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Objectifs La pervenche francaise (Vinca minor) est une plante grimpante de la famille des apocynacees. Les tiges sont fines, les feuilles sont opposees, ovales ou oblongues, et les fleurs, tres souvent violettes, ont cinq petales. La floraison a lieu pendant les mois de mars a juin et les fruits, qui se trouvent au milieu de la fleur contiennent 7-8 graines en juin et juillet. Toute la plante est toxique et contient plus de 50 alcaloides. Un de ces alcaloides, la vincamine, est aussi utilise dans le traitement des troubles de la perfusion cerebrale. Nous decrivons un rare cas d’intoxication collige en France metropolitaine apres ingestion de fleurs et de feuilles de cette espece dans une salade. Methode Une dame de 71 ans s’est fait pour son repas du soir une salade avec 8 fleurs et feuilles de Vinca minor avec des asperges et de la vinaigrette. Resultats Quelques minutes apres, une vasodilatation persistante avec une forte rougeur apparait au niveau du visage de la dame, ce qui l’amene a appeler le centre antipoison de Marseille 2h30 apres son repas. La dame precise par ailleurs qu’elle presente comme antecedent une HTA traitee par irbesartan et qu’elle s’est deja auto-traitee avec du charbon. Il lui est conseille de se reposer et de rappeler s’il y a de moindres soucis. Lorsque le CAP rappelle pour prendre des nouvelles une demi-heure plus tard, la dame presente toujours une rougeur du visage et une tension systolique a 170 (ce qui serait habituel les derniers jours). Au troisieme appel (3h30 de l’ingestion) la dame se sent bien, mais son visage est toujours un peu rouge. Vu le temps passe et la non-aggravation des symptomes pendant les dernieres heures, il est decide de laisser la dame a la maison. Au suivi le lendemain la dame indique que pendant la nuit elle aurait fait une petite malaise, qui serait passe apres l’ingestion d’un biscuit. Depuis elle se sentait bien et est consideree comme guerie. Conclusion Le cas clinique illustre la dangerosite potentielle des intoxications involontaires avec des plantes du jardin non comestibles mais attirantes en insistant sur la necessite d’identifier l’espece avant toute ingestion.

International audience; Buprenorphine has been used in pain and opioid addiction management for nearly 25 years. Compared to methadone, buprenorphine is thought to exhibit less side effects and respiratory depression in case of accidental or suicidal overdose. The aim was to describe the characteristics of exposures reported to a French Poison Control Center (PCC). We conducted a retrospective study including all buprenorphine exposures for which advice of our PCC was required between 2009 and 2018. After data extraction from the electronic medical files and anonymous transfer to an Access base, a statistical descriptive analysis was performed focusing on adolescents over 10 years old and adults. One hundred and ninety-nine cases were analyzed. The major circumstances of exposure were suicide attempts and overdoses in patients with previously identified substance abuse. Buprenorphine exposures have been reduced by 50% between 2009 and 2018. Coingestions, often with benzodiazepines or antidepressants, were almost systematic and 79% of all the series exhibited at least one symptom. Among the symptomatic cases, neurological effects were the most frequent (83%) and respiratory symptoms occurred in 13%. No deaths were registered. Severity did not exceed PSS1 in 80% of all the cases. Treatment was mainly symptomatic even though naloxone was required in at least 5% of the symptomatic cases. Within 24 h after exposure, 120 patients were discharged from the emergency department. Despite loss to follow-up, our results suggest that buprenorphine is relatively safe.

Objectif Explorer l’exploitabilite des appels a la Reponse Telephonique d’Urgence (RTU) pour suivre la pathologie psychiatrique d’un patient et l’efficacite de sa prise en charge. Historique du cas Mme F contacte a partir de mi-2015 de plus en plus frequemment la RTU du CAP de Marseille (CAPM). Ses premiers appels sont assez agites, voire agressifs ou injurieux, ses plaintes vagues et polymorphes, souvent a motif de persecution et d’empoisonnement (mais sans focalisation d’objet ni de personne), et les echanges sont trop difficiles pour recueillir quelque information. Neanmoins ses appels se poursuivent, parfois pluriquotidiens ou distants de plusieurs semaines, s’apaisent (toujours courts, se terminant par un remerciement meme quand entames vifs), s’orientent plus regulierement vers la nourriture et son ressenti gastro-intestinal, et permettent de recueillir peu a peu quelques donnees. Elle a 58 ans, vit en milieu rural avec son pere de 90 ans, et recoit regulierement a domicile une injection d’antipsychotique d’action prolongee. Ayant obtenu d’elle l’accord de contacter son medecin traitant, nous avons decide de dresser l’historique des appels de Mme F a la RTU et d’y chercher une eventuelle correlation avec son parcours clinique et therapeutique. Methodes Exploitation retrospective (uniquement quantitative et graphique : date et heure) des enregistrements telephoniques de la RTU correspondant au numero de Mme F du 01/06/2017 au 31/12/2019, et consultation du dossier medical de son medecin traitant sur la meme periode. Resultats Mme F a appele 352 fois le CAPM en 31 mois (1 seul mois sans appel, 3 mois Discussion Les variations d’humeur de notre patiente ont evidemment d’autres determinants qu’exclusivement medicamenteux, que les limites (duree, nature…) de cette etude ne permettent pas d’explorer. Neanmoins elle montre que tout en restant dans le cadre des recommandations « pour la moyenne », les changements de specialite et posologies ont eu un impact sur la pathologie propre a Mme F, qui s’est traduit de maniere visible par une sollicitation bien plus frequente du CAPM. Conclusion Meme si ce cas n’est bien sur qu’un exemple isole, il ouvre des pistes pour, en complement de la mission collective de toxicovigilance, exploiter a des fins individuelles la tracabilite des appels a la RTU, et prendre en compte ce genre de signal chez des patients bien connus de la regulation telephonique pour declencher sans attendre une consultation et une reevaluation personnalisee de leur traitement, notamment chez ceux moins bien entoures et suivis que Mme F.

International audience; Buprenorphine is a µ-partial agonist and k-antagonist acting on central opioid receptors. Patented for analgesia in 1968, buprenorphine has been used as opioid substitutive therapy since the 1990s, as well as methadone. The aim was to document pediatric poisoning, to discover the severity, and to evaluate the treatment with naloxone. All pediatric poisonings reported to the poison control center Marseille (France)-from January 1, 2009 to December 31, 2018-were included. Analysis put value on gender, age, estimated quantity, symptoms and their delay, place of treatment, medical treatment, utilization of antidotes, severity of intoxications, and patients' outcome. Fifty-four infant poisonings with buprenorphine were recorded, doses varied between 1 and 36 mg, and children showed mainly neurological (somnolence, miosis.. .) and gastroenteric (vomiting) effects. Pulmonary effects were described for four children. According to the poisoning severity score, 8 intoxications were classified as 'no symptoms or signs', 37 as minor poisonings, 3 as moderate, none as severe or fatal and 6 were unknown. Medical care was required for 46 children, and four of them were treated with naloxone. Buprenorphine poisoning can cause neurological, gastroenteric, and respiratory symptoms. Even licking a tablet leads to intoxication because of maximal tablet's absorption while placing it under the tongue. Hospital admission is necessary even at small doses. Naloxone was efficient in the four described cases. Parents have to be aware of the poisoning risk with buprenorphine. Recently, commercialized instantly dissolving formulations could cause more severe intoxications.

Introduction Peganum harmala, aussi appele rue sauvage, est une plante herbacee vivace, a l’origine rencontree dans les milieux semi-arides du bassin mediterraneen et en Asie centrale mais repandue aujourd’hui en Afrique, Amerique du Sud et Australie. Graines, feuilles et fleurs sont utilisees pendant des rites, pour leurs effets medicaux, comme drogues ou comme teinture des tapis. Les graines de Peganum harmala contiennent les alcaloides Harmine et Harmaline. Il s’agit d’inhibiteurs de la monoamine oxidase A qui potentialisent ou demasquent les effets psychoactifs de certaines drogues. Melangees avec de la dimethyltryptamine (DMT, extrait de Psychotria Viridis) dans une infusion, elles sont utilisees en medecine traditionnelle [1] , [2] . Nous decrivons un cas d’automedication survenu a Mayotte avec apparition d’effets indesirables ayant necessite une prise en charge aux urgences. Observation Pour traiter l’enuresie nocturne d’un garcon de 12 ans, ses parents ont prepare une infusion en melangeant une poignee de graines d’harmal dans un litre d’eau. Le garcon a bu plusieurs gorgees le matin avant de partir a l’ecole. Arrive sur place, il a presente des nausees, des vomissements, une vision floue et un malaise avec perte de connaissance. Transporte aux urgences via le SAMU, l’examen clinique retrouvait une somnolence. La gazometrie montrait une acidose respiratoire avec hypercapnie (pH 7,27, pCO2 = 60 mmHg). L’ECG et le reste du bilan etaient normaux. Le medecin des urgences a contacte le centre antipoison de Marseille pour avis concernant la prise en charge. Une hydratation intraveineuse associee a une surveillance avec controle de la gazometrie et de l’ECG a ete proposee. L’etat clinique du garcon s’est ameliore apres le traitement, le controle de la gazometrie dans l’apres-midi se revelait normal ainsi que le deuxieme ECG. L’enfant a pu regagner son domicile le jour meme. Conclusion Les parents ont utilise les graines de Peganum harmala pour traiter l’enuresie nocturne de leur enfant. Or, la revue de la litterature n’a pas retrouve l’enuresie nocturne comme indication de ce traitement. Au contraire, les inhibiteurs de la monoamine oxidase A harmine et harmaline provoquent l’effet oppose, soit une polyurie. Par ailleurs, les parents, non conscients des effets indesirables potentiels de leur traitement, n’ont pas surveille leur enfant et l’ont envoye a l’ecole ou il a perdu connaissance. Le cas clinique illustre la dangerosite de l’automedication en medecine traditionnelle par des usagers n’ayant pas forcement les connaissances requises.

Resume Introduction Le cannabis est la substance psychotrope illicite la plus utilisee en Europe et particulierement en France. Cette large diffusion a provoque une augmentation du nombre et de la severite des intoxications accidentelles par les enfants dans l’entourage des consommateurs. Observation Nous rapportons le cas typique, domine par une somnolence et une hypotonie marquees, d’un enfant de 14 mois pris en charge aux urgences une heure apres avoir ingere une boulette de resine de cannabis. Devant la degradation de son etat de conscience 35 min plus tard (score de Glasgow pediatrique PGCS 10/15), il a fait l’objet d’une prise en charge originale par l’administration i.v. de 3 fois 10 μg/kg de flumazenil a 1 min d’intervalle. L’amelioration a ete franche (GCS 15/15), rapide ( Discussion-Conclusion Cette observation souligne l’interet de travaux plus approfondis pour evaluer l’hypothese d’un recours au flumazenil dans certains cas d’intoxications pediatriques au cannabis. En l’etat actuel des connaissances, le faible niveau de preuve et les nombreuses inconnues sur le mecanisme d’action ou le benefice–risque ne permettent pas pour l’instant de le recommander.

Objective Description of a fatal case of aconite poisoning after ingestion of leaves of Aconitum napellus, documented by the dosages of 3 aconite alkaloids on various matrices in a deceased patient. Case history After accidental ingestion of aconite plant as a Couscouil salad, a 78-years-old man with non-insulin-dependent diabetes mellitus, and his wife felt buccal paraesthesia and numbness. Quickly, these symptoms become widespread. The man finally admitted in reanimation unit where he developed cardiovascular decompensation on acute arrhythmia and deceased. To confirm the aconite toxidrome, several samples were collected from the wife and the deceased patient. Methods Large screenings of drugs and toxics were performed on blood samples. An aconite specific and sensitive LCMSMS (3200 QTrap, ABSciex) method was developed to determine aconite alkaloids aconitine (A), hypaconitine (H) and mesaconitine (M). Clinical and autopsy samples were analysed after precipitation with methanol [1] , [2] . Bile and urine were hydrolysed before extraction. The limit of quantitation was 1 ng/mL for A, H and M. Results The toxicological findings were only amiodarone, lidocaine (intensive care) and metformin in non-toxic level in the fatal case. Aconitine was the only alkaloid found in all samples, with traces only for the wife. Measured concentrations in autopsy samples are presented in Table 1 . Discussion The concentration of A measured in peripheral blood was higher than those reported in other aconitine-related deaths [2] , even if the digestive absorption might have not been finished. The heart/peripheral concentrations ratio is about 3, which is in accordance to the heart accumulation and the cardiotoxicity of the compound. The concentrations of A in spleen, lung and heart were similar (about 4-fold the peripheral blood). In contrast, diffusion in skeletal muscle was close to blood distribution (34.2 ng/mL). Both diffusion in brain and vitreous humor represented half of blood. Unchanged and conjugated A forms seemed to be low compared to the blood concentrations and the other published cases despite liver and kidney distributions, suggesting a potential renal impairment during resuscitation cares. As another French intoxication case, H and M were not found, may be because of a lack of these compounds in the French species of Aconite. Blood A concentration above 30 ng/mL seems to be lethal even with appropriate cares. Conclusion In France, toxicological investigation should focus only on A in peripheral blood, and if not available postmortem distribution must be taken into account. Vitreous humor could have an interest.

A quantitative method using ultra performance liquid chromatography-tandem mass spectrometry is described for simultaneous determination of nicotine and its metabolites (cotinine and trans-3'- hydroxycotinine) in human plasma. Aliquots of 0.25 mL of plasma specimens were used for analysis, and 3 analytes were extracted by liquid-liquid extraction. The main problem was blank plasma contamination with environmental nicotine. Activated charcoal was used to avoid this analytical interference. For optimized chromatographic performance, a basic mobile phase consisting of 0.2% ammonia in water (mobile phase A, pH10.6) and acetonitrile (mobile phase B) was selected. The analytes were separated on a 50 mm × 2.1 mm BEH C18 column, 1.7 μm particle size, and quantified by MS/MS using multiple-reaction monitoring (MRM) in positive mode. The chromatographic separation was achieved in 3 min followed by 1.2 min of column equilibration. The calibration curves were linear in the concentration range of 10-1000 ng/mL with correlation coefficients exceeding 0.99. Within-day precisions and between-day precisions (CV, %) were15 %. The accuracy expressed as bias was within ±15% for all analytes. The recovery values ranged from 50% to 97%. The ions used for quantification of nicotine, cotinine and 3-OH-cotinine were 166.9129.7; 176.979.7; 192.979.7 m/z, respectively. The original blank sample preparation solved the problem of contamination in a cost-effective and efficient way. The validated method has been routinely used for analysis of nicotine and metabolites and determination of hydroxycotinine/cotinine metabolic ratio. This biomarker seems to be interesting at predicting response of nicotine patch replacement therapies.

La Presse Medicale - In Press.Proof corrected by the author Available online since samedi 5 novembre 2016

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7-10 kg; patient's postnatal age: 0-206 days; GA: 27-42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1-10.6 mg/kg) per day was administered by 30-min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed-effect population model software). Data were modelled with an allometric pharmacokinetic model, using three-fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (Vd ) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, Vd , F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.

Ertapenem is a parenteral broad-spectrum carbapenem active against Gram-negative pathogens, which has been approved for treatment of different infectious situations in adults and children. Favourable pharmacokinetics and pharmacodynamics have been established in young adults. In the elderly, dosing regimen adaptations are not recommended. Nevertheless, pharmacokinetic studies in paediatrics have not been published yet. The aim of this study was to document whether age influenced ertapenem disposition by comparing its pharmacokinetics in three groups of rats. Rats were separated into three groups: very young rats 21-day-old, 10-week-old and 7-month-old rats. A population pharmacokinetic model was built and evaluated, using the NONMEM software. Pharmacokinetic parameters, interindividual variability and residual variability were estimated. The final model was evaluated by a bootstrap procedure and visual predictive check. The ertapenem concentration-time data were best described by a one-compartment model with zero-order input and first-order elimination. Effect of very young and old ages was estimated on central volume and clearance. Model evaluation indicated that the model was robust and parameter estimates were accurate. Central volume was found to be dependent on age and increase with age. Although the dosing regimen was weight adjusted, clearance was found to depend not only on age but also on weight. This study clearly documents changes in ertapenem pharmacokinetics according to group of age. These results suggest that paediatric dosing regimen cannot be directly extrapolated from a pharmacokinetic model in young adults unless it took into account age-induced modifications.

In pediatric cancer patients, determination of optimal vancomycin dosage is essential because of high risk of inadequate concentrations and bacterial resistance. The aim of this study was to determine vancomycin pharmacokinetic parameters in this population and propose dosage optimization to achieve optimal concentration.We retrospectively reviewed the use of vancomycin in pediatric cancer patients with febrile neutropenia (hematological or solid tumor disease). Vancomycin was administered by continuous infusion, and dosages were adapted according to therapeutic drug monitoring results. Blood cultures were performed before the first dose of antibiotic. Vancomycin pharmacokinetic population parameters were determined using NONMEM software, and dosage simulations were performed according to the target concentration (20-25 mg/L).One hundred twenty-one patients were included in this study, representing 301 vancomycin concentrations. Blood cultures were positive in 37.5% of patients, and observed pathogens were mainly Staphylococcus spp. (43.8% methicillin resistant). Volume of distribution (95% confidence interval) was 34.7 L (17.3-48.0), and total apparent clearance (CL) (95% confidence interval) was correlated to body weight, tumor disease, and cyclosporine coadministration: CL = θCL × (WT/70) L/h with θCL = 3.49 (3.02-3.96), 4.66 (3.98-5.31), and 4.97 (4.42-5.41) in patients managed for hematological malignancies with or without cyclosporine coadministration and for solid malignancies, respectively. Based on simulation results, vancomycin dosage (milligram per kilogram) should be adapted to each child on the basis of its body weight and cyclosporine coadministration.Our results highlight the requirement to adapt vancomycin dosage in cancer pediatric population. Simulations have allowed to describe new dosage schedules, and a chart was created for clinicians to adapt vancomycin dosage.

Three decades after its introduction, pharmacokinetic population approaches have become a reference method for drug modelling, particularly in paediatrics. The main practical limitation in this specific population is the collected blood volume. Pharmacokinetic population approaches using sparse sampling may resolve this issue. The pharmacokinetics of many drugs have been studied during the last 25 years using such methods. This review summarizes all of the published studies concerning population pharmacokinetic approaches in paediatric subjects from neonate to 2 years old. A literature search was conducted using the PubMed database, from 1985 to December 2010, using the following terms: pharmacokinetic(s), population, paediatric/pediatric and neonate(s). Articles were excluded if they were not pertinent according to our criteria. References of all relevant articles were also evaluated. Ninety-eight studies were included in this review. The following information was extracted from the articles: drug name, therapeutic class, population size, age of patients, number of samples per patient, covariates used for clearance and volume of distribution estimates, software used for modelling and validation methods. An increasing rate of publications over the years was observed; 44 different drugs were studied using a pharmacokinetic population approach. Antibacterials were the most studied class of drugs, including a large number of studies devoted to vancomycin and gentamicin. It must be underlined that few studies have been performed on anticonvulsant drugs and anaesthetics used in clinical daily practice conditions.

Introduction: Model evaluation is an important issue in population pharmacokinetic analyses. The objectives were to evaluate the predictive performance of previously published pediatric population pharmacokinetic models for vancomycin in a new data set and to propose an optimal dose to obtain a vancomycin concentration target. Methods: External evaluation was conducted for all the published models of vancomycin in neonates and young infants with a new data set of 70 patients. Bias and accuracy were calculated. Advanced analyses were performed to evaluate the predictive performance of the best model. This population pharmacokinetic analysis was performed to simulate doses of vancomycin according to the appropriate target concentration. Results: All models gave almost the same results, except 2 that were not acceptable. Nevertheless, the model described by Oudin et al presented the best results with a bias and accuracy of 4.0% and 27.8%, respectively. Simulations showed that the maintenance dose should be adjusted more precisely to each neonate based on his or her weight and serum creatinine value. Conclusion: Simulations have allowed the authors to describe new dosage schedules, and a chart was created to help clinicians to adapt dosage of vancomycin. Because of pharmacokinetic variability, vancomycin still requires therapeutic drug monitoring.

Introduction Une analyse des cas d’exposition a des specialites contenant du dextromethorphane (DXM) et recus par les centres antipoison et de toxicovigilance (CAPTV) a ete realisee pour completer l’evaluation du potentiel d’abus et de dependance de cette molecule. L’action antagoniste du recepteur au NMDA par le DXM -avec son metabolite principal le dextrorphane- peut provoquer, selon la dose, une euphorie, des hallucinations et un etat de dissociation pouvant contribuer a des abus du DXM a visee recreative [1] , [2] . Methodes A ete analyse l’ensemble des cas d’exposition impliquant du DXM recenses entre janvier 1999 et decembre 2014 par les CAPTV. Un focus a ete fait sur les expositions volontaires, en particulier addictions, mesusages et conduites suicidaires. Resultats Au total, 1474 cas d’exposition au DXM ont ete identifies : 478 etaient symptomatiques (32,4 %). Les resultats montrent une augmentation progressive du nombre de cas, notamment a partir de 2007. Apres analyse selon les circonstances d’exposition et ajustement sur l’activite des CAPTV et sur les ventes de DXM, une tendance a l’augmentation continue est uniquement confirmee pour les addictions. Parmi les 478 cas symptomatiques, 135 (28 %) concernaient une consommation volontaire de DXM sans autre molecule associee. Les conduites addictives (n = 51) concernaient davantage des hommes (65 %) et des sujets plus jeunes que ceux ayant fait un mesusage (n = 56) ou une tentative de suicide (n = 28) [âge median : 16 ans versus respectivement 38 et 18 ans]. Les formes solides de DXM etaient largement impliquees dans les prises de DXM seul a usage recreatif (70 %). La dose de DXM consommee seul etait du meme ordre de grandeur pour les conduites suicidaires et les conduites addictives (mediane respectivement 375 mg et 360 mg), tandis qu’elle etait moindre pour les cas de mesusage (mediane 180 mg). Discussion Cette etude retrospective des cas rapportes aux CAPTV a confirme le signal observe par le reseau d’addictovigilance d’un usage detourne du DXM a visee recreative impliquant principalement des formes solides, consommees a fortes doses, par de jeunes adultes et adolescents de sexe masculin a la recherche d’hallucinations.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

Teicoplanin is a glycopeptid antibiotic used for treatment of serious infections caused by Gram+ bacteriae. The treatment scheme corresponds to an initial loading dose followed by maintenance dose. High interindividual pharmacokinetic variability and strong relation between high through concentrations, dose and clinical success, support the need of therapeutic drug monitoring using through concentrations. Achieving through concentrations ≥ 10-15 mg/L or ≥ 20-40 mg/L, regarding the measurement method and the infection severity, is recommended to increase clinical success rate. The level of proof of therapeutic drug monitoring is evaluated: "necessary".

Objectif Rapporter un cas de piqure par Isometrus maculatus sur l’atoll de rangiroa en polynesie francaise. Description du cas Il s’agit d’une femme de 55 ans, sans antecedents, qui est piquee au niveau de l’index a son domicile, sur l’atoll de rangiroa, en polynesie francaise. Elle consulte son medecin traitant 1h30 plus tard qui constate un œdeme et un erytheme autour de la zone de piqure. La patiente ne se plaint que d’une douleur locale. La frequence cardiaque et la pression arterielle sont normales. Le medecin contacte le centre antipoison de Marseille, et fait parvenir au toxicologue de garde la photographie de l’animal, tue par la patiente. Il s’agit d’un scorpion beige, macule de tâches et au profil filiforme, ne laissant aucun doute sur son identite : I. maculatus , scorpion de la famille des Buthides. Un traitement antalgique simple par paracetamol et glacage est conseille, ainsi qu’une auto-surveillance simple au domicile. Conclusion Scorpion ubiquitaire dans la zone intertropicale, I. maculatus est probablement le buthide le plus repandu au monde. Originaire du bassin asiatique, ses facultes d’adaptation et de reproduction importantes expliquent le pouvoir invasif de cette espece ; sa presence sur une ile aussi isolee le confirme. Arthropode timide et craintif, les envenimations semblent extremement rares : seulement quatre cas [1] , [2] sont decrits dans la litterature. Ce cinquieme cas, survenu dans un territoire ou la presence de ce scorpion n’etait pas decrite, confirme la faible toxicite du venin d’ I. maculatus . Contrairement a d’autres membres bien plus dangereux de la meme famille des Buthides, sa piqure n’induit qu’un syndrome douloureux local, associe ou non a des paresthesies/dysesthesies au niveau de la zone d’injection.

Objectif Rapporter un cas d’intoxication humaine par Mercurialis annua lors d’une erreur d’identification. Description du cas Une femme de 46 ans, sans antecedents, recolte dans son jardin ce qu’elle pense etre du chenopode blanc (Chenopodium album), plus connu sous le nom d’epinard sauvage. Elle en consomme, apres cuisson, une pleine assiette au « bon gout d’epinard ». Une heure plus tard, une diarrhee et des spasmes douloureux, associes a des signes generaux (asthenie, frissons) apparaissent. Les symptomes se majorent et poussent la patiente a solliciter a 5 heures de l’ingestion le centre antipoison referent, qui avec l’aide du reseau national « Phytoliste », confirme la source des symptomes : l’ingestion d’une euphorbiacee, M. annua. Devant l’importance des signes digestifs, la patiente consulte au service des Urgences. Le bilan sanguin retrouve un bilan hepatique tres legerement perturbe (ASAT = 40 UI/L, ALAT = 70 UI/L, GGT = 160 UI/L), une fonction renale normale, une legere anemie (Hb = 12,9 g/dL) avec presence de sang dans les urines a la bandelette. La prise en charge est purement symptomatique et les symptomes s’amendent rapidement, permettant un retour au domicile le jour meme. Conclusion En Europe, la mercuriale fait partie des mauvaises herbes les plus communes. Les intoxications tant humaines qu’animales restent rares en raison d’une odeur desagreable et d’une saveur acre de cette plante, bien que cela ne semble pas avoir gene notre patiente. Les toxicologues veterinaires connaissent bien la toxicite de cette plante, source d’intoxications collectives chez le betail ovin et bovin : l’animal intoxique est apathique et anorexique, il souffre de diarrhee et d’une anemie hemolytique avec hemoglobinurie. L’autopsie des betes retrouve des lesions hepatiques et renales [1] . Chez l’homme, aucun autre cas d’intoxication a M. annua n’a ete rapporte. Deux cas d’intoxications a une espece proche, Mercurialis perennis, ont ete decrits [2] , le tableau etant essentiellement digestif (douleurs abdominales et vomissements intenses), associe a une hemoglobinurie pour l’un des deux patients. Cette premiere observation clinique d’une intoxication a M. annua d’evolution favorable, souligne le risque toujours present d’intoxication par les plantes sauvages, dont la consommation est actuellement tres a la mode.

Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 degrees C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median +/- inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 +/- 0.000800 L/min vs. 0.0134 +/- 0.00134 L/min), apparent volume of distribution (V(d)) (2.19 +/- 0.27 L vs. 1.57 +/- 0.73 L) and a significant decrease in exposure (488 +/- 50.6 mgxmin/L vs. 572 +/- 110 mgxmin/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 +/- 8.42 microg/g vs. 3.48 +/- 3.26 microg/g) and no significant difference between cardiac concentrations in the two groups (5.38 +/- 4.83 microg/g vs. 3.73 +/- 2.44 microg/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood-brain barrier permeability during hyperthermia. The hyperthermia-induced increase in V(d) could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients.

The aim of this study was to document the influence of hyperthermia on the pharmacokinetics of ertapenem. Two groups of Wistar rats, normothermic (n = 6) and hyperthermic (n = 8), were injected a single intravenous bolus of ertapenem (15 mg/kg of body weight). Hyperthermia-induced animals were placed in a water-bath at 47 degrees C and control group animals were kept in a water-bath at 25 degrees C to obtain a stable mean core temperature of 39.8 and 36.9 degrees C respectively. Hyperthermia induced significant higher plasma concentrations and exposure, whereas total apparent clearance and volume of distribution were significantly decreased. If confirmed in humans, these results will be of interest to take into account such modifications in hyperthermic clinical situations.

Biological rhythms may influence drug response (chronopharmacology) and some chronopharmacological studies have underlined the influence of time of day on drug pharmacodynamics and pharmacokinetics. The aim of the present review is to underline how biological rhythms may interfere with drug kinetics and to try to underline when, how, and why taking into account the moment of administration of a drug. Many physiological factors, possibly implicated in different steps of the fate of drugs in the organism (e.g., absorption, distribution, metabolism, and elimination) vary along the 24 h scale. Taking into account biological rhythms in kinetic studies, should be indicated when the concerned drug will be used in a chronobiological disease (e.g., asthma, cancer, depression, hypertension, gastrointestinal diseases, rheumatisms), etc. In case of a drug characterised by a high inter- and intra-variability, a narrow therapeutic range or when the drug will be further used following a once-a-day formulation. It is of importance to rigorously control factors which are known to influence pharmacokinetic processes in chronokinetic studies. Time of day has to be regarded as an additional variable to influence the kinetics of a drug.

The present study was conducted to evaluate the effect of a 7 d continuous infusion of ropivacaine on the 24 h rhythms of body temperature, heart rate, and locomotor activity. After an initial 7 d baseline, rats were randomly divided into two groups of 4 rats each to receive ropivacaine or saline via an osmotic pump for 7 consecutive days. The pumps were removed thereafter and observed during a 7 d recovery span. The studied circadian rhythms were measured by radiotelemetry throughout each of the 7 d periods. An additional group of 4 rats was studied under the same experimental conditions to assess the plasma levels of ropivacaine on days 3 and 8 following pump implantation. Our results indicate that ropivacaine does not induce loss of the circadian rhythms of body temperature, heart rate, or locomotor activity; a prominent period of 24 h was found for all variables in all animals, before, during, and after ropivacaine treatment. However, ropivacaine treatment did modify some characteristics of the rhythms; it increased the MESOR (24 h mean) of the heart rate and locomotor activity rhythms and advanced the acrophase (peak time) of the locomotor activity circadian rhythm. The present study indicates that the circadian rhythms of heart rate and locomotor activity are modified after continuous infusion of ropivacaine, which is of particular interest, given the potential cardiotoxicity of this local anesthetic agent.

Introduction Le T61 ® est un euthanasiant injectable reserve a l’usage veterinaire et parfois detourne a des fins suicidaires. Il est compose de 3 principes actifs : l’embutramide (anesthesique general, narcotique et depresseur respiratoire), le mebezonium (curarisant) et la tetracaine (anesthesique local). Le tableau clinique d’une intoxication par le T61 ® se deroule en general en deux phases : une phase initiale se traduisant pas un coma brutal et une depression respiratoire (fatale en l’absence de prise en charge rapide) puis une phase secondaire caracterisee par une cytolyse hepatique. Cette hepatotoxicite retardee est causee par le dimethylformamide (DMF), solvant de la preparation. La ketamine est un medicament a usage humain et veterinaire. Il est utilise pour ses proprietes anesthesiques, analgesiques et psychotropes. Observation Une femme de 48 ans, assistante veterinaire, est retrouvee inconsciente a son domicile apres une double injection de T61 ® et de ketamine, avec ingestion de boissons alcoolisees. A l’arrivee des secours, la patiente est dans le coma (score de Glasgow a 8), cyanosee et en detresse respiratoire (SpO 2 = 70 % en air ambiant), elle est rapidement intubee/ventilee et transferee en service de reanimation. L’evolution neurologique est favorable mais a j2, elle presente une cytolyse hepatique retardee, classique avec le T61 ® , et ce malgre l’administration precoce (des j1) de N-acetylcysteine. Resultats L’hepatotoxicite s’est aggravee progressivement durant l’hospitalisation avec un pic a j4 (ALAT/ASAT = 60 N/90 N) puis a regresse spontanement de facon surprenante des j5. Devant l’evolution favorable exceptionnelle du bilan hepatique, la patiente est autorisee a rentrer a domicile a j6. Discussion, conclusion Lors d’une intoxication volontaire au T61 ® , l’issue est souvent fatale soit en phase aigue par neurotoxicite, soit dans les jours qui suivent par hepatotoxicite. La survie du patient reste exceptionnelle. Dans notre cas, la chronologie du tableau clinique est assez classique : depression du systeme nerveux central puis hepatite cytolytique. Cependant, la guerison spontanee et rapide de la cytolyse hepatique tout a fait inhabituelle a pousse les reanimateurs a emettre une autre hypothese : l’injection de ketamine et de quantites ± minimes de T61 ® pourrait etre a l’origine de l’atteinte aigue neurologique suivie d’un foie de choc avec recuperation rapide de la cytolyse (et sans role du DMF).

Introduction The French National Agency for Medicines and Health Products Safety (ANSM) has requested the Committee for Coordination of Toxicovigilance to analyze all dextromethorphan (DXM)-containing formulations cases reported to the French Toxicovigilance and Poison Control Centers (CAPTV). The main objective of this retrospective study was to complete the evaluation of the potential for abuse and dependence of DXM. DXM is indicated as antitussive therapy, mediated by agonist activity at the sigma receptors, however, mainly at larger doses, DXM may cause euphoria, hallucinations and a dissociative state. These effects are mostly due to its primary metabolite, dextrorphan, which is a potent N-methyl-D-aspartate (NDMA) receptor antagonist. This last pharmacological action may contribute to a recreational abuse of DXM-containing formulations [1] , [2] . Material and methods We conducted a retrospective review analyzing all cases involving DXM-containing formulations reported to the CAPTV from January, 1999, through December, 2014. The severity of poisonings was graded using Poisoning Severity Score. We mainly focused our study on cases related to the intentional use of DXM, including addictive behaviors, misuse, and suicide attempts. Results Over the study period, 1474 DXM-containing formulations exposures were recorded. Among them, 478 were associated with symptoms and 14 serious cases were identified. One case of death related to the intentional use of DXM in combination with other psychoactive substances was also reported. The number of exposures as well as symptomatic cases gradually increased over the study period, especially from 2007. But if we take into account variables (i.e. circumstances of exposure, total number of cases reported to the CAPTV and total sales of DXM), a continuous increase was only observed for addictive cases. An increase in suicide attempts involving DXM was also highlighted until 2012, but then followed a downward trend. Among the 478 symptomatic cases, 196 (41.0%) were an intentional use of DXM-containing formulations: 67 addictive behaviors, 63 misuses and 66 suicide attempts; 135 of the 196 cases of intentional exposure involved only DXM use (and no other drugs). Among these 135 cases, addictive behaviors (n = 51) were over represented in men (64.7%) and younger subjects as compared with misuses (n = 56) or suicide attempts (n = 28) (median age 16 versus 38 and 18-year-old, respectively). Solid dose forms of DXM-containing formulations were the most used in the addictive behaviors (n = 38 among the 54 cases with DXM only). In addition, doses of DXM were of the same order of magnitude for suicidal attempt and addictive behavior cases (mean and median respectively 500 and 375 mg versus 450 and 360 mg), while they were lower for cases of misuse (mean and median 200 and 180 mg). Conclusion This retrospective study of cases highlighted the increasing recreational use of DXM for hallucinogenic effects confirming addictovigilance network data. Further assessments of exposures are necessary to evaluate the impact of preventive measures set up at the end of 2014.

Objectif Rapporter un cas d’intoxication aigue avec une dose potentiellement letale d’isoniazide suite a une erreur therapeutique chez un nourrisson de 21 mois. Description Un enfant de 21 mois, pesant 13 kg, aux antecedents d’asthme avec bronchiolites a repetition, dont le pere est atteint de tuberculose pulmonaire, se voit prescrire un traitement prophylactique par isoniazide (Rimifon ® comprimes) 100 mg 1 fois par jour et rifampicine (Rifadine ® suspension buvable). L’enfant, souffrant depuis 2 j d’une toux associee a une asthenie, recoit en une seule fois 30 cps de Rimifon ® 50 mg, soit 115 mg/kg (cps ecrases puis dilues dans l’eau), sa mere n’ayant pas compris la posologie. Trente minutes plus tard, l’enfant presente des tremblements et une hypotonie. A son arrivee aux urgences pediatriques a H1, il est en etat de mal epileptique, avec un coma Glasgow 4 et une acidose respiratoire (pH = 6,8, pCO 2 = 129 mmHg, pO 2 = 71 mmHg, HCO 3 = 22 mmol/L, lactates = 4,9 mmol/L). Il est intube (H2), transfere en service de reanimation, ou il est traite par anticonvulsivants (diazepam, clonazepam, midazolam) et vitamine B6 (pyridoxine) sur les conseils du centre antipoison de Marseille. La concentration d’isoniazide a H4 est a 76,1 μg/mL (HPLC-UV). Le lendemain, a J1, les convulsions ont cesse, l’EEG ne retrouve pas d’anomalie, les bilans biologiques hepatiques et renaux sont normaux, il n’y a pas de rhabdomyolyse, l’enfant est extube sans complication, puis transfere en neuropediatrie ou l’evolution clinique est favorable. A J3, la concentration d’isoniazide est inferieure a 0,3 μg/mL, le bilan hepatique objective une cytolyse moderee (ASAT/ALAT = 161/39 UI/L) et l’enfant rentre a domicile. Une consultation de controle effectuee a J5 retrouve un test tuberculinique negatif et une cytolyse en voie de regression (ASAT/ALAT = 52/66 UI/L). Compte tenu du risque toujours important de contage via le pere de l’enfant, il est decide de reintroduire le traitement prophylactique avec isoniazide forme buvable, qui est sous ATU, toujours associe a la rifampicine. La mere est sensibilisee aux modalites d’administration des medicaments. Discussion L’intoxication aigue a l’isoniazide se caracterise par une triade de symptomes : convulsions par carence en pyridoxine cerebrale, resistantes aux traitements conventionnels, acidose metabolique secondaire aux convulsions et coma. Notre patient a bien developpe la triade pathognomonique mais avec une acidose plutot respiratoire probablement du fait de ses antecedents pulmonaires. Une intoxication severe est caracterisee par une concentration superieure a 3,2 μg/mL a H2 ou superieure a 0,2 μg/mL a H6 [1] . Une dose d’isoniazide superieure a 80 mg/kg peut etre fatale [2] . Le traitement est symptomatique associe a l’antidote, la vitamine B6 administree a dose equivalente a la dose d’isoniazide supposee ingeree. Conclusion Bien que l’incidence de la tuberculose soit faible en France, sa prise en charge est toujours d’actualite. Comme l’illustre notre cas, le risque d’erreur therapeutique est important car cette maladie touche essentiellement les populations en situation de precarite telles que les migrants qui ne maitrisent pas toujours completement la langue francaise.

Introduction Les surdosages en paracetamol representent l’une des plus frequentes intoxications medicamenteuses, avec une toxicite hepatique bien connue. Toutefois, la toxicite renale de cet antalgique reste mysterieuse et bien moins etudiee. Au centre antipoison (CAP) de Marseille, bien que les notifications de surdosage en paracetamol soient quotidiennes, les cas documentes d’insuffisance renale aigue (IRA) semblent pourtant rares dans ce contexte. Nous decrivons une serie de 9 cas notifies au CAP de Marseille. Methode Etude retrospective analysant les cas d’insuffisance renale aigue secondaires aux surdosages en paracetamol notifies au CAP de Marseille entre le 01/01/2010 et le 30/06/2016. Resultats Neuf observations (6 tentatives de suicides, 3 erreurs lors d’automedication) ont ete analysees. Elles concernaient 6 femmes et 3 hommes, âges de 13 a 70 ans. Les modes d’intoxication etaient de type « aigus et massifs » dans 7 cas, subaigus (posologies supra-therapeutiques sur 2 a 5 jours) dans les 2 autres cas. Une insuffisance hepatique grave (TP [1] ) dont 4 ont necessite une epuration extra-renale ; 2 patients ont ete evalues grade II et 2 patients grade I. L’oligurie ou l’anurie etait notee le plus souvent a j3 et resolutive dans les 14 jours. Une ponction biopsie renale etait realisee dans 2 cas et montrait des lesions de necrose tubulaire aigue. Aucune sequelle renale ou hepatique ne fut rapportee. Conclusion La toxicite renale du paracetamol est un phenomene qui semble rare. Elle n’est le plus souvent constatee qu’a l’occasion de la recherche etiologique d’une anurie ou d’une oligurie. Cependant, en pratique quotidienne la fonction renale n’est que rarement controlee au decours des intoxications au paracetamol et il est probable que l’incidence de ce type d’IRA toxique soit sous-estimee. Peu d’etudes analytiques sont disponibles sur le sujet ; une etude recente [2] sur 120 patients met en evidence un lien significatif entre severite de l’atteinte hepatique et survenue d’une IRA. Ceci implique que la prevention de l’hepatite toxique par N-acetylcysteine previendrait egalement la survenue d’une IRA, mais aussi que les prises en charges tardives sont a risque de complications renales. Les premieres lignes soignantes doivent etre sensibilisees au potentiel nephrotoxique du paracetamol, notamment lorsque la prise en charge medicale est differee.

Objectif Rapporter deux cas d’intoxication par palytoxines, dont un collectif, survenus lors de la manipulation de coraux mous ornementaux issus d’aquariums. Description Cas no 1 : Monsieur D, 45 ans, sans antecedent medical, decide de nettoyer son aquarium domestique. Il sort les coraux mous (Palythoa heliodiscus) sans protection, les brosse puis les trempe dans un sceau d’eau tiede quelques minutes. Il replace ensuite les coraux et se rend compte de la presence d’une coupure sur sa main de 2 cm. Trois heures plus tard, sa femme, âgee de 45 ans, aux antecedents d’asthme, et qui n’a pas participe au nettoyage, souffre soudain de dyspnee. Elle inhale une dose de salbutamol (Ventoline®) qui la soulage. Une heure apres, le mari ressent egalement des difficultes a respirer qui s’ameliorent apres inhalation du salbutamol de sa femme. Dans l’heure qui suit, ils souffrent de tremblements, de crampes musculaires et de vertiges, puis de troubles digestifs a type de nausees et vomissements. Environ 12 heures apres le debut des signes, les symptomes ont regresse mais une asthenie intense se developpe chez les 2 patients, empechant meme le mari de se lever. A la 48e heure, une conjonctivite apparait chez le mari, accompagnee de troubles visuels. Sa femme se plaint egalement de vision floue. A J4, les patients sont encore un peu astheniques, la conjonctivite a regresse. Cas no 2 : un chercheur de 30 ans, aux antecedents de bronchite asthmatiforme, travaillant dans un centre d’oceanographie, se presente aux urgences 8 heures apres s’etre coupe en manipulant des coraux mous (sans plus de precision) sur son lieu de travail. Il rapporte avoir presente d’abord une irritation nasale, puis des rhinorrhees avec une dyspnee, des nausees et des vertiges. L’examen clinique effectue aux urgences retrouve une epigastralgie et une tachycardie sinusale a 115 bpm. La sensation de gene respiratoire a l’inspiration profonde du patient s’ameliore apres administration d’aerosols de salbutamol. A la 21e heure, les symptomes ont regresse, le patient rentre a domicile. Discussion La palytoxine est une toxine marine puissante decouverte en 1961 a Hawai. A l’origine identifiee dans divers coraux mous du genre Palythoa et Zoanthus, la palytoxine et ses analogues (en anglais palytoxin-like) ont ensuite ete retrouves dans des dinoflagelles du genre Ostreopsis mais aussi dans certaines cyanobacteries. Leur presence a egalement ete retrouvee dans des poissons et crustaces comestibles. Ces dernieres annees, de plus en plus d’intoxications ont lieu chez les aquariophiles. En effet, ces derniers s’intoxiquent lors du brossage et du rincage a l’eau bouillante de leurs coraux mous effectues sans protection. Lors de ces manipulations, les toxines sont inhalees via les micro-gouttelettes ou les vapeurs degagees. Elles peuvent meme penetrer par voie cutanee. La symptomatologie varie en fonction de la voie d’intoxication. Peuvent survenir des signes respiratoires (rhinite, toux, dyspnee) associes a des troubles neuromusculaires (vertiges, myalgies, crampes, faiblesse musculaire, paresthesies…) et des troubles digestifs (nausee, vomissement diarrhee). L’intoxication peut etre severe par ingestion d’aliments contamines avec survenue de troubles cardiovasculaires, de convulsions, de detresse respiratoire, voire de deces. Dans tous les cas, le traitement est symptomatique [1] . Conclusion Il semble que les coraux mous du genre Palythoa et Zoanthus soient frequemment vendus aux particuliers pour leurs qualites ornementales sans aucune precaution ou information concernant leur potentiel toxique, alors que certains specimens peuvent contenir de grandes quantites de toxines comme l’illustrent nos cas.

Thiopental is a thiobarbiturate given in the case of brain injuries to reduce intracranial pressure and to manage cerebral ischemia. A pharmacokinetic model has been described previously in critically ill patients with a different therapeutic strategy. New treatment options prompted us to investigate if drug–drug interactions occur. A new model is proposed describing the influence of concomitant administration of esomeprazole on the distribution of thiopental. The study population comprised 52 critically ill patients (body weight 47.1–114 kg) aged 18–78 years who had been admitted into the critical care unit for treatment of intracranial hypertension. A total mean dose of 282.8 ± 172.7 mg/kg was given in 96 ± 72 h. Pharmacokinetic analysis was performed by using a nonlinear mixed-effect population model. A one-compartment open model with first-order elimination identified two covariates, namely, body weight on clearance and volume of distribution, and the administration of esomeprazole on volume of distribution. The mean values (% relative standard error) for total clearance (CL) and for central volume of distribution (Vd) in patients with and without concomitant esomeprazole were 5.3 L/h (9.2 %) and 256.1 (6.4 %) and 153.2 l (19.2 %), respectively. Based on these results, we conclude that concomitant administration of esomeprazole increases the volume of distribution and the half-live of thiopental. This drug–drug interaction should be considered when a target concentration has to be reached.

Teicoplanin is a glycopeptid antibiotic used for treatment of serious infections caused by Gram+ bacteriae. The treatment scheme corresponds to an initial loading dose followed by maintenance dose. High interindividual pharmacokinetic variability and strong relation between high through concentrations, dose and clinical success, support the need of therapeutic drug monitoring using through concentrations. Achieving through concentrations ≥ 10-15 mg/L or ≥ 20-40 mg/L, regarding the measurement method and the infection severity, is recommended to increase clinical success rate. The level of proof of therapeutic drug monitoring is evaluated: "necessary".

Teicoplanin is a glycopeptid antibiotic used for treatment of serious infections caused by Gram+ bacteriae. The treatment scheme corresponds to an initial loading dose followed by maintenance dose. High interindividual pharmacokinetic variability and strong relation between high through concentrations, dose and clinical success, support the need of therapeutic drug monitoring using through concentrations. Achieving through concentrations ≥10-15 mg/L or ≥20-40 mg/L, regarding the measurement method and the infection severity, is recommended to increase clinical success rate. The level of proof of therapeutic drug monitoring is evaluated: "necessary".

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 microl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA--loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

Aminoglycosides are major antibiotics indicated for the treatment of infection with gram-negative bacilli. They are characterized by high clinical effectiveness but their main drawback is the occurrence of toxicity in a significant number of patients. Pharmacokinetic parameters of aminoglycosides exhibit wide inter-individual variability and the relationships between concentration and effect have been clearly demonstrated. Consistent studies have demonstrated that therapeutic drug monitoring (TDM) of aminoglycosides administered in multiple daily doses was cost-effective in maximising antibiotic efficacy and/or reducing incidence of toxicity. Therefore TDM of aminoglycosides should be considered "essential". Level of evidence for TDM of aminoglycosides administered once daily is not so clearly demonstrated however it should be highly recommended.

Ropivacaine is a local anaesthetic used for epidural anaesthesia and postoperative pain relief. Hyperthermia is a very common sign of infection associated with variations in physiological parameters, which may influence drugs pharmacokinetics. The aim of this study was to determine the effects of induced hyperthermia on ropivacaine pharmacokinetics in rats. Two groups of six rats were given a single subcutaneous ropivacaine injection. Hyperthermia-induced animals were placed in a water bath to obtain a stable mean core temperature of 39.7 degrees C. After blood samples collection, ropivacaine serum concentrations and pharmacokinetic parameters were determined. Two other groups of six rats were sacrificed 30 min after ropivacaine injection to determine serum and tissues (brain and heart) concentrations. Our results (median +/- inter quartile range) reveal a significant increase of the total apparent clearance (0.0151 +/- 0.000800 L/min vs. 0.0134 +/- 0.00134 L/min), apparent volume of distribution (V(d)) (2.19 +/- 0.27 L vs. 1.57 +/- 0.73 L) and a significant decrease in exposure (488 +/- 50.6 mgxmin/L vs. 572 +/- 110 mgxmin/L) in induced-hyperthermia group. We observed a significant increase in brain ropivacaine concentration in hyperthermic rats (8.39 +/- 8.42 microg/g vs. 3.48 +/- 3.26 microg/g) and no significant difference between cardiac concentrations in the two groups (5.38 +/- 4.83 microg/g vs. 3.73 +/- 2.44 microg/g). Results suggest a higher tissular distribution of ropivacaine and an increase in blood-brain barrier permeability during hyperthermia. The hyperthermia-induced increase in V(d) could be responsible for an increase in cerebral ropivacaine toxicity. These experimental data provide a basis for future clinical investigations in relation to local anaesthetic use in hyperthermic patients.

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C(max), T(max), elimination half-life (t(1/2)), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C(max) (49%), T(max) (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.

Introduction L’hypervitaminose A aigue, se traduit par un tableau clinique compose notamment de cephalees, de nausees, de vomissements, de myalgies, d’une erythrose voire d’une hypertension intracrânienne. Dans les jours qui suivent, apparait une desquamation cutaneo-muqueuse qui peut persister plusieurs semaines. Differentes causes de surdosage aigu existent, dont l’ingestion d’une quantite importante de foie de poisson comme l’illustre notre cas clinique. Observation Un homme de 62 ans, aux antecedents d’hypercholesterolemie traitee par atorvastatine peche un thon d’environ 75 kg dans les Bouches du Rhone puis partage avec 2 convives, au dejeuner, le foie de ce thon qui pese environ 1 kg, poele en persillade. Deux heures apres le repas, les 3 convives developpent nausees, hepatalgie, erytheme facial et cephalees intenses. Le patient se presente aux urgences le lendemain matin devant la persistance des signes. Un scombrotoxisme est d’abord evoque mais le CAP-TV de Marseille, interroge dans les heures suivantes, evoque le diagnostic d’une hypervitaminose A par ingestion d’une grande quantite de foie. Le patient recoit un traitement symptomatique. A J2 les cephalees et nausees regressent mais l’erytheme persiste et la peau du patient commence a peler. Les 2 autres convives ayant partage le foie desquament egalement alors que les convives n’ayant mange que la chair du thon sont restes asymptomatiques. Au total, la peau du patient a pele progressivement du cuir chevelu (j3) aux membres inferieurs (a j19) en passant par les epaules et les membres superieurs. Discussion L’ingestion d’une grande quantite de foie de gros poissons carnivores tels que les requins, thons, ou bars peut induire un vrai tableau d’hypervitaminose A. Ce mode d’intoxication est tres rare en Europe. Il ne faut pas le confondre avec le scombrotoxisme qui est du a une veritable intoxication a l’histamine suite a l’ingestion de chair de poisson bleu mal conservee. Un cas d’hypervitaminose A dans un contexte similaire a ete relate par le CAP-TV de Marseille en 2010, il s’agissait de l’ingestion d’un foie de seriole pechee en Mediterranee. Le traitement est principalement symptomatique avec antalgique, hydratation et surveillance medicale car une hypertension intracrânienne peut se developper. Conclusion L’hypervitaminose A par ingestion de foie de poisson bleu etant tres rare, il est important que les cliniciens identifient precisement les circonstances de toute intoxication par poisson afin de traiter les patients de facon appropriee.

Introduction L’intoxication au paracetamol est parmi les intoxications medicamenteuses volontaires (IMV) l’une des plus frequemment rencontree. Le nombre d’appels pour ce motif aux centres antipoison ne cesse de croitre au cours des dernieres annees. Si le risque de toxicite hepatique est connu de tous les praticiens, celui de la toxicite renale l’est beaucoup moins. Nous rapportons ici le cas d’une adolescente de 16 ans hospitalisee pour la prise en charge d’une IMV au paracetamol compliquee d’une insuffisance hepatocellulaire aigue et d’une insuffisance renale aigue. Observation Une adolescente de 16 ans consulte le service des urgences pour un tableau de vomissements et d’intolerance alimentaire, avec notion d’oligurie. Ce tableau evolue depuis 3 jours, suite a une IMV au paracetamol (16 g, prise etalee sur plusieurs heures). Le bilan initial a j3 met en evidence une insuffisance hepatocellulaire (ASAT = 2835 UI/mL ; ALAT = 5076 UI/mL ; TP = 45 %) associee a une insuffisance renale aigue (creatinemie = 531 μmol/L). La paracetamolemie est a 6,45 mg/L. Un traitement empirique par N-Acetylcysteine est instaure. Parallelement a une amelioration rapide de la fonction hepatique, s’installait une insuffisance renale anurique necessitant plusieurs seances d’hemodialyse iteratives (l’hemodialyse n’a pas d’interet dans l’elimination du paracetamol). Devant une proteinurie a 15 g/L avec des ionogrammes urinaires en faveur d’une insuffisance renale aigue organique, une ponction biopsie renale au 6 e jour de l’intoxication est effectuee : aucun argument pour une glomerulopathie mais multiples signes de souffrance tubulaire aigue L’evolution est ensuite favorable avec une reprise progressive de la diurese, ainsi qu’une normalisation de la fonction hepatique. A 5 semaines de l’IMV, la patiente ne garde aucune sequelle apparente, la fonction renale est normale (creatinemie a 64 μmol/L, proteinurie negative) ainsi que la fonction hepatique. Discussion L’atteinte renale, lors de l’intoxication aigue au paracetamol, est rarement constatee, mais egalement peu recherchee. Les lesions histologiques constatees sont de type necrose tubulaire aigue. Si la physiopathologie hepatique est bien connue, celle renale l’est beaucoup moins ; il semblerait pourtant qu’ils aient une mecanique commune, a savoir une production de metabolites toxiques, conduisant a une mort cellulaire apoptotique par liaisons cellulaires covalentes directes. Les dernieres hypotheses, la plupart basees sur des modeles murins, impliquent le cytochrome P450, mais aussi la prostaglandine endoperoxydase synthetase, enzyme responsable egalement d’une production de metabolites toxiques (essentiellement le NAPQI) a partir de paracetamol. Le processus exact reste pourtant inconnu, comme le suggerent certains cas de toxicite renale sans toxicite hepatique associee. Conclusion Bien que peu connu et de mecanisme encore mal compris, le potentiel nephrotoxique du paracetamol est pourtant bien reel et peut amener dans les cas extremes a l’emploi de l’hemodialyse ; a l’heure actuelle, aucun traitement preventif n’a fait ses preuves.

Introduction La rilmenidine est un antihypertenseur commercialise depuis 1988. Elle agit essentiellement sur les recepteurs I1-imidazolines mais aussi sur les α2 centraux. Observation Nous decrivons le cas d’une fillette de 3 ans, 15 kg, ayant probablement ingere 2 comprimes de rilmenidine soit 2 mg. Une heure apres l’ingestion, dans le service d’accueil des urgences, l’examen neurologique relevait une agitation, une somnolence et un myosis serre peu reactif. Par ailleurs, l’enfant etait bradycarde et bradypneique (FR = 8–10 cycles/min) avec des pauses respiratoires. La perfusion intraveineuse de naloxone proposee par le medecin du CAP sollicite etait partiellement efficace. La guerison complete etait observee en 24 heures. Entre 2002 et 2014, 99 cas relatifs a la rilmenidine ont ete enregistres au CAPTV de Marseille dont 28 concernaient des enfants en moyenne âges de 1,7 an (1,3–7) et pesant 14 kg (10–22). Dans 26 % des cas pediatriques, la rilmenidine avait ete ingeree a la dose moyenne de 1,25 mg (0,25–6) et dans 65 % des cas aucun signe d’intoxication n’etait rapporte. Parmi les 9 patients symptomatiques, 5 presentaient, dans les 30 a 60 min suivant l’ingestion, une somnolence dont 3 une bradycardie et 2 une hypotension arterielle. Enfin, chez 2 patients, une symptomatologie « opiacee » associant bradypnee et myosis etait observee. Discussion Ce recensement illustre la diversite des manifestations cliniques lors d’une intoxication impliquant la rilmenidine. Le syndrome opiace, lorsqu’il est present, pourrait justifier l’utilisation de naloxone. Ces essais therapeutiques seraient motives par le lien entre les recepteurs α2 centraux et opiaces. Ainsi, plusieurs etudes, chez l’animal, ont montre, que les effets cardiovasculaires de la clonidine impliquaient la stimulation des recepteurs opiaces. En effet, par son effet α2-agoniste, la clonidine provoque la liberation de β-endorphine, agoniste opiace endogene. Neanmoins, l’efficacite de la naloxone, dans les intoxications a la clonidine, est inconstante. Conclusion Hormis le cadre du diagnostic differentiel de l’intoxication vraie aux opiaces, l’interet de la naloxone dans le traitement des intoxications a la rilmenidine ou a la clonidine n’est pas scientifiquement etabli.

Introduction De nombreuses especes de chenilles peuvent induire des tableaux cliniques locoregionaux des le moindre contact. C’est ainsi le cas des especes du genre Megalopyge, notamment l’espece M. opercularis , bien connue aux Etats-Unis. En Guyane francaise, quelques rares cas d’envenimations induites par des chenilles d’especes du meme genre ont deja ete rapportes. Les auteurs decrivent ici trois nouvelles observations apres contact cutane avec des chenilles du genre Megalopyge et probablement de l’espece M. albicollis . Observations Entre juin 2011 et mai 2014, trois patientes adultes dans la commune de Mana ont eu un contact cutane accidentel avec une chenille du genre Megalopyge. Immediatement elles ont presente des douleurs intenses necessitant une consultation medicale en urgence. L’examen clinique etait sans particularite hormis un œdeme generalise chez une patiente. Le traitement instaure a comporte antalgiques, corticoides, antihistaminiques, et deux patientes ont necessite une injection d’anesthesique local. L’evolution a ete favorable pour toutes en quelques heures sans aucune sequelle. Discussion Malgre le nombre eleve d’especes du genre Megalopyge, on ne retrouve dans la litterature medicale que des references rapportant des envenimations induites par l’espece M. opercularis . Le tableau clinique classique d’un tel accident comprend une atteinte cutanee peu douloureuse avec lesions erythemateuses bien visibles, pouvant s’associer a des manifestations systemiques (cephalee, tachycardie…). Les 3 cas guyanais rapportes ici concernent egalement une chenille du genre Megalopyge mais d’une espece autre qu’ opercularis (l’espece en cause serait M. albicollis ). Le tableau clinique presente par nos 3 patientes a ete atypique, avec une douleur plus intense qu’habituellement sans aucune lesion cutanee visible. Deux tableaux cliniques distincts semblent donc se retrouver apres un contact avec une chenille du genre Megalopyge en Amerique du sud.

Pharmacokinetic studies can be performed before or after a drug is marketed. Indeed, extensive use of a new drug can uncover situations that it has not been possible to investigate before market application. Hospital departments of pharmacology are often involved in these complementary studies. They can design the study, initiate it in a clinical investigation centre, measure plasma concentrations, analyse the pharmacokinetic data, and write the report. If the extent of the scientific involvement of public pharmacology laboratories is strictly demarcated, financial support for nonsponsored studies by the pharmaceutical industry is problematical. Indeed, it is difficult to obtain funds to study the concentration-toxicity relationship or a drug-drug interaction for a compound for which the patent has expired. In addition, such studies have an excess cost, mainly because of the expense associated with drug measurements. Also, the medical time devoted to research is not rewarded by institutions. This situation will become more complicated because of the restrictive legislative framework imposed by the European directive.

Mitochondrial experiments are of increasing interest in different fields of research. Inhibition of mitochondrian activities seems to play a role in Parkinson's disease and in this regard several animal models have used inhibitors of mitochondrial respiration such as rotenone or MPTP. Most of these experiments were done during the daytime. However, there is no reason for mitochondrial respiration to be constant during the 24 h. This study investigated the circadian variation of oxidative phosphorylation in isolated rat brain mitochondria and the administration-time-dependent effect of rotenone and melatonin. The respiratory control ratio, state 3 and state 4, displayed a circadian fluctuation. The highest respiratory control ratio value (3.01) occurred at 04:00 h, and the lowest value (2.63) at 08:00 h. The highest value of state 3 and state 4 oxidative respiration occurred at 12:00 h and the lowest one at 20:00 h. The 24 h mean decrease in the respiratory control ratio following incubation with melatonin and rotenone was 7 and 32%, respectively; however, the exact amount of the inhibition exerted by these agents varied according to the time of the mitochondria isolation. Our results show the time of mitochondrial isolation could lead to interindividual variability. When studies require mitochondrial isolation from several animals, the time between animal experiments has to be minimized. In oxidative phosphorylation studies, the time of mitochondria isolation must be taken into account, or at least specified in the methods section.

We report a chemical interaction between imipenem–cilastatin and amoxicillin that occurred during treatment of a patient in a critical care unit. The patient received imipenem– cilastatin 1 g each diluted in 100 mL of 0.9% sodium chloride injection through a B. Braun Metriset infusion set. After