivir and 12.5, 125, 2000 μg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h.

Conclusions: This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.
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http://dx.doi.org/10.1515/cclm-2020-0612DOI Listing
August 2020

Development and validation of liquid chromatography-tandem mass spectrometry targeted screening of 16 fentanyl analogs and U-47700 in hair: Application to 137 authentic samples.

Drug Test Anal 2020 Sep 7;12(9):1298-1308. Epub 2020 Jul 7.

Department of Pharmacology and Toxicology, Paris-Saclay University (Versailles Saint-Quentin-en-Yvelines University), Inserm U-1173, Raymond Poincaré Hospital, AP-HP, Garches, France.

This study was to validate a LC-MS/MS method for the determination of 17 new synthetic opioids (NSOs) in hair including 3-fluorofentanyl, 3-methylfentanyl, acetylfentanyl, acetylnorfentanyl, alfentanyl, butyrylfentanyl, butyrylnorfentanyl, carfentanil, fentanyl, furanylfentanyl, furanylnorfentanyl, methoxyacetylfentanyl, norcarfentanil, norfentanyl, ocfentanil, sufentanil, and U-47700, and to apply it to 137 authentic samples. Twenty milligrams of hair was decontaminated in dichloromethane and underwent liquid extraction. 10 μL of the reconstituted residue were injected onto the system. The separation was performed in 12 minutes in a gradient mode at a flow rate of 300 μL/min using a Hypersyl Gold PFP column (100 × 2.1 mm i.d., 1.9 μm) maintained at 30°C. Compounds were detected in positive ionization and MRM modes using a TSQ Endura mass spectrometer (ThermoFisher). The method was validated according to EMA guidelines. The LLOQ was in the range 1-50 pg/mg, and the calibration ranged from the LLOQ-1000 pg/mg. Intra- and inter-day accuracy (bias) and precision were < 15%. Extraction recoveries of parent drugs and metabolites were 74-120% and 7-62%, respectively. The matrix effect was in the range 59-126% (CVs ≤ 12.9%). Fentanyl was found in six cases at concentrations of < 1-1650 pg/mg (n = 14 segments). Five fentanyl analogs were quantified in two cases: 3-fluorofentanyl (25-150 pg/mg, n = 5), furanylfentanyl (15-500 pg/mg, n = 5), methoxyacetylfentanyl (500-600 pg/mg, n = 2), acetylfentanyl (1 pg/mg, n = 2), carfentanyl (2.5-3 pg/mg, n = 2). This fully validated method allowed us to test for the first time 3-fluorofentanyl and norcarfentanil in hair among 15 other NSOs, and brings new data regarding 3-fluorofentanyl and methoxyacetylfentanyl hair concentrations.
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http://dx.doi.org/10.1002/dta.2868DOI Listing
September 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 cannabidiol induce cannabinoid hyperemesis syndrome?

Clin Toxicol (Phila) 2020 12 12;58(12):1351-1352. Epub 2020 Mar 12.

Centre AntiPoison et de Toxicovigilance de Paris - Fédération de toxicologie de l'APHP (FeTox), Hôpital Fernand-Widal - APHP, Paris, France.

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http://dx.doi.org/10.1080/15563650.2020.1736298DOI Listing
December 2020

Vemurafenib for Refractory Multisystem Langerhans Cell Histiocytosis in Children: An International Observational Study.

J Clin Oncol 2019 11 12;37(31):2857-2865. Epub 2019 Sep 12.

Centre Hospitalier Universitaire de Lille, Lille, France.

Purpose: Off-label use of vemurafenib (VMF) to treat mutation-positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated.

Patients And Methods: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score.

Results: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the clone.

Conclusion: VMF seemed safe and effective in children with refractory -positive LCH. Additional studies are needed to find effective maintenance therapy approaches.
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http://dx.doi.org/10.1200/JCO.19.00456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823889PMC
November 2019

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

Poisoning associated with inappropriate use of a eutectic mixture of lidocaine and prilocaine before laser-assisted hair removal: about 3 cases.

Int J Legal Med 2019 May 21;133(3):843-846. Epub 2018 May 21.

Centre antipoison et de toxicovigilance de Paris, hôpital Fernand-Widal, Paris, France.

Background: Eutectic mixtures of lidocaine and prilocaine are used during painful dermatological procedures. Poisoning is rarely reported in adults.

Material And Method: We report three cases of women who experienced lidocaine and prilocaine poisoning after laser-assisted hair removal. Plasma levels of local anesthetics were assayed by a fully validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method.

Case Reports: The rules of application of the anesthetic cream were observed apart from the maximum dose and/or maximum surface area. One patient applied a higher dose than the maximum recommended dose (140 instead of 60 g) and all patients failed to comply with the maximum recommended surface area (600 cm). The patients presented an unusual clinical pattern as compared with other local anesthetics overdose: signs of cardiac toxicity with no ECG changes or arrhythmia, neurological toxicity without seizures or coma, and methemoglobinemia.

Discussion: Health authorities should publish explicit recommendations targeting users and prescribers with particular emphasis on the maximal surface area of application.
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http://dx.doi.org/10.1007/s00414-018-1858-9DOI 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

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

An epidemic of dystonic reactions in central Africa.

Lancet Glob Health 2017 02;5(2):e137-e138

Lao-Oxford-Mahosot Hospital-Welcome Trust Research Unit, Microbiology Laboratory, Mahosot Hospital, Vientiane, Laos; University of Oxford, Oxford, UK; WorldWide Antimalarial Resistance Network (WWARN) and Infectious Disease Data Observatory (IDDO), Oxford, UK.

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http://dx.doi.org/10.1016/S2214-109X(16)30287-XDOI Listing
February 2017

An Automated Method for the Determination of Trimebutine and N-Mono-Desmethyl Trimebutine by On-Line Turbulent Flow Coupled with Liquid Chromatography-Tandem Mass Spectrometry in Human Plasma: Application to a Fatal Poisoning Case with Toxicokinetic Study.

J Anal Toxicol 2015 Nov-Dec;39(9):720-5. Epub 2015 Sep 4.

Laboratoire de Pharmacologie - Toxicologie, Centre Hospitalier Universitaire Raymond Poincaré, AP-HP, Garches et Université Versailles Saint-Quentin, 104 Boulevard R. Poincaré, Saint-Quentin 92380, France

A liquid chromatography-MS-MS turbulent flow on-line extraction method was developed for the determination of trimebutine (TMB) and its main active metabolite N-mono-desmethyltrimebutine (nortrimebutine or nor-TMB) in human plasma. After protein precipitation and internal standard (IS, haloperidol-d4) addition, 50 µL of the supernatant were transferred onto a Cyclone-Turbo-Flow extraction column followed by an Hypersil PFP Gold analytical column. Detection was carried out on a triple quadrupole tandem mass spectrometer using positive electrospray ionization. The transitions used were m/z 388.0→343.0, 374.0→195.0 and 380.1→169.0 for TMB, nor-TMB and IS, respectively. The method was validated over the concentration range of 10-1,000 ng/mL for both compounds. The accuracy evaluated at three concentrations was within 90.0-98.5% and the intra- and interday coefficient of variation's for the two molecules were <8.7%. The method was applied to a toxicokinetic study of a self-poisoning case with TMB in a 19-old girl. The concentration of TMB decreased from 747 to 77 ng/mL, while nor-TMB decreased from 9,745 to 205 ng/mL after 5 days and the fatal issue. This case confirms the literature underlining the potential toxicity of TMB, which has long time been considered as a harmless molecule.
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http://dx.doi.org/10.1093/jat/bkv098DOI Listing
August 2016