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Introduction L’administration des traitements chez des patients dysphagiques necessite souvent une denaturation de la forme galenique par broyage des comprimes ou ouverture des gelules. Ceci peut pourtant induire une inefficacite therapeutique. Objectifs Nous avons propose une approche pluridisciplinaire pour evaluer les difficultes de prises orales des traitements et adapter les formes administrees en creant pour chaque patient un plan pharmaceutique personnalise. Patients et methodes Pendant 6 mois, chaque patient hospitalise en neurologie a beneficie d’une evaluation de la prise orale des traitements par une IDE. L’orthophoniste precisait le type de dysphagie et, si besoin, la dieteticienne intervenait. Une proposition d’adaptation des galeniques etaient formulee par le pharmacien en fonction du risque d’inefficacite ou de toxicite. Au final, un plan pharmaceutique personnalise etait preconise. En cas de gastrostomie, une education des aidants a l’administration correcte etait realisee. Resultats Cent patients consecutifs ont beneficie du dispositif (34 % maladie de Parkinson, 15 % SLA et 3 % AMS). Le nombre moyen de traitements per os etait de 7,34 (± 2,73). Pour 64 % des traitements, une adaptation des formes a administrer a pu etre proposee : 46 % denaturation de la forme, 54 % de switch (24 % orodispersible, 19 % suspension buvable, 7 % pour une autre molecule et 4 % pour une autre formulation de la meme molecule). Discussion L’adaptation des formes a administrer est indispensable en cas d’administration du traitement dans une sonde naso-gastrique ou une gastrostomie. La revision medicamenteuse permet egalement d’arreter certains traitements (6 % dans notre etude). Enfin, aucune donnee n’etait disponible sur la possibilite d’alterer la forme a administrer pour 7 % des traitements (bisoprolol ou mianserine par exemple). Conclusion L’adaptation des formes a administrer est essentielle dans la prise en charge des patients dysphagiques. L’intervention de differents acteurs permet de personnaliser, de securiser et faciliter l’administration des therapeutiques.

A micellar electrokinetic chromatography (MEKC) method was developed for the determination of three anti-vomiting drugs (aprepitant, dexamethasone and ondansetron) in pharmaceutical formulations. The method was optimized using a central composite design (CCD). Four main factors (borate buffer concentration, pH, methanol content and sodium dodecyl sulfate concentration) were optimized in order to obtain best resolutions and peak efficiencies in a minimum runtime. The separation was performed in a fused-silica capillary. After optimization, the background electrolyte consisted of a borate buffer (62.5mM, pH 8.75) containing sodium dodecyl sulfate (77.5mM) and methanol (3.75%). Under these conditions, a complete separation of each antiemetic drug and its respective internal standards was achieved in 38min. The method was validated with trueness values from 94.9 to 107.2% and precision results (repeatability and intermediate precision) lower than 5.9%. MEKC-UV was the first method allowing the separation of aprepitant, dexamethasone and ondansetron and was suitable for the quantitation of these three antiemetic drugs in organogel formulations. The rapid sample preparation coupled with an automated separation technique make this method convenient for quality control of extemporaneous magistral ready-to-use formulation.

Introduction La prise en charge du melanome avance ou metastatique a beaucoup evolue ces dernieres annees avec notamment la mise sur le marche des therapies ciblees orales (TCO). Avec ces medicaments, de nouvelles problematiques apparaissent dans la prise en charge des patients dont la gestion des effets indesirables au domicile, l’adherence au traitement et le risque d’interactions medicamenteuses avec les autres traitements du patient pouvant diminuer l’efficacite ou augmenter la toxicite. Afin de securiser la prise en charge des patients, une consultation pharmaceutique a ete mise en place. Le but de ce travail est de presenter les premiers resultats du suivi pharmaceutique realise. Materiel et methodes Six patients chez lesquels une TCO a ete initiee etaient inclus depuis janvier 2017 dans une etude prospective de faisabilite. La consultation pharmaceutique avait lieu le jour de l’initiation de la TCO apres la consultation medicale afin d’informer le patient sur la TCO et de realiser une conciliation medicamenteuse pour etablir la liste exhaustive des traitements pris a domicile. Puis, une analyse des interactions medicamenteuses entre la TCO et les autres traitements etait realisee. Une consultation pharmaceutique de suivi a 1 mois etait realisee. Le nombre d’interactions medicamenteuses, d’interventions pharmaceutiques (IP) et l’adherence au traitement a l’aide du score de Morisky etaient evalues. Resultats Les 6 patientes sont des femmes et la moyenne d’âge est de 56,8 ans (min : 42 ; max : 77). Les TCO concernees sont l’association dabrafenib + trametinib dans 3 cas et vemurafenib + cobimetinib dans 3 cas. Seules 2 patientes etaient revues a 1 mois, le traitement ayant ete arrete pour iatrogenie pour 4 patientes. Au total, 11 interactions medicamenteuses etaient retrouvees lors de la consultation initiale (moy : 1,8 ; min : 0 ; max : 3) et 5 interactions medicamenteuses lors de la consultation a 1 mois. Les medicaments impliques etaient les antiacides dont l’esomeprazole dans 6 cas, les corticoides dans 3 cas, les antiemetiques dans 2 cas, les anxiolytiques et hypnotiques dans 3 cas et les neuroleptiques dans 1 cas. Une interaction avec l’alimentation enterale etaient relevee. Les IP ont conduit a un arret du traitement associe a la TCO dans 2 cas, une modification de posologie dans 2 cas, un suivi clinique dans 2 cas, une optimisation des modalites d’administration dans 1 cas et une reevaluation de la prescription dans les autres cas. L’adherence au traitement a 1 mois etait cotee a 7/8 (adherence moyenne) et 8/8 (bonne adherence). Discussion Ces premiers resultats montrent un reel risque d’interactions medicamenteuses et de iatrogenie avec les TCO. L’adherence semble globalement bonne mais ces chiffres doivent etre confirmes sur un echantillon plus grand. Conclusion Une prise en charge pluridisciplinaire avec un temps dedie pour un pharmacien est necessaire pour optimiser la prise en charge des patients.

Objectives Noradrenaline (NA) can be infused through various systems including single or double syringe pumps. The aim of this study was to define the best and most efficient infusion system in an emergency context. Study design This was a retrospective clinical study based on the analysis of patients’ hemodynamic data. Patients and method Three infusion lines used presently in our postoperative ICU were compared through a retrospective clinical study: an NA syringe pump at 2 mL/h and a saline carrier solution syringe pump at 8 mL/h (infusion system 1- IS1) or 5 mL/h (IS2), both connected to a very low dead-space volume set (V = 0.046 mL); IS3 with the same NA syringe at 2 mL/h directly connected to the central venous catheter. Mean arterial pressure (MAP) was obtained from retrospective data analysis of ICU patients with postoperative septic shock criteria. Infusion systems were compared according to the time required to reach an MAP greater than 65 mmHg after the onset of infusion. Results Data from 37 patients was analysed. The MAP objective was attained in 14:00 minutes (9:20 – 26:10, n = 15) with IS1, in 19:10 minutes (12:20 – 27:20, n = 13) with IS2 and in 34:10 minutes (23:10 – 62:30, n = 9) with IS3 ( P = 0.00032). Conclusion The use of a double syringe pump system associated with a very low dead-space volume infusion set appears to be the most appropriate system for NA infusion.

Resume Introduction Depuis un an, notre unite est equipee de detecteurs portatifs en H 2 O 2 Drager contribuant a la protection du personnel vis-a-vis d’une eventuelle exposition a ce gaz inodore et toxique. Ce travail expose les donnees actuelles disponibles sur la toxicite de l’H 2 O 2 , decrit l’organisation de mise en place et l’analyse des valeurs mesurees sur 12 mois. Materiel et methodes Les donnees sur la toxicite de l’H 2 O 2 ont ete obtenues grâce a une revue de la litterature. Les valeurs mesurees sont presentees en valeur instantanee et en valeur moyenne d’exposition sur huit heures. Resultats Le pourcentage moyen, sur six manipulateurs, de valeurs detectees superieures a zero a atteint un maximum de 1,06 % en aout. La valeur maximale instantanee detectee etait de 2,2 ppm en mai. Ces expositions isolees ont peu d’incidence lorsqu’on les rapporte au temps d’exposition de huit heures avec une valeur moyenne d’exposition (VME) sur 12 mois de 0,072 ppm. Discussion et conclusion La mise en place de cet outil a permis de mettre en evidence un probleme technique du sas de sterilisation qui a pu etre resolu. Ce moyen de mesure, en temps reel, de la concentration de l’H 2 O 2 dans l’air permet de securiser les conditions de travail et d’alerter le personnel d’une eventuelle defaillance technique. Cependant, les donnees de la litterature concernant la toxicite chronique sont reduites et limitent l’analyse des valeurs mesurees.

Background Medication non-adherence is a major issue after transplant that can lead to misdiagnosis, rejection, poor health affecting quality of life, graft loss or death. Several estimations of adherence and related factors have previously been described but conclusions leave doubt as to the most accurate assessment method. Aim of the review To identify the factors most relevant to medication non-adherence in kidney transplant in current clinical practice. Method This systematic review is registered in the PROSPERO data base and follows the Prisma checklist. Articles in English in three databases from January 2009 to December 2014 were analysed. A synthesis was made to target adherence assessment methods, their prevalence and significance. Results Thirty-seven studies were analysed rates of non-adherence fluctuating from 1.6 to 96%. Assessment methods varied from one study to another, although self-reports were mainly used. It appears that youth (≤50 years old), male, low social support, unemployment, low education, ≥3 months post graft, living donor, ≥6 comorbidities, ≥5 drugs/d, ≥2 intakes/d, negative beliefs, negative behavior, depression and anxiety were the factors significantly related to non-adherence. Conclusion As there are no established guidelines, consideration should be given to more than one approach to identify medication non-adherence although self-reports should remain the cornerstone of adherence assessment.

Medical devices are generally made of polyvinyl chloride plasticized by six authorized plasticizers as alternatives to di-(2-ethylhexyl)-phthalate (DEHP) classified as reprotoxic class 1b. These are acetyl tri-n-butyl citrate (ATBC), di-(2-ethylhexy) adipate (DEHA), di-(2-ethylhexyl) terephthalate (DEHT), di-isononyl cyclohexane-1,2-dicarboxylate (DINCH), di-isononyl phthalate (DINP), and tri-octyl trimellitate (TOTM). The main objective of this study was to propose a new method using

One of the fundamental principles guiding the pharmaceutical quality of parenteral products is to prevent injecting contaminants from microbiological, chemical or physical sources. It is just as difficult to ensure the absence of chemical and particulate contaminants in injectable products as it is to weigh up the microbiological risk. The problem of particulate matter is mainly related to the preparing and administrating of injectable drugs rather than through the contamination of marketed products. Particulate contamination also arises in situ during the simultaneous intravenous (IV) infusion of incompatible drugs. A complete overview of these problems in the context of IV infusion was carried out to assess their clinical impact. Many studies had already been performed on this theme, but the majority date from the 1970s and 1980s. Clinicians have expressed a renewed interest since the early 2000s, focusing on the impact of particles on patients.

International audience; PURPOSE: Plastic materials such as polyurethane (PUR), polyethylene (PE), polypropylene (PP) and polyvinyl chloride (PVC) are widely used in double-lumen extension tubing. The purposes of our study were to 1) compare in vitro drug delivery through the double extension tubes available on the market 2) assess the plastic properties of PUR in infusion devices and their impact on drug delivery.METHODS: The study compared eight double-lumen extension tubes in PUR, co-extruded (PE/PVC) plastic and plasticised PVC from different manufacturers. Isosorbide dinitrate and diazepam were used as model compounds to evaluate their sorption on the internal surface of the infusion device. Control experiments were performed using norepinephrine known not to absorb to plastics. Drug concentrations delivered at the egress of extension tubes were determined over time by an analytical spectrophotometric UV-Vis method. The main characteristics of plastics were also determined.RESULTS: Significant differences in the sorption phenomenon were observed among the eight double-lumen extension tubes and between pairs of extension tubes. Mean concentrations of isosorbide dinitrate delivered at the egress of double-lumen extension tubes after a 150-minute infusion (mean values ± standard deviation in percentage of the initial concentrations in the prepared syringes) ranged between 80.53 ± 1.66 (one of the PUR tubes) and 92.84 ± 2.73 (PE/PVC tube). The same parameters measured during diazepam infusion ranged between 48.58 ± 2.88 (one of the PUR tubes) and 85.06 ± 3.94 (PE/PVC tube). The double-lumen extension tubes in PUR were either thermosetting (resin) or thermoplastic according to reference.CONCLUSIONS: Clinicians must be aware of potential drug interactions with extension tube materials and so must consider their nature as well as the sterilisation method used before selecting an infusion device.

Objectives Plastic intravenous containers can be categorised as flexible polyvinyl chloride (PVC), flexible non-PVC and semirigid plastic. The characteristics of the container may have an effect on the total volume of fluid delivered, thus impacting the amount of drug a patient receives, but these have been insufficiently studied. This work was an open-label analytical study quantifying the average of the residual volumes for three different types of plastic intravenous containers following infusion under simulated conditions that mimic clinical practice. Methods A total of 280 containers of three different types (seven different brands) were tested. Containers were also separated according to container volume size (50, 100, 250, 500 and 1000 ml). Each container size was tested 10 times under non-vented conditions. Results The flexible PVC containers were consistently found to have the lowest mean residual volume of all and were significantly different from the semirigid containers whatever the container size (p Conclusion The residual volume after gravity drainage differed significantly from one container type to another. High amounts of residual volume in a container may potentially lead to medication errors by which a patient receives suboptimal therapy due to incomplete administration of the drug. This should be taken into consideration when admixing drugs for intravenous infusion.

Resume Objectif Comparaison dans une etude retrospective monocentrique de deux catheters d’hemodialyse : un bi-catheter (Dualcath) et un catheter a branches separees (Hemosplit). Patients et methodes Les patients ayant recu ces catheters entre le 1er janvier 2007 et le 31 decembre 2008, ont ete selectionnes. Dans leurs dossiers de dialyse ont ete releves les evenements thrombotiques et infectieux, survenus durant cette periode. Principaux resultats L’etude a porte sur 50 patients, 30 ont recu un Dualcath, 23 un Hemosplit (trois patients ayant recu les deux catheters). Une analyse de Kaplan-Meier a permis d’etablir les courbes de survie des catheters et le test log-Rank permet d’etablir une survie de 93,1 % a 20 mois pour le Dualcath contre 42,4 % pour l’Hemosplit (p = 0,016). L’incidence des complications thrombotiques de type « incident » sur site est de 25,6 et 46,4 pour 1000 jours-catheters (p Conclusion Le catheter Dualcath presente une survie plus importante que le catheter Hemosplit, accompagnee d’une incidence plus faible de complications thrombotiques de type « incident » sur site.

Stopping and resuming carrier fluid flow can lead to potentially dangerous transient disturbances in drug mass flow rate. We compared the impact of 2 infusion sets, one with very low dead-space volume and the other with greater dead-space volume, on the amount of drug delivered during stop-and-go carrier fluid flows.Two infusion sets, both with antireflux, connected to an angiocatheter and with dead-space volumes of 6.185 mL and 0.071 mL, respectively, were assessed. Two protocols were studied: carrier fluid flow of 90 mL/h associated with noradrenaline infused at 7 mL/h and carrier fluid flow of 350 mL/h with a noradrenaline infusion flow of 65 mL/h. During both protocols, the carrier fluid was stopped and resumed at the same rate 30 minutes later. Effluent noradrenaline concentration was measured using UV spectrophotometry. Flow change efficiency was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve.For both flow rate conditions, flow change efficiency was significantly different for the 2 infusion sets during the 10-minute period after stopping carrier fluid flow and the 10-minute period after restarting it. The major phenomena were sudden decreases in drug delivery after stopping carrier flow and sudden, temporary increases when it was resumed. The very low dead-space volume infusion set resulted in significant reduction in changes in drug delivery compared with the standard set, even at high flow rates.The use of a very low dead-space volume set attenuates disturbances in drug delivery caused by interrupting and resuming carrier fluid flow.

Purpose: Evaluation of containment safety devices designed and introduced to protect preparers and administrators of hazardous drugs, through a multiple-test assessment. Methods: Six devices were compared: (1) Kis1 gravity-fed infusion set (Doran International, France), (2) Tevadaptor Spike Port Adapter (Teva Pharma AG, France), (3) Phaseal Infusion Adapter C100 (Carmel Pharma AB, France), (4) Codan Connect Z (Codan, France), (5) Pchimx with or without a cap (Doran International, France), and (6) Clave extension set 011-H1225 with or without Spiros (Hospira, France). Assessment of exposure to hazardous drugs was performed using quinine as fluorescent marker. Mechanical tests included tightness, tension tests, and estimation of the force required to connect the infusion device to the bag. Ergonomic tests were performed by six pharmaceutical technicians. Microbiological contamination was tested with media-fill, on connected bag. Results: No cytotoxic contamination was detected when using Phaseal, Tevadaptor or the Clave extension set with Spiros, Pchimx with a cap or Connect Z devices. For mechanical tests, all devices complied with the norm. Microbiological growth was observed neither in bags nor in tubings. The ergonomic study revealed differences between the devices for potential cytotoxic contamination risk only, but not for handling. Conclusions. The use of containment safety devices offers improved handling conditions of hazardous compounds. As this study takes various selection criteria into account, its results offer assistance in choosing the most suitable device.

Gravity-fed infusion (GFI) systems are acknowledged as being unable to keep their flow-rate constant. This may affect drug plasma levels such as aminoglycosides. Numerous factors have previously been cited, but their relative importance has never been quantified so far. The objective of this work is to identify the main factors that influence GFI in vitro outflow and to propose a mathematical model of flow-rate evolution as a function of time. In this model, pressure loss and infusion device creep have been considered as the main variation factors. Concomitantly, two experiments were undertaken. Firstly, the flow-rate evolution of an in vitro infusion of 250 mL of dextrose 5% was assessed. Secondly, the creep occurring on an infusion device was measured through a stress relaxation experiment. The experimental infusion flow-rate decreased by as much as 28.5% over 1 h. Simulated and experimental data are well correlated (r = 0.987; P < 0.0001). The maximum creep effect happens during the first 15 min of infusion. In this work, height of the liquid in the bag and tube creep were found to be the main variation factors in GFI flow-rate. This new mathematical model should help to explain the differences observed in drug plasma levels with gravity-fed devices.

The use of medical devices containing highly criticized phthalates including di(2-ethylhexyl) phthalate (DEHP) has been challenged by European directive 2007/47/CE, put into effect in March 2010. New plasticizers are now being used to soften PVC in medical devices: trioctyltrimellitate (TOTM), di-isononyl-cyclohexan-1,2-dicarboxilate (DINCH) and di(2-ethylhexyl) terephthalate (DEHT). To quantify DEHP in nine DEHP-free medical devices made of PVC softened by alternative plasticizers, high performance liquid chromatography analysis with ultraviolet detection at 220 nm wavelength was achieved. An NMR spectroscopy was performed to confirm DEHP presence. Only two medical devices out of the nine tested were truly without DEHP. One of them showed traces of DEHP exceeding the threshold contamination of 0.1% in plastic mass set by REACH regulations. TOTM plasticizer is still incriminated when polyvinyl-chloride (PVC) is contaminated with DEHP. Manufacturers must verify the purity of their raw material, not only on PVC, but also on other soft plastics entering into the composition of medical infusion devices. The clinical consequences of exposure to certain levels of DEHP have not been evaluated. A solution could be to use alternative PVC-free materials.

Resume L’utilisation des dispositifs medicaux contenant des phtalates a risque toxique dont le plus representatif est le di(2-ethylhexyl)phtalate (DEHP) a ete remise en cause recemment par la directive europeenne 2007/47/CE, applicable depuis mars 2010. De nombreux dispositifs medicaux utilises en nutrition artificielle sont concernes par cette mesure. Les fondements de cette evolution reglementaire et notamment les donnees toxicologiques ainsi que les aspects pratiques et les options concernant les alternatives sont revus dans cet article. Les donnees de la litterature permettent d’orienter les choix a mettre en œuvre au niveau des etablissements de sante. Toutefois, des questions restent posees sur la toxicite humaine de certains composes alternatifs.

The ability of an infusion set to deliver a specific amount of drug to the patient can be directly related to the presence of an antireflux valve and dead-space volume. In this study we quantified separately the impact of these 2 components on drug delivery.Various infusion sets were assessed differing in length, in dead-space volume, and with or without an antireflux valve. Noradrenaline was infused with a syringe pump simultaneously with a carrier flow. Effluent drug concentration was measured using ultraviolet spectrophotometry. Flow change efficiency (FCE) was calculated from the ratio of the area under the experimental mass flow rate curve to the area under the theoretical instantaneous mass flow rate curve.The FCE for infusion sets with or without antireflux valves were significantly different 10 to 15 minutes after the start of an infusion at flow rates of 7 mL/h for noradrenaline and 35 mL/h to 70 mL/h for the carrier fluid. They were not different with a carrier flow of 115 mL/h.These findings suggest that antireflux valves have a significant impact on FCE when the ratio of drug flow rate to carrier fluid flow rate is high. Infusion sets with very low dead-space volume connectors yield better FCE. There is a nonlinear relationship between dead-space volume and FCE 5 to 10 minutes after the onset of drug infusion.Care providers must consider dead-space volume and the presence of an antireflux valve when choosing their infusion sets.

Introduction et but de l’etude L’instruction DGOS du 20/03/15 relative a la gestion des risques liee a l’activite de nutrition parenterale (NP) en neonatalogie et en pediatrie insiste sur le recours en premiere intention aux poches avec autorisation de mise sur le marche (AMM). En octobre 2016, Numetah® G E 13 % obtenait l’AMM pour les prematures. Cette poche tri-compartimentee permet d’administrer un melange binaire ou ternaire (emulsion lipidique [ELI] olive/soja [OS]), denue de micronutriments, pouvant etre dilue. L’objectif de ce travail etait de statuer sur l’emploi en reanimation neonatale (RNN) de l’ELI OS (rationnel scientifique, impact ligne perfusion), definir les modalites d’utilisation (binaire/ternaire, dilution) de la poche puis suivre son utilisation. Materiel et methodes Une revue de la litterature a ete menee sur l’emploi de l’ELI OS en RNN (recherche PubMed, mots cles « olive oil » & « preterm neonates »). L’impact de l’emploi d’un melange ternaire sur le circuit de perfusion a ete etudie au cours d’echanges avec l’equipe soignante et medicale. L’impact de la dilution sur les apports a ete evalue a partir des recommandations de dilution du fournisseur, en considerant un premature de 800 grammes et un debit de 160 mL/kg/jour pour lequel nous avons compare aux valeurs moyennes des recommandations de l’ESPGHAN 2005 les apports obtenus selon les volumes prescrits en fonction de la dilution. L’etude retrospective a consiste a identifier dans le logiciel de prescription l’ensemble des poches prescrites entre janvier et mars 2017 et verifier leurs modalites d’utilisation. Resultats et analyse statistique L’emploi de l’ELI OS chez les prematures est peu decrite dans la litterature, ou elle est surtout comparee aux ELI a base d’huile de poisson (HP) : absence de difference sur la croissance et la morbidite vs une ELI HP (Deshpande e t al.), taux plasmatiques en acide docosahexaenoique (DHA) plus eleves dans le groupe HP (Najm et al.), role benefique du DHA dans la retinopathie du premature dont l’incidence est diminuee chez les prematures du groupe HP (Pawlik et al). Par ailleurs l’emploi d’un melange ternaire n’est pas adapte aux procedures de montage de la ligne de perfusion du service. Les medecins ont donc decide de maintenir l’emploi de l’ELI HP administree en Y de la NP binaire. L’emploi de Numetah® non dilue mene a des apports superieurs aux recommandations : acides amines (AA) (+421 %), glucose (+281 %), sodium (+116 %) et potassium (+ 246 %). La correction par dilution avec 155 mL d’eau mene a des apports insuffisants en calcium (−10 %) et phosphore (−2 %). Les modalites d’emploi diluee et non diluee ont ete retenues au sein de notre etablissement, le choix se fondant sur l’etat clinique des patients. Ainsi, de janvier a mars 2017, 134 poches de Numetah® ont ete utilisees dont 79,9 % diluees et 20,1 % non diluees. Conclusion L’utilisation de Numetah® dans notre service de RNN se fait systematiquement en binaire avec supplementation en electrolytes et micronutriments, et dans 79,9 % des cas apres dilution, etape a risques septique et d’erreur. Nous envisageons donc la realisation de poches standardisees de composition correspondant a la version diluee et supplementee de Numetah®.

Introduction La vaccination anti-pneumococcique est recommandee pour tous les enfants de moins de 2 ans et pour les enfants et adultes a risque eleve d’infections a pneumocoque. En 2016, le schema vaccinal comportait une dose de vaccin 13-valent conjugue suivie d’une dose de vaccin 23-valent non conjugue huit semaines plus tard pour les personnes immunodeprimees et une seule dose de vaccin 23-valent en l’absence d’immunodepression. Depuis 2017, le schema 13-valent conjugue puis 23-valent s’applique dans tous les cas. Depuis octobre 2017, le vaccin 23-valent connait une penurie obligeant a prioriser les patients a vacciner et a le dispenser au sein des pharmacies hospitalieres. L’objectif de ce travail a ete d’analyser, pendant 4 mois, les prescriptions de vaccins anti-pneumococcique en termes d’indication et de respect du schema vaccinal. Materiels et methodes A chaque demande de vaccin 23-valent (appel telephonique ou prescription), nous avons demande au patient son statut vaccinal, l’indication, le schema vaccinal prescrit et le statut du prescripteur. Si le schema n’etait pas conforme aux recommandations, le pharmacien a contacte le prescripteur. Resultats L’etude a concerne 28 patients immunodeprimes : infecte par le VIH (1) ; aspleniques (3) ; transplantes d’organe solide (7) ; greffe de CSH (1) ; traites par biotherapie, immunosuppresseur et/ou corticotherapie (9) ; sous chimiotherapie pour hemopathie maligne ou tumeur solide (7) et 15 patients non immunodeprimes : pathologie pulmonaire (9) ; pathologie renale (2) ; pathologie cardiaque (1) et risque de breche osteomeningee (3). La primo vaccination anti-pneumococcique concerne 82,2 % (37) des patients. Parmi les prescripteurs, 58,2 % (25) sont des praticiens hospitaliers, 39,5 % (17) sont des medecins generalistes et 2,3 % (1) sont des specialistes exercant en ville. Le schema vaccinal est non conforme pour 16,3 % (7) des prescriptions avec une non-prescription de vaccin 13-valent huit semaines avant celle du vaccin 23-valent. Dans 1 cas, elle est justifiee par le prescripteur et dans 6 cas, elle est due a une meconnaissance du nouveau schema. Parmi ces dernieres, 2 sont prescrites par un praticien hospitalier (1 pneumologue et 1 gastro-enterologue) et 4 sont prescrites par un medecin generaliste. Ces non-conformites du schema de prescription ne concernent que des patients non immunodeprimes. Conclusion Une prescription de vaccination anti-pneumococcique sur cinq n’est pas conforme aux nouvelles recommandations pour les patients non immunodeprimes contrairement a celles concernant la prise en charge des immunodeprimes qui sont bien respectees. Cette etude met en evidence la meconnaissance par les prescripteurs de l’actualisation des recommandations en 2017 et l’importance de diffuser annuellement celles-ci aupres des medecins generalistes et des officinaux.

International audience

Background Multiaccess infusion sets allow multiple simultaneous infusions but may induce interference in drug delivery resulting from large variations in the delivery rate of potent drugs. In this study, we sought to understand the influence of multiaccess infusion device properties (dead space volume and antireflux valve [ARV]) on drug delivery during multi-infusion therapy. Methods Infusion sets differing in length, dead space volume, and presence of an ARV were assessed. Three drugs were infused simultaneously through different access points, and their concentrations were obtained using UV spectrophotometric analysis of the effluent. Different infusion configurations were compared by assessing (1) the amount of drug delivered to the patient per unit of time, (2) the mean amount of drug delivered to the patient per unit of time during the steady-state infusion (mass flow rate plateau), and (3) flow change efficiency calculated from the ratio of the area under the experimental instant mass flow rate curve to the area corresponding to theoretical instant mass flow rate curve. Results Infusion sets with lower dead space volumes offered significantly higher flow change efficiency (53.0% +/- 15.4% with a dead space volume equal to 0.046 mL 5 min after the start of infusion) than infusion sets with higher dead space volume (5.6% +/- 8.2% with a dead space volume equal to 6.16 mL), whatever the flow rate changes. Even in case of large dead space volumes, the presence of an ARV significantly increased the mass flow rate plateau (from 92.4% to 99.3% of the theoretical plateau without and with the presence of an ARV, respectively). Conclusions Multi-infusion therapy induces perturbation in drug delivery. These perturbations (lag time, backflow, and bolus) could be reduced by using infusion sets including very low dead space volume and an ARV.

The configurational stability of 9-hydroxyrisperidone, an atypical antipsychotic, was studied under acidic, basic and physiological conditions. The analysis of 9-hydroxyrisperidone was performed using a recently validated chiral capillary electrophoretic method developed using a dual cyclodextrin mode (hydroxypropylated-β-CD and sulfated-α-CD). The kinetic parameters (rate constants, half-lives, and apparent free energy barriers) of the racemization were calculated through a mathematical model of the first-order reaction. The influences of the pH, the temperature, the nature and the concentration of the buffer, and the presence of an organic co-solvent were investigated. The fastest racemizations were observed under acidic conditions with high phosphate buffer concentrations and high temperatures. Under these conditions, the cyclodextrins (β-CD, methyl- β-CD, or hydroxypropylated-β-CD) added to both enantiomers in various molar ratios were not able to retard the racemization. Finally, the mechanism of racemization was investigated using nuclear magnetic resonance (NMR) and the proton–deuterium exchange of the proton H 9 borne by the chiral carbon has proven the presence of an imine–enamine tautomerism.

Objective: To compare plasma concentrations of acetylsalicylic acid (ASA) and its metabolites between genetic polymorphisms in the gene encoding for UDP-glucuronosyltransferase 1A6 (UGT1A6), an enzyme involved in ASA metabolism. Methods: Five UGT1A6*1 and 4 UGT1A6*2 homozygote females were given 320 mg ASA once daily for 8 days. During the first and last day of treatment, several blood samples were taken over a 10-hour time period and analyzed for plasma levels of ASA and its main metabolites salicylic acid (SA) and salicyluric acid (SUA), using a validated HPLC method. The pharmacokinetic data were assessed with the Time Constant Approach and both genotypes were compared using the Mann-Whitney U test. Results: ASA and SUA showed similar pharmacokinetic parameters in the two UGT1A6 genotypes. However, pharmacokinetic parameters for SA differed significantly: the mean area under the pharmacokinetic curve for the UGT1A6*1 and UGT1A6*2 homozygotes was 136 and 94 μg/ml·h (p = 0.04), and median Cmax was 23 and 17 μg/ml (p = 0.01), respectively. Conclusion: In females receiving ASA, the presence of the UGT1A6*2 compared to the UGT1A6*1 homozygote genotype is associated with lower plasma levels of SA, indicating faster pharmacokinetics.

The aim of this work is to establish a correlation between water uptake by anhydrous sodium naproxen (ASN) at two different relative humidities and modifications in tableting and densification behaviour under hydration. Water uptake was evaluated at different relative humidities. Models for the hydration kinetics of ASN at 55% and 86%, corresponding to the formation of the dihydrated and tetrahydrated forms, respectively, were evaluated assuming Eyring's dependence on temperature. Tabletability, compressibility, compactibility, and densification behaviour were determined using an instrumented single punch tablet machine. Kinetic data are consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between sodium naproxen molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression. Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration mechanism of ASN explain in an original way the improved tableting and densification properties under hydration.

The effect of oil-in-water submicron emulsion (SE) droplet surface charge on absolute bioavailability of a poorly water-soluble drug (griseofulvin, as model drug) after oral administration was studied in conscious rat. Positively, negatively, and neutrally charged SE were designed and characterized (size, polydispersity index, zeta potential, and pH). Three emulsion formulations, whose compositions included 40% oil phase and differed only in the nature of the emulsifying agent, were retained. Only the positively charged SE showed a higher area under the plasma concentration-time curve (AUC(0 --> infinity)) in comparison with the tablet and with the other SE.

Resume Dans le cadre de la securisation du circuit des dispositifs medicaux steriles (DMS), la pharmacie du Centre Hospitalier de Dunkerque (990 lits) a entrepris de rationaliser le circuit des demandes hebdomadaires des services de soins. Une etude portant sur la realisation des demandes par un preparateur de la pharmacie directement dans les services de soins, a l’aide d’un support papier puis a l’aide d’un lecteur de code barres a ete realisee dans certains services Medecine Chirurgie Obstetrique (MCO). La part du stock de DMS repris au moment de la determination des dotations des services est de 21 %, soit 0,68 semaine de consommation. Le temps preparateur hebdomadaire supplementaire necessaire avec support papier est de 49,9 minutes par service. Le temps infirmier economise avec cette organisation est evalue a 83 minutes par service. Extrapolees a l’ensemble des services MCO, ces donnees permettent d’estimer le temps preparateur hebdomadaire supplementaire a 16,6 heures et le temps infirmier economise a 27,7 heures par semaine. Le lecteur code barres permet au preparateur de passer 20 minutes de moins par demande. En extrapolant a l’ensemble des services MCO, l’economie serait donc de 6,7 heures par semaine. Cette organisation montre un interet certain en termes de gestion des stocks et de temps economise pour le personnel.

Infusion practices have been modified, especially for antineoplastic drugs, through the use of specific infusion devices with postadministration rinsing (PAR) so as to decrease occupational exposure to drugs. The aim of this study was to highlight how such infusion devices may impact the drug delivery of injectable drugs.Drug infusions were simulated with a radiotracer (99mTc) for 30 minutes to assess nine different infusion lines: 2 infusion methods without PAR (1 gravity-fed infusion and 1 pump infusion), 2 extension lines to be connected to standard infusion devices to allow PAR, and 5 specific infusion sets allowing a PAR. 99mTc was compounded in 250 or 100 mL of 0.9% NaCl solution. From the continuous recording of drug concentrations at device outlets, the areas under the drug concentration-time curve (AUC) were computed and divided in 2 parts: the AUCadm corresponding to the administration phase and the AUCrin corresponding to the rinsing phase. Their comparison to the initial activity led to compute the drug delivery. Results between groups were compared using a Kruskal-Wallis test (P0.05).Using standard infusion devices leads to administer only 91% and 88% when the drug is diluted in 250 and 100 mL, respectively. During the administration phase with the extension lines connected to infusion sets, between 90.8 ± 6.9% and 94.2 ± 1.8% of the drug is infused for 250 mL dilutions and 87.7 ± 2.0% for 100 mL dilutions. For specific infusion sets, the proportion of infused drug varied between 88.6 ± 6.0% and 95.3 ± 1.5% for dilutions in 250 mL and 71.2 ± 3.1% and 90.4 ± 2.8% for dilutions in 100 mL. Rinsing the lines means the remaining drug is administered a rinsing volume ranging between 47.0 ± 6.6 and 92.2 ± 8.9 mL according to the device and drug dilution.This study shows that drug delivery may differ according to infusion line and dilution volume. Further study is required to assess the impact of these devices on pharmacokinetics.

French guidelines recommend central intravenous (i.v.) infusion for high concentrations of vancomycin, but peripheral intravenous (p.i.v.) infusion is often preferred in intensive care units. Vancomycin infusion has been implicated in cases of phlebitis, with endothelial toxicity depending on the drug concentration and the duration of the infusion. Vancomycin is frequently infused in combination with other i.v. antibiotics through the same administrative Y site, but the local toxicity of such combinations has been poorly evaluated. Such an assessment could improve vancomycin infusion procedures in hospitals. Human umbilical vein endothelial cells (HUVEC) were challenged with clinical doses of vancomycin over 24 h with or without other i.v. antibiotics. Cell death was measured with the alamarBlue test. We observed an excess cellular death rate without any synergistic effect but dependent on the numbers of combined infusions when vancomycin and erythromycin or gentamicin were infused through the same Y site. Incompatibility between vancomycin and piperacillin-tazobactam was not observed in our study, and rinsing the cells between the two antibiotic infusions did not reduce endothelial toxicity. No endothelial toxicity of imipenem-cilastatin was observed when combined with vancomycin. p.i.v. vancomycin infusion in combination with other medications requires new recommendations to prevent phlebitis, including limiting coinfusion on the same line, reducing the infusion rate, and choosing an intermittent infusion method. Further studies need to be carried out to explore other drug combinations in long-term vancomycin p.i.v. therapy so as to gain insight into the mechanisms of drug incompatibility under multidrug infusion conditions.

Objective The aims are to identify critical parameters influencing the drug mass flow rate of infusion delivery to patients during multidrug infusion and to discuss their clinical relevance. Data sources A review of literature was conducted in January 2016 using Medline, Google Scholar, ScienceDirect, Web of Science and Scopus online databases. Data extraction References relating to the accuracy of fluid delivery via gravity-flow intravenous (IV) infusion systems and positive displacement pumps, components of IV administration sets, causes of flow rate variability, potential complications due to flow rate variability, IV therapies especially at low flow rates and drug compatibilities were considered relevant. Data synthesis Several parameters impact the delivery of drugs and fluids by IV infusion. Among them are the components of infusion systems that particularly influence the flow rate of medications and fluids being delivered. By their conception, they may generate significant start-up delays and flow rate variability. Performing multidrug infusion requires taking into account two main points: the common dead volume of drugs delivered simultaneously with potential consequences on the accuracy and amount of drug delivery and the prevention of drug incompatibilities and their clinical effects. Conclusion To prevent the potentially serious effects of flow rate variability on patients, clinicians should receive instruction on the fluid dynamics of an IV administration set and so be able to take steps to minimise flow rate changes during IV therapy.

Objective Drug incompatibilities can jeopardize the safety and effectiveness of intravenous drug therapies, especially in the field of anaesthesia and intensive care. Patients receive many drugs simultaneously through limited venous accesses. This study was designed to confirm the impact of a multilumen infusion device on the occurrence of known physical drug incompatibilities. Study design In vitro laboratory work. Methods Two infusion devices were studied: a standard single-lumen set and a multilumen infusion access device (Edelvaiss Multiline-8, Doran International). Up to six drugs were infused simultaneously: three acidic solutions of midazolam, amiodarone and dobutamine, and three alkaline solutions of furosemide, pantoprazole and amoxicillin/clavulanate. Saline, Ringer’ solution and 5% dextrose were used as hydration vehicles with an infusion rate initially set at 100 mL/h and with stepwise decreases of 10 mL/h until precipitation. Two methods were used to highlight physical drug compatibility according to the European Pharmacopoeia: visual inspection of the extension set and an obscured-light sub-visible particle count test of infusions. The lowest infusion rate value for vehicle infusion to satisfy the two tests in all trials is reported for each infusion device. Results The standard set did not satisfy the test in 82% of the assessed drug combinations. The Edelvaiss Multiline-8 was able to prevent the occurrence of drug incompatibilities in 49% of the drug combinations tested. This device is therefore advantageous, especially when simultaneously infusing two or four incompatible drugs. Conclusions Infusion device characteristics have an impact on physical drug incompatibilities. Our results confirm that the Edelvaiss Multiline-8 device prevents physical drug incompatibilities under specified conditions.

International audience

Peripheral intravenous therapy is frequently used in routine hospital practice and, due to various factors, its most common side effect is phlebitis. The infusion of vancomycin is particularly associated with phlebitis despite its widespread use. French guidelines recommend central intravenous infusion for high concentrations of vancomycin, but peripheral intravenous therapy is often preferred in intensive care units. Methods of vancomycin infusion are either intermittent infusion or continuous infusion. A comparison of these methods under in vitro conditions simulating clinical use could result in better infusion efficacy. Human umbilical vein endothelial cells (HUVECs) were therefore challenged with clinical doses of vancomycin over a 24- to 72-h period using these infusion methods. Cell death was measured with the alamarBlue test. Concentration-dependent and time-dependent vancomycin toxicity on HUVECs was noted with a 50% lethal dose at 5 mg/ml after 24 h, reaching 2.5 mg/ml after 72 h of infusion, simulating long-term infusion. This toxicity does not seem to be induced by acidic pH. In comparing infusion methods, we observed that continuous infusion induced greater cell toxicity than intermittent infusion at doses higher than 1 g/day. The increasing use of vancomycin means that new guidelines are required to avoid phlebitis. If peripheral intravenous therapy is used to reduce infusion time, along with intermittent infusion, vein irritation and localized phlebitis may be reduced. Further studies have to be carried out to explore the causes of vancomycin endothelial toxicity.

International audience; OBJECTIVE: This study aimed to evaluate two cleaning solutions for the chemical decontamination of antineoplastic agents on the surfaces of two biosafety cabinets routinely used for chemotherapy preparation in a hospital pharmacy. METHODS: For almost 1 year (49 weeks), two different solutions were used for the weekly cleaning of two biosafety cabinets in a hospital pharmacy's centralized cytotoxic preparation unit. The solutions evaluated were a commercial solution of isopropyl alcohol (IPA) and water (70:30, vol:vol), and a detergent solution constituted by 10(-2)M of sodium dodecyl sulfate (SDS) with 20% IPA. Seven areas in each biosafety cabinet were wiped 14 times throughout the year, before and after the weekly cleaning process, according to a validated procedure. Samples were analyzed using a validated method of high-performance liquid chromatography coupled to mass spectrometry. The decontamination efficacy of these two solutions was tested for 10 antineoplastic agents: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. RESULTS: Overall decontamination efficacies observed were 82±6% and 49±11% for SDS solution and IPA, respectively. Higher contamination levels were distributed on areas frequently touched by the pharmacy technicians-such as sleeves and airlock handles-than on scale plates, gravimetric control hardware, and work benches. Detected contaminations of cyclophosphamide, ifosfamide, gemcitabine, and cytarabine were higher than those of the others agents. SDS solution was almost 20% more efficient than IPA on eight of the antineoplastic agents. CONCLUSION: Both cleaning solutions were able to reduce contamination levels in the biosafety cabinets. The efficacy of the solution containing an anionic detergent agent (SDS) was shown to be generally higher than that of IPA and, after the SDS cleaning procedure, biosafety cabinets demonstrated acceptable contamination levels.

An in vitro study was carried out to determine the anti-Xa activity of heparin in binary parenteral nutrition (BPN) admixtures for premature neonates in our neonatal intensive care unit (NICU) after a 24-hour infusion, as well as to assess drug interaction with a 50% glucose solution. Two types of bags were prepared: (1) BPN admixtures (composition defined in the NICU) including sodium heparin at 77 UI/mL and (2) bags containing only G50% with sodium heparin at 193 UI/mL. The anti-Xa activity of heparin was measured in bags at T0, after the 24-hour infusion and in eluates at the outlet of the infusion line after 24hours, using a validated chromogenic anti-Xa method. Comparisons of the mean concentration observed with the theoretical value for anti-Xa activity were performed with the Student t-test. Mean values of anti-Xa activity do not differ significantly from the values expected for all conditions. We found a slight variation in anti-Xa activity when infused over 24hours for both types of bags, with and without in-line filtration, showing that heparin remains stable during this infusion period in both BPN admixtures and G50%.

The disposition of naltrexone (NLT) (REVIA), an opioid antagonist intended for patients with impaired renal function and with severe intractable itching refractory to regular antipruritic therapy, was characterized. Hemodialysis effects on both efficacy and elimination of NLT also were assessed. We developed a simple, sensitive and selective reverse-phase high-performance liquid chromatographic (HPLC) method for measuring NLT plasma concentration in hemodialysis patients treated to relieve pruritus. NLT and the internal standard, naloxone (NLX) were extracted from plasma using a solid-phase extraction method with sep-pack C18 cartridge. The method was employed to determine both naltrexone pharmacokinetics and dialysability parameters during 4-h in dialyzed patients with chronic renal impairment. Thus, seven patients (2 men, 5 women) with end-stage renal disease and pruritus on regular hemodialysis were included. They received one tablet of NLT (Revia, 50 mg) orally prior dialysis session. The Cmax at the inlet and at the outlet the dialyzer were higher (255+/-117 ng/mL and 206+/-137 ng/ml respectively) in comparison with healthy subjects (9 - 44 ng/mL). The decrease hepatic first-pass metabolism of NLT consecutive to end-stage renal disease and the renal impairment could explain the increased levels of the drug in plasma. Tmax before and after dialysis plates remain unchanged as healthy subjects (approximately 1h). With regard to dialysability, a high dialyzer extraction ratio averating 30 % was found with a low dialysis clearance of 58.70+/-17 mL/min. The amount removed by dialysis is only 1.27 mg. We concluded that hemodialysis has little effect on NLT blood levels, and consequently on drug pharmacokinetics, when the drug is delivered to dialyzed patients following oral route. Thus, dosage adjustement is not required in the presence of advanced dialysis-dependant renal failure. In patients with end-stage renal disease, hemodialysis does not result in clinically significant alterations in the disposition of NLT. Post-dialysis supplementation is not required. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but in view of NLT plasma concentration levels in the patients, a clinician could determine whether dosage adjustment are necessary and, if so, make the required calculations accurately.

Introduction L’evolution de la place du patient dans sa prise en charge implique l’acces a une information claire, complete et comprehensible, principe reaffirme dans la loi Kouchner. L’objectif de ce travail etait d’evaluer le transfert d’information lors de la consultation orthopedique et l’evolution des connaissances des patients au cours de leur prise en charge. Materiels et methodes Etude prospective, monocentrique, realisee entre janvier 2014 et mars 2015 en consultation et dans deux services d’orthopedie sur 84 patients consecutifs consultant pour la 1 re fois un des deux chirurgiens participant et se voyant proposer une arthroplastie de hanche ou de genou a l’issue de la consultation. Un observateur assistait aux consultations. Les patients completaient un auto-questionnaire anonymise a 3 moments de leur prise en charge a l’issue de la consultation (T1), a leur entree dans le service (T2) et a leur sortie apres l’arthroplastie (T3). Le transfert d’information a ete evalue en analysant la concordance entre les informations donnees par le chirurgien et les reponses des patients. Le niveau de connaissance des patients etait apprecie a travers 4 scores semi-quantitatifs thematiques (pathologie, prise en charge, prothese, complications) et un score global (somme des 4 scores partiels). Resultats La concordance entre l’information transmise et la reponse donnee par le patient a T1 etait variable de 33 % pour la duree d’utilisation de cannes a 88 % pour la duree de vie d’une prothese. Les scores moyens de connaissance observes a T1 etaient bas score global de 16,71 ± 6,42 sur 42 ; pathologie score de 0,31 ± 1,31 sur 2 ; complications score de 2,48 ± 1,85 sur 13 ; prothese score de 5,74 ± 2,96 sur 12. Le niveau de connaissance evoluait au cours de la prise en charge scores de connaissance globale, connaissance de la prise en charge et connaissance de la prothese a T3 superieurs aux scores a T1 ( p p p Discussion L’originalite de notre etude etait d’apprecier l’evolution des connaissances au cours de la prise en charge, montrant une augmentation du niveau global de connaissance entre T1 et T3. Conclusion Cette etude revele un niveau de connaissance des patients relativement bas et tres variable selon le sujet et le moment de la prise en charge et suggere d’ameliorer les moyens de transfert d’information (ecrit, video, accessibilite), prealable indispensable au consentement eclaire du patient.

Resume La restauration de la pression arterielle moyenne (PAM) des patients apres echec du remplissage vasculaire est permise grâce a l’utilisation d’amines vasopressives telles que la noradrenaline. Or, il s’avere que les modalites de perfusion de cette amine vasoactive ne font l’objet d’aucune recommandation : concentration de la noradrenaline dans la seringue, administration simple ou double chariot via un vehicule tel que le serum sale isotonique, utilisation de prolongateurs a volume residuel minimise. Nous rapportons le cas d’une patiente ayant necessite un traitement par noradrenaline au cours duquel elle a presente rapidement un incident hemodynamique majeur (elevation brutale de la pression arterielle systolique depassant 220 mmHg associee a une tachycardie atteignant 189 b/min). Nous discutons des principales causes a l’origine de cet incident et des parametres de perfusion a prendre en compte afin d’elaborer une methode de perfusion optimale d’un medicament a marge therapeutique etroite.

Twenty-five percent of epileptic patients present refractory seizures to current frontline antiepileptic drugs, needing new treatments and leading to the introduction of several new AEDs, among which is oxcarbazepine (Trileptal ® ). This 10-ketoanalogue of carbamazepine seems to be a weaker inducer of cytochrome P450 3A4. However, pharmacokinetic interactions with clinical significance have already been reported, before the marketing of Trileptal ® in France. The aim of this study was to develop and validate a HPLC method allowing simultaneous dosage of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin. After plasma defecation by acetonitrile, dosage was obtained by analysis of the supernatants on a C 18 reversed-phase column coupled with UV detection (240 nm). The statistical validation was performed according to the recommendations of a European technical commission. This method seems to provide a quite good selectivity from the psychotropic therapeutics, which is commonly coprescribed with AEDs. Linearity was established for the whole concentration range, whatever the compound. Quantization limits of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin are 0.58, 3.5, 2.35, 0.66, 1.02 and 3.13 μg/ml, respectively, and absolute recoveries are 105.15, 84.76, 94.45, 96.52, 98.62 and 95.08%, respectively.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin. After protein precipitation by acetonitrile, the supernatant was analysed on a C18 reversed-phase HPLC column. Antiepileptic drugs and oxazepam (internal standard) were detected by ultraviolet absorbance at 240 nm. Linearity was established for the whole concentration range for each compound. Quantitation limits of oxcarbazepine, 10-hydroxycarbamazepine, epoxycarbamazepine, carbamazepine, phenobarbital and phenytoin were 0.58, 3.5, 2.35, 0.66, 1.02 and 3.13 microg/mL, respectively, and mean recoveries added to serum were 105.15, 84.76, 94, 45, 96.52, 98.62 and 95.08%, respectively. This method has been used for the simultaneous determination of steady-state serum concentration of antiepileptic drugs in patients treated by one or more anticonvulsive treatment.

Introduction La vancomycine est indiquee dans les meningites a pneumocoques en administration en continu sur 24 h pour augmenter les penetrations meningees et cerebromeningees. Pour le traitement des meningites, les posologies recommandees sont de 60 mg/kg/j en pediatrie [1] et de 35 a 45 mg/kg/j chez l’adulte [2] . Les seules donnees de stabilites sont a 10 mg/mL [3] . L’objectif est d’etudier la stabilite de la vancomycine a 83,3 mg/mL (4 g dans une seringue de 48 mL) et a 41,7 mg/mL (2 g dans une seringue de 48 mL) lors d’une perfusion continue de 24 h. Materiels et methodes Pour la vancomycine (Sandoz, France) a 83,3 mg/mL : 4 flacons de 1 g sont dilues chacun dans 12 mL de serum sale isotonique (SSI) (n = 3). Pour la vancomycine a 41,7 mg/mL : 2 flacons de 1 g de vancomycine sont reconstitues chacun par 20 mL de SSI et dilues par 10 mL de SSI (n = 3). Ces solutions sont perfusees a 2 mL/h via des prolongateurs en polyethylene (L = 150 cm, diametre interne = 1 mm) (Vygon, France) pendant 24 h a 18 °C. Les solutions sont dosees par une methode indicatrice de stabilite apres degradation forcee selon les recommandations SFPC-GERPAC [4] en chromatographie liquide-UV [5] . Les resultats sont exprimes en % de la concentration mesuree aux differents temps par rapport a la concentration initiale dans la seringue. Les solutions sont considerees comme stables si la concentration reste superieure a 90 % de la concentration initiale. La stabilite microbiologique (Pharmacopee europeenne 2.6.1) et un comptage particulaire (APSS-2000, Particle Measuring Systems, Pharmacopee europeenne 2.6.19) ont ete realises en debut de perfusion. Resultats Pour la vancomycine a 83,3 mg/mL, les concentrations sont inferieures a 90 % a partir de 12 h de perfusion. Pour la vancomycine a 41,7 mg/mL, les concentrations sont superieures a 90 % pendant les 24 h de perfusion. Le nombre de particules de plus de 10 μm de diametre est superieur au seuil tolere (6000 particules) dans les solutions a 83,3 mg/mL (12 347 ± 137 particules), et inferieur pour les solutions a 41,7 mg/mL (4708 ± 143 particules). Les echantillons sont stables microbiologiquement. Conclusion Les solutions de vancomycine a 83,3 mg/mL ne sont pas stables et ne sont pas compatibles avec une perfusion de 24 h et ne doivent pas etre administrees aux patients compte tenu de leur charge particulaire. Dans le cadre du traitement des meningites, nous preconisons la dilution de 2 g de vancomycine maximum dans une seringue de 48 mL de SSI a perfuser sur 12 h, et realiser un changement de seringue toutes les 12 h ou toutes les 8 h selon la posologie prescrite.

This study aimed to compare in vitro two syringe changeover techniques to determine which was better at minimising variations in norepinephrine (NE) delivery: the manual quick-change or automated technique. NE concentration was measured continuously using a UV spectrophotometer, and infusion flow rate was monitored by an infusion pump tester. Syringe changeovers were made with either of the two techniques studied. Relays induced disturbances in drug delivery. The temporary increase in NE mass flow rate was significantly higher with manual relays than with automated ones. The automated relay offered a better control of the amounts of NE administered than the quick-change technique.

Drug incompatibilities, recognizable through precipitate, may have clinical consequences for patients, especially during multidrug IV therapies, where vancomycin and piperacillin are present. Drug concentration and infusion set influence the overall particulate contamination of pediatric infusion protocols. The use of multi-lumen infusion sets could prevent such incompatibilities. Our goal was to define and assess a new way to infuse these drugs during leukemia treatment in children.This in vitro study focused on a pediatric multidrug protocol for patients diagnosed with lymphoblastic leukemia and receiving allogeneic transplantation. Different vancomycin concentrations were tested to infuse incompatible drugs simultaneously without any particle formation (optimized multidrug protocol). A dynamic particle count test was used over 24 hr to evaluate the overall particulate contamination of our standard and optimized multidrug protocols, using both a standard and a multi-lumen infusion set.No visible particles were detected on a decreased vancomycin concentration compared to the standard dose. For the optimized multidrug protocol, the use of a multi-lumen infusion set reduced overall particulate contamination by 68%, compared to the standard infusion set (P = 0.002). Large-sized particles were significantly reduced when using the multi-lumen infusion set approximately 60% (P = 0.027) and 90% (P = 0.009) for particle sizes ≥10 μm and 25 μm, respectively.This study demonstrates that a large number of particles can be administered during parenteral multidrug infusion. The choice of drug concentration and/or the type of infusion set may reduce this. Further studies are required to evaluate adverse clinical effects.

Background/Aims: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. Methods: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. Results: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 μg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. Conclusion: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

BACKGROUND At this center, therapeutic drug monitoring of methotrexate (MTX) used to be performed by fluorescence polarization immunoassay (FPIA). We observed an increasing number of unusual high MTX concentrations at 48 and 72 hours during a couple of years. This study aimed to identify the causes of this variation. METHODS A retrospective analysis was conducted on 272 patients hospitalized between January 2008 and October 2012. The whole MTX use system was analyzed using Ishikawa's method. The proportion of MTX concentrations ≤0.2 μmole/L at 48 (P48h) and 72 hours (P72h) was recorded and compared between both FPIA and EMITSiemens assays. A χ or a Fisher exact test was used (α = 0.05). RESULTS Because of an announced withdrawal of the FPIA reagent, the method was switched in 2009 to an immunoenzymatic technique (EMITSiemens). Both P48h and P72h dropped significantly after 2009 (P48h: 45% versus 5% and P72h: 91% versus 47%; P < 0.0001). The replacement of the EMITSiemens reagent by the EMITARK Diagnostics reagent in 2012 led to an increase in both P48h and P72h. No significant difference was found in the proportions of MTX ≤0.2 μmole/L concentrations between FPIA and EMITARK Diagnostics at 48 (45% and 40%; P = 0.556) and 72 hours (91% and 100%; P = 0.231). Both internal and external quality control assessments gave regular satisfactory results during the study period. Furthermore, the interassay comparisons that were performed with internal quality controls and spiked serum samples showed similar results at the time of both shifts. The other changes observed in the MTX circuit were not associated with MTX concentration variations. CONCLUSIONS The overestimation of the plasma concentration of MTX was concluded to be because of the assay reagent. A further study is consequently necessary to assess the impact of this analytical pitfall on the patients' survival.

Introduction L’objectif de ce travail est de developper une methodologie d’audit permettant de controler le respect des referentiels de bon usage, la tracabilite sanitaire et la tracabilite financiere des dispositifs medicaux implantables remboursables en sus. Materiels et methode Une procedure, une grille d’audit et un fichier d’analyse Excel ont ete elabores. Les donnees sont recueillies a partir du logiciel de tracabilite Sedistock, du dossier patient (papier et informatise) et du classeur de bloc. Les resultats sont exprimes en pourcentage de poses conformes. Toute absence de preuve est consideree comme non-conforme. Cette methodologie a ete appliquee a l’analyse retrospective des poses d’implants sphincteriens peri-uretraux sur un an. Resultats et discussion Sur les 46 poses realisees, 79 % sont conformes au referentiel de bon usage, 73 % au niveau de la tracabilite sanitaire, 49 % au niveau de la tracabilite financiere et 28 % aux 3 items. Les non-conformites ont ete analysees : pour le bon usage, c’est l’ absence de preuve et pour la tracabilite sanitaire, les absences de resume de pose d’implant dans le dossier patient (10 % des cas) et des erreurs de saisie informatique (23 % des cas) qui ont ete principalement mises en evidence. Ces dernieres, ajoutees a des erreurs de choix de codes produits (39 % des cas), engendrent une perte financiere potentielle de 24 000 euros. Conclusion Chaque type de non-conformite a fait l’objet de mesures correctives, permettant, entre autres, de limiter la perte financiere a 300 euros. Cette demarche permet de securiser la prise en charge globale des patients. D’autres DMI sont en cours d’audit.

Aminoglycosides are broad-spectrum antibiotics with peak-dependent bactericidal activity, administered by gravity infusion or for more accuracy by electronic pump infusion. The aim of this study was to assess the difference between the two systems and its pharmacokinetic impact. Twenty-four patients hospitalised for community-acquired pulmonary infections received amikacin by IV route over 1 h with a targeted peak concentration of 35 mg/L. They were randomly distributed into two groups, one receiving infusion through a pump system, the other by gravity. Amikacin serum levels were determined at the end of infusion and 24 h later. C(max) values were significantly lower with gravity than pump (40.2 +/- 12.3 vs. 50.6 +/- 17.6 mg/L, respectively; p = 0.04). Elimination half-life time, volume of distribution and clearance did not differ significantly from one group to the other. The percentage of patients who failed to achieve the targeted peak concentration was significantly higher with gravity than pump (41.7% vs. 16.7%, respectively; p < 0.001). Improving infusion flow-rate provides better control over amikacin C(max). This study underlines the fact that infusion device characteristics should be added to the physiopathological information of a patient if we are to make a better estimation of pharmacokinetic parameters.