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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.

Oxetorone is a serotonin antagonist antimigraine drug but literature relating to its toxic properties is poor. The aim of this study is to describe the toxicological profile of oxetorone and to highlight any relationship between clinical and analytical findings.This is a retrospective and observational study of cases exposure to oxetorone, reported to the Angers Poison and Toxicovigilance Centre between January 2002 and May 2016. Severity was assessed using the Poisoning Severity Score (PSS). Cases where data were incomplete, where oxetorone was deemed not accountable, where clinical signs were linked mainly to a co-ingested drug or where the plasma concentration of oxetorone was negative were all excluded.We included 43 cases of exposure, 31 of whom were suicide attempts. The assumed ingested dose (60-3600 mg) was correlated to severity (rSeveral clinical and paraclinical parameters strongly point towards membrane-stabilising properties of the molecule and the risk of a delayed occurrence of symptoms or a secondary worsening.

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

Resume Les AINS sont connus pour leurs effets indesirables les plus frequents (digestifs, renaux, metaboliques) mais d’autres le sont moins, comme les perturbations de la coagulation. Le cas d’une femme de 38 ans ayant ingere plusieurs medicaments dont le naproxene (dose supposee ingeree de 26 g) est rapporte. Elle est admise aux urgences avec un coma (Glasgow score de 4/15), necessitant une intubation endotracheale. Outre des troubles cardiaques (bradycardie sinusale), un allongement de l’espace QT a l’ECG, une acidose metabolique, elle presente une hypocoagulabilite et une thrombopenie a H7. Apres correction des troubles, elle est extubee a j3. L’analyse des prelevements d’admission a montre la presence d’acebutolol, de citalopram, d’oxazepam, de zopiclone et de naproxene (1320 mg/L). Les concentrations en naproxene diminuent sur les prelevements suivants avec une concentration de 250 mg/L a H47. Peu de cas d’hypocoagulopathie sont decrits avec les AINS, il s’agit du premier cas imputable au naproxene. Outre une inhibition des cyclo-oxygenases, des auteurs ont pose l’hypothese d’une action sur les facteurs de coagulation vitamine K dependants ou d’un mecanisme immunologique pouvant expliquer ce phenomene.

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

Resume La prise en charge d’une intoxication repose avant tout sur l’anamnese et sur l’identification d’un toxidrome a partir de l’evaluation clinique et biologique. Les analyses toxicologiques peuvent completer l’evaluation clinico-biologique. La Societe de toxicologie clinique (STC) a propose une liste restreinte de molecules pouvant etre dosees en urgence dans le sang, pour lesquelles une relation effet-concentration a ete decrite en lien avec le pronostic. Les techniques de depistage sont realisees en premiere intention par immunochimie et permettent de detecter la presence de molecules ou famille de molecules. Ces techniques ont l’avantage d’etre rapides mais leurs performances analytiques doivent etre considerees en fonction de leur sensibilite et de leur specificite (possibles reactions croisees). Les resultats obtenus en depistage sont generalement verifies par des techniques plus specifiques comme la chromatographie couplee a la spectrometrie de masse qui permet d’identifier et de quantifier precisement les molecules. Aujourd’hui, de nouvelles molecules apparaissent quotidiennement sur le « marche », avec une accessibilite simplifiee sur Internet. L’identification et la quantification de ces nouvelles molecules constituent un nouveau defi pour les laboratoires.

Resume Objectifs Le T61 ® est un produit a usage veterinaire destine a l’euthanasie d’animaux ; cependant, son usage a pu etre detourne dans le cas d’intention suicidaire. Il est compose de 3 principes actifs : embutramide, mebezonium et tetracaine solubilises dans un melange N,N-dimethylformamide/eau (60/40, v/v). Nous presentons le cas d’une femme (47 ans) qui a injecte du T61 ® et du Clorketam ® a sa fille (7 ans), avant de s’administrer du T61 ® . A l’admission, l’enfant presente un arret cardiorespiratoire, une mydriase bilaterale non reactive, un œdeme cerebral et une acidose lactique et la femme est en coma profond et presente un etat de mal epileptique. Methodes Des analyses chromatographiques (LC-UV-BD, CPG-SM) ont porte sur des prelevements sanguins qui ont ete effectues a l’admission et sur le liquide retrouve dans un flacon pres des corps. Resultats et discussion Les analyses ont confirme la presence d’embutramide chez l’enfant (5,0 mg/L), ainsi que de la ketamine (0,55 mg/L) et de la norketamine (0,90 mg/L). Une concentration d’embutramide de 2,5 mg/L a ete mise en evidence dans le prelevement sanguin de la mere. L’enfant est en etat de mort cerebrale 10 heures plus tard. Apres la phase de coma, un traitement par N-acetylcysteine est administre a la femme de facon a prevenir les effets hepatotoxiques dus au N,N-dimethylformamide. Huit cas d’intoxications letales au T61 ® documentes avec une concentration sanguine en embutramide ont ete deja decrits avec des concentrations comprises entre 1,4 et 90 mg/L. Conclusion Les cas d’intoxication au T61 ® restent peu nombreux mais engagent generalement le pronostic vital en l’absence de prise en charge medicale rapide et adaptee. Outre la toxicite propre des principes actifs, il est primordial de considerer, de ne pas oublier la toxicite inherente au solvant.

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; Baclofen is often prescribed in high doses to fight cravings experienced by alcohol-dependent patients. Such an increase in the availability of baclofen is concerning. This study aimed to determine the change in number and profile of self-poisoning with baclofen over time, as baclofen has become increasingly popular, in order to describe the severity of self-poisoning with baclofen and to focus on co-existing alcohol use disorders, and psychiatric illnesses determine predictors of severity. This was a retrospective study of self-poisoning with baclofen as reported by the western France Poison Control Center (PCC), which represents a population of more than 12 million people from January 2008 to March 2014. One hundred and eleven cases of self-poisoning with baclofen were reported to the western France PCC (62 males and 49 females; average age 39 +/- 12). Poisoning severities were as follows: 'null' (nine cases), 'minor' (37 cases), 'moderate' (19 cases) and 'high' (46 cases, including four deaths). The most frequently reported symptoms were neurological (45%) and cardiovascular (27%). The severity was significantly associated with psychiatric disorders (OR = 2.9; p = 0.03). Baclofen, prescribed in high doses, may lead to severe poisoning, particularly in patients with psychiatric illnesses. Authorities should put forward a new policy for prescribing the drug as a treatment for alcohol dependence.

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.

Introduction: Sulcotrione is a herbicidal agent belonging to the family of triketones. Sulcotrione herbicides are used for weed control in maize and flax crops. To date, no cases of human poisoning had been reported in the literature linked to different herbicidal agents in the triketone family. We report here on two cases of the voluntary ingestion of this substance in the form of the branded product MikadoTM, which were recorded by the Angers Poison Centre. Case report: Both cases of voluntary ingestion constituted attempted suicide, and involved two men aged 30 and 37 years. Their symptoms linked to sulcotrione were limited to vomiting, despite elevated plasma concentrations of sulcotrione. In one case, hypertyrosinemia has been demonstrated. The outcome was favourable in both patients and at follow up, no ocular disorders were observed. In the second case, hypotension and transient renal failure could be linked to the concomitant ingestion of chlorophenoxy herbicides. Discussion: In animal toxicity studies, sulcotrione inhibit 4-hydro-phenylpyruvate dioxygenase leading to hypertyrosinemia and corneal opacities. In both cases, no ocular disorders were observed despite hypertyrosinemia in one case. These case reports were consistent with the animal toxicology findings concerning triketones, and particularly their relative safety in mammals following acute poisoning. However it seems prudent to monitor plasma tyrosine concentrations and to screen prospectively for corneal deposits if further acute intoxication events occur.

Methoxetamine (MXE; 2-(3-methoxyphenyl)-2-(N-ethylamino)-cyclohexanone), a ketamine analog, is a new designer drug and synthesized for its longer lasting and favorable pharmacological effects over ketamine. The aims of the presented study were to identify the phases I and II metabolites of MXE in rat and human urine by GC-MS and LC-high-resolution (HR)-MS n and to evaluate their detectability by GC-MS and LC-MS n using authors’ standard urine screening approaches (SUSAs). Furthermore, human cytochrome P450 (CYP) enzymes were identified to be involved in the initial metabolic steps of MXE in vitro, and respective enzyme kinetic studies using the metabolite formation and substrate depletion approach were conducted. Finally, human urine samples from forensic cases, where the ingestion of MXE was suspected, were analyzed. Eight metabolites were identified in rat and different human urines allowing postulation of the following metabolic pathways: N-deethylation, O-demethylation, hydroxylation, and combinations as well as glucuronidation or sulfation. The enzyme kinetic studies showed that the initial metabolic step in humans, the N-deethylation, was catalyzed by CYP2B6 and CYP3A4. Both SUSAs using GC-MS or LC-MS n allowed monitoring an MXE intake in urine.

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.

Objectifs : Internet est une source incontrolable de vente de drogues ou de derives de medicaments. Nous rapportons le cas d’un homme de 32 ans, ayant des antecedents de polytoxicomanie, qui a consomme, 3 jours avant son admission, 250 mg de desoxypipradrol (ou 2-DPMP), substance derivee du pipradrol, medicament retire du marche en France en raison des risques d’abus a visee recreative dont il a fait l’objet. Cliniquement, il presente des hallucinations auditives et visuelles, des propos incoherents, une anorexie, une insomnie, des cephalees et une legere mydriase. Les symptomes du patient ont dure 7 jours. Methodes : Des analyses chromatographiques (LC-DAD, GC-MS et UPLC-MS/MS) portant sur des prelevements effectues a l’admission (sang) et 4 jours plus tard (sang et urines) ont ete realisees. Resultats et discussion : Elles ont mis en evidence la presence uniquement de desoxypipradrol a une concentration plasmatique de 136 μ g/L a l’admission (J3) et 93 μ g/L a J4; la concentration urinaire etait egale a 4 805 μ g/L a J4. D’apres la litterature, le desoxypipradrol est consomme par les toxicomanes a des doses comprises entre 10 et 20 mg pour ses proprietes psychostimulante et anorexigene. Ses effets durent 5 a 7 jours en moyenne. Trois cas de deces ont ete decrits pour des patients ayant consomme de facon concomitante d’autres drogues et/ou de l’alcool. Conclusion : Ce cas illustre aussi l’un des problemes auquel est confronte le toxicologue, a savoir l’identification rapide des nouvelles drogues facilement accessibles par Internet.

International audience; INTRODUCTION: Medicine diversion for recreational use is a constant concern for health authorities. Parachuting, also refered to as bombing, is used in order to increase the expected effect, to accelerate time-to-onset and to create mixtures of medicines and substances. Aeras covered: Firstly, we analyzed all available scientific literature (PRISMA) and internet forums without any limiting timeframe. Secondly, we collected cases of parachuting reported in the west of France by the addictovigilance and poison control centres. Our study confirms the reality of this emerging issue associated with a higher medical risk (60% of intoxication cases were moderate-to-severe in our study). The substances involved in parachuting were primarily stimulants, with a majority of MDMA, although the use of diverted medication and psychotropes is also of concern. Expert opinion: Parachuting is a dangerous way of using substances and of diverting medicines. This type of administration gives users a certain pharmacokinetic latitude to 'play' with respect to substances and medicines. Medicine abuse deterrent formulations do not seem to be sufficient in preventing diversions. This dangerous method of using substances and of diverting medicines should drive pharmaceutical companies to innovate in the interest of public health and safety.

Peganum harmala L. is commonly used in traditional medicine in Morocco for its sedative and emmenagogue properties but expose to the risk of overdose and poisoning. The aim of our study was to analyze a series of 200 cases of poisoning collected in poison control and pharmacovigilance center of Morocco in order to describe the epidemiological, clinical, therapeutic features and outcome of patients and indicate the toxicity of this plant used primarily for therapeutic purposes. Methods. This retrospective study performed over a period of twenty four years from January 1984 to December 2008. Results. The mean age of patients was 24.4±16.8 years with a female predominance (167 women against 33 men). Therapeutic circumstance was found in 32.5%, followed by suicide (28.5%) and abortion (13.5%). The symptomatology was dominated by neurological, gastrointestinal and cardiovascular signs respectively 34.4%, 31.9 % and 15.8%. The evolution has been specified in 114 cases, 7 deaths have been deplored with a fatality rate of 6.2%. Language: fr

Objectif Une des principales difficultes rencontrees par les toxicologues analystes reside dans la veille scientifique et la mise a jour des bibliotheques des spectres de masse avec de nouveaux produits stupefiants, ou non. Nous presentons le cas d’une jeune femme ayant porte plainte pour viol et pour laquelle des analyses ont ete realisees dans trois laboratoires. Description du cas Lors d’une soiree, une jeune femme de 16 ans declare avoir bu quelques bieres, puis s’etre sentie mal, ne pouvant plus ni bouger, ni parler, tout en demeurant consciente. Le lendemain, soit environ 16 a 20 h plus tard, elle porte plainte et des prelevements sanguins et urinaires sont realises. Methode Dans un premier temps, apres extraction liquide/liquide en milieu alcalin, les prelevements sont analyses par LC-DAD. Les urines sont analysees par GC-MS sans et apres derivation avec du HFBA ou du BSTFA. Une recherche de psychotropes et benzodiazepines est egalement effectuee par LC-MS/MS dans les deux prelevements. Dans un second temps, l’echantillon urinaire a ete envoye au laboratoire d’Hombourg pour recherche de nouvelles drogues de synthese et drogues d’abus. Enfin, les echantillons ont ete adresses au CHRU de Lille ou des analyses par LC-HRMS ont ete realisees. Resultats Les analyses initiales ont mis en evidence un pic (temps de retention de 7,6 min) dans le sang et un pic additionnel a 6,0 min dans les urines. Les recherches de nouvelles drogues de synthese ou drogues d’abus sont negatives. Les dernieres analyses ont mis en evidence la presence de bilastine dans le sang peripherique (677 μg/L) et dans les urines (traces). Conclusion La bilastine est un nouvel anti-histaminique H1 non sedatif. Sa demi-vie est d’environ 15 h ; elle est peu metabolisee et son elimination est majoritairement urinaire. Les concentrations plasmatiques therapeutiques sont comprises entre 100 et 300 μg/L [1] . En cas de surdosage, les concentrations sanguines mesurees sont comprises entre 1 000 et 2 000 μg/L [2] . Les effets indesirables sont de type cephalees, somnolence, sensations vertigineuses et asthenie. L’absence de troubles de la conscience relates par la patiente ne semble pas en coherence avec une prise de bilastine ; il est cependant legitime de considerer que la concentration sanguine de bilastine pouvait etre compatible avec la survenue d’une somnolence. Dans tous les cas, sur le plan analytique, ce dossier illustre la necessite d’associer differents laboratoires et techniques d’analyse dans le but d’identifier de nouvelles substances. Il montre egalement l’importance de confronter les resultats analytiques aux donnees cliniques.

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.

Objectives: The aims of this study were (i) to investigate the population pharmacokinetics of tacrolimus in renal transplant recipients, including the influence of biological and pharmacogenetic covariates; and (ii) to develop a Bayesian estimator able to reliably estimate the individual pharmacokinetic parameters and inter-dose area under the blood concentration-time curve (AUC) from 0 to 12 hours (AUC12) in renal transplant patients. Methods: Full pharmacokinetic profiles were obtained from 32 renal transplant patients at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modelling software NONMEM® version VI. Patients’ genotypes were characterized by allelic discrimination for PXR −25385C>T genes. Results: Tacrolimus pharmacokinetics were well described by a two-compartment model combined with an Erlang distribution to describe the absorption phase, with low additive and proportional residual errors of 1.6 ng/mL and 9%, respectively. Both the haematocrit and PXR −25385C>T single nucleotide polymorphism (SNP) were identified as significant covariates for apparent oral clearance (CL/F) of tacrolimus, which allowed improvement of prediction accuracy. Specifically, CL/F decreased gradually with the number of mutated alleles for the PXR −25385C>T SNP and was inversely proportional to the haematocrit value. However, clinical criteria of relevance, mainly the decrease in interindividual variability and residual error, led us to retain only the haematocrit in the final model. Maximum a posteriori Bayesian forecasting allowed accurate prediction of the tacrolimus AUC12 using only three sampling times (at 0 hour [predose] and at 1 and 3 hours postdose) in addition to the haematocrit value, with a nonsignificant mean AUC bias of 2% and good precision (relative mean square error = 11%). Conclusion: Population pharmacokinetic analysis of tacrolimus in renal transplant recipients showed a significant influence of the haematocrit on its CL/F and led to the development of a Bayesian estimator compatible with clinical practice and able to accurately predict tacrolimus individual pharmacokinetic parameters and the AUC12.

Ellipsometry porosimetry (EP) is an emerging technique that is dedicated to porous thin films analysis; it is non-contact and non-destructive. EP tools developed at SOPRALAB, allows us to obtain adsorption isotherms with many different adsorptives at an ambient temperature. EP leads to the same results as classical adsorption experiments (e.g. porosity and pore size distribution), but it also has some particular features leading to new information. For instance, our optical setup (Spectroscopic Ellipsometry) allows us to determine the variation of the thickness of the samples during the adsorption experiment. It is also very sensitive to interfaces; it is thus possible to detect a porosity gradient or to study a bi-layer sample and plot the two corresponding adsorption isotherms at the same time [A. Bourgeois, A. Brunet-Bruneau, V. Jousseaume, N. Rochat, S. Fisson, B. Demarets, J. Rivory, Description of the porosity of inhomogeneous MSQ films using solvent adsorption studied by spectroscopic ellipsometry in the visible range, Thin solid films 455–456 (2004) 366]. For porous thin films with a non-porous barrier layer deposited on top, it is also possible to study the lateral diffusion phenomenon in the film (see figure below). In this paper, we will illustrate a part of the different features of EP for adsorption on porous thin films and more particularly for diffusion phenomenon.

Ellipsometry porosimetry (EP) is an emerging technique that is well adapted to porous thin films analysis; it is non contact and non destructive. EP tools developed at SOPRA, allows us to obtain adsorption isotherms with many different adsorptives at an ambient temperature. EP leads to the same results as classical adsorption experiments (e.g. porosity, pore size distribution …), but it also has some particular features leading to new information. For instance, our optical setup (Spectroscopic Ellipsometry) allows us to determine the variation of the thickness of the samples during the adsorption experiment. It is also very sensitive to interfaces; it is thus possible to detect a porosity gradient or to study a bi-layer sample and plot the two corresponding adsorption isotherms at the same time (Bourgeois et al. 2004). For porous thin films with a non porous barrier layer deposited on top, it is also possible to study the lateral diffusion phenomenon in the film (see figure below). In this paper, we will demonstrate a part of the different features of EP for adsorption on porous thin films.