Can inhaled cannabis users accurately evaluate impaired driving ability? A randomized controlled trial

AimsTo study the effect of inhaled cannabis on self-assessed predicted driving ability and its relation to reaction times and driving ability on a driving simulator.Participants and methods30 healthy male volunteers aged 18–34: 15 chronic (1–2 joints /day) and 15 occasional (1–2 joints/week) consumers. Self-assessed driving confidence (visual analog scale), vigilance (Karolinska), reaction time (mean reciprocal reaction time mRRT, psychomotor vigilance test), driving ability (standard deviation of lane position SDLP on a York driving simulator) and blood concentrations of delta-9-tétrahydrocannabinol (THC) were measured before and repeatedly after controlled inhalation of placebo, 10 mg or 30 mg of THC mixed with tobacco in a cigarette.ResultsCannabis consumption (at 10 and 30 mg) led to a marked decrease in driving confidence over the first 2 h which remained below baseline at 8 h. Driving confidence was related to THC dose and to THC concentrations in the effective compartment with a low concentration of 0.11 ng/ml for the EC50 and a rapid onset of action (T1/2 37 min). Driving ability and reaction times were reduced by cannabis consumption. Driving confidence was shown to be related to driving ability and reaction times in both chronic and occasional consumers.ConclusionsCannabis consumption leads to a rapid reduction in driving confidence which is related to reduced ability on a driving simulator.Clinical trial registrationClinicalTrials.gov, identifier: NCT02061020

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

New psychoactive substances : Analysis, prevalence and metabolism; Clinical and forensic applications

L’objectif de ce travail a été de développer deux approches analytiques dédiées à l’analyse toxicologique des nouveaux produits de synthèse (NPS) dans différentes matrices biologiques (sang, urine et cheveux). La première est basée sur le criblage non ciblé par chimiluminescence sur biopuces et chromatographie liquide couplée à la spectrométrie de masse haute résolution (LC-HRMS) et la deuxième correspond à un criblage ciblé par spectrométrie de masse en tandem (LC-MS/MS). Ces deux approches ont ensuite été appliquées dans des études observationnelles pour évaluer la consommation de NPS dans des populations à risques de surdosage, de pharmacodépendance ou de soumission chimique dans un contexte clinique ou médico-judiciaire.La dernière partie a été consacrée au développement d’un nouvel outil analytique de traitement des données issues de la LC-HRMS qui a permis d’étudier le métabolisme de 9 NPS in vitro sur des cultures de microsomes du foie humain (HLM) et in vivo sur des échantillons biologiques d’usagers de ces drogues. Cette dernière approche a permis la création d’une bibliothèque de spectres de haute résolution composée de 228 métabolites dont certains ont été proposés comme marqueurs pertinents d’exposition aux NPS dont ils sont issus.Ce travail a été concrétisé par la rédaction de 10 publications scientifiques et a permis d’initier plusieurs collaborations pluridisciplinaires.The aim of the present work was to develop two analytical approaches dedicated to the analysis of new psychoactive substances in different biological matrices (blood, urine and hair). The first approach is based on untargeted screening by both biochip array technology chemiluminescence assay and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and the second corresponds to a targeted screening by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). These two approaches were then applied in observational studies to assess the consumption of NPS in high risk populations (overdose, drug abuse, drug facilitated crimes) in clinical and forensic settings. The last part of the work was devoted to the development of a new analytical tool for LC-HRMS data processing which made it possible to study the metabolism of 9 NPS In vitro on human liver microsomes (HLM) and In vivo in biological samples from drug users. This approach has enabled the creation of HRMS spectral library containing 228 metabolites, some of which have been proposed as relevant markers of NPS exposure.This work has resulted on 10 scientific publications and allowed to initiate many multidisciplinary collaborations

Nouveaux produits de synthèse : analyse, consommation et métabolisme ; Applications cliniques et médicolégales

The aim of the present work was to develop two analytical approaches dedicated to the analysis of new psychoactive substances in different biological matrices (blood, urine and hair). The first approach is based on untargeted screening by both biochip array technology chemiluminescence assay and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) and the second corresponds to a targeted screening by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). These two approaches were then applied in observational studies to assess the consumption of NPS in high risk populations (overdose, drug abuse, drug facilitated crimes) in clinical and forensic settings. The last part of the work was devoted to the development of a new analytical tool for LC-HRMS data processing which made it possible to study the metabolism of 9 NPS In vitro on human liver microsomes (HLM) and In vivo in biological samples from drug users. This approach has enabled the creation of HRMS spectral library containing 228 metabolites, some of which have been proposed as relevant markers of NPS exposure.This work has resulted on 10 scientific publications and allowed to initiate many multidisciplinary collaborations.L’objectif de ce travail a été de développer deux approches analytiques dédiées à l’analyse toxicologique des nouveaux produits de synthèse (NPS) dans différentes matrices biologiques (sang, urine et cheveux). La première est basée sur le criblage non ciblé par chimiluminescence sur biopuces et chromatographie liquide couplée à la spectrométrie de masse haute résolution (LC-HRMS) et la deuxième correspond à un criblage ciblé par spectrométrie de masse en tandem (LC-MS/MS). Ces deux approches ont ensuite été appliquées dans des études observationnelles pour évaluer la consommation de NPS dans des populations à risques de surdosage, de pharmacodépendance ou de soumission chimique dans un contexte clinique ou médico-judiciaire.La dernière partie a été consacrée au développement d’un nouvel outil analytique de traitement des données issues de la LC-HRMS qui a permis d’étudier le métabolisme de 9 NPS in vitro sur des cultures de microsomes du foie humain (HLM) et in vivo sur des échantillons biologiques d’usagers de ces drogues. Cette dernière approche a permis la création d’une bibliothèque de spectres de haute résolution composée de 228 métabolites dont certains ont été proposés comme marqueurs pertinents d’exposition aux NPS dont ils sont issus.Ce travail a été concrétisé par la rédaction de 10 publications scientifiques et a permis d’initier plusieurs collaborations pluridisciplinaires

Characterization of 3-Hydroxyeticyclidine (3-HO-PCE) Metabolism in Human Liver Microsomes and Biological Samples Using High-Resolution Mass Spectrometry

International audience3-Hydroxyeticyclidine (3-HO-PCE) is a ketamine derivative that produces dissociative, hallucinogenic, and euphoric effects when consumed, but little is known about its pharmacological properties, metabolism, and toxicity compared to other designer ketamine analogs. To address this gap in knowledge, this study explored for the first time the metabolism of 3-HO-PCE. Based on this investigation, it is hypothesized that combining the use of Human Liver Microsomes (HLM) as an In vitro model with urine and hair samples from drug users may enable the identification of key analytes that can extend the detection window of 3-HO-PCE, particularly in cases of overdose. The analysis identified 15 putative metabolites, 12 of which are produced through phase I metabolism involving N-dealkylation, deamination, and oxidation, and 3 through phase II O-glucuronidation. The metabolism of 3-HO-PCE is similar to that of O-PCE, another designer ketamine of the eticyclidine family. The study identified M2a and hydroxy-PCA as reliable biomarkers for untargeted screening of the eticyclidine family in urine and hair, respectively. For targeted screening of 3-HO-PCE, M10 is recommended as the target analyte in urine, and M5 shows promise for long-term monitoring of 3-HO-PCE using hair analysis

Déterminations des teneurs en atractyloside dans les racines d’

Objectif : Atractylis gummifera L., ou chardon à glu, est une plante d’Afrique du Nord appartenant à la famille des Astéracées. Elle se caractérise par la production d’un métabolite hautement toxique, appelé atractyloside (ATR). L’objectif de cette étude est d’apprécier la toxicité de cette espèce par la détermination des teneurs en atractyloside des échantillons de racine récoltés dans différentes régions d’Algérie. Méthode : Des échantillons de racine sont récoltés dans six régions différentes du pays (Alger, Tizi-Ouzou, Médéa, Béjaïa, Guelma et Tlemcen, et les extraits méthanoliques de ces derniers sont analysés par chromatographie liquide haute performance couplée à un détecteur à barrette de diode (HPLC-DAD). Résultats : La concentration en atractyloside varie de 0,1 % à 0,27 % d’atractyloside en fonction de la région avec une moyenne de 0,17 %. Discussion : Les teneurs les plus faibles sont retrouvées dans les échantillons provenant des villes côtières, et les teneurs les plus élevées proviennent de régions plus éloignées de la côte. Les quantités d’atractyloside retrouvées sont rapportées aux doses létales 50 (DL50). Le calcul montre que 260 g de racine sèche correspondent à la DL50 chez le rat par voie orale, et que pour les voies intra-péritonéale, intramusculaire, et sous-cutanée, seulement 10 à 35 g permettent d’atteindre la DL50. Chez l’Homme, il n’existe pas de données concernant les doses létales de l’atractyloside et la transposition des données animales à l’Homme ne peut être appliquée en raison de l’absence de données relatives à son volume de distribution dans l’organisme. Conclusion : L’évaluation des teneurs en atractyloside a fait l’objet de quelques études sporadiques. La plupart de ces études sont anciennes et reposent sur l’emploi de techniques d’analyse qui manquent de sensibilité et de spécificité. Ainsi, nous avons jugé utile d’initier un travail permettant d’enrichir et d’actualiser les données sur les teneurs en atractyloside du chardon à glu. Il ressort de notre étude que les teneurs en atractyloside dans la racine varient selon la région, et par conséquent, en fonction des conditions climatiques du milieu. Les chiffres obtenus présentent un appui solide pour le clinicien dans l’appréciation du degré d’imprégnation toxique lors des intoxications aiguës. Enfin, à travers ce travail, il convient d’attirer l’attention sur la nécessité d’entreprendre des travaux de recherche visant à évaluer les doses létales de l’atractyloside chez l’Homme, qui restent toujours méconnues dans la littérature scientifique

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

International audienceObjectives 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- 13 C 6 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- 13 C 6 . 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 H 24 with a half-life around 12 h. Conclusions This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic

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

International audienceThe 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