Nicolas Fabresse

L’objectif de ce travail a été d’étudier deux approches permettant le traitement des intoxications. La première est un antidote de type Fab, permettant de prendre en charge les intoxications aiguës à la colchicine. L’étude pré-clinique a été réalisée chez le cochon nain Göttingen. Un modèle d’intoxication reproductible a préalablement été défini. L’efficacité de l’antidote a ensuite été évaluée à différents horaires post-administration de colchicine (T+1h, T+3h et T+6h). Chez tous les animaux traités (n=6), il a été observé une redistribution tissulaire importante des tissus vers le compartiment sanguin. Seule l’administration précoce de l’antidote (T+1h et T+3h) permet la survie des animaux à T48h, cela souligne l’importance d’une administration précoce afin de garantir une éfficacité chez l’homme.La deuxième partie de ce travail a consisté à évaluer l’efficacité du système de dialyse hépatique MARS dans l’épuration du vérapamil et du diltiazem dans un modèle in vitro. Le système MARS a également été comparé à un système de dialyse conventionnelle (CVVHDF). L’efficacité des deux systèmes a été évaluée à trois concentrations pour le vérapamil (1, 2,5 et 5 mg/L) et 2 concentrations pour le diltiazem (0,75 et 5 mg/L), sur des sessions de 6 heures. Le MARS est le système le plus efficace pour les deux molécules. L’épuration du vérapamil par la CVVHDF est principalement liée à l’adsorption de la molécule à la surface de la membrane de dialyse. Concernant le système MARS, la cartouche de charbon est responsable de l’épuration des deux molécules.

Synthetic cathinones, frequently used in chemsex, are difficult to identify in postmortem blood due to their short half-life and in vitro degradation. This unusual case of chemsex involving 3-CMC highlights the importance of freezing a blood aliquot and testing for metabolites. A 62-year-old man was found dead with chemsex paraphernalia beside him. Peripheral blood with sodium fluoride (PB), cardiac blood (CB) and urine were collected at autopsy. A PB sample was frozen at −20 °C for cathinone testing. In PB at +4 °C, alcohols were measured by HS-GC/FID, drugs and narcotics by LC-HRMS, GHB by GC-MS and cannabinoids by LC-MS/MS. Analysis of PB at +4 °C revealed a toxic concentration of GHB (330 µg/mL). Determination of cathinones in frozen PB revealed the presence of 3-CMC (17 ng/mL), dihydro-3-CMC and N-desmethyldihydro-3-CMC, while no cathinones or metabolites were identified in samples stored at +4 °C. Only metabolites were detected in urine. This case confirms the need to systematically screen for cathinones in suspected chemsex cases and, due to their instability, to screen for different metabolites and to freeze a blood sample after autopsy.

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid with both endogenous and exogenous origins, complicating its detection in clinical and forensic toxicology. Due to its rapid metabolism and short detection window in conventional biological matrices, identifying reliable biomarkers of GHB exposure is crucial. This literature review aims to assess current knowledge on potential GHB biomarkers that may extend the detection window or improve specificity. A systematic search of scientific databases was conducted to identify studies investigating GHB metabolites, conjugates, and related biochemical markers using advanced analytical techniques such as LC-MS/MS and GC-MS. The review highlights promising candidates, including glycolic acid, carnitin-GHB, and glycin-GHB, as well as 3,4-dihydroxybutyric acid, which show potential for distinguishing exogenous intake. However, significant interindividual variability and limited validation studies hinder their widespread implementation. Despite promising findings, further research is needed to confirm the specificity, stability, and reproducibility of these biomarkers. This review underscores the importance of developing standardized protocols to enhance GHB exposure detection in both clinical and forensic settings.

IntroductionThe use of weight loss supplements is increasing, often driven by online marketing. However, many of these supplements are adulterated with undeclared pharmaceutical substances, potentially posing significant health risks. We investigated the presence of sibutramine and sildenafil in weight loss supplements and assessed the associated clinical outcomes.Materials and methodsA total of 12 weight loss supplement samples (capsules, tea, and coffee bags) were analyzed using liquid chromatography-high resolution mass spectrometry. Demographic and clinical data were collected by the Marseille Regional Pharmacovigilance Centre from 29 patients who reported using these products.ResultsAll samples were found to contain sibutramine, with concentrations ranging from 7.5 mg to 15.4 mg per unit. Sildenafil was detected in all samples, with concentrations ranging from 1.7 mg to 4.8 mg per unit. Clinical data from 29 users showed significant weight loss, with an average of 7.5 kg after 37 days of use. Adverse effects included anorexia (n = 15), tachycardia (n = 13), insomnia (n = 2) and chest pain (n = 4). In some cases, more serious effects such as seizures and dependence were observed.DiscussionBoth sibutramine and sildenafil were withdrawn from the market due to cardiovascular risks. As such, the unregulated use of these products pose a serious risk to public health, particularly in individuals with underlying cardiovascular disease.ConclusionWe detected sibutramine and sildenafil in all 12 weight loss supplements tested, which highlights the need for stricter regulation and monitoring.

Background: The increasing diversity of psychoactive substances on the unregulated drug market poses significant health, psychological, and social risks to people who use drugs (PWUD). To address these risks, various harm reduction (HR) policies have been implemented, including drug checking services (DCS). Many analytical methods are used for DCS. While qualitative methods (e.g., thin layer chromatography, spectroscopy) are easier to implement, they are not as accurate as quantitative methods (e.g., LC-UV, LC-MS). Some HR programmes have implemented high-performance liquid chromatography coupled with UV detection (LC-UV). This article presents the cross-validation of this quantitative method with a reference liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) method. Methods: Drug samples were provided by PWUD to a DCS called DrugLab in Marseille, France. The samples were weighed and prepared through dissolution in methanol, followed by ultrasonic bathing. Samples were analysed onsite using LC-UV analysis. They were then subsequently analysed with the reference LC-HRMS method. The LC-UV instrument in DrugLab was calibrated after being purchased; analysis of standard solutions was routinely performed once a month and after maintenance operations. For the LC-HRMS instrument, calibration and quality control procedures followed European Medicines Agency (EMA) guidelines. Statistical analyses were conducted including Spearman correlation tests using IBM^® SPSS^® Statistics version 20. Results: A total of 102 samples representing different product classes and cutting agents were cross-validated. Differences between both analyses methods for each molecule analysed were ≤ 20%, with significant correlations between both methods’ results for most substances. Notably, LC-HRMS provided lower concentration values for cocaine and acetaminophen, whereas it provided higher values for other substances. Correlations were significant for cocaine, ketamine, MDMA, heroin, amphetamine, caffeine, acetaminophen, and levamisole. Conclusions: This study demonstrates that the results provided by DrugLab were accurate and reliable, making LC-UV an adaptable, stable, and suitable analytical method for simple matrices like drugs in a DCS context. However, this cross validation does not guarantee accuracy over time. A proficiency test project in HR laboratories across France is currently under development in order to address potential drifts in LC-UV accuracy.