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Cu isotopic analysis can provide valuable insight when investigating Wilson's disease (WD), but one of the problems related to this type of study is that usually low sample volumes are available and/or low Cu concentrations are found in these samples. This paper presents a new approach for Cu isotope ratio determination that requires only 1 μL of pre-treated serum sample per replicate (after Cu separation and preconcentration to a Cu concentration range between 0.3 and 4 mg L−1). Cu determination was carried out by direct μ-injection of 1 μL of pretreated serum samples into an ICP-MS, offering a LOD of 3 μg L−1. For Cu isotopic analysis, the method presented is based on micro-volume deposition on a pure silicon wafer and subsequent ablation analysis by fsLA-MC-ICP-MS. Cu isotopic analysis of NIST 3114 at 1 mg L−1 Cu concentration with the self-bracketing method provided average δ65Cu values of −0.01 ± 0.19‰ (2SD) and an internal precision value of 517 ppm. This method was deployed for the analysis of serum samples from WD patients under different treatments, as well as healthy newborns and patients with other liver disorders. The results seem to link decreased δ65Cu values to Cu release from the liver, further demonstrating the potential of this type of analysis in the biomedical context.

Aims We aimed at assessing the effectiveness of renal replacement therapy in patients severely self-poisoned with baclofen and with normal kidney function. Methods A population pharmacokinetic model was built using analytical data extracted from 26 baclofen poisoning cases reported to a French Poison Centre: 8 patients underwent renal replacement therapy (RRT), 18 did not. In the RRT group, 2 patients suffered from kidney failure. Mechanical ventilation was required for 20 patients with normal kidney function; 15 were not treated by RRT and 5 were. Pharmacokinetic profiles of baclofen were measured in 28 patients and further modelled by a non-parametric approach (PMetrics®). The total data set was divided into a building data set (26 patients, 57 observations) and a validation set (2 external patients, 6 observations). Then, the estimated elimination half-life of baclofen and the duration of intubation were compared in patients with or without RRT using Wilcoxon–Mann–Whitney test. Results A model using three parameters plus a lag time and bioavailability was necessary to determine the pharmacokinetics of baclofen. Estimated elimination half-life in the ‘RRT’ group and the ‘no RRT’ group were respectively 3.1 [2.2−4.8] h (n = 6 patients) and 3.4 [1.4−5.5] h (n = 19 patients, p = 0.53). The median duration of intubation was not significantly different between groups (72 [48−72] h and 72 [24−96] h, respectively; p = 0.38). Conclusion Renal replacement therapy did not appear to significantly increase baclofen clearance in patients without kidney failure.

Background High‐dose chemotherapy (HDCT) with TI‐CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug. Methods Patients with unfavorable relapsed GCT were treated according to TI‐CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate. Results Eighty‐nine patients who received HDCT were included in the modified intent‐to‐treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty‐five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow‐up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5–25.9) and OS was 46.3 m (95% CI: 18.6–not reached). For high‐ and very high‐risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2‐year PFS rate was 41.1%. Conclusion The rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug., The superiority of HDCT over standard chemotherapy as initial salvage treatment of patients with relapsed or refractory germ cell tumors remains a valid question. In the TI‐CE regimen, TDM was demonstrated to be feasible in routine practice and really allowed to control target AUC more accurately compared to previous reports, avoiding both underexposure and overexposure to carboplatin. In our study, the rate of CR observed in this population with very poor prognosis was 44.3% and increased to 69.6% of favorable responses. Based on our study and if the benefit of HDCT is proven in the TIGER trial, we suggest that the use of carboplatin TDM for dose individualization in current practice should be considered.

Objectives Occupational exposure to molybdenum has been poorly documented to date. Here, we present a retrospective study evaluating urinary molybdenum concentration before and after shift over a period of 2 years in exposed workers. Methods This retrospective study was conducted across eight industrial sites in France and included all workers undergoing medical follow-up for occupational molybdenum exposure. A mean of six sequential samples (before and after shift) was performed for each worker. The urinary molybdenum concentration was determined using a validated method of inductively coupled plasma-mass spectrometry. A mixed linear model was built and linear regression was used to verify the extent to which the urinary molybdenum concentration depends on the age of the workers and the sampling period. Additionally, an analysis based on individual trajectory was also performed. Results Seventy-seven workers were included in the present study. Post-shift urinary molybdenum concentrations were significantly higher than pre-shift values [median (95th percentile) 37.9 (91.1), versus 60.6 (190.0) µg g−1 creatinine, respectively, P < 0.009]. No accumulation of molybdenum over time was observed. The urinary molybdenum concentrations were not influenced by age. Four workers presented high post-shift values as a result of not adhering to protection measures (maxima of 529.8, 359.7, 386.3, and 1459.7 µg g−1 creatinine, respectively). Conclusions To our knowledge, this is the first study of occupational molybdenum exposure in France to include an individual trajectory analysis. No accumulation of molybdenum was seen but high post-shift molybdenum urinary concentrations were observed for some workers. The study emphasizes the importance of molybdenum monitoring in exposed workers.

Background In France, the prevalence of childhood lead poisoning is becoming rare since the avoidance of lead in paints in 1949 and the gradual replacement of water pipes. Chronic lead toxicity is well known and is well correlated to blood lead concentration. Aim Here we report a case of severe lead poisoning occurring in a young female child with a pica behavior. Methods A blood sample and four environmental samples were analyzed using inductively coupled plasma- mass spectrometry (ICP-MS). Lead concentration, lead isotopes and elemental ratios were compared. Results The determination of 208Pb/206Pb, 206Pb/207Pb and Cd/Pb has allowed us to identify the origin of lead poisoning. Discussion-conclusion The source of contamination was eliminated and the child benefited from a psychological and medical follow up. Her outcome was positive. This case illustrated the potential interest of the use of elemental and isotopic ratios for clinical practice as the ICP-MS measurement has allowed a quick response and a rapid eviction of the contamination’s source.

Summary For the last 10 years, recreational use of new psychoactive substances (NPS) with hallucinogenic properties was more and more described either in a context of consumption during a rave-party or at home alone or in small group. A review of 62 cases (56 M, 6 F, 16–46 y) registered from 2011 to 2016 at the French Grand Ouest centre antipoison of Angers is presented. Some of them (n = 15) presented a severe clinical state (poison severity score, PSS = 3) and only one was a fatal intoxication (PSS = 4). Treatment of acute intoxication was mainly based on supportive care with a quick recovery in less than 48 h. A high number of these cases were documented by plasma (pl) and/or urine analyses using LC-UV, GC-MS and LC-MS2. Several powders or other forms bought on the web market by the patients were also analysed. Six amphetamines derivates were detected such as methiopropamine (pl: 50 – 430 μg/L, n = 6) or 5 others (6-APB, 6-APDB, 5-EAPB, 5-MAPB, 2-FA each once). Four 2,5-dimethoxy-derivates of phenylethylamines (2Cs) or of amphetamines (DOs) were detected as 2C-P (pl

Summary Designer drugs appear to be increasing in popularity because of easy obtaining on the Internet, the lack of ability to identify the compound(s) in routine toxicology screening and being marketed as ‘legal’ substitute of drugs of abuse. 2,5-dimethoxy-4-chloroamphetamine (DOC) is a substituted alpha methylated phenethylamine and acts as a selective serotonin receptor partial agonist. There is limited literature on this particular compound, which is rarely encountered in biological matrices, and only one case-report attributed death to the use of this drug alone. We present five cases of non-fatal exposure to DOC with sever clinical symptoms (ages range 18–23 years). DOC was identified using data from LC/UV and GC/MS screening procedures. DOC in plasma and urine samples was quantified using a validated LC/MS/MS method and results showed that DOC plasma concentrations were less than 18 μg/L and DOC urine concentrations ranged from 300 to 1300 μg/L. This is the first documentation of DOC consumption in France, and in 4 cases, the patients believed that they were ingesting LSD. This indicates the emergence of designer drugs use as ‘legal’ LSD substitutes and we are concerned by the discrepancies in legal status of such compounds in the EU, which limit the effectiveness of drug enforcement policies.

Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for their most frequent side effects (digestive, renal and metabolic disorders) but are lesser known for other effects, such as coagulation disturbances. In this issue, we report the case of a 58-year-old woman who ingested 26 g of naproxen in a suicidal attempt and developed cardiovascular shock, hypocoagulability and thrombopenia. Her outcome was positive (extubation 3 days after admission [D3], correction of haemostatic disruptions on D5 and of thrombopenia on D6). Naproxen plasma concentration was at a toxic concentration of 1320 mg/L at 6 hours after drug ingestion. Only few cases of hypocoagulopathy are reported with the NSAIDs, and this is the first case that can be attributed to naproxen. A possible explanation of this phenomenon following naproxen ingestion is an inhibition of thromboxane A2, usually attributed to NSAIDs, combined with an inhibition of activation of downstream the cascade.

A fixed-dose association of bismuth subcitrate, metronidazole and tetracycline (BMT) (Pylera®, Allergan, NJ, USA) was made available in France in 2013 for the eradication of Helicobacter pylori. Due to a historical issue of bismuth encephalopathy, the French Health Authorities requested a study of blood and plasma bismuth concentrations with BMT in daily practice. The aim of the study was to measure eventual bismuth accumulation and neurological toxicity in patients prescribed BMT. Patients initiating BMT for H. pylori between March 2014 and December 2015 were included. A blood sample was taken before first BMT intake and 24 h after the last intake, for assay of bismuth. A concentration > 50 μg/L was considered abnormal. Neurological complaints were assessed at inclusion, at the end of the 10-day treatment course, and 28 days later. 202 patients were included, of whom 190 took at least one dose of BMT, and 167 provided both required blood samples. Mean blood bismuth concentrations after the BMT course were 16.9 μg/L (95% confidence interval 15.6–18.3). Concentrations were > 50 μg/L (56.0 μg/L and 50.9 μg/L) in two elderly patients, one of whom presented mild, transient memory impairment during treatment. Non-serious neurological symptoms occurred in 20% of all patients and treatment failure was documented in 5% of patients. In this study measuring blood bismuth concentrations in real-life practice, in 50 μg/L. No serious neurological adverse events were observed. EU-PAS register EUPAS3142 at www.encepp.eu ; ENCePP study seal.

Resume Un cas medicolegal de decouverte de cadavre en lien avec une ingestion d’un herbicide, le dimethenamide-P, substance de la famille des chloroacetamides, est rapporte. Plusieurs approches analytiques sont mises en œuvre : CG-SM apres extraction sur microfibre (SPME) pour l’analyse de substances volatiles, CL-UV/BD et CG-SM apres extraction liquide-liquide pour la recherche large de toxiques et CL-SM/SM apres simple precipitation des proteines. L’analyse du liquide gastrique par SPME-CG-SM montre la presence de nombreux hydrocarbures aromatiques : isomeres de tetramethyl- et pentamethyl-benzene, naphtalene et ses derives mono- et dimethyles ou encore biphenyl-methyle, ces differents produits etant caracteristiques de naphta lourd. Le dimethenamide, identifie par son spectre de masse en CG-SM, est confirme par comparaison (spectre UV, MS et MS 2 ) avec la substance pure. La concentration, mesuree par CL-SM/SM 4 mois apres l’autopsie, dans le surnageant de centrifugation du sang cardiaque est egale a 10 mg/L pour l’echantillon conserve a −20 °C mais seulement egale a 1,3 mg/L pour le meme milieu conserve a +4 °C. La concentration dans le sang cardiaque conserve a +4 °C est egale a 0,66 mg/L. Les concentrations dans le liquide gastrique et dans la bile sont respectivement egales a 130 et 6 mg/L. En l’absence d’autre substance mise en evidence et d’autre cause formelle de deces, basee sur les donnees d’autopsie et d’anatomopathologie, la seule explication probable au deces est la presence du dimethenamide, le role du solvant naphta restant difficile a preciser. Aucun cas de deces ni d’intoxication par ce produit n’a ete retrouve dans la litterature.

Summary Alpha-methyltryptamine (AMT) is an analogue of endogenous tryptamine with psychotropic effects and is available on the web as designer drug or new psychoactive substance (NPS). A clinical case of a severe serotoninergic syndrome after ingestion of this substance is reported. The patient (male, 33 years), known as autist and poly-addict with a substitution treatment by methadone, was admitted at hospital (H0) for agitation. Tablets found in a bag at home should be methoxphenidine (MXP). Clinical symptoms suggested serotoninergic syndrome with Glasgow Score 10/15, diaphoresis, mydriasis, hyperthermia and tachycardia (140 beats/min). The major hyperthermia (42 °C) needed to transfer the patient in an intensive care unit (H4). The biological constants showed metabolic and respiratory acidosis with pH at 7.28, PaCO 2 6.5 kPa and lactates at 3.7 mmol/L. Creatinine was 156 μmol/L (325 on day D2), creatine phosphokinase (CPK) was 1973 U/L (26,895 on D2), ASAT and ALAT enzymes were at 75 N on D2 with prothrombin time

Background Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations. Methods U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU. Results The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%]. Conclusions The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.

Objective Propofol is an intravenous anesthetic agent widely used in the induction and maintenance of general anesthesia. Acute intoxications with propofol are rare and remain primarily related to the acquisition of the product in hospital. If propofol can induce fatal respiratory depression alone, in a number of cases the clinical situation is exacerbated by the presence of other drugs like neuromuscular-blocking agents. Laudanosine, the circulating form of atracurium or cisatracurium, two non-depolarizing neuromuscular-blocking agents, is more frequently observed in toxicology. Such agents are widely used for tracheal intubations. Laudanosine has no pharmacological activity, which is exclusively due to the parent drugs. These agents can be fatal at any concentration, due to respiratory failure. Here, two cases of anesthesiologists’ suicide following self-administration of propofol-atracurium combination are reported. Case history Case 1: a 48-years-old anesthesiologist was found without vital signs at his office. The drugs and paraphernalia used for delivery were discovered at the scene. Case 2: a 61-years-old anesthesiologist was found dead at home with a cannula connected to an infusion set at the bend of the elbow. Next to the body several empty ampoules of Diprivan® and Atracurium besylate® were found. For both cases, several biological specimens were collected for toxicological investigation. Methods Comprehensive screenings of drugs and toxic compounds were performed using LC-DAD and GC-MS. Ethanol concentrations were determined using GC-FID. Laudanosine was quantified using LC-DAD. Propofol was quantified using GC-MS and LC-MS/MS. Results Propofol blood concentrations were 1 and 1.91 mg/L for case 1 and case 2, respectively (therapeutic range: 2–8 mg/L). Laudanosine blood concentrations were 0.13 and 1.18 mg/L for case 1 and case 2, respectively. Paroxetine, N-demethyldiazepam and ethanol were detected in the first case. Hydroxyzine was detected in the second case. In both cases, levels of these substances could not explain the death. Discussion Propofol related fatalities are rare, even more when combined with neuromuscular- blocking agents [1] . Propofol and atracurium concentrations documented here, are in agreement with those reported in the literature, these being characterized by a high inter-individual variability [2] . However, the concentrations observed in suicide cases compared to those observed in accidental fatalities (chronic abusers) appear to be much higher. In fact, three manners of death have been described with propofol: suicide, accidental overdose in chronic abusers, and more exceptionally, murder [3] . In the cases described here, circumstances and the use of atracurium suggest suicide. It should be noted that the concentrations of laudanosine and propofol observed here are in the usual anesthetic range. Albeit, it should be pointed out that for anesthetic agents, therapeutic concentrations are established for patients being supported respiratory-wise, while in non-supported or non-intubated patients such concentrations may be fatal. Therefore, the interpretation of the blood concentration in the forensic toxicological analysis must take into account the context and the circumstances of the death.

Summary Introduction 2,5-dimethoxy-4-(n)-propylphenethylamine-P (2C-P) is a synthetic derivative belonging to the new so-called 2C-series family of phenethylamine recreational drugs. The exact mechanism of 2C compounds is unknown, but they show affinity for the 5-HT2 serotoninergic receptors. We report on the toxicological analysis findings on five cases of exposure to 2C-P. Case-series The five cases involved five men aged from 17 to 21 years old. They ingested 2C-P (powder or liquid form) in a festive setting. Their major symptoms were mydriasis, severe agitation, confusion, visual hallucinations, sinus tachycardia and high blood pressure. The outcome was favourable for the five patients. Methods For the five patients, toxicological analyses of blood and urine samples obtained on admission were performed using both GC-MS and HPLC-DAD. Specific 2C-P assays were performed by HPLC-DAD and UPLC-MS/MS. Results Toxicological analysis identified 2C-P as the main active substance in urines of all five cases and in the plasma of only one case (20 μg/L). Conclusion Our results showed that 2C-P was active at very low levels. Clinicians should be alert to this substance and they should confirm exposure by blood and urine analysis.

International audience; OBJECTIVE: We report two cases of elevated digoxin plasma levels in patients receiving enzalutamide. Cases reported: The first patient, an 84-year-old male treated with enzalutamide, was hospitalized due to deterioration in his general state. Atrial fibrillation was discovered and treatment with digoxin was initiated. Supratherapeutic digoxin concentrations (4 µg/L and 3.5 µg/L 3 days later) led to treatment being stopped despite the lack of clinical or biological signs of overdose. The second patient, an 84-year-old male treated with digoxin and enzalutamide, was hospitalized for the same reasons. Digoxin concentration upon admission was 2.8 μg/L. Despite stopping treatment, digoxin blood levels were observed to have increased on D3 and D7 following admission (3 and 3.6 μg/L, respectively). However, no clinical or biological findings indicated an overdose. Blood samples were sent to the Pharmacology and Toxicology Laboratory for analysis.METHODS: The second patient's digoxin plasma level was determined using the chemiluminescent microparticle immunoassay (CMIA®, Abbott, Illinois) method. Enzalutamide levels were determined using HPLC-UV/DAD method. An interference study was performed using different assay methods by adding enzalutamide to control plasma at various concentrations from a Xtandi (40mg) capsule.RESULTS: Plasma concentration of digoxin at D7 for patient 2 was identical in both laboratories (3.5 vs. 3.6 µg/L). Enzalutamide was found in the patient's plasma (12,5 mg/L). Adding 4, 10, 20, and 40 mg/L of enzalutamide to the untreated plasma showed that the plasma concentration of digoxin was positive (from 0.35 to 3.69 µg/L) using the CMIA method.CONCLUSIONS: Our results highlight the analytical interferences of enzalutamide with digoxin assays using the CMIA method.

International audience; Glioblastoma is the most frequent and aggressive primary malignant tumor of the central nervous system with a gloomy prognosis. Platinum derivatives and one among them, cisplatin, exhibited promising results when locally administered into the brain of glioblastoma bearing rats. Nanovectorization of anticancer agents through polymeric nanoparticles may even promote drug accumulation within cells, thus concentrating the drug efficiently at its target. Anchorage of gadolinium complexes on the corona of such smart drug delivery systems could further allow magnetic resonance imaging (MRI) monitoring of the nanoplat-form biodistribution in the damaged parenchyma and its therapeutic benefit. For this purpose, a biocom-patible amphiphilic triblock copolymer, made of degradable polyester and polycarbonate and bioelimin-able polyethylene oxide (PEO), was synthesized by successive ring-opening polymerizations. After micelli-zation in water, gadolinium complexes were grafted onto the PEO micelle corona and the carboxylate functions, located at the surface of the micelle's core, were able to cross-link with Pt(II) complexes. A macromolecular prodrug was therefore recovered in which more than one third of the carboxylate functions were linked to a platinum atom. By this strategy, stable cisplatin cross-linked nanoparticles were formulated with a mean size in the range of 100.63 ± 12.04 nm consistent with biological investigations. Relaxometry measurements both in water and in plasma at 7 T, 25 °C, confirmed the intrinsic potential of these hybrid nanoparticles as alternative MRI contrast agents with a substantial increase in the r 2 /r 1 ratio by a factor of 3.3 and 2.7, respectively, compared to the conventional low molar mass Gd-DTPA. As a result, their infusion within the striatum of glioblastoma-bearing mice resulted in a hypersignal on T 2-weighted MR images that persisted over time. Ultimately, the formulated prodrug exhibited up to 50-fold increased accumulation in human glioblastoma cell lines and up to 32-fold enhanced subsequent Pt-DNA adduct formation in comparison with free cisplatin, thus supporting the potential of this innovative bimodal tool for further applications.

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative. Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/mL over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction. Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83)−0.826 × (BW/76)+0.907 × (Age/36)−0.223 with Scr in μmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations. Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171–9. ©2017 AACR.

Summary Objective 4-Methyl-N-ethylcathinone (4-MEC) is a novel designer drug of the β-keto amphetamine family. A case of a mixed poisoning by 4-MEC and gamma-butyrolactone (GBL) is described. Two and half hours after an injected 0.25–0.5 g 4-MEC dose and thirty minutes after GBL ingestion, a 39-year-old man became unconscious and presented after admission to the hospital, transient apnea needing oxygenation and stimulation. After 30 min, he woke up, but remained confused for 4 hours. He was discharged 13 hours later without particular symptoms. For confirmation of the poisoning, different analytical procedures such as HPLC-UV/DAD, GC-MS, UPLC-MS/MS, and LC-HR-MS/MS were applied. Blood and urine levels (8 h after injection) were respectively 353 μg/L and 100 mg/L for 4-MEC and 300 mg/L and 1000 mg/L for gamma-hydroxybutyric acid. In urine, three metabolites (dihydro-, nor-, and nor-dihydro-4-MEC) could be identified for the first time and were similar to those described for other molecules of this class.

International audience; 4-methyl-N-ethcathinone (4-MEC), the N-ethyl homologue of mephedrone, is a novel psychoactive substance of the beta-keto amphetamine (cathinone) group. The aim of the present work was to study the phase I and phase II metabolism of 4-MEC in human urine as well as in pooled human liver microsome (pHLM) incubations. The urine samples were worked up with and without enzymatic cleavage, the pHLM incubations by simple deproteinization. The metabolites were separated and identified by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-high resolution-tandem mass spectrometry (LC-HR-MS/MS). Based on the metabolites identified in urine and/or pHLM, the following metabolic pathways could be proposed: reduction of the keto group, N-deethylation, hydroxylation of the 4-methyl group followed by further oxidation to the corresponding 4-carboxy metabolite, and combinations of these steps. Glucuronidation could only be observed for the hydroxy metabolite. These pathways were similar to those described for the N-methyl homologue mephedrone and other related drugs. In pHLM, all phase I metabolites with the exception of the N-deethyl-dihydro isomers and the 4-carboxy-dihydro metabolite could be confirmed. Glucuronides could not be formed under the applied conditions. Although the taken dose was not clear, an intake of 4-MEC should be detectable in urine by the GC-MS and LC-MS(n) standard urine screening approaches at least after overdose.

Objective The consumption of new psychoactive substances (NPS), such as cathinones, has been on the rise over the last few years, with adverse effects ranging from agitation, anxiety and hallucinations to convulsions, severe cardiac, hepatic and renal failures [1] . This work aims to report and discuss a fatal case related to the concomitant use of two cathinone derivatives (CDs). Case history A 39-year-old man, known for drug addiction history, was found dead in his caravan. Multiple injection points were observed. The medical examiners concluded to a non-specific asphyxia syndrome combined with pulmonary and pericerebral edema and multivisceral congestion. Hence, the hypothesis of a death related to drug abuse was retained. Methods Blood and urine samples were collected for NPS identification and quantification using LC-HRMS. A metabolic study using human liver microsomes was also conducted to identify human metabolites compared to published studies in animals. Ethanol concentrations were determined using GC-FID and toxicological screenings were performed using LC-UVDAD, LC-MS/MS and GC-MS. Results Various analyses detected the presence of two CDs, 4′methyl-α-pyrrolidinohexanophenone (MPHP) and N-ethyl-4′methylnorpentedrone (4-MEAP), as well as tetrahydrocannabinol [(THC): 1.4 μg/L and (THC-COOH): 6.6 μg/L] and ethanol (0.5 g/L in cardiac blood). The concentrations of MPHP/4-MEAP in the femoral blood, cardiac blood and urine were 47/1.6, 97/3.5 and 2380/49,700 μg/L, respectively. The in vitro metabolic study allowed us to identify five metabolites for MPHP and three for 4-MEAP, but only two metabolites were detected at low levels in biological samples. One metabolite of MPHP, the 4′-carboxy-PHP, was detected in all biological samples, with higher chromatographic signals than those of MPHP. Conclusion Regarding the growing phenomenon of CD abuse, analytical toxicologists must have: – efficient tools to detect such NPS focusing on relevant biomarkers; – interpretation data (toxic and fatal blood levels) on CD. In this study, the CD concentrations found appeared to be of the same order of magnitude as the only two reports found in the literature, one concerning a case of death due to MPHP with a plasma (supernatant of heart blood) concentration of 32.9 μg/L [2] and another one on two cases of 4-MEAP intoxication with a positive outcome showing urine concentrations of 7676 and 4554 μg/L, respectively [3] . It is very likely that an additive or synergistic effect between both CDs might have precipitated the fatal outcome.

3,4-methylenedioxypyrovalerone (MDPV) et methoxetamine (MXE) font partie des nouvelles substances dites «recreatives» facilement obtenues sur Internet. Neuf cas d’exposition a ces substances sont rapportes pour 8 patients, l’un d’entre eux ayant consomme les 2 produits. Methodes : Plusieurs approches analytiques sont decrites par CLHP/UV-BD apres extraction alcaline eventuellement suivie d’une reextraction acide, par CPG/SM apres extraction alcaline et par CLHP/SM-SM apres simple precipitation des proteines. Resultats : Les concentrations plasmatiques mesurees dans les prelevements d’admission sont, pour la MDPV, egales a 45 μ g/L et inferieure a la limite de quantification et, pour la MXE, comprises entre 122 et 366 μ g/L sauf 1 cas inferieur a la limite de quantification. Les concentrations urinaires sont comprises entre 0,3 et 165 mg/L selon le produit et les patients. Plusieurs metabolites supposes sont mis en evidence comme la N-desethyl-MXE et la O-demethyl-N-desethyl-MXE. Les symptomes decrits sont tachycardie, hypertension arterielle, agitation, convulsions et coma. Deux patients ont necessite des soins de reanimation. L’evolution etait favorable pour tous. Conclusion : Si la MDPV vient d’etre classee comme stupefiant en France, la MXE beneficie encore d’une absence de statut. L’augmentation des donnees clinico-biologiques concernant cette substance doit conduire a une reflexion sur un classement futur comme stupefiant.

BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS The injection of pralidoxime combination with atropine and avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS The two approaches, non-compartmental and compartmental, showed that the administration of avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.

International audience; Background:Dimethyl fumarate (DMFu) is a fungicide which is used in Chinese manufactures of furniture and shoes to avoid mould spoiling of fabrics. In 2008, DMFu was found the responsible allergen for several cases of contact dermatitis from armchairs and shoes observed in Europe. In France a national toxicovigilance survey was set up and importation of products containing dimethyl fumarate is now forbidden. Case report: a 36 year-old woman, with no history of previous allergy, was hospitalized because of a severe acute eczema of her feet after wearing a new pair of boots inside which she had noticed desiccant sachets. She strongly reacted on patch testing to DMFu and to the content of a sachet which was identified as DMFu, both at 0.01%, 0.1%, 1% in petrolatum, and also to a piece of the fabric of her boots, patch tested as is.Materials and method: Boot fabrics and mould-proof sachets found in the boots were analysed by HPLC/UV/DAD and GC/MS after methanol extraction. Further samples of anti mould agent sachets or shoe fabrics from 5 other patients with suspicion of DMFu dermatitis were analysed with the same procedure. Some of them were transferred to the laboratory several months after healing of the dermatitis.Results: DMFu was found in all the samples from 1 to 100% in sachets or from 20 to 2000 μg/g in the fabrics of shoes, even after one year. These findings contributed to ensure the responsibility of DMFu in the dermatitis of the patients and demonstrate that DMFu may remain a long time in the contaminated fabrics after removal of the sachets. This study also points out the usefulness of the collaboration between dermatologists, biologists and poison centre practitioners.

International audience; Background: Immunochromatographic drug tests are more and more involved in the initial biological survey of acute poisoning, even with “on site” use at the emergency unit. Specificity of the drug-antibody interaction is both an advantage (rapid, easy-to-perform tests, no apparatus) and a limitation (cross-reactivity, interferences).Patient cases: A 13-year-old girl was admitted at an emergency unit for somnolence and respiratory acidosis. A multi8 rapid drug test was positive for benzodiazepines, methadone (MTD) and phencyclidine (PCP). To avoid false diagnosis, fluorescence polarization immunoassay, liquid- and gas-chromatography were also performed on both plasma and urine. Rapid tests (different batches) from the same and other manufacturers were involved for this patient and other therapeutic, acute or forensic cases.Results:Bromazepam was identified in plasma (0.4 mg/L) and urine but also tramadol (respectively 0.5 and 25 mg/L), its metabolites and, in urine only, norpropoxyphene (NPPX). No methadone was detected. Among 7 other cases with tramadol detected in urine, 5 were positive with PCP test and 5 with MTD. Drug-added urines confirmed false-positive results for PCP with tramadol but for MTD with NPPX. While tramadol cross-reactivity is very low (0.05%), positive tests, even in a therapeutic context, were observed because phencyclidine cut-off is only 25μg/L. Tramadol can also positive MTD test at very high urine level. The NPPX cross-reactivity, initially 100%, was theoretically reduced to less than 0.025% after a modification of antibody by the manufacturer. Structurally-related formulas could explain such positive results but tests from other manufacturers were negative except in one case with tramadol.Conclusion: The analytical performances (sensitivity, specificity) of such rapid tests must be known by clinicians to avoid false-positive diagnosis. The “on site” use at the emergency unit must be considered as a preliminary test that should be confirmed by alternative methods in a laboratory area. Data exchange between biologists, clinicians and manufacturers is needed to improve the quality of results.

Objectif L’α-methyl-tryptamine (AMT) est une « nouvelle drogue de synthese » disponible sur le web. Nous presentons un cas grave d’exposition a cette « tryptamine » encore tres peu decrite. Cas clinique : un homme, 33 ans, autiste et polytoxicomane traite par methadone, loxapine et lorazepam, est admis aux urgences (H0) pour agitation. Des comprimes trouves dans sa chambre font evoquer une prise de methoxphenidine (MXP). Le tableau clinique suggere un syndrome serotoninergique (Glasgow Score 10/15, sueurs profuses, mydriase, hyperthermie, tachycardie a 140/min). Devant l’hyperthermie a 42 °C, le patient est transfere en reanimation (H4). Le bilan biologique initial est : pH 7,28, lactates 3,7 mmol/L, PaCO2 6,5 KPa, creatininemie 156 μmol/L (j2 : 325 μmol/L), CPK 1973 U/L (j2 : 26895 U/L), TGP et TGO 75 N a j2 avec TP Methodes Deux recherches larges de toxiques ont ete realisees par CLHP-UV-BD et CPG-SM de meme qu’une analyse par CPG-SM avec derivation par HFBA. Les quantifications ont ete effectuees par CLHP-SM/SM, en mode ESI+ et MRM (AMT : 175,09 > 158 ; 175,09 > 143,1), apres precipitation des proteines par methanol (2/3 v/v) puis dilution 1/4 dans l’eau suivie d’une chromatographie 2D (injection 10 μL) avec piegeage sur precolonne Strata-X (25 μm On-Line Extraction 20 × 2 mm) et separation sur colonne Kinetex 2,6 μm Phenyl-Hexyl 100 × 3,0 mm. Le gradient d’elution est un melange 90-10 de formiate NH4 (2 mM) et d’acetonitrile contenant chacun 0,2 % d’acide formique, puis 65–35 en 8,5 min et 10–90 en 0,5 min. Resultats Du lormetazepam (0,2 mg/L), du lorazepam (0,05 mg/L), de la methadone (0,3 mg/L) sont trouves, par CLHP, dans le plasma d’admission (H2) ainsi qu’un produit avec un spectre UV analogue a une structure indole. Ce produit est retrouve dans l’urine ainsi que la methadone, son metabolite EDDP et la mirtazapine. L’analyse du comprime montre le meme produit, la CPG/SM orientant vers une methyl-tryptamine. La presence de l’AMT et non de molecules isomeres comme la N-methyl-tryptamine (NMT) ou le 5-aminopropyl-indole (5IT), a pu etre determinee par une legere difference de Tr selon les methodes et par une fragmentation un peu differente en CLHP-SM/SM. La methode de quantification (CLHP-SM/SM) a ete validee pour 6 molecules (AMT, NMT, 5IT, MXP, Methiopropamine, Diphenidine) avec un domaine de linearite de 10 a 1000 μg/L (CV(r) Conclusion Ce syndrome serotoninergique majeur avec defaillance multiviscerale s’explique par la presence d’AMT et illustre la potentielle dangerosite des tryptamines de synthese.