OBJECTIVES:There are few data on the penetration of daptomycin into the cerebrospinal fluid (CSF) of patients with bacterial meningitis. This ancillary study of the AddaMap trial aimed to assess the CSF penetration of intravenous daptomycin in 13 patients with pneumococcal meningitis. PATIENTS AND METHODS:Daptomycin was administered at 10 mg/kg/day to 13 patients with pneumococcal meningitis admitted to the Dijon University Hospital. Blood and CSF samples were collected on days 3 and 8. The population pharmacokinetics of daptomycin in plasma and CSF were studied using a two-compartment model. RESULTS:A large inter-individual variability in plasma areas under the curve (median, 25-75-percentile), 7843 h.mg/L (6606-9264), plasma peak, 107.5 mg/L (81.4-126.3) and trough 14 mg/L (7.6-19.3) concentrations and elimination half-lives, 8.8 hours (7.9-10.8), was observed. In CSF, the maximum concentration was 0.88 mg/L (0.57-2.82), and the elimination half-life was 23.8 hours (18.7-39.3). The AUC CSF/plasma ratio was 2.20% (1.7-2.3). Daptomycin CSF penetration was significantly correlated with CSF levels of proteins and lactate. CSF concentrations, 0.67 mg/L (0.39-0.86), were above the MIC90 of pneumococci resistant to beta-lactam. Simulations showed that a loading dose could reduce the time required to reach a biologically active concentration in CSF. CONCLUSION:We conclude that daptomycin administered at a dose of 10 mg/kg/day achieves CSF concentrations that may exert non-lytic anti-pneumococcal effects and demonstrate significant activity against highly resistant pneumococcal strains. These findings suggest that daptomycin could be considered as a valuable adjunctive therapy in the treatment of pneumococcal meningitis.

Aim Amlodipine is a calcium channel blocker, used in cardiac pathologies. At toxic doses, amlodipine is responsible for death by cardiogenic shock and vasoplegia. Its pharmacokinetic properties suggest that post-mortem redistribution is possible, precluding interpretation based on living data (generally, between 6.5 and 20.9μg/L). Our objective was to determine the toxic concentrations of amlodipine post-mortem. Method Plasma samples were analyzed using a Q-Exactive Focus high-resolution mass spectrometer coupled to the Transcend LX2 UHPLC system (Thermo Scientific™). The various compounds in the liquid sample were extracted using in-line extraction due to two different TurboFlow™ columns, assembled in series. The first is a Cyclone™ and the second is a Phenyl™ (50mm×0.5mm) (Thermo Scientific™). After extraction, the compounds were separated by an analytical column, here, a phenylhyexyl™ column (100mm×2.1mm, 2.6μm) (Thermo Scientific™). The composition of mobile phase A was water with 0.1% formic acid and 2mM ammonium formate. For phase B, acetonitrile:methanol:water (49.5: 49.5: 1 v/v) with 0.1% formic acid and 2mM ammonium formate was used. Phase C was a mixture of acetone:acetonitrile:isopropanol (20: 40: 40 v/v). All solvents were of LCMS quality. The flow rate of the mixture of mobile phases A and B was set at 2mL/min for the TurboFlow™ columns and 0.5mL/min for the analytical column. The temperature of the analytical column was set at 40°C. Once the sample had been extracted and separated, it was transferred to the mass spectrometry system. The sample is ionized by an H-ESI probe, switching positive and negative. Amlodipine ionizes positively. The ions are analyzed by Full Scan MS and a ddMS2 analysis is applied to fragment the ions and obtain confirmation. The calibration curve ranged from 0.05 to 0.25μg/L. With the autopsy findings, we classified the data into three groups, independent of the toxicological findings: unrelated death (group 1), possibly related death (group 2), and Amlodipine-related death (group 3). All samples were post-mortem femoral whole blood. Results Of the 31 cases, 1 case was classified in group 3 (Amlodipine concentration 275μg/L); 13 in group 2 (median concentration 83.0μg/L [42; 127.5]); and 17 cases in group 1 (median concentration 49μg/L [35.75; 85.25]). Conclusion Our results show that in group 1 (death not related to Amlodipine), the median concentration of 49μg/L is 2.33 times higher than the therapeutic concentration observed in living patients.According to our results, post-mortem concentrations below 85.25 (3rd quartile) μg/L, can be considered non-toxic. The use of therapeutic concentrations in living patients is therefore not reliable in post-mortem for this drug with a strong cardiovascular tropism. A larger-scale study would allow the definition of reference tables for post-mortem toxic concentrations of Amlodipine.

Présentation du cas Les analyses toxicologiques accompagnent très souvent les autopsies et prennent une place conséquente dans les conclusions du décès. Pour autant, elles ne sont pas toujours à suivre aveuglement. Nous présentons ici le cas de Monsieur X., 33 ans, atteint de schizophrénie et de déficience intellectuelle majeure et décédé lors d’une hospitalisation dans une unité psychiatrique fermée. Le patient a été décrit par l’équipe infirmière comme conscient et ne présentant pas de vomissements, quelques heures avant son décès. S’étant plaint, le matin de son décès, de douleurs abdominales, le patient avait reçu du « DIFFU-K », une antalgie par paracétamol et phloroglucinol, ainsi que son traitement journalier habituel, dont des laxatifs à posologie maximale. Monsieur X n’a pas bénéficié d’imagerie ou d’un transfert au centre hospitalier le plus proche. Monsieur X. est retrouvé en arrêt cardiorespiratoire en début de soirée, et décèdera malgré les tentatives de réanimation. Un obstacle médicolégal est posé et une autopsie est réalisée. Objectif L’objectif de ce travail est de montrer l’importance de la communication entre experts en toxicologie et en médecine légale. Méthode Après autopsie et recueil de sang cardiaque, sang périphérique, bile et contenu gastrique, les experts de médecine légale et de toxicologie ont confronté leurs résultats. Résultat Les résultats toxicologiques montraient des concentrations sanguines potentiellement toxiques et mortelles pour l’amisulpride, clozapine, tropatépine, des concentrations suprathérapeutiques pour la loxapine, et des concentrations thérapeutiques pour le diazépam, paracétamol et zuclopenthixol. À l’autopsie et l’examen externe, l’implication d’un tiers dans le processus du décès a pu être écartée. L’examen externe retrouvait des signes de putréfaction débutant sur la face antérieure de l’abdomen, une cyanose unguéale et digitale bilatérale, et des écoulements buccaux et nasaux de liquide gastrique brunâtre et noirâtre, comparables à des vomissements fécaloïdes. L’autopsie a permis de mettre en évidence un important syndrome occlusif bas (1m de stase stercorale à partir de l’anus), associé à une colectasie mesurée au maximum à 12cm, à une dilatation grêlique et à des signes d’ischémie de la paroi digestive. De plus, un épanchement pleural bilatéral et péritonéal citrin de faibles abondances, ont été mis en évidence. Ces éléments ont permis de conclure à un décès d’origine médical, par choc hypovolémique, suite à des vomissements à un syndrome occlusif et de la constitution d’un troisième secteur digestif. Discussion La prescription de neuroleptiques en association, encore plus à haute dose, est encore pratique courante en service de psychiatrie, bien que hors AMM. Elle est souvent motivée par le phénomène de tolérance qui peut s’installer chez des patients traités depuis des années. Ces médicaments ont des effets indésirables souvent graves nécessitant une surveillance régulière. Il est tentant, lors d’un décès, de conclure à une cause toxique lorsque les concentrations sanguines retrouvées sont décrites comme potentiellement mortelles dans la littérature. Mais la confrontation de la toxicologie à l’autopsie et aux circonstances du décès peut amener à une conclusion différente. En effet, les doses médicamenteuses étaient bien tolérées par ce patient. C’est donc la non maîtrise sur plusieurs jours des effets indésirables des psychotropes, conduisant à une constipation majeure, qui est la cause principale du décès. Conclusion L’apport des techniques de pointe servant pour les dosages pharmaco-toxicologiques est un progrès indéniable, permettant une analyse sensible et précise des concentrations sanguines des xénobiotiques. Elles demeurent cependant un examen complémentaire de l’autopsie faite par le médecin légiste. Le toxicologue et le médecin légiste doivent donc interpréter ensemble ces données toxicologiques en prenant en compte tous les facteurs ayant conduit au décès pour éviter le risque de conclusion erronée.

Accidental or intentional carvedilol poisoning is rarely reported. Here, we describe a case of attempted suicide with a large quantity of immediate-release carvedilol (75 mg) and alcohol. In order to determine the kinetics, liquid chromatography-high-resolution mass spectrometry analyses were performed. The results for the plasma concentration of carvedilol were 906 mu g/L 3 h after ingestion, 288 mu g/L 12 h after ingestion and 103 mu g/L 24 h after ingestion. A one-compartment model with linear and first order best described the elimination of the carvedilol, and the estimated half-life was 5.8 h. The result 3 h after ingestion represented the highest concentration ever observed for this drug. However, the patient was cirrhotic, and liver function was impaired with decreased Factor V (45%) and prothrombin ratio (61%). These conditions may explain the high concentrations of carvedilol. The patient was treated with glucagon and discharged from the hospital the following day.

Les intoxications accidentelles ou intentionnelles au carvédilol sont rarement rapportées. Ce cas de tentative de suicide avec une quantité importante de carvédilol à libération immédiate (75 mg) et d'alcool permet une description d'une validation de méthode du dosage du carvédilol en LC-HRMS conforme aux standards américains « ANSI/ASB Standard » ainsi qu'une meilleure compréhension de l'intoxication au carvédilol. Pour analyser la concentration de carvédilol, 100 μL de plasma et 25 μL d'étalon interne (halopéridol-d4, LGC™) sont précipités par 125 μL d'acétonitrile puis centrifugés à 13 000 rpm pendant 5 min à 20 °C. Au total, 10 μL de surnageant sont ensuite injectés et analysés sur une chromatographie liquide de type Transcend LX II couplée à un spectromètre de masse à détection orbitrap Q-Exactive Focus. Une extraction en ligne du composé et de son standard interne est réalisée sur deux colonnes Turboflow de type Cyclone et Phenyl montées en série, puis les molécules d'intérêt sont séparées sur une colonne analytique de type Phenyl-Hexyl (Thermo Fischer Scientific™). Afin de déterminer la cinétique de la molécule, une analyse compartimentale a été réalisée à l'aide de GraphPad ® Prism 9. Les coefficients de variation (CV) pour les contrôles qualités 0,25 mg/L et 1 mg/L étaient, respectivement de 10,51 % et 12,68 % pour la fidélité intermédiaire et 4,67 % et 3,25 % pour la répétabilité. Pour la justesse, le biais ne dépassait pas 20 %. La reproductibilité et la justesse obtenues pour les dilutions de carvédilol au 1:2 étaient, respectivement, de 4,35 % et 7,6 % (< 20 %). La contamination inter-échantillon après une forte concentration de carvédilol (4 mg/L) ne dépasse pas 10 % du signal de la plus faible concentration (0 mg/L). Nous n'avons observé aucun effet matrice (CV < 20 %), aucun effet sur l'ionisation (< 25 %) et bon rendement d'extraction pour le carvédilol (104 %) et l'étalon interne halopéridol-d4 (100 %). La LOD et la LOQ sont définies comme le premier point de la gamme d'étalonnage (0,01 mg/L). Les résultats concernant la concentration plasmatique de carvédilol étaient les suivants : 906 μg/L trois heures après l'ingestion, 288 μg/L douze heures après l'ingestion et 103 μg/L 24 heures après l'ingestion. Le modèle C(t) = 1288e–0,1183t a décrit au mieux l'élimination du carvédilol, et la demi-vie estimée était de 5,8 heures. L'alcoolémie à l'admission était de 3,81 g/L. Le patient a été traité avec du glucagon et a quitté l'hôpital le jour suivant. Le résultat obtenu 3 heures après l'ingestion représentait la plus forte concentration jamais observée pour ce médicament chez l'être humain. Cependant, le carvédilol est soumis à un effet de premier passage hépatique, et le patient était cirrhotique avec une fonction hépatique altérée (diminution du facteur V (45 %) et du rapport de prothrombine (61 %)). Ces conditions peuvent expliquer les concentrations élevées de carvédilol. De plus, le carvédilol est administré sous forme de composé racémique. Les énantiomères R (+)− et S (−)− du carvédilol sont des α1-antagonistes de même puissance, mais seul l'isomère S (−) est un β1-antagoniste. Les résultats de la littérature (Neugebauer et al. J. Cardiovasc Pharmacol 1992; S142–146.) mettent en évidence l'exposition accrue des cirrhotiques au S (−)- carvédilol par rapport aux individus sains, ce qui pourrait être responsable d'effets pharmacologiques plus importants.

Nitrites are commonly used in the chemical, pharmaceutical, and food industries. Recently, they have been identified in cases of voluntary intoxication. We report the case of a 13-year-old girl who was found lifeless on her bed next to a glass containing a white powder and a bottle containing a white powder with a moistened appearance. External examination and autopsy revealed a nonspecific asphyxia syndrome, which was confirmed by the pathological analysis. Analysis of the samples revealed metoclopramide in the peripheral blood at a concentration of 0.402 mg/L (LC-HRMS). An analysis of the gastric contents was carried out after sodium nitrite was detected in the powders found near the body (Raman spectrometry). Nitrites were found in the gastric fluid at a concentration of 30.9 mg/L. Death occurred secondary to anoxia, following ingestion of nitrites; suicide kits are available on the web and nitrites are relatively easy to source and inexpensive. Nitrites are delivered in powder form to be dissolved in liquid, which may then be consumed with metoclopramide (or an alternative anti-emetic drug) to maximize absorption and reduce emesis. The toxic effect of nitrites lies in their oxidizing power, causing the transformation of hemoglobin into methemoglobin, which, when it accumulates, induces tissue anoxia resulting in death. There has been an alarming increase in the number of cases linked to suicide using nitrites or a nitrite suicide kit. The fact that nitrites are readily available online underscores the importance of establishing effective preventive measures such as limiting the access and use of this chemical.

ImportanceThe DRAMES (Décès en Relation avec l’Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses.ObjectiveTo describe drug-related deaths in France and report trends over an 11-year period.Design, Setting, and ParticipantsThis case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022.Main Outcomes and MeasuresDemographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports.ResultsAmong the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin—44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%).Conclusions and RelevanceThis case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored.

Denial of pregnancy is a rare psychic process associated with an increased risk of infant death. Forensic examinations to determine viability at birth can heavily influence the legal proceedings in cases of clandestine deliveries that result in the death of the infant. A 32-year-old woman who experienced a denial of pregnancy up to 30 weeks of amenorrhea reported giving birth at home at an estimated term of 35 weeks of amenorrhea. No one witnessed the delivery. She claimed the infant was stillborn. Forensic examinations revealed characteristic features of a live born infant. The mother tested positive for mifepristone. Mifepristone is an anti-progestin drug used for early abortion and to induce labor in cases of in-utero fetal death in later pregnancy. Even if mifepristone crosses the placenta, it has no direct toxic effect on the fetus. Our observations suggest premature live birth caused by mifepristone, followed by asphyxia due to meconium inhalation syndrome associated with lung immaturity especially since the birth occurred at home and no medical care was provided after the birth. The tragic outcome of this clinical case calls for vigilance and global management, including the psychiatric care of parturients in the context of late discovery of pregnancy. In France, this situation showed a legal gap between the consideration of the fetus and laws concerning abortion. To our knowledge, in France, this case has allowed the court to set a legal precedent as a similar case had never been reported elsewhere.

We report the case of a 13-year-old girl, found dead by her father, with a glass containing 15 g of white powder and a bottle containing 5 g of white powder with a moistened appearance. The autopsy was performed four days after the death. The anatomopathological study of the specimens was included in formaldehyde and prepared according to the Saffron Eosin Hematein technique. First of all, a post-mortem toxicological screening was performed on cardiac blood, peripheral blood, urine and gastric contents by high performance liquid chromatography coupled to high resolution mass spectrometry (HPLC-HRMS). Ethanol testing was performed by gas chromatography coupled to a flame ionization detector (GC-FID), and drug testing by liquid chromatography coupled to a mass spectrometer (LC-MS/MS, opiates, cocaine, amphetamine) or gas chromatography coupled to a mass spectrometer (GC-MS, cannabis). A rapid analysis of powders found near the body was carried out by RAMAN spectrometry, and confirmed by ion chromatography coupled with mass spectrometry and X-ray diffractometry. In order to establish the concentration of the substance found by those analyses in peripheral blood and gastric contents, we later used the saltzman reaction after addition of potassium ferrocyanide and zinc sulfate. External examination and autopsy revealed a non-specific asphyxia syndrome. This was confirmed by the anatomopathological study which showed signs of non-specific acute heart failure: diffuse visceral congestion (heart, lungs, spleen, liver, pancreas, kidneys, thyroid, stomach) and pulmonary haemorrhage. First of all, toxicological analyses revealed the presence of metoclopramide, in cardiac blood (0.37 mg/L), urines (0.20 mg/L), gastric contents (0.24 mg/L) and in peripheral blood at a concentration of 0.40 mg/L. However, no ethanol and presence of drugs of abuse (cannabinoids, opiates, cocaine, and amphetamines) were detected. Secondly, powders found close to the body were analysed by three different techniques, and revealed the presence of sodium nitrite in pure form. Finally, the analysis of gastric contents confirmed the presence of nitrites at a concentration of 30.9 mg/L. This analysis could not be performed on the blood samples due to colour interference. This young girl died of anoxia secondary to the ingestion of a suicide kit containing sodium nitrite. Diverted from their original use as euphoriants (poppers), nitrites are now used for suicidal purposes. Specific kits have emerged on the internet. They contain sodium nitrite, metoclopramide and antacid. NaN02 is presented in the form of a powder, similar to salt, which dissolves easily in a liquid to reconstitute a toxic drink (Durão C, J Forensic Leg Med, 2020;73:101989). The lethal dose of nitrites is estimated for an adult at 2.6 g (Hwang C, Forensic Sci Med Pathol, 2021;17(3):475–80). This dose seems variable since a fatal case is described in the literature for an ingestion of 1 g (Gowans WJ, Br J Gen Pract J R Coll Gen Pract, 1990;40(340):470–1) and one non-fatal case following ingestion of 6 g (Chui JSW, Anaesthesia, 2005;60(5):496–500). In our victim's case, metoclopramide was also detected, at a concentration of 0.40 mg/L in the peripheral blood. The metoclopramide's concentration is therapeutic between 0.05 and 0.15 mg/L and toxic from 0.2 mg/L (Schulz M, Crit Care,2012;16(4):R136). Such a concentration of metoclopramide is therefore potentially toxic and can cause extrapyramidal symptoms (tremors), drowsiness, impaired consciousness, confusion, hallucinations, even cardiorespiratory arrest (Vidal) and may have contributed to death. The alarming increase in the number of cases and the access facility to these suicide kits on the internet shows that it is essential to implement measures to regulate this substance to prevent its diversion and use.

Background We report here a case where no everolimus pleural diffusion was evidenced at the same time of pleural progression of a metastatic breast cancer treated with everolimus and exemestane. Case description A 69-year-old woman was diagnosed in October 2006 with stage III invasive ductal breast adenocarcinoma. After nine months of everolimus and exemestane treatment, she presented with a pleural progression. Everolimus concentration was measured in blood and in pleural fluid. Residual blood concentration was at 9.1 ng/mL, while no everolimus was observed in the pleural fluid. Management and outcome Due to inefficacy of everolimus in this patient, she was switched to palbociclib and fulvestrant. Conclusion Everolimus seems to have a poor diffusion in the pleural fluid.

A 67-year-old man was found dead, at his home. On external examination, we found a voluminous purplish black ecchymosis of the anterior neck area. On internal examination, we found a voluminous epiglottis hematoma completely obstructing the upper airway. It was associated with other sites of intra-abdominal hemorrhage. Toxicological studies revealed the presence of warfarin at a concentration of 8.4 mg/L in peripheral blood, which supposes an INR well above 4.5. To conclude, we supposed death was due to asphyxia secondary to a spontaneous epiglottic hematoma caused by a high blood concentration of warfarin. Hemorrhage in the epiglottis is very rare. To our knowledge, our patient is the only case of "sudden death" reported with spontaneous epiglottic hematoma due to high blood concentration of warfarin. In forensic practice, an anterior neck ecchymosis, without trauma, may suggest hemorrhage into soft airway tissues. Pathology findings make it possible to exclude exogenous trauma.

STUDY OBJECTIVE:Dilution is often required to obtain appropriate concentrations of intrathecal morphine for analgesia. We compared techniques of diluting by measuring the quantity of morphine actually obtained in the final solution.DESIGN:This is an experimental study by 3 experienced anesthesiologists.SETTING:The setting is at a university teaching hospital.PATIENTS:There are no patients.INTERVENTIONS:There are no interventions.MEASUREMENTS:Five techniques for obtaining 100 μg from 10 mg/mL were compared: technique 1 (T1) = extraction up to 0.1 graduation on a 1-mL syringe, followed by simple dilution (SD). Technique 2 (T2) = As for T1 but syringe was shaken to mix solution. Technique 3 (T3): SD with 10-mL syringe. Technique 4 (T4): Double dilution with 10-mL syringe. Technique 5 (T5): Extraction up to the 0.1 graduation of a 1-mL syringe, then SD, then shake solution by hand. Three tests using high-performance liquid chromatography with ultraviolet were performed on each syringe prepared 3 consecutive times, namely, at the first (beginning, B), fifth (middle, M) and last (end, E) milliliter or 0.1 mL (depending on syringe type).MAIN RESULTS:Average overall concentrations were 208 ±19, 199 ±24, 120 ±13, 136 ±9, and 119 ±16 μg/0.1 mL, T1-T5, respectively. By Kruskal-Wallis test, we classified the techniques according to the magnitude of the difference between the observed concentration of morphine and the desired (theoretical) concentration of 100 μg/0.1 mL. In ascending order, techniques ranked as follows: T5 (smallest difference), T3, T4, T2, and T1 (greatest difference) (P = .0001).CONCLUSIONS:There is significant variability in the concentration of morphine actually contained in final solutions after dilution. Morphine presented in different premixed concentrations increases the risk of error. We advocate technique 5 as described above, whereas technique 1 should be prohibited.

Concerns have recently emerged about the quality of generic vancomycin products. Our aim is to analyze serum vancomycin concentrations measured 48hours after the start of an empirical treatment regimen in patients with acute myeloid leukemia (AML) who received one of the two generic vancomycin products available in France.

Summary Background A phase I dose‐escalation trial of transarterial chemoembolisation ( TACE ) with idarubicin‐loaded beads was performed in cirrhotic patients with hepatocellular carcinoma ( HCC ). Aim To estimate the maximum‐tolerated dose ( MTD ) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug‐eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose‐limiting toxicity (DLT) in 20% of patients. Results Twenty‐one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase ( AST ) at 5‐, 10‐ and 15‐mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST , elevated γ‐glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEB s to release idarubicin slowly. Conclusions Using drug‐eluting beads, the maximum‐tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted ( NCT 01040559).

Un enfant de 6 ans est hospitalisé en réanimation pédiatrique en raison d’une encéphalite d’aggravation rapide l’ayant mené dans le coma, sans diagnostic précis. Le quatrième jour, une recherche sanguine de toxiques révèle la présence d’halopéridol et de rispéridone non prescrits a priori à l’enfant, à des concentrations thérapeutiques. Cinq mois plus tard, cet enfant est transféré pour rééducation à l’hôpital de Garches. Devant le contexte psychiatrique familial, les médecins évoquent la possibilité d’un syndrome de Münchausen par procuration. Une analyse de cheveux est demandée afin de confirmer l’éventuelle administration des deux neuroleptiques. Les cheveux étant relativement courts, un prélèvement de poils de jambe est également réalisé. L’halopéridol et la rispéridone n’ont pas été retrouvés en chromatographie liquide couplée à la spectrométrie de masse (CL-SM/SM) ni dans les cheveux ni dans les poils, ne permettant pas d’éclairer le diagnostic. En revanche, il a été retrouvé les molécules correspondant au traitement reçu durant l’hospitalisation. Ont ainsi été mis en évidence dans les deux segments de cheveux étudiés et les poils du métoclopramide (301 et 210 pg/mg dans les cheveux, 799 pg/mg dans les poils), de la dompéridone (respectivement 703 pg/mg, 1176 pg/mg et 108 pg/mg), et du diazépam ainsi que ses métabolites le nordiazepam et l’oxazepam dans les cheveux, (respectivement 373 et 391 pg/mg, 271 et 249 pg/mg, et 68 et 111 pg/mg). Il s’agit des premières concentrations en dompéridone et métoclopramide décrites dans les cheveux et les poils d’un enfant blond de type caucasien lors d’une utilisation thérapeutique chronique.