Publications by authors named "Jean-Claude Alvarez"

105 Publications

PPAR-y agonists promote the resolution of myelofibrosis in preclinical models.

J Clin Invest 2021 Apr 29. Epub 2021 Apr 29.

Department of Innovative Therapies, CEA/DRF/IbFJ, UMR-007, University Paris-Saclay, Fontenay Aux Roses, France.

Myelofibrosis (MF) are a non-BCR-ABL myeloproliferative neoplasms (NMPs) associated with poor outcomes. Current treatment has little effect on the natural history of the disease. MF results from complex interactions between 1) the malignant clone, 2) an inflammatory context, and 3) remodeling of the bone marrow (BM) microenvironment. Each of these points is a potential target of PPAR-y activation. Here, we demonstrated the therapeutic potential of PPAR-y agonists in resolving MF in three mouse models. We showed that PPAR-y agonists reduce myeloproliferation, modulate inflammation, and protect the BM stroma in vitro and ex vivo. Activation of PPAR-y constitutes a relevant therapeutic target in MF and our data support the possibility of using PPAR-y agonists in clinical practice.
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http://dx.doi.org/10.1172/JCI136713DOI Listing
April 2021

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

Could we measure hair colchicine to assess colchicine observance in familial Mediterranean fever?

Rheumatology (Oxford) 2021 Mar;60(3):1563-1564

Paris Saclay University, Pharmacology and Toxicology Laboratory, Inserm U-1173, Raymond Poincaré hospital, AP-HP, Garches, France.

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http://dx.doi.org/10.1093/rheumatology/keaa811DOI Listing
March 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

Reply to the letter to the Editor "Prediction of lopinavir/ritonavir effectiveness in COVID-19 patients: a recall of basic pharmacology concepts".

Eur J Clin Pharmacol 2021 05 26;77(5):793-794. Epub 2020 Nov 26.

Département de Pharmacologie-Toxicologie, Hôpitaux Universitaires Paris-Ile de France-Ouest, APHP, Hôpital Raymond Poincaré, FHU Sepsis, MasSpecLab, Plateforme de spectrométrie de masse, Inserm U-1173, Université Paris Saclay (Versailles Saint Quentin-en-Yvelines), 92380, Garches, France.

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http://dx.doi.org/10.1007/s00228-020-03056-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690333PMC
May 2021

Management of pharmaceutical and recreational drug poisoning.

Ann Intensive Care 2020 Nov 23;10(1):157. Epub 2020 Nov 23.

Intensive Care Unit, Foch Hospital, Suresnes, France.

Background: Poisoning is one of the leading causes of admission to the emergency department and intensive care unit. A large number of epidemiological changes have occurred over the last years such as the exponential growth of new synthetic psychoactive substances. Major progress has also been made in analytical screening and assays, enabling the clinicians to rapidly obtain a definite diagnosis.

Methods: A committee composed of 30 experts from five scientific societies, the Société de Réanimation de Langue Française (SRLF), the Société Française de Médecine d'Urgence (SFMU), the Société de Toxicologie Clinique (STC), the Société Française de Toxicologie Analytique (SFTA) and the Groupe Francophone de Réanimation et d'Urgences Pédiatriques (GFRUP) evaluated eight fields: (1) severity assessment and initial triage; (2) diagnostic approach and role of toxicological analyses; (3) supportive care; (4) decontamination; (5) elimination enhancement; (6) place of antidotes; (7) specificities related to recreational drug poisoning; and (8) characteristics of cardiotoxicant poisoning. Population, Intervention, Comparison, and Outcome (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Analysis of the literature and formulation of recommendations were then conducted according to the GRADE methodology.

Results: The SRLF-SFMU guideline panel provided 41 statements concerning the management of pharmaceutical and recreational drug poisoning. Ethanol and chemical poisoning were excluded from the scope of these recommendations. After two rounds of discussion and various amendments, a strong consensus was reached for all recommendations. Six of these recommendations had a high level of evidence (GRADE 1±) and six had a low level of evidence (GRADE 2±). Twenty-nine recommendations were in the form of expert opinion recommendations due to the low evidences in the literature.

Conclusions: The experts reached a substantial consensus for several strong recommendations for optimal management of pharmaceutical and recreational drug poisoning, mainly regarding the conditions and effectiveness of naloxone and N-acetylcystein as antidotes to treat opioid and acetaminophen poisoning, respectively.
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http://dx.doi.org/10.1186/s13613-020-00762-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683636PMC
November 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

Pharmacological data of a successful 4-days-a-week regimen in HIV antiretroviral therapy (ANRS 162-4D trial).

Br J Clin Pharmacol 2021 Apr 5;87(4):1930-1939. Epub 2020 Nov 5.

Département de Pharmacologie-Toxicologie, Hôpitaux Universitaires Paris-Ile de France-Ouest, APHP, Hôpital Raymond Poincaré, MasSpecLab, Plateforme de spectrométrie de masse, Inserm U-1173, Université Versailles Saint Quentin-en-Yvelines, Garches, France.

Introduction: Few data are available on plasma concentrations of antiretroviral therapy (ARV) during intermittent treatment.

Objective: To compare plasma concentrations in OFF vs ON treatment periods at several time points during treatment.

Methods: During a successful 48-week multicenter study (ANRS 162-4D trial) of 4 days with treatment (ON) followed by 3 days without treatment (OFF) in adults treated by two nucleoside analogues and a third agent belonging to a boosted protease-inhibitor (PI, darunavir [DRV], atazanavir [ATV], lopinavir [LPV]) or a non-nucleoside-reverse-transcriptase inhibitor (NNRTI, efavirenz [EFV], etravirine [ETR], rilpivirine [RPV]) conducted in 100 patients (96% success), we determined the plasma concentrations of ARV. Blood samples were collected for analysis at inclusion (W0, 7/7 strategy for all patients), W16 and W40 (ON) and at W4, W8, W12, W24, W32 and W48 (OFF).

Results: A total of 866 samples was analysed. Plasma concentrations were not statistically lower after 4 days (ON) vs 7/7 days of treatment except for RPV (-30 ng/mL at 4/7, P = 0.003). Significant lower plasma concentrations were observed for OFF vs ON except for ETR (n = 5, P = 0.062). Overall, 87.1% of ON concentrations (ATV 92.1%, DRV 51.1%, LPV 62.5%, EFV 94.4%, ETR 100% and RPV 94.9%) and 21.8% of OFF concentrations (ATV 1.4%, DRV 0.0%, LPV 0.0%, EFV 16.0%, ETR 92.6% and RPV 39.0%) were above the theoretical limit of efficacy of the molecule. In the OFF period, 85.8% of PI concentrations were under the limit of quantification, while 98.0% of NNRTI concentrations were quantifiable.

Conclusion: Despite low/undetectable PI/NNRTI plasma concentrations in the OFF period, patients maintained an undetectable viral load. The mechanistic explanation should be investigated.
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http://dx.doi.org/10.1111/bcp.14586DOI Listing
April 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

Impact of medical care, including use of anti-infective agents, on prognosis of COVID-19 hospitalized patients over time.

Int J Antimicrob Agents 2020 Oct 2;56(4):106129. Epub 2020 Aug 2.

Maladies Infectieuses, Université Paris-Saclay, AP-HP Hôpital Raymond Poincaré, Garches, France.

Introduction: The effect of anti-infective agents in COVID-19 is unclear. The impact of changes in practice on prognosis over time has not been evaluated.

Methods: Single center, retrospective study in adults hospitalized in a medicine ward for COVID-19 from March 5 to April 25 2020. Patient characteristics were compared between two periods (before/after March 19) considering French guidelines. The aim of the study was to evaluate how medical care impacted unfavorable outcome, namely admission to intensive care unit (ICU) and/or death.

Results: A total of 132 patients were admitted: mean age 59.0±16.3 years; mean C-reactive protein (CRP) level 84.0±71.1 mg/L; 46% had a lymphocyte count <1000/mm. Prescribed anti-infective agents were lopinavir-ritonavir (n=12), azithromycin (AZI) (n=28) and AZI combined with hydroxychloroquine (HCQ) (n=52). There was a significant decrease in ICU admission, from 43% to 12%, between the two periods (P<0.0001). Delays until transfer to ICU were similar between periods (P=0.86). Pulmonary computerized tomography (CT)-scans were performed significantly more often with time (from 50% to 90%, P<0.0001), and oxygen-dependency (53% vs 80%, P=0.001) and prescription of AZI±HCQ (from 25% to 76%, P<0.0001) were also greater over time. Multivariate analyses showed a reduction of unfavorable outcome in patients receiving AZI±HCQ (hazard ratio [HR]=0.45, 95% confidence interval [CI: 0.21-0.97], P=0.04), particularly among an identified category of individuals (lymphocyte ≥1000/mm or CRP ≥100 mg/L).

Conclusion: The present study showed a significant decrease in admission to ICU over time, which was probably related to multiple factors, including a better indication of pulmonary CT-scan, oxygen therapy, and a suitable prescription of anti-infective agents.
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http://dx.doi.org/10.1016/j.ijantimicag.2020.106129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396133PMC
October 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

Transplacental transfer of glyburide in women with gestational diabetes and neonatal hypoglycemia risk.

PLoS One 2020 7;15(5):e0232002. Epub 2020 May 7.

Department of Gynecology-Obstetrics, Assistance Publique-Hôpitaux de Paris, Bicêtre Hospital, Le Kremlin-Bicêtre, France.

Background: In pregnant women with gestational diabetes, glyburide can be an alternative to insulin despite concerns about its transplacental transfer. However, transplacental transfer of glyburide is poorly quantified and the relationship between cord blood glyburide concentration and hypoglycemia has not been studied. Our objective was to quantify the transplacental transfer of glyburide at delivery and to study the association between the cord blood glyburide concentration and the risk of neonatal hypoglycemia in patients with gestational diabetes treated with glyburide.

Methods And Findings: INDAO was a multicenter, noninferiority, randomized trial conducted between May 2012 and November 2016 in 914 women with singleton pregnancies and gestational diabetes. An ancillary study was conducted in the 87 patients of the Bicêtre University Hospital Center. The sample consisted of 46 patients with utilizable assays at delivery. The relationships between glyburide concentration and the time since the last intake of glyburide and between fetal glyburide concentration and neonatal hypoglycemia were modeled with linear or logistic regressions using fractional polynomials. There was placental transfer of glyburide at a fetal to maternal ratio of 62% (95% CI [50; 74]). Umbilical cord blood glyburide concentration decreased steeply after the last maternal glyburide intake. After 24 hours, the mean umbilical cord blood concentration was less than 5 ng/mL. Neonatal hypoglycemia risk was increased with an odds ratio of hypoglycemia equal to 3.70 [1.40-9.77] for each 10 ng/mL increase in the cord blood glyburide concentration. However, no newborns were admitted to the NICU because of clinical signs of hypoglycemia or for treatment of hypoglycemia.

Conclusion: Considering that neonatal glyburide exposure may be limited by stopping treatment a sufficient time before labor, there may still be a place for glyburide in the management of gestational diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232002PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205195PMC
July 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

Trends in severe opioid-related poisonings and fatalities reported to the Paris poison control center - a 10-year retrospective observational study.

Fundam Clin Pharmacol 2020 Aug 29;34(4):495-503. Epub 2020 Jan 29.

French Armed Forces Biomedical Research Institute, 1 Place du Général Valérie André, Brétigny-sur-Orge, 91223, France.

France is experiencing an increase in the number of opioid prescriptions and related fatalities. We carried out a retrospective observational study using data from the Paris PCC over a 10-year period. The main objective was to obtain an epidemiological description of the severe reported cases. The secondary objectives were to assess the evolution of the number of these cases and their severity defined by the use of fentanyl and its derivatives, the use of the opioid-poisoning treatment naloxone, and the number of fatalities. During 2008-2017, 268 511 cases were recorded, including 1 122 cases of opioid-related poisoning that required medical management. These poisonings involved tramadol (43%), codeine (25%), dextropropoxyphene (13%), and morphine (8%); most resulted from self-exposure (60%). During the 10-year study period, 130 opioid-related fatalities were recorded in the Paris area, mainly resulting from suicides (39%) in men and were attributed to morphine (27%), tramadol (24%), and methadone (21%). We did not identify an increase in the number of severe opioid-related poisonings or fatalities or in the use of fentanyl or its derivatives. Conversely, we observed an increase in the use of naloxone, suggesting an increase in the severity of opioid poisonings. Our findings show that, until 2017, the opioid overdose epidemiology in the Paris area is different to that in the USA. The systematic analysis of data from the PCCs could be a good tool for health monitoring. To assess trends in France, a national study over a longer period would also be useful.
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http://dx.doi.org/10.1111/fcp.12534DOI Listing
August 2020

Efficacy and safety of subcutaneous administration of ceftazidime as a salvage therapy in geriatrics: a case report.

Fundam Clin Pharmacol 2020 Aug 25;34(4):521-524. Epub 2019 Nov 25.

Service de Maladies Infectieuses, Hôpitaux Universitaires Paris Ile-de-France Ouest, site Raymond Poincaré, AP-HP, 104 Bd Raymond Poincaré, Garches, 92380, France.

Ceftazidime is a third-generation cephalosporin used for the treatment of Gram-negative bacteria only approved for parenteral use by intravenous and intramuscular route. In some clinical situations, off-label subcutaneous injection could be a salvage route for the administration of antibiotics, especially in geriatrics, despite the paucity of evidence about efficacy and safety. We report a case of a successful and well-tolerated subcutaneous ceftazidime therapy in a 90-year-old woman for the treatment of an acute urinary tract infection caused by Pseudomonas aeruginosa with therapeutic drug monitoring data.
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http://dx.doi.org/10.1111/fcp.12520DOI Listing
August 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

Positive plasma cotinine during platinum-based chemotherapy is associated with poor response rate in advanced non-small cell lung cancer patients.

PLoS One 2019 1;14(7):e0219080. Epub 2019 Jul 1.

Department of Respiratory Diseases and Thoracic Oncology, APHP-Hopital Ambroise Paré, Boulogne-Billancourt, France.

Introduction: Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC.

Materials And Methods: All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered.

Results: Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation.

Conclusion: Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219080PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602197PMC
March 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

A high-resolution ICP-MS method for the determination of 38 inorganic elements in human whole blood, urine, hair and tissues after microwave digestion.

Talanta 2019 Jul 20;199:228-237. Epub 2019 Feb 20.

Plateforme de spectrométrie de masse MasSpecLab, INSERM UMR 1173, UFR Simone Veil - Santé, Université Versailles Saint Quentin, Université Paris Saclay, Montigny le Bretonneux, France; Laboratoire de toxicologie, Hôpital Raymond Poincaré, AP-HP, Garches, France.

Inductively coupled plasma-mass spectrometry (ICP-MS) is currently the reference method for the determination of inorganic elements, and has many applications in healthcare and the environmental field. The objective of the present study was to develop and validate a high-resolution ICP-MS method for the simultaneous quantification of 38 elements in samples of human whole blood, urine, hair and tissues after microwave mineralization. The samples were incubated with nitric acid, hydrogen peroxide and internal standards prior to microwave mineralization for 25 min. The analysis was performed with an Element XR ICP-MS and validated using commercial reference standards (whole blood, urine, and hair) and in-house quality control samples. The 38 elements were detected in low-, medium- or high-resolution mode, depending on interferences and sensitivity. The lower and upper limits of quantification were adjusted for each element. The method was linear for all elements (correlation coefficient >0.996), and the inter- and intraday precision values (coefficient of variation) were below 15%. Samples from a clinical trial were used to confirm the high-resolution ICP-MS method's suitability for the assessment of patient samples.
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http://dx.doi.org/10.1016/j.talanta.2019.02.068DOI Listing
July 2019

Effect of Smoked Cannabis on Vigilance and Accident Risk Using Simulated Driving in Occasional and Chronic Users and the Pharmacokinetic-Pharmacodynamic Relationship.

Clin Chem 2019 05 14;65(5):684-693. Epub 2019 Mar 14.

AP-HP, Hôpital Raymond Poincaré, Service de Pharmacologie Toxicologie, Garches, INSERM U-1173, Université de Versailles-St. Quentin, France;

Background: The pharmacokinetic-pharmacodynamic relationship between whole blood δ-9-tetrahydrocannabinol (THC) and driving risk is poorly understood.

Methods: Fifteen chronic cannabis consumers (1-2 joints/day; CC) and 15 occasional cannabis consumers (1-2 joints/week; OC) of 18 to 34 years of age were included. A pharmacokinetic study was conducted with 12 blood samplings over a 24-h period before and after controlled random inhalation of placebo or 10 mg or 30 mg of THC. THC and metabolites were quantified using LC-MS/MS. Effects on reaction time by psychomotor vigilance tests and driving performance through a York driving simulator were evaluated 7 times. A pharmacokinetic-pharmacodynamic analysis was performed using R software.

Results: Whole blood peak THC was 2 times higher in CC than in OC for a same dose and occurred 5 min after the end of consumption. THC remained detectable only in CC after 24 h. Despite standardized consumption, CC consumed more available THC from each cigarette regardless of dose. Maximal effect for reaction time was dose- and group-dependent and only group-dependent for driving performance, both being decreased and more marked in OC than in CC. These effects were maximal around 5 h after administration, and the duration was longer in OC than in CC. A significant pharmacokinetic-pharmacodynamic relationship was observed only between for blood THC and the duration effect on mean reciprocal reaction time.

Conclusions: Inhalation from cannabis joints leads to a rapid increase in blood THC with a delayed decrease in vigilance and driving performance, more pronounced and lasting longer in OC than in CC. NCT02061020.
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http://dx.doi.org/10.1373/clinchem.2018.299727DOI Listing
May 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

Synthetic cannabinoid isomers characterization by MALDI-MS imaging: Application to single scalp hair.

Anal Chim Acta 2018 Dec 19;1041:87-93. Epub 2018 Sep 19.

Aix Marseille Univ, APHM, CHU Timone, Service de Médecine Légale, 27 boulevard Jean Moulin, 13005, Marseille, France.

New designer drugs, as synthetic cannabinoids (SCs), continuously appear on the market and are booming due to their cannabis-like effect. New generation of smokable SCs, structurally dissimilar from Δ9-tetrahydrocannabinol (THC), have isomers with distinguishable pharmacokinetic parameters and therefore different in vivo effects. The isoforms are misidentified using conventional techniques such as gas or liquid chromatography coupled to mass spectrometry - or tandem mass - spectrometry. The aim of this study was to differentiate three positional isomers (JWH-007, JWH-019 and JWH-122) in single human hair samples, which store numerous substances revealing a way of life and consumption style. Matrix-assisted laser desorption/ionization (MALDI) combined with imaging is an innovative and powerful tool used since few years, especially in forensic research. Herein, we propose an innovative method to monitor the drugs of abuse consumption through direct mapping of the compounds with a high spatial distribution in human hair samples, by state-of-art imaging MALDI-MS. Three positional SC isomers (JWH-007, JWH-019 and JWH-122) were analysed using high and low fragmentation energy and the resulting MS/MS and even MS spectra differentiated the SCs. The MALDI-MS/MS and MS imaging was performed on hair soaked in a mixture of the three SCs as well as on hair from self-reported SC user, proving the potential of the technique for a forensic use. Keeping in mind that spatial distribution of organics from whole hair remains a challenge, the described methodology is a very promising analytical tool to probe the consumption of complex drugs and obtain correlation with its origin.
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http://dx.doi.org/10.1016/j.aca.2018.09.036DOI Listing
December 2018