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Background: Risperidone is an atypical antipsychotic drug that has been marketed in France since 1996. Therapeutic failures have been observed with risperidone. Objective: To investigate whether interactions with the cytochrome P450 (CYP) isoenzymes implicated in risperidone metabolism could explain these treatment failures. Design and Setting: This was a retrospective study of clinical and drug monitoring data from 50 patients treated by five psychiatrists in northern France. Methods: The concentration of active drug (risperidone + 9-hydroxy-risperidone) in serum was evaluated by high performance liquid chromatography and radio receptor assay. Clinical efficacy was assessed by the global improvement (CGI2) item of the Clinical Global Impression rating scale. Results: Statistical analysis revealed a significant increase in efficacy when the serum concentration of active drug was between 25 and 150 μg/L compared with when it was out of this range. Carbamazepine, a CYP3A4 inducer, dramatically decreased the concentration of the active moiety of risperidone; on the contrary, CYP3A4 inhibitors (alprazolam and valproic acid) increased the concentration of active drug. The metabolism of risperidone by CYP3A4 did not lead to the formation of metabolite(s) with anti-D2 dopaminergic activity. Drugs interacting with CYP2D6 altered the risperidone/9-hydroxy-risperidone ratio but did not change the total amount of active drug. Conclusions: We have established a therapeutic range for risperidone. CYP3A4 is a major pathway for risperidone metabolism. Consideration of these factors in clinical practice should lead to improved outcomes for patients treated with risperidone.

A simple, sensitive, selective and reliable reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection is described for the determination of naltrexone in plasma samples. Naltrexone and the internal standard, naloxone, were isolated from plasma either with a liquid-liquid extraction method using ethyl acetate or with a solid-phase extraction method using Sep-Pack C18 cartridge before chromatography. The extracts were dried under a stream of nitrogen and the samples were reconstituted in the mobile phase, then 20 microL were injected on a Waters Symmetry C18 column (5 microm particle size, 4.6 x 150 mm). The mobile phase consisted of 0.06% triethylamine (pH 2.8)-acetonitrile (92:8, v/v) pumped at 1 mL/min. The peak-area ratio versus plasma concentration was linear over the range of 10-500 ng/mL and the detection limit was less than 8 ng/mL. Quantification was by ultra-violet detection at 204 nm. The present method was applied to the determination of the plasma concentration of naltrexone in dialyzed patients. Patients (n = 8) with severe generalized pruritus received 50 mg of naltrexone orally per day for 2 weeks. The variability in the therapeutic response in treated patients required plasma concentration investigations of this opioid antagonist.

Summary Background: Omeprazole has been marketed in France since 1989, for the healing of peptic ulcers, erosive reflux oesophagitis, and the Zollinger–Ellison syndrome. However, the drug has been associated with serious adverse reactions, including haemolytic anaemia and acute interstitial nephritis. More recently, an autoimmune syndrome induced by omeprazole has been described. Objective: We present here a clinical history and an in vitro test of cytotoxicity linking leukopenia to omeprazole. Results: A 37-year-old woman was hospitalized in the intensive care unit of our hospital with acute pulmonary insufficiency secondary to pneumonia. 72 h after starting omeprazole treatment, a decrease in leucocyte count was observed. The leukopenia was maximal on day 22: total white cell count was 2·1×109/l, and neutrophil count was less than 0·75×109/l. In order to find the cause of this leukopenia, an in vitro cytotoxicity test was performed. The test was positive only when patient neutrophils and patient serum were in the presence of omeprazole. This cytotoxicity seems to be complement-dependent, as in the presence of heated serum, the omeprazole toxic effect was substantially reduced. Conclusion: This case report suggests that the leukopenia was associated with omeprazole.

Midazolam is a benzodiazepine with short elimination half-life, used as induction or continuous agent for general anesthesia. At present, only injectable solution is available from French hospital pharmacies. The aim of the study is the development of 5 mg midazolam sublingual tablets to realize a short general anesthesia without intravenous or intramuscular injection. Incorporation of citric acid in the tablet formulation leads to an increase of dissolution rates of active drug, but a decrease of diffusion through lipid membranes is observed with 10 mg of citric acid when using the Dibbern's Resomat three phases apparatus. One explanation of this result is that midazolam (pKa = 6.1) in presence of 10 mg of citric acid is ionised. The ionised form, more hydrophilic, cannot cross the artificial lipid membrane and therefore the diffusion decreases. On the other hand, the decrease of diffusion's rate, when pH increases, is explained by the precipitation of midazolam at pH higher than 6. A compromise between dissolution and diffusion results leads us to choose the sublingual formulation containing 5 mg of citric acid per tablet.

Introduction et but de l’etude La nutrition enterale a domicile (NEAD) est largement developpee dans la region Nord Pas de Calais. Initiee en milieu hospitalier, celle-ci peut etre poursuivie a domicile avec une surveillance et une adaptation constantes. Le pharmacien d’officine doit contribuer a l’information et a l’education sanitaire du public, quelle que soit la pathologie. Il est identifie comme soignant de recours pour l’administration des medicaments lors de l’administration concomitante a la NE. L’etude a pour but d’evaluer le role du pharmacien d’officine dans la prise en charge du patient avec NEAD, au travers d’enquetes croisees. Materiel et methodes Trois types d’enquetes ont ete realises aupres de patients et de pharmaciens d’officine du Nord-Pas-De-Calais. La premiere a ete menee aupres de patients d’un prestataire public dans cette region, hors instituts medico-educatifs, residant dans la metropole lilloise : un questionnaire (19 items) a ete distribue par l’intermediaire du chauffeur du prestataire en decembre 2013, avec possibilite de laisser les coordonnees du pharmacien d’officine. Ces derniers ont ensuite ete interroges par telephone pour la seconde enquete. La troisieme (18 items), envoyee sous forme de lien hypertexte, a ete soumise a l’ensemble des pharmaciens d’officine du Nord-Pas De Calais par l’intermediaire du Conseil Regional de l’Ordre des Pharmaciens en novembre puis en decembre 2013. Resultats et Analyse statistique Sur les 185 patients interroges, 85 ont repondu a l’enquete (45,95 %). 11 patients ont laisse les coordonnees de leur pharmacien de ville, 9 de ces professionnels ayant accepte de repondre. En ce qui concerne l’enquete menee aupres de l’ensemble des pharmaciens d’officine du Nord-Pas-De-Calais, 42 reponses ont ete obtenues mais le nombre de pharmaciens interroges reste inconnu (non reception du lien hypertexte, impossibilite de cliquer sur le lien). Malgre l’echantillon limite de l’etude aupres des patients (un seul prestataire public) et la non-exhaustivite des reponses de pharmaciens (42 + 9 reponses), differents problemes ont ete mis en evidence : manque de communication au sein de l’equipe officinale, manque de dialogue entre les patients et leur pharmacien sur cette problematique, manque de formation et d’information aussi bien des patients que des pharmaciens sur la nutrition enterale et l’administration des medicaments par sonde, manque de coordination avec les autres professionnels de sante. Les patients sont fideles a une pharmacie dans 86 % des cas. Dans 76 % des cas, les patients ont informe leur pharmacien du recours a la nutrition enterale. Dans 46 % des cas, les formes dispensees etaient adaptees a l’administration par sonde. Or dans 17 % des cas, les patients indiquent ne pas avoir recu, lors de la dispensation, de conseil specifique aux modalites d’administration des medicaments oraux via la sonde. Du cote des reponses des pharmaciens, 41 % ont des patients sous NE, et 30 % servent de relais dans la transmission des poches aux patients. La formation (initiale ou continue) sur le sujet est jugee insuffisante. 20 % ne donnent pas de conseil particulier relatif a l’administration des medicaments au travers des sondes, dans la majorite des cas du fait d’un manque d’information. 26 % seulement disent proposer des formes adaptees. Mettre un commentaire dans le dossier du patient sonde est insuffisamment employe pour informer l’equipe officinale. Conclusion Dans les suites de notre enquete, une fiche conseil a ete adressee a l’ensemble des pharmaciens ayant repondu afin de leur fournir des conseils. Ainsi, pour permettre une meilleure prise en charge medicamenteuse du patient porteur d’un materiel de NE, une information systematique du pharmacien serait a realiser lors de la mise en place d’une NEAD. Des formations continues destinees aux pharmaciens d’officine sont egalement a developper. Enfin, La formation delivree aux patients est souvent insuffisante, et ceux-ci devraient beneficier d’une education therapeutique initiee a l’hopital et poursuivie a domicile.

Introduction et but de l’etude L’utilisation de verrous de taurolidine au long cours (VTLC) semble etre efficace dans la prevention secondaire des infections liees aux catheters (ILC) veineux centraux. L’objectif de ce travail etait d’evaluer l’efficacite de cette pratique chez les patients adultes recevant une Nutrition Parenterale a Domicile (NPAD). Materiel et methodes Cette etude a ete realisee chez les patients adultes d’un centre agree de NPAD. A partir du 1er juillet 2011, les VTLC ont ete instaures au decours du troisieme episode d’ILC survenant en moins de 12 mois. Le nombre d’ILC prouvees et d’ILC probables, de changements de catheters, le nombre et la duree des sejours en hospitalisation conventionnelle en rapport avec une ILC ont ete recueillis prospectivement depuis l’initiation des VTLC et ce jusqu’a la date de point du 1er juillet 2013. Pour chaque patient, la duree de ce recueil determinait la duree de recueil retrospective de ces memes donnees avant que ne soient inities les VTLC, de sorte que les temps de recueil avant et apres initiation des VTLC etaient identiques. Les analyses statistiques ont ete realisees par une methode de bootstrap non parametrique sur series appariees, avec un seuil de significativite de 1 %. Resultats et Analyse statistique Les donnees de 37 patients, âges en moyenne de 56 ± 17 ans et ayant recu les VTLC pendant 13,8 ± 7,8 mois ont ete analyses. En cas d’ILC prouvee, l’instauration des VTLC permettait d’observer une diminution : du taux d’ILC (passant de 3,18 a 0,39 /1000 jours catheters, p Conclusion Il s’agit a notre connaissance de la plus large cohorte etudiee, en prevention secondaire. L’utilisation de la nouvelle strategie liee au VTLC semble reduire significativement la survenue d’ILC, et reduit le taux de remplacement des catheters. Le nombre de sejour et la duree ayant diminuee, une evaluation medico-economique est en cours afin de determiner le rapport coutefficacite de cette nouvelle strategie.

This work was dedicated to the development of a simple and direct multivariate UV spectrophotometric method for the simultaneous determination of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) in a new organogel formulation developed for their simultaneous transdermal administration. This method that does not require separation of the drugs and sophisticated instrument will permit to control quality of this new transdermal form both during the optimization step and for a further routine control of this preparation at the pharmacy department of the hospital. Hence, a partial least squares regression model using the spectral data record from 260 to 288 nm and 5 components, has firstly been validated thanks to the evaluation of the REP% (under 7.9%) and secondly using an accuracy profile approach (acceptance limit of ±10%). Thereby, the method allows the quantitation of the drugs in the ranges (5-15 mg L(-1)), (4-8 mg L(-1)) and (20-50 mg L(-1)) for ondansetron, dexamethasone and aprepitant, respectively. An HPLC/UV reference method has also been developed. Optimal separation (2.52Rs9.49) of the three drugs and their internal standards has been obtained in less than 15 min with a C18 stationary phase using a gradient separation protocol. This method has been validated similarly for the quantitation of ondansetron, dexamethasone and aprepitant in the ranges (0.3-3.5 mg L(-1)), (0.2-10 mg L(-1)) and (3.5-35 mg L(-1)), respectively. Both methods used for quality control of an organogel pharmaceutical formulation, have shown recoveries between 95% and 105%, hence validating the UV/PLS method and the formulation preparation process. Lower limits of quantitation obtained with the HPLC/UV method will be in favor of its use for permeation studies.

Objective Stopping and restarting carrier fluid flow and performing simultaneous drug infusions can lead to hazardous disturbances in drug delivery. The present study was designed to assess in vitro whether using a multi-lumen infusion access device could prevent noradrenaline disturbances. Study design In vitro laboratory work. Methods Two infusion devices were studied: a standard device with a four-port manifold and a 150 cm extension line and a nine-lumen infusion device (Edelvaiss-Multiline®) with eight accesses connected to nine separate lumens in a single tube of 150 cm: seven accesses connected to seven peripheral lumens and one for the carrier fluid access connected to two lumens. Two experimental protocols of noradrenaline infusion were made: (a) drug flow rate change and (b) stop-and-go carrier fluid flows. Two parameters were studied: drug mass flow rate and flow change efficiency (FCE) 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. Results Variations in noradrenaline mass flow rate were more rapid with the Edelvaiss-Multiline® when the noradrenaline infusion rate was increased or decreased. FCE was significantly different from one infusion device to the other during both noradrenaline flow rate increase (standard vs. nine-lumen: 58% vs. 84%; P = 0.008) and decrease (175% vs. 108%; P = 0.008). Decreased drug delivery after stopping carrier fluid flow (standard vs. nine-lumen: 21% vs. 98%; P = 0.008) and sudden temporary increases on resumption (253% vs. 103%; P = 0.008) were reduced in magnitude and duration when using the Edelvaiss-Multiline® with a significant difference in FCE between the two infusion devices. Conclusions Using the nine-lumen infusion device reduces drug delivery disturbances during continuous intravenous infusion.

International audience; OBJECTIVE: We report preliminary results from use of a radioreceptor assay (RRA) to measure serum haloperidol levels and their relation to clinical response and adverse effects in 19 psychotic patients with positive symptoms treated with haloperidol. METHODS: Blood samples were taken on Days 7, 14 and 21. Clinical evaluation was based on the PANSS, and UKU scales. The D2 antidopaminergic RRA was used to measure haloperidol serum levels. RESULTS: Our results show a correlation between psychosis with positive symptoms assessed by positive scores in the PANSS and the serum drug level measured by RRA concentrations. The observed relationship made it possible to establish a therapeutic serum range of haloperidol equivalents 15-30 ng/ml-1. This range contained no "non-responders". Analysis of the correlation between each item on the positive subscale of the PANSS and the RRA concentration suggested that there was no specific symptom of psychosis closely related to RRA concentration during the first 15 days of treatment. In the third week, however, certain specific symptoms were closely connected to the RRA concentration. CONCLUSION: From these results, it can be concluded that antipsychotic activity can be related to blockade of serum D2 dopamine receptors. In future would be desirable to monitor neuroleptic treatment in this way. The study also showed that the antipsychotic treatment did not correct any specific component of the psychosis during the first stage of the treatment but that it did so at later times.

OBJECTIVES: The handling of antineoplastic agents results in chronic surface contamination that must be minimized and eliminated. This study was designed to assess the potential of several chemical solutions to decontaminate two types of work surfaces that were intentionally contaminated with antineoplastic drugs. METHODS: A range of solutions with variable physicochemical properties such as their hydrophilic/hydrophobic balance, oxidizing power, desorption, and solubilization were tested: ultrapure water, isopropyl alcohol, acetone, sodium hypochlorite, and surfactants such as dishwashing liquid (DWL), sodium dodecyl sulfate (SDS), Tween 40, and Span 80. These solutions were tested on 10 antineoplastic drugs: cytarabine, gemcitabine, methotrexate, etoposide phosphate, irinotecan, cyclophosphamide, ifosfamide, doxorubicin, epirubicin, and vincristine. To simulate contaminated surfaces, these molecules (200ng) were deliberately spread onto two types of work surfaces: stainless steel and glass. Recovered by wiping with a specific aqueous solvent (acetonitrile/HCOOH; 20/0.1%) and an absorbent wipe (Whatman 903®), the residual contamination was quantified using high-performance liquid chromatography (HPLC) coupled to mass spectrometry. To compare all tested cleaning solutions, a performance value of effectiveness was determined from contamination residues of the 10 drugs. RESULTS: Sodium hypochlorite showed the highest overall effectiveness with 98% contamination removed. Ultrapure water, isopropyl alcohol/water, and acetone were less effective with effectiveness values of 76.8, 80.7, and 40.4%, respectively. Ultrapure water was effective on most hydrophilic molecules (97.1% for cytarabine), while on the other hand, isopropyl alcohol/water (70/30, vol/vol) was effective on the least hydrophilic ones (85.2% for doxorubicin and 87.8% for epirubicin). Acetone had little effect, whatever the type of molecule. Among products containing surfactants, DWL was found effective (91.5%), but its formulation was unknown. Formulations with single surfactant non-ionics (tween 40 and span 80) or anionic (SDS) were also tested. Finally, solutions containing 10(-2) M anionic surfactants and 20% isopropyl alcohol had the highest global effectiveness at around 90%. More precisely, their efficacy was the highest (94.8%) for the most hydrophilic compounds such as cytarabine and around 80.0% for anthracyclines. Finally, the addition of isopropyl alcohol to surfactant solutions enhanced their decontamination efficiency on the least hydrophilic molecules. Measured values from the stainless steel surface were similar to those from the glass one. CONCLUSION: This study demonstrates that all decontamination agents reduce antineoplastic contamination on work surfaces, but none removes it totally. Although very effective, sodium hypochlorite cannot be used routinely on stainless steel surfaces. Solutions containing anionic surfactant such as SDS, with a high efficiency/safety ratio, proved most promising in terms of surface decontamination.

BACKGROUND: Drug incompatibility is a problem, especially when managing patients in intensive care units. We designed the present study to assess the impact of multilumen infusion access devices on the occurrence of known physical drug incompatibility through a controlled in vitro study. METHODS: Three infusion devices connected to a single-lumen catheter were studied: a standard set with 2-port manifold and 1-m extension set and 2 multilumen infusion access devices: a 3-lumen extension set and a 9-lumen extension set (Edelvaiss-Multiline™; Doran International, Toussieu, France). For the 9-lumen extension set, 3 infusion access combinations were studied. Furosemide, midazolam, and saline were infused simultaneously through 3 infusion devices. Three concentrations of furosemide were tested. The infusion rate of saline (carrier) was initially set at 100 mL/h and stepwise decreased by 10 mL/h until precipitate formation. Physical incompatibility was assessed by 2 tests: visual inspection and the subvisible particle count test according to the European Pharmacopeia. The lowest saline infusion rate to prevent visible precipitate and attain an acceptable particle count (i.e., to pass “the 2 tests”) was reported for each infusion set. RESULTS: The standard set revealed visible precipitate even at the highest saline flow rate (100 mL/h). The 3-lumen device prevented drug precipitation using the 2 lowest furosemide concentrations with a saline infusion rate that decreased with furosemide concentration. The 9-lumen infusion access device prevented drug precipitation whatever the furosemide concentration for 2 access combinations using saline infusion rates of between 20 and 60 mL/h but not for a third access combination, despite saline infusion rates equal to 100 mL/h. CONCLUSIONS: Infusion device characteristics appear to have an impact on the physical compatibility of the 2 drugs. Under specified conditions, the 9-lumen infusion access device prevents physical furosemide-midazolam incompatibility.

International audience; BACKGROUND: The objective of this randomized, prospective and controlled study was to investigate the ability of a closed-system transfer device (CSTD; BD-Phaseal) to reduce the occupational exposure of two isolators to 10 cytotoxic drugs and compare to standard compounding devices. METHODS AND FINDINGS: The 6-month study started with the opening of a new compounding unit. Two isolators were set up with 2 workstations each, one to compound with standard devices (needles and spikes) and the other using the Phaseal system. Drugs were alternatively compounded in each isolator. Sampling involved wiping three surfaces (gloves, window, worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicine and ganciclovir) was assessed on wipes by LC-MS/MS analysis. Contamination rates were compared using a Chi2 test and drug amounts by a Mann-Whitney test. Significance was defined for p

Contexte Au vu de l’augmentation d’utilisation des cytotoxiques et des effets sanitaires notamment cancerogenes, mutagenes et reprotoxiques rapportes, le service de medecine du travail du personnel hospitalier du centre hospitalier universitaire de Lille a souhaite optimiser sa demarche de prevention relative a la manipulation et dispensation des cytostatiques, sur les bases d’observations d’activites, et de resultats de metrologie surfacique et biologique. Methode L’evaluation de l’exposition a ete realisee, au sein de l’unite de reconstitution centralisee des cytotoxiques, et de 4 services de soins, administrant des cytotoxiques, par des prelevements urinaires (4 echantillons etages par agent : debut de cycle – debut de poste, avant-dernier jour du cycle – debut et fin de poste ; fin de cycle – debut de poste) et surfaciques, permettant l’identification de 10 molecules cytotoxiques d’interet (cyclophosphamide, ifosfamide, gemcitabine, ganciclovir, cytarabine, 5-fluorouracile, methotrexate, dacarbazine, doxorubicine, irinotecan). L’activite a ete analysee par auto-questionnaires, et etudes de postes. Resultats Trente-huit sujets volontaires ont ete inclus de novembre 2013 a novembre 2014 ; 31 % (n = 129/411) des resultats des prelevements surfaciques etaient superieurs ou egaux a la limite de detection (LDD) pour au moins l’une des molecules recherchees, et sur des surfaces inattendues, temoignant d’une contamination manu-portee, et de la remanence de certaines substances, malgre le nettoyage. Les niveaux maxima d’exposition mesures par molecule se repartissaient entre des traces (pour la doxorubicine), et 2746,1 ng/100 cm2 (pour le cyclophosphamide). Les resultats des dosages urinaires etaient tous inferieurs a la LDD. L’analyse des pratiques a identifie la categorie de personnel regroupant les agents de pharmacie, les aides-soignants, et les agents de services hospitaliers comme les moins formes et informes des risques lies a ces produits, de la conduite a tenir en cas d’exposition, ou d’incident. Conclusion En depit d’une contamination significative des surfaces, et d’une insuffisance de port d’equipements de protection individuelle dans la plupart des services, cette etude a confirme l’absence de contamination individuelle interne. Ce projet temoigne de la complementarite de la biometrologie et des prelevements surfaciques dans l’evaluation de l’exposition aux cytotoxiques et permet de disposer de donnees objectives pour sensibiliser le personnel expose lors du rendu des resultats collectifs et individuels. Il contribue au developpement d’outils utiles a la prevention des risques professionnels applicables en pratique courante en milieu de soins ou dans d’autres secteurs d’activite exposes.

The interactions between nine drugs (baclofen, bupivacaine, chlorpheniramine, ketoconazole, paliperidone, promethazine, propranolol, risperidone and verapamil) and six cyclodextrins (α-CD, β-CD, γ-CD, HP-β-CD, HP-γ-CD and Me-β-CD) or six polymers of cyclodextrins (polyα-CD, polyβ-CD, polyγ-CD, polyHP-β-CD, polyHP-γ-CD and polyMe-β-CD) were studied by affinity capillary electrophoresis and/or (1)H NMR at pH 2.5. An exhaustive qualitative study was performed through the determination of the retardation factor. Then, four compounds and both β-CD and polyβ-CD were selected for the quantitative study of the interactions at pH 2.5 and 7.0. By comparing the results obtained with the β-CD and polyβ-CD, it appears that the apparent binding constants are up to five times higher with the polymer. The 2D-NMR results seem to indicate that the structure of the polymeric network favours the inclusion of the guest in the hydrophobic cavity of the CD units. Moreover, the poly-CDs have shown very high enantioselective abilities at both pH.

Background Patients in intensive care units receive many drugs simultaneously but through limited venous accesses. Several intravenous therapies have to be administered through the same catheter, thus increasing the risk of physicochemical incompatibility. The purpose of this work was to assess and to quantify the impact of physical incompatibility on the mass flow rates of drugs infused simultaneously to the patient, through an in vitro study. Methods Furosemide-midazolam incompatibility was used to assess the impact of physical incompatibility on drug mass flow rates. Furosemide, midazolam, and saline were simultaneously infused. A filter was added at the end of the infusion line to retain visible particles. Two infusion conditions were tested with and without visible particles. A partial least square method on UV spectra was used to determine simultaneously the concentrations of the two drugs at the egress of the terminal extension line. The drug mass flow rate (expressed as mg/h) was calculated as the product of drug concentration versus total flow rate. Observed/theoretical mass flow rate ratios for each drug (%) were determined per infusion condition. Results Even in the absence of visible particles, precipitation of furosemide led to a drug loss estimated at between 10% and 15%. Furosemide is more impacted by interaction because the pH of the mixture is acid and this form is poorly soluble in an aqueous solution. Conclusions Physical incompatibility between furosemide and midazolam leads to a significant reduction in drug delivered to the patient and may result in treatment failure.

In a monocentric retrospective study, two tunneled hemodialysis catheters have been compared: a twin cylinder catheter (Dualcath) and a split tip catheter (Hemosplit).Patients who got catheters from January 1st 2007 to December 31st 2008 have been selected. Thrombotic events, as well as infectious events, were recorded in their dialysis file during this period of time.The study was carried out on 50 patients. Thirty of them were given Dualcath, 23 were given Hemosplit, and three both of them. A Kaplan-Meier analysis has enabled to draw up the catheter survival curves, and the log-rank test enables to establish a survival of 93.1% at 20 months for Dualcath while 42.2% for Hemosplit. As far as the thrombotic complications with catheter incident are concerned, their incidence is 25.5 and 46.4 out of 1000 catheter-days (P0,0001). The ones with catheter manipulation have incidences of 6.78 and 9.33 out of 1000 catheter-days, respectively for Dualcath and Hemosplit (NS). Dualcath presents catheter-related infections with a rate of 4.38 out of 1000-catheter days while 5.07 for Hemosplit (NS).The Dualcath catheter presents a better survival than the Hemosplit catheter as well as weaker incident type thrombotic complications.

Summary Background: Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients. Methods: Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other. Results: A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs. Conclusion: The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary.

The complexation of risperidone (Risp) and 9-hydroxyrisperidone (9-OH-Risp), atypical antipsychotics, with seven cyclodextrins (CDs) of pharmaceutical interest (native and hydroxypropylated (HP) alpha-, beta-, gamma-CDs and methyl (Me)-beta-CD) was studied by affinity capillary electrophoresis (ACE) and nuclear magnetic resonance spectroscopy (NMR) for acidic pH 2.5 and physiological pH 7.4. The 1:1 stoichiometry of the complexes was established by (1)H NMR spectroscopy using the continuous variation method developed by Job. The apparent binding constants of the 14 complexes at both pH were determined by ACE through the linear Scott's plots. The NMR spectroscopy investigation of the binding constants was achieved for the two CDs allowing the highest complexation: the beta-CD and Me-beta-CD. Both ACE and NMR spectroscopy studies provide similar conclusions by considering the influence of the 9-hydroxylation, the influence of the CD substitution and the influence of the pH. Moreover, the NMR spectroscopy results have allowed to suppose a pH-dependent inclusion mechanism. A thermodynamic study was then performed by ACE at both pH for the Risp.Me-beta-CD and 9-OH-Risp.Me-beta-CD complexes: the opposite signs of the entropic change (DeltaS degrees0 at pH 2.5 and DeltaS degrees0 at pH 7.4) confirms the influence of the pH on the complexation mechanism and the possible difference in the depth of the analyte inclusion in the hydrophobic cavity of the CD. Last, the two-dimensional ROESY (rotating-frame Overhauser spectroscopy) ((1)H-(1)H) and HOESY (heteronuclear Overhauser effect spectroscopy) ((19)F-(1)H) experiments have proved the inclusion of the aromatic part of the Risp and 9-OH-Risp in the hydrophobic CD cavity and lead us to propose a model of complexation.

An analytical method for the enantioseparation of the 9-hydroxyrisperidone, main metabolite of the antipsychotic risperidone (Risp), was developed by CD-EKC in the dual CDs mode using anionic and neutral CDs at acidic pH 2.5. Preliminary experiments allowed us to select the more suitable couple of CDs composed of sulfated-alpha-CD and hydroxypropylated-beta-CD. The optimization of the main experimental parameters (concentrations of both CDs and concentration of the phosphate buffer) was based on a central composite design through the response surface methodology. Then, the influence of the voltage and the temperature on the enantioseparation was studied using the classical univariate approach. The final method permits to resolve the enantiomers of the 9-hydroxyrisperidone with a resolution of 3.13 and an analysis time of about 13 min. Finally, this method was successfully applied for the simultaneous determination of Risp and the enantiomers of 9-hydroxyrisperidone (9-OHRisp).

The HPLC semipreparative enantioseparation of 9-hydroxyrisperidone (9-OHRisp) was studied by optimizing various experimental conditions: the nature of the chiral stationary phase (CSP), mobile phase composition, temperature and analyte loading. This semipreparative enantioseparation was successfully completed using the polysaccharide Chiralcel OJ chiral stationary phase and a n-hexane/ethanol/methanol (50/35/15, v/v/v) ternary mobile phase. To assess the enantiomeric purity of both isolated isomers, three analytical methods using UV detection were developed and validated: one CE method using dual cyclodextrin mode and two HPLC methods using either the Chiralcel OJ CSP in normal-phase mode or the alpha-acid glycoprotein (alpha-AGP) CSP in reversed-phase mode. The three methods make it possible to obtain excellent enantioseparations (R(s)3) with analysis times lower than 15 min, and the calculated limits of detection allow for the determination of minor enantiomeric impurities (0.1%). Enantiomeric purity obtained for dextrorotatory and levorotatory enantiomers was superior to 99.9% and equal to 98.9%, respectively, which proved the success of the semipreparative enantioseparation. A brief comparison of the performances of the analytical methods completes this work.

Introduction Un controle glycemique strict en postoperatoire immediat induit une morbi-mortalite plus importante [1] , l’hypoglycemie induite devenant alors un facteur de mauvais pronostic. Cependant, l’impact de la variabilite glycemique est beaucoup moins decrit. La pratique nous enseigne que les schemas d’administration de l’insuline laissent place a des variations glycemiques importantes avec apparitions d’hyperglycemies, parfois majeures. L’objectif de cette etude etait de demontrer qu’une variabilite glycemique importante en postoperatoire immediat majorait le risque de complication. Materiel et methodes Tous les patients hospitalises en unite de soins intensifs postoperatoire entre septembre 2012 et decembre 2013 ayant beneficie d’une chirurgie abdominale lourde, ont ete inclus apres obtention d’un consentement eclaire. Cette etude prospective, randomisee, en ouvert, a ete acceptee par un comite de protection des personnes. Les patients recevaient des leur admission et pendant 48 h de l’insuline perfusee en continu avec adaptation des posologies selon les resultats des mesures de glycemie capillaire realisees toutes les 3 h. L’objectif glycemique etait compris entre 140 et 180 mg/dL. La variabilite glycemique des patients a ete calculee a partir de l’index GLI (Glycemic Lability Index) [2] ( Fig. 1 ) sur ces valeurs de glycemie. Les complications (cardiovasculaires, respiratoires, infectieuses et chirurgicales), quant a elles, ont fait l’objet d’un recueil sur dossier retrospectivement. Le lien entre l’index GLI et les complications a ete analyse a l’aide d’un test de Wilcoxon (p Resultats Parmi les 172 patients inclus, 157 etaient exploitables. La population etait homogene. Le taux de mortalite etait de 5,73 %. Cent trois patients (65,60 %) ont presente au moins une complication dont 22,33 % une complication cardiovasculaire, 44,66 % une complication respiratoire, 63,10 % une complication infectieuse et 35,92 % une complication chirurgicale. Le score GLI (moyenne ± deviation standard) apparaissait significativement different entre le groupe avec complications et le groupe sans complication ( Tableau 1 , Fig. 1 ). Discussion Cette etude met en relation la variabilite glycemique avec un risque accru de survenue de complications en postoperatoire. Toutefois, un controle glycemique strict induit une morbi-mortalite plus importante [1] . Si l’objectif de maintien d’une faible glycemie (comprise entre 120 et 140 mg/dL) est aujourd’hui abandonne, il conviendrait d’adapter nos pratiques afin de limiter les variations glycemiques. Identifier les mecanismes responsables d’une plus grande variabilite glycemique ainsi que les moyens a disposition pour y remedier doit faire partie aujourd’hui de nos preoccupations.

Background Closed-system transfer devices (CSTD) are promoted in all recommendations to reduce the occupational exposure to antineoplastic drugs during the compounding process. Numerous in vitro studies have shown that using the PhaSeal system may limit chemical contamination. Purpose To compare the chemical contamination inside isolators between a standard (S) and a PhaSeal (P) compounding process in routine practice. Material and methods A 6-month prospective study started at the opening of a new compounding unit (checked as not contaminated). Two isolators with 2 workstations were used, one to compound with standard devices (needles and spikes) and the other one using the PhaSeal devices. Drugs were alternatively compounded in each isolator (90 preparations/day). Sampling was performed by wiping three surfaces (gloves, window (inner surface), worktop), before and after a cleaning process. Exposure to ten antineoplastic drugs (cyclophosphamide, ifosfamide, dacarbazine, 5-FU, methotrexate, gemcitabine, cytarabine, irinotecan, doxorubicin and ganciclovir) was evaluated on wipes by LCMSMS analysis. Contamination rates (% of samples revealing contamination) were compared using a Chi 2 test and the drug amounts by a Mann-Whitney test. Significance was defined as p Results 655 samples were analysed (P: n = 327, S: n = 328). The amounts of drugs compounded in each isolator were not significantly different, excepted for methotrexate. The overall contamination rate before cleaning was significantly lower in the PhaSeal isolator (P: 12.6% vs. S: 25.4%; Conclusion This study demonstrates that using a CSTD significantly reduces the overall contamination without cancellation. This intermediate analysis will be implemented by an analysis of the drug amounts handled and the occurrence of incidents. Reference Sessink PJ, Trahan J, Coyne JW. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. Hosp Pharm 2013;48(3):204–12 Conflict of interest

Background Drug incompatibilities, such as precipitates, may contribute to the clinical deterioration of paediatric patients (sepsis), especially when infusing vancomycin and piperacillin (VAN/PIP). Drug concentration and infusion sets affect the overall particulate contamination of paediatric infusion protocols. Using multilumen infusion sets could prevent these incompatibilities. Purpose To define and assess a new way to infuse VAN/PIP during leukaemia treatment in paediatric patients, without any visible precipitate. Material and methods Two infusion sets were studied, which differed in design and drug dead-space volume (V): 1) a standard single lumen set with 2 four-port manifolds with extension lines (ref RPB4320, Cair LGL, France; V ∼ 12 mL) and 2) a 5-lumen infusion set (ML-5) (Edelvaiss-Multiline, Doran International, France; V ∼ 1 mL). Different vancomycin concentrations (VANc) were tested to infuse VAN/PIP simultaneously without any precipitate (optimised multidrug protocol). A dynamic particle count test was performed (N = 5) over 24 h to evaluate the overall particulate contamination of our standard (VANc = 42 mg/mL) and optimised (VANc = 4 mg/mL) protocols, using both standard and ML-5. We performed a t-test. Results No visible particles were detected on reducing VANc (4 mg/mL) instead of the standard dose (42 mg/mL). For the optimised multidrug protocol, using the ML-5 reduced the overall particulate contamination by 68%, compared to the standard infusion set (716,349 ± 89,322 vs. 251,980 ± 49,429; p = 0.002). The number of large particle sizes was significantly reduced when using the ML-5 ∼ 60% (p = 0.027) and 90% (p = 0.009) for particle sizes ≥10 and 25 µm, respectively. Conclusion This study demonstrated the large number of particles administered during parenteral multidrug infusion. This can be minimised through the choice of the drug concentration and/or the type of infusion set. Although this kind of contamination is invisible, further studies are required to evaluate its adverse clinical impact. References and/or acknowledgements No conflict of interest.

Background For several years, many infusion systems have been marketed for the administration of antineoplastic drugs (AD). Purpose To compare the ability of these devices to deliver the expected volume of antineoplastic drug in solution. Material and methods Seven infusion devices were assessed (see table 1) by simulated infusions with a radiotracer ( 99m TcO 4 − ) as drug substitute. The same activity (370 MBq) was diluted in 250 mL 0.9% NaCl bags. The evolution of the drug concentration at the egress of the infusion system was recorded continuously with a sodium iodine crystal detector. The area-under-curve of drug concentration according to time of both administration (AUC adm ) and rinsing (AUC rin ) steps were calculated using the linear trapezoidal rule after correcting for radioactivity decay. The rinsing volumes (V rin ), volumes required to get no more radioactivity, were measured in a graduated test tube. The values were compared using a Kruskall-Wallis test (p Results Despite the differences in dead-space volume, AUC adm were not significantly different (see table 1). The rinsing volumes were significantly different between the tested devices, ranging between 46.8 ± 5.7 mL and 92.2 ± 8.9 mL. Conclusion The rinsing conditions required to administer the same dose are really different between devices. The impact of good handling practice of these devices has to be assessed on the pharmacokinetic parameters. Reference Kontny NE, Boos J, Wurthwein G, et al . Minimization of the preanalytical error in pharmacokinetic analyses and therapeutic drug monitoring: focus on IV drug administration. Ther Drug Monit 2012;34:460–6 No conflict of interest.

Background Medicines Reconciliation on Admission (MRA) aims to identify and solve Unintended Medicines Discrepancies (UMDs) defined as differences between the home treatment prescription and the first hospital prescription. Purpose To assess the impact of MRA on UMDs and to identify risk factors for the development of UMDs. Material and methods This retrospective study was conducted in six services: vascular surgery, geriatrics, haematology, infectious diseases, nephrology and urology. Pharmacy students, who were supervised by clinical pharmacists, performed MRA within 48 h of the patient’s admission. Students asked the patients about the treatment prescribed at home, self-medication, allergies, adverse events and therapeutic adherence. Students called community pharmacists to get information on the drugs dispensed in the last 3 months and collected further information from other sources: the patient’s medical record, an interview with the family, letters from community doctors. Two pharmacists retrospectively assessed the potential harm of each UMD (high, moderate or minor risk). Correlations between the parameters were tested statistically. Results In 2013, 645 patients were enrolled (5,673 medicines analysed). 23.4% of patients had at least one UMD and 10.1% of patients had at least three UMDs. Of the UMDs detected, 47.3% were associated with a moderate to major risk for the patient. The number of lines on the home treatment prescription was a risk factor for UMD, as was the type of service in which the activity took place (R = 0.1918; p Conclusion MRA is a useful process for detecting UMDs. Pharmacy students sometimes have trouble identifying UMDs, so it is necessary to supervise them. MRA will develop in parallel with the use of new information technologies for communications. It plays a role in structuring the “community-hospital” link. References and/or Acknowledgements I would like to thank all those who worked on this project. No conflict of interest.

Background The indicatons for rituximab in haematology are classified into 3 categories: group 1: indications for which the medicine was initially marketed (MA), group 2: additional recommendations for temporary use (RTU), and group 3: indications that are not authorised or are lacking sufficient documentation for authorisation by the French Medicines Agency (ANSM), but for which the medicine can be used based on the literature and recommendations. We have a prescription form in which all of the drug’s indications authorised by the ANSM (group 1 and 2) are already written and classified, to encourage safe use of medicines. Purpose To check if rituximab prescriptions for these indications reflect the actual use of the drug. Material and methods For each prescription of rituximab from January to April 2014, we compared the indication on the prescription to the one in the patient’s files (multidisciplinary meetings reports and discharge letters). Every indication was classified by group and we analysed the divergence. Results In our cohort of 52 patients, 80.8% were in prescription group 1, 3.8% in prescription group 2, and 15.4% in prescription group 3. We calculated a 25% divergence between the prescribed indication and the actual one. 16.66% of prescription group 1 and 100% of prescription group 2 indications were in reality group 3 indications. 52.94% of real group 3 prescriptions were not declared as such. Conclusion This study might question the safety of prefilled prescriptions because doctors might supply incomplete information and pharmacists might therefore approve dispensing of this medicine for incorrect indications. In order to improve safety, we suggest a new kind of prescription form in which all of the medicine’s indications are written without being classified and with more blank spaces to allow the doctor to give additional information about the chemotherapy, the state of the cancer and the number of relapses. References and/or acknowledgements Thanks to my supervisors for their support and advice. No conflict of interest.

The possible involvement of P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 in risperidone transport was investigated using in vitro and in vivo models. Firstly, uptake studies were performed on a Caco-2/TC7 cell monolayer; the effects of 1 microg ml(-1) risperidone on apparent permeability were determined for secretory and absorptive directions, in the presence or absence of various P-gp and CYP3A4 inhibitors (verapamil, ketoconazole, erythromycin), and of an associated multidrug-resistant protein inhibitor (indomethacin). Secondly, on a conscious rat model, risperidone pharmacokinetic parameters, notably absorption parameters, were determined using compartmental and deconvolution methods. Three groups of seven rats received respectively an IV risperidone dose, an oral risperidone dose (PO group) and the same oral risperidone dose after verapamil administration (POV group). No formation of 9-hydroxyrisperidone was observed on Caco-2 cells after risperidone administration; there was no evidence that intestinal CYP3A4 is involved in risperidone metabolising. Risperidone secretory permeation was higher than absorptive permeation. Verapamil increased risperidone absorption permeation and decreased its secretory permeation. Indomethacin did not modify these permeation values. In rats, verapamil led to an increase in both risperidone and 9-hydroxyrisperidone plasmatic concentrations. The fraction absorbed in the verapamil group was 3.18 times higher than in the oral group (65.9% and 20.7% for POV group and PO group). The absorption rate constant was lower in the verapamil group. Our results indicate that P-gp decreases the intestinal absorption of risperidone and that intestinal CYP3A4 is not involved in risperidone metabolism.

Summary New treatments for relapse of acute myeloid leukaemia (AML), include gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody. We describe a second case of GO-induced sinusoidal obstructive syndrome (SOS) effectively treated with defibrotide (DF). No stem-cell transplantation was involved. On day 23 after the first GO dose, a patient presented with ascites, weight gain, liver enlargement and pain in the right upper quadrant. Sudden hepatic cytolysis (transaminases at six times the normal range: grade 3) and cholestasis [alkaline phosphatase ALP and gamma-glutamyltransferase (GGT) respectively at four and eight times the normal range: grade 2] were observed but there was no evidence of increase serum bilirubin. Treatment with DF (Prociclide®, Crinos; 10 mg/kg/day, or 200 mg, q.i.d.) improved the hepatic abnormality within a few days (serum transaminases decreased from 312 to 103 IU/L for aspartate aminotransferase (AST) and from 141 to 80 IU/L for alanine aminotransferase (ALT) within 3 days ALP increased from 253 to 383 IU/L and gamma-GT from 238 to 417 IU/L 4 days after administration of DF. The clinical and biological features of our case suggest a direct involvement of GO in causing SOS, even when used as monotherapy, without allogenic stem-cell transplantation. Low dose DF (10 mg/kg/day) given early during the development of SOS associated with GO was effective. Unfortunately, in our case the patient eventually died of multi-organ failure probably because of failure of GO.

Nimesulide is a typical nonsteroidal anti-inflammatory drug (NSAID), widely used in solid oral formulations. By crystallizing nimesulide from an ethanol solution a crystalline form was obtained, different from the reference sample, as confirmed by X-ray powder diffraction (XRPD), Differential Scanning Calorimetry (DSC) and solid cross polarization-magic angle spinning ((13)C-CPMAS) NMR. Moreover, when crystallized from dioxane nimesulide forms a solvate. The solvate was characterized by XRPD, IR-spectrometry, DSC, thermo-gravimetric analysis (TGA) and by (13)C-CPMAS NMR. In particular, through this technique, the presence of several conformational isomers was demonstrated. In addition to the physico-chemical characterization, the technological properties of nimesulide, namely densification and tableting, were evaluated. Contrarily to the other forms that are affected by capping phenomena at increasing compression pressures, the form obtained by desolvation of dioxane solvate has positive effect on tableting properties, increasing both compressibility and tabletability of nimesulide.

Introduction et but de l’etude Dans le cadre d’un appel d’offre national, nous avons realise une evaluation technique ainsi qu’un essai de manipulation des poches de nutrition parenterale (NP) disponibles sur le marche. L’objectif etait de verifier la conformite des poches de NP aux normes existantes et d’apprecier le temps et la facilite de remise en melange des poches compartimentees. Materiel et methodes 42 specialites pharmaceutiques provenant des 3 laboratoires fournissant ce type de specialite ont ete evaluees. Pour chaque type de poche, 3 tests in vitro ont ete effectues en triplicate : 1) mesure du volume extractible selon la Pharmacopee europeenne ; 2) test de mise en place du perfuseur : mesure de la force necessaire pour percuter les poches de NP selon la norme NF EN ISO 15747 ; 3) test de tenue du perfuseur : mesure de la force necessaire au retrait du perfuseur selon la norme NF EN ISO 15747. Ces 2 derniers tests ont ete realises avec les 2 tubulures pour pompe les plus utilisees dans notre hopital a l’aide du dynamometre Mecmesin multiTest-1 sur banc test motorise avec capteur de force ILC 250N pilote par le logiciel Emperor. La remise en melange des poches compartimentees a ete evaluee par 12 a 18 manipulateurs qui apres avoir lu la notice, devaient reconstituer une poche de chaque type et quotter sur une echelle de Likert en 5 points (1 = complique, 5 = tres facile) la clarte de la notice, la pelabilite, la facilite de rupture des soudures internes, de remise en melange et de suspension de la poche. Les temps de lecture des instructions de la notice et de preparation de la poche etaient chronometres. Resultats et Analyse statistique Toutes les poches etaient conformes aux referentiels utilises : aucun volume mesure inferieur au volume nominal de la poche et tous les couples percuteur/cheminee testes respectaient les normes en terme de force de penetration (F 15N). Le test de remise en melange a montre des disparites concernant les appreciations et les temps de manipulation entre les gammes. Les 2 gammes de poches bicompartimentees ont obtenu une appreciation generale similaire (3,64 et 3,78 ; Student bilat. α = 0,05 ; p = 0,591), mais des temps de manipulation differents (111,00s vs 70,22s ; Student bilat. α = 0,05 ; p = 0,004). Deux gammes de poches tricompartimentees pour administration par voie centrale presentaient des appreciations generales differentes (4,06 vs 3,17 ; Anova puis HSD Tukey, α = 0,05 ; p = 0,001) et un temps de manipulation different (80,89s vs 109,5s ; Anova puis HSD Tukey, α = 0,05 ; p = 0,048), la 3 e gamme presentait des resultats non differents des 2 autres. Une des 3 gammes de poches tricompartimentees pour administration peripherique a recu de meilleures appreciations (4,00 vs 3,13 et 2,67 ; Anova puis HSD de Tukey : α = 0,05 ; p 1 = 0,048 ; p 2 = 0,002) et un temps de manipulation inferieur aux 2 autres (75,33s vs 111,25s et 128,25s; Anova puis HSD de Tukey: α = 0,05; p 1 = 0,020 ; p 2 = 0,001) elles-memes presentant des resultats similaires. Conclusion Ces tests in vitro ont permis de verifier que l’ensemble des poches proposees par les fournisseurs etait conforme aux referentiels normatifs en terme de volume extractible et de relation percuteur/cheminee. Le test de manipulation a permis d’objectiver des disparites en terme de temps de manipulation et d’appreciation de facilite de remise en melange des poches compartimentees, etape delicate et chronophage pour les soignants.

A routine high-performance liquid chromatographic method for measuring midazolam in human serum has been developed. The sample preparation procedure consisted of simple liquid–liquid extraction with dichloromethane, followed by evaporation under nitrogen. The mobile phase used was a mixture of acetonitrile at 0.02 M and sodium acetate at pH 3.0 (80:20, v/v) and a flow-rate of 1.2 mL/min. The separation was performed on two cyanopropyl columns (150×4.6 mm). The detection was by UV absorption at 240 nm. A linear range from 10 to 1000 ng/mL and a quantification limit of 7.4 ng/mL of serum was reached. The mean intra-assay and inter-assay reproducibility from serum sample spiked with 100 ng/mL were 4.1 and 4.7%, respectively. The recoveries from serum sample spiked with 50, 100, 500 ng/mL were 85.46, 85.38 and 85.57%, respectively. This method was developed to allow pharmacokinetic study of midazolam in young patients in short surgical interventions. © 1997 by John Wiley & Sons, Ltd.

Summary Objective: To develop a model based on mean residence time for better understanding the effect of grapefruit juice on the metabolism of nifedipine (NIF). Material and methods: Sixteen healthy volunteers from an urban population were included. For each trial, the subjects drank water, fresh grapefruit juice or bottled grapefruit juice. Thirty minutes later, the subjects took a 10 mg capsule of NIF, orally. Plasma concentration of NIF was measured and the kinetic parameters were calculated with a non-compartmental model. Results: Grapefruit juice increased the bioavailability of NIF, but did not significantly reduce the drug's metabolism as shown by the approximately constant metabolite to parent drug AUC ratio (P = 0·948). There was no significant increase in the amount of non-metabolized drug absorbed during first-pass: 0·12 and 0·16 (P = 0·470) without and with grapefruit juices respectively. There was an increase in the relative bioavailability (P = 0·039) and the apparent volume of distribution (Vdm) (P =0·025) of dehydronifedipine with grapefruit co-administration. A second peak was also observed in the NIF plasma-concentration profile when the drug is co-administered with grapefruit juice. Therefore, the most likely explanation for the double peak phenomenon is a delay in gastric emptying (+32 min with grapefruit juice) caused by the pH of grapefruit juice. Conclusion: This study shows that grapefruit juice interferes with the metabolism of NIF by inhibiting NIF metabolism and slowing down the rate of gastric emptying. This study also confirms that the metabolic inhibition is not a first pass effect, but is a secondary oxidative step.

Introduction La noradrenaline (NA) est actuellement le vasoconstricteur recommande dans la prise en charge du choc septique. En raison de sa marge therapeutique etroite, le relai de seringues est une periode a risque d’instabilite hemodynamique. Deux techniques de relai de seringues sont couramment utilisees : la technique du clic-clac (Quick-change) consistant a remplacer la seringue vide par la nouvelle seringue sur un meme pousse-seringues (avec changement de prolongateur de seringue) et la technique du relai automatise sur une base intelligente (smart pump). Les donnees de la litterature se contredisent quant a la superiorite d’une technique sur l’autre. Ce travail a pour objectif de comparer in vitro ces deux techniques afin de determiner celle minimisant les variations de mise a disposition de la NA. Materiel et methodes Les seringues de NA (noradrenaline bitartrate, Mylan) (0,5 mg/mL-2 mL/h) etaient co-perfusees par pousse-seringues electriques (Station Orchestra, Fresenius) en Y avec des seringues de serum sale isotonique (Baxter) (5 mL/h) via un prolongateur a faible volume residuel (Vset + M, Doran International) [1] . La concentration de NA etait mesuree en continu, toutes les 10 secondes, pendant 4500 secondes, en sortie du systeme de perfusion via un spectrophotometre UV (UV2550, Shimadzu), de meme que le debit de perfusion par un debitmetre (Lagu, Metron) selon le meme intervalle de temps (n = 10). Le debit massique calcule correspondait au produit de la concentration mesuree par le debit mesure. Le changement de seringue etait realise selon l’une ou l’autre des deux techniques etudiees a 1800 secondes du demarrage de la perfusion. Le critere de jugement principal etait le temps d’obtention de l’equilibre du debit massique de NA apres un relai effectue par une des deux techniques (T1). Le critere de jugement secondaire etait : le ratio exprime en % entre la quantite experimentale de NA perfusee au cours du relai et la quantite theorique, les quantites etant determinees a partir de l’aire sous courbe de la courbe debit massique en fonction du temps. Les resultats (mediane [min–max]) etaient compares par un test de Mann–Whitney (p = 0,05). Resultats La technique de relai n’influence pas de maniere significative le delai d’obtention de l’equilibre massique de la NA. En revanche, la quantite de NA est significativement plus importante que la quantite theorique lors d’un relai opere selon la technique du clic-clac. Cette derniere est realisee plus rapidement que la technique smart pump ( Tableau 1 et Fig. 1 ). Discussion Ce travail montre de maniere experimentale que la technique de relai de la NA influence le debit massique du principe actif. Aussi, le relai automatise par la technique de smart pump est associe a un meilleur controle des quantites administrees de catecholamines que la technique manuelle (clic-clac). La technique automatisee semble donc meilleure pour limiter l’instabilite hemodynamique et les effets deleteres. La reproductibilite de ces donnees selon le type de stations de perfusion reste a demontrer.

Background Intraspinal administration errors are identified in the list of ‘never events’ of the French Health Authority (ANSM). New devices with different connectors incompatible with standard Luer-lock connectors (Univia syringe, Becton-Dickinson) could be used to make the spinal administration of cytotoxic drugs safer. Purpose To perform a feasibility study regarding to the minimum capacity (2 mL). Materials and methods A comparative study between Univia (U, 2 ml) and Tuberculin (T, BD) syringes was performed. Volumes of water (0.6mL, 0.48mL, 0.15mL, 0.1mL) simulating usual volumes of cytotoxics were measured by an operator and weighed on a precision scale (n = 30). For each volume, accuracy (%) and precision (CV%) were determined. A difference of 10% from the nominal volume was the chosen threshold. Results For U, the accuracy was 0.2%, 6.5%, 11.2% and 21.8% for 0.6, 0.48, 0.15 and 0.1 mL, respectively. It was 1.2%, 2.0%, 6.1% and 6.1% for T. For U, the precision was 2.4%, 2.3%, 5.9% and 6.2% for 0.6, 0.48, 0.15 and 0.1 mL, respectively whereas it was 1%, 1.0%, 7.3% and 8% for T. Accordingly, the volumes of 0.6 and 0.48 mL may be prepared with U. For both, 0.15 and 0.1 mL, a transfer step with a tuberculin syringe increases both accuracy (3.9%) and precision (3.9%). Conclusions This study suggests the possibility of using U to compound cytotoxic drugs for intraspinal injection. It remains to evaluate the practical constraints related to the administration. No conflict of interest.

Background Polyvinyl chloride (PVC) infusion tubes are too widely used in our hospital. Even in intensive care units (ICU), PVC is commonly used although polyethylene (PE) is specifically recommended to limit container-content interactions. For example, insulin is used to achieve tight glucose control in ICU patients. Its adsorption on PVC is well known, but rarely considered in the choice of infusion device when nurses compose their infusion assemblies. Purpose This model of interaction was used as a tool, to educate nurses in the issue of choosing the right equipment and to illustrate the clinical impact of an unsuitable medical device in the administration of a drug. For this, we showed healthcare workers how the insulin concentration changed by comparing the infusion between two devices available in our hospital. Materials and methods ICU nurses prepared 40 mL insulin syringes (1 IU/mL) according to the ICU preparation protocol. The concentration was determined by UV-spectrophotometry at 4 points in the syringes to assess their homogeneity and dose accuracy. Then, PVC and PE syringe extension lines (SEL, L:150 cm, ID:1 mm) used in our hospital were evaluated. Firstly, each SEL was filled with 1 IU/mL insulin solution and closed with Luer-lock plugs. Measurements were achieved after 15 and 60 min of contact. Secondly, the insulin levels were measured at the egress of both SEL every 5 min over a 24 h time period at a flow rate of 2 mL/h. Results were expressed as a percentage of the theoretical value. All experiments were repeated 5 times. Statistical comparisons were performed with a Mann-Whitney test (p = 0.05). Results Eleven nurses prepared 48 insulin syringes with an average proportion of 100.6 ± 3.9% of the theoretical value in all points of the syringes. After 15 min of contact, the insulin levels dropped significantly in PVC SEL compared to PE SEL (46.2 ± 2.4% vs 98.4 ± 1.7%, p = 0.01, respectively). The level continued to drop at 60 min (30.1 ± 4.0% vs 96.0 ± 0.6%, p = 0.01, respectively). During infusion tests, the insulin concentration after a 24 h infusion was only 64.6 ± 2.0% using PVC SEL whereas it was maintained at 101.7 ± 0.8% with PE SEL (p = 0.01). Conclusions A paradoxical situation exists in the insulin infusion context. Although this interaction with PVC is well documented and confirmed by this study, ICUs still use it. This study allowed us to demonstrate that even if the preparation process is performed correctly and the concentration is homogeneous, PE SEL are really more suitable for insulin administration and must replace PVC SEL. The use of such a tool may help pharmacists in the ongoing education of nurses. Other drugs are being considered to enhance the study and to support our infusion training group. An evaluation of the impact of our training course on daily practice is planned. No conflict of interest.

Objective Aspirin administered orally is one of most widely self-prescribed drugs to treat headaches or other pains. The aim of this study was to evaluate whether the influence of different beverages may be used to help in the ingestion of an aspirin tablet on the pharmacokinetic parameters of this drug. Method This study was undertaken in five healthy volunteers. Seven beverages were tested: water, tea, coffee, orange juice, milk, beer and 40 degrees distilled alcohol. After plasma extraction, aspirin and salicylic acid were measured by HPLC with UV detection. The main pharmacokinetic parameters were determined by the compartimental method and drug disposition profiles by the Wagner-Nelson modified method. Results Elimination was not modified by any of the beverages but absorption was affected. Two opposing effects were observed: 40 degrees alcohol seemed to increase AUC and Cmax. Milk and beer seemed to decrease these parameters. With 40 degrees alcohol and tea, the amount absorbed and the disposition rate were higher. For milk and orange juice, the amount absorbed was lower and the disposition rate was unaffected. For beer, both the amount absorbed and the disposition rate increased. For coffee, both the amount absorbed and disposition rate were not significantly modified. Conclusion The bioavailability of salicylates on the healthy volunteers in this study was significantly affected by concomitant administration of 40 degrees alcohol (spirit), beer and milk. The beverages seem to interfere with aspirin absorption and the drug disposition profile was modified.

In France, the legal routes used to administer midazolam to a patient are intravenously and intramuscularly. For anaesthetists, these routes are not well adapted to paediatric use; they lead to pain at injection site and stress on children. The sublingual route should be a good compromise between stress and quick efficiency. We have developed a sublingual tablet of midazolam. The aim of the present investigation is to compare the pharmacokinetic parameters of midazolam tablets administered by the sublingual and intravenous routes in 6 rabbits to determine the bioequivalence between these routes. We have estimated the 1-hydroxy-midazolam serum level by difference between RRA and HPLC values. By the sublingual route, midazolam absorption is substantial and fast. The statistical analysis, on data obtained with HPLC dosage, shows no significant difference between pharmacokinetic parameter values calculated after intravenous and sublingual administration (0.5 mg). The absolute bioavailability was close to 100%. With RRA dosage, however, AUCs were greater than those obtained by HPLC dosage (174%). 1-hydroxy-midazolam seems to have a great importance in BZD activity. To estimate the bioequivalence between intravenous and sublingual midazolam administration, it is necessary to take into account the active metabolites.