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Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects. Methods: Twelve fetal lambs (127–133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored. Results: The transplacental sildenafil transfer was 2.9% (range: 1.4–7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38–78%) and increased both pulmonary blood flow (32–132%) and heart rate (13–49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion. Conclusion: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe.

International audience; The use of immunomodulatory and/or immunosuppressive therapy (IT) is increasingly common in the management of chronic inflammatory disease. Skin reactions to any drug (IT or not) are not rare in these patients, justifying allergological investigations. The influence of IT on allergological tests for drugs is not clearly described. IT cannot be interrupted due to the underlying disease. The data assessing the benefit and the safety of allergological test for drug allergy in patients under IT are missing.

Errors in injectable preparations with high-risk drugs can be fatal. This study aimed to identify the factors influencing the accuracy of high-risk injectable drug concentrations in appliances used for intensive care unit preparation practices. Norepinephrine (NE) was chosen as an example of a high-risk medication drug. The concentration (0.2 and 0.5 mg/mL), the diluent (sodium chloride 0.9% and 5% dextrose), and the container type (prefilled- and empty-infusion bag and syringe) were tested as potential variability factors. An ultraviolet spectrophotometric method was used for NE dosage. 108 NE solutions were prepared by five individuals (pharmacists or laboratory technicians) with clinical experience as well as experience in the aseptic preparation of solutions. The container type was found to be the only factor influencing the accuracy of NE concentration. NE solutions in syringes proved to be the most accurate while preparations in prefilled bags tended to underdose NE.

Objectives Norepinephrine is a vasopressor frequently administered after dilution to treat hypotension and shocks in intensive care units. The stability of norepinephrine is known to be highly sensitive to storage conditions. Moreover, medication errors linked to the dilution step are frequent and may be deleterious for critically-ill patients, especially in intensive care units. This study aimed to evaluate the stability of ready-to-use diluted norepinephrine solutions prepared at two target concentrations (0.2 and 0.5 mg/mL), according to the summary of product characteristics, and stored for 365 days in two containers: AT-closed cyclic olefin copolymer vials, and polypropylene syringes. Methods A fast reversed-phase liquid chromatography method coupled with an ultra-violet detector was developed to assess the chemical stability of norepinephrine solutions. Validation was conducted according to the linearity of the calibration ranges, selectivity, sensitivity, accuracy and precision. Dosage, sub-visible particle contamination, pH monitoring and sterility assays were performed. Chemical stability was maintained if the measured concentration respected the lower limit of 90% of the initial concentration. Containers were stored at −20±5°C, +5±3°C and +25±2°C with 60±5% relative humidity in a dark closed enclosure. Results Stability was successfully maintained for every concentration and container tested when stored at −20±5°C and +5±3°C. In these storage conditions, particle contamination, pH monitoring and sterility assay respected the required criteria. Chemical degradation and colouring of solutions appeared before the end of the 1 year study period for most norepinephrine solutions stored at room temperature. Conclusions Ready-to-use solutions containing 0.2 and 0.5 mg/mL norepinephrine in polypropylene syringes or cyclic olefin copolymer vials must be stored at refrigerated or frozen temperatures to obtain acceptable 1 year shelf-stability. Exposure to higher temperatures significantly decreases shelf-stability. Our study protocol for compounding polypropylene syringes and cyclic olefin copolymer vials containing norepinephrine is adapted to implementation in centralised intravenous additive services.

Vancomycin hydrochloride is an antibiotic belonging to the glycopeptide family and acts by inhibiting the synthesis of the peptidoglycan wall. This antibiotic is active against Gram-positive aerobic and anaerobic bacteria1 2 and is commonly used in hospitals to treat serious infections.3 4 Vancomycin has slow bactericidal time-dependent activity and can be administered by continuous or intermittent intravenous infusion. In France, administering vancomycin by continuous infusion over 24 hours is recommended.5 6 The Summary of Product Characteristics (SmPC) recommends reconstituting a 1 g vial with 20 mL of water for injection (WFI), then diluting it in 100 mL of saline solution. The amount of vancomycin to treat an adult infection is superior to 1 g and so the volume administered can be higher than 100 mL. This volume must be limited in children or in patients on water restriction, such as those suffering from hyponatraemia and cardiovascular diseases or are in intensive care.7 Some studies on vancomycin stability have already been performed. Solutions at 5 and 10 mg/mL were stable for 58 days at +4°C in 100 mL polyvinyl chloride (PVC) infusion bags with no specification with regard to protection from light.8 Vancomycin was stable at 5 mg/mL in PVC bags for 48 hours at +22°C without protection from light and for 7 days at +4°C with protection from light.9 Raverdy et al 10 examined the stability of vancomycin diluted in 5% dextrose at high concentration (83 mg/mL) and was stable for 72 hours at +37°C. However, none of these studies reflects real infusion conditions as vancomycin is usually administered at 30 mg/kg/day.11 12 In practice, clinical services infuse vancomycin into electric syringe pumps using 50 mL (for adults) or 20 mL (for children) syringes. No stability study has yet been performed for such concentrations, in 50 or 20 mL syringes, at room temperature, nor has the reconstitution procedure13 been …

BACKGROUND: Transforming a drug from its commercial form into a ready-to-use drug is common practice, especially in pediatrics. However, the risk of compounding error is real and data on drug stability in practice are not always available. OBJECTIVE: The aim of this study was to assess, in real conditions, both the error rate and stability of three drugs: ketamine, remifentanil, and sufentanil. METHODS: A new rapid and easy-to-use high-performance liquid chromatography method with a diode array detector has been developed and validated to quantify these drugs and detect their degradation products. Over a 1-month period, 151 syringes were collected in the postanesthesia care unit. Seventy-three were stock solution syringes containing a 10-fold dilution of commercial drugs and 78 were serial dilution syringes made from successive dilutions of stock solutions. A comparison between real and expected concentrations as well as the detection of possible degradation products was carried out on these samples. RESULTS: All stock solution syringes had good chemical stability throughout the working day. A 4-µg/mL remifentanil serial dilution syringe, however, had to be discarded as a degradation peak was detected. Overall, 15.3% (95% CI, 9.5-21.1%) of syringes had a drug concentration outside the ±10% acceptability range, that is, 11.0% (95% CI, 3.7-18.2%) and 19.5% (95% CI, 10.6%-28.4%) of stock and diluted syringes respectively, with drug amounts ranging from -25.3% to 22.0%. The highest error rates were observed with sufentanil syringes: 20% and 28% for stock solution and serial dilution, respectively. CONCLUSIONS: The study shows that stock solution syringes prepared in advance are chemically stable throughout the day, unlike certain serial dilution syringes, indicating that the latter should be prepared just before administration to ensure chemical stability. Our results show that the error rate for serial dilution syringes is twice that of stock solution. Different safety measures are under discussion and have to be further studied.

Background: Parenteral nutrition (PN) is a complex medium in which added insulin can become unstable. The aim of this study is, therefore, to evaluate the stability of insulin in PN and to identify influencing factors. Methods: A total of 20 IU/L of regular insulin was added to PN in either glass or Ethylene Vinyl Acetate (EVA) containers. A 24 h stability study was performed via an electrochemiluminescence immunoassay in different media: A ternary PN admixture, separate compartments of the PN bag and a binary admixture. This study was repeated in the absence of zinc, with the addition of serum albumin or tween and with pH adjustment (3.6 or 6.3). Insulin concentration at t time was expressed as a percentage of the initial insulin concentration. Analysis of covariance (ANCOVA) was applied to determine the factors that influence insulin stability. Results: In all PN admixtures, the insulin concentration ratio decreased, stabilising at a 60% and then plateauing after 6 h. At pH 3.6, the ratio was above 90%, while at pH 6.3 it decreased, except in the amino acid solution. ANCOVA (r2 = 0.68, p = 0.01) identified dextrose and pH as significant factors influencing insulin stability. Conclusion: A low pH level seems to stabilise insulin in PN admixtures. The influence of dextrose content suggests that insulin glycation may influence stability.

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient’s respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

The use of long-term taurolidine locks (LTTL) seems to be effective in preventing catheter-related blood stream infections (CRBSI), especially in patients on home parenteral nutrition (HPN). This work targets the cost-effectiveness of LTTL in a cohort of adult HPN patients.A monocentric mirror-image design study was conducted in our referral centre among long-term HPN patients experiencing recurrent CRBSI. From 7th January 2011, LTTL were started after the third CRBSI episode within 12 months. CRBSI data was prospectively collected until 7th January 2013, in the same way as it had retrospectively been done before initiating LTTL. A cost-effective analysis was conducted to estimate the incremental costs and effects on CRBSI with LTTL. The efficacy of LTTL on CRBSI rate was assessed over 1000 days of catheter use.A total of 31,100 catheter days were analysed in 37 patients (median [interquartile range (IQR)]) aged 58 [42-68] years. The mean ± SD proven CRBSI rate was 3.18 ± 3.51 per 1000 catheter days before the introduction of LTTL and 0.39 ± 1.50 per 1000 catheter days after its introduction (p 0.0001). Considering both proven and probable CRBSI requiring hospital management, LTTL reduced by (mean [bootstrap CI 95%]) -2.63 [-3.26 to -2.06] infections per patient (from 2.89 [2.31 to 3.49] before to 0.26 [0.13 to 0.41] after) as well as incremental costs by -7 258 [-10 450 to -4 016] € (from 11 176 [8 004 to 14 968] € before to 3 918 [2 390 to 5 445] € after).Implementing LTTL to prevent recurrent CRBSI is cost-effective by dramatically decreasing their incidence.

Insulin aspart (Novorapid) is a rapid-acting insulin analog that is maintained in hexameric form by phenolic preservatives (phenol and metacresol) and stabilized by insulin-zinc complex. According to the manufacturers, insulin can be independently diluted either in 5% dextrose solution (D5%) or 0.9% sodium chloride solution. In reality, in most clinical units, such as the neonatal intensive care unit (NICU), insulin aspart is more frequently diluted in D5% than in saline solution due to sodium restriction. However, injectable dextrose solutions contain glucose degradation products (1) that are capable of binding proteins—like insulin—through a glycation phenomenon. Therefore, dilution of Novorapid in D5% would be more likely to cause glycated insulin and may raise a worrisome problem in terms of insulin stability. The objective of this study was to investigate the stability of insulin aspart diluted in D5% at both adult and neonate therapeutic concentrations in order to ensure its appropriateness in the preparation of insulin aspart. To address this issue, insulin aspart diluted in D5% was assayed by a stability-indicating method using high-performance liquid chromatography (HPLC) coupled with an ultraviolet (UV) detector. The nature of the formed product was determined by HPLC coupled with a mass spectrometer. The effect of …

Purpose To assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera). Methods Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20 °C in amber glass (n = 32), classical LDPE (n = 32) or innovative LDPE (n = 31) bottles. Stability-indicating (HPLC-UV-DAD) and chiral chromatography methods were developed. The stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D – (2S,3R)-voriconazole) were assessed at the beginning and end of the study. Results are expressed as mean ± standard deviation. Statistical analyses were performed using non-parametric tests (α Results When stored frozen, concentration was between 95.2 ± 1.4% and 103.6 ± 1.3% of the initial concentration (C0) with no difference between the three containers (p = 0.564; non-significant). Fifteen days after thawing, concentration was between 97.1 ± 1.6% and 98.6 ± 0.8% of C0 with no difference between containers (p = 0.278 and 0.368 for VED thawed at room temperature and at 2–8 °C, respectively). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ± 8.93 mOsm/Kg) than in plastic containers (522.17±3.31mOsm/Kg, classical LDPE; 517.5 ± 12.42 mOsm/Kg, innovative LDPE) (p = 0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected. Conclusion We have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability does not differ from that of amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.

Background Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are innovative digestive endoscopic approaches allowing ‘en bloc’ tumour removal – which facilitates histological analysis and lowers the risks of local relapse. To ease complete tumour removal, both techniques require submucosal fluid injections. Nevertheless, no ready-to-use commercial solutions for submucosal injection are available. Purpose To implement a simple production of a ready-to-use 5% fructose and 10% glycerol sterile solution (FGSS) for submucosal injection and appropriate quality controls. Material and methods FGSS were aseptically compounded according to good manufacturing practices. Fructose and glycerol were mixed with isotonic sodium chloride in an ISO 5 controlled atmosphere area. The solution was sterile-filtered using rapid flow 0.22 µm filter units (ThermoScientific) and aseptically-filled into glass containers (125 mL) in a vertical laminar flow hood. An alternative method, using terminal sterilisation (121°C for 20 min), was also tested. Quality controls were performed on three vials (beginning-middle-end of production). Fructose and glycerol concentrations were assessed by colorimetric-enzymatic methods adapted on a chemistry analyser (acceptance limits±10%). We developed a method of quantifying two fructose degradation products (5-hydroxymethylfurfural (5HMF) and 2-furaldehyde (2FA)) in FGSS, using a high-performance liquid chromatography UV Diode-Array-Detector. Accuracy profile serves for validation (relative acceptance limits:±10%). Sterility assay and endotoxin testing (kinetic chromogenic method) were performed. Sub-visible particles contamination was assessed using a light-obscuration method (European pharmacopoeia (EP) 2.9.19 threshold: respectively 25 and 3 particles/mL for particles size ≥10 µm and ≥25 µm). Results Our sterile-filtered compounding method allows the production of a sterile and bacterial-endotoxin-free FGSS. Particle load was 9.99 and 0.37 particles/ml respectively for ≥10 µm and ≥25 µm particles. Fructose and glycerol concentrations (g/L) were respectively at (mean (min-max)) 48.99 (47.04–50.39) and 127.39 (123.4–129.8)). Both 5HMF and 2FA concentrations were below our method’s limits of quantification (3.39 and 1.69 ng/mL respectively). When using the moist heat sterilisation method, the solution became light yellow and 5-HMF was 19.61 mg/L (far above EP specification). Conclusion Our compounding method is simple, limits 5HMF production and can be implemented in any hospital. Produced FGSS complies with the EP quality requirements. We developed the first specific and sensitive method for 5HMF and 2FA concentrations measurement in a FGSS preparation. References and/or acknowledgements No conflict of interest.

Background Congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome (CHILD) syndrome is a rare X-linked dominant disorder of cholesterol metabolism that clinically expresses as an epidermical hamartoma. Using co-application of topical formulation of simvastatin and cholesterol (TFSC) on skin lesions after previous failures has recently been reported.1 Purpose To describe protocol of use, efficacy and safety of TFSC. Material and methods A woman, born in 1988, presented at birth with an extensive epidermal hamartoma due to CHILD syndrome. The cutaneous presentation was ichtyosiform erythroderma with sharp midline demarcation involving the right side of the body and a homolateral lower limb. She had skeletal malformations of her upper and lower limbs. Partial lower limb amputation was necessary when she was 2 years’ old. In February 2016, since skin lesions did not improve with acitretine, topical corticoid and various types of dressings, TFSC was began after obtaining informed consent. We developed an original ethanol-free formulation with simvastatin, cholesterol in Excipial Lipocreme (Galderma). The preparation consists of incorporating simvastatin in powder and triturated ground powder of cholesterol with Excipial: physical stability was satisfactory for at least 30 days. We used the following protocol1: in the first month, 0.5% simvastatin and cholesterol in Excipial Lipocreme, twice per day on a limited area to test tolerance; then afterwards at 2%, twice per day on a wider area. Efficacy was clinically assessed (aspect and extension of the skin lesion) and tolerance was clinically and biologically assessed. Results TFSC was started in February 2016. Erythema whitened after 10 months and totally disappeared after 18 months. After 24 months, improvement began on the papillomatous aspect of the stump. After 30 months, whitening areas were stable, with persisting papillomatosis in the stump and flexion areas. A 2 month supply disruption of simvastatin powder during the first year led to the reappearance of erythema. When TFSC resumed, the lesions improved again. The main reported side effect was the skin’s dryness on application, leading to emollient use. Complete blood counts, electrolytes, urea, triglycerides, cholesterol, CPK and liver function remained normal. Conclusion This case shows the interest and safety of TFSC in hamartoma lesions, indicating a potential interest in other types of hamartoma. Reference and/or acknowledgements Alexopoulos A, Kakourou T. Pediatr Dermatol 2015;32:e145–7. No conflict of interest.

Background In hospital, medications for infusion are mostly diluted in saline. In neonatal resuscitation, glycaemic instabilities are frequently observed in premature newborns, hence insulin treatment is started. In our establishment, insulin aspart is used and diluted in a 5% dextrose solution (D5%), due to sodium restrictions in newborns. Purpose To evaluate the impact of the choice of D5% diluent on the stability of the insulin aspart at 1 U/mL. Material and methods The pharmaceutical specialty composed of insulin aspart and its two preservatives (phenol and metacresol) were diluted in saline or D5%. The impact of the diluent on the stability of insulin aspart was studied by high-performance liquid chromatography with UV detection (HPLC-UV). A stability indicator method,1 adapted from the method of Poulsen et al.2 and developed for insulin aspart diluted in saline, was used. The prospective formation of a new compound in the different diluents was evaluated by HPLC with a mass spectrometry detection (HPLC-MS) in full-scan mode. The kinetic of the new compound’s appearance was studied by relative evaluation of HPLC-UV signals during 1 week for insulin at 1 U/mL diluted in D5% (n=4). Results The three products contained in the pharmaceutical specialty diluted in saline correspond to the three signals identified in HPLC-UV (elution order: phenol, metacresol and insulin aspart). After dilution of insulin aspart in D5%, we noted a fourth signal. pH influence and forced degradation tests failed to attribute this signal to insulin or preservatives’ degradation. HPLC-MS analysis revealed a mass difference of 162 daltons between insulin and this product, which corresponds to a glycation phenomenon of insulin aspart. Finally, the kinetics shows that the insulin glycation phenomenon seems to increase with the contact time between insulin and glucose until a plateau is reached after 24 hour of contact. Conclusion This work highlighted the instability of insulin in D5% and showed the phenomenon of insulin aspart glycation. To better characterise this phenomenon, the biological effect of glycation on insulin activity have to be determined, since a decrease in activity has been observed for human insulin. References and/or acknowledgements 1. Methodological guidelines for stability studies of hospital pharmaceutical preparations. https://www.gerpac.eu/IMG/pdf/guide_stabilite_anglais.pdf 2. Poulsen, et al. Pharmal Res2008. No conflict of interest.

BACKGROUND: The repeated blackening of in-line filters has been observed during the infusion of parenteral nutrition 2-in-1 mixtures (binary parenteral nutrition [BPN]) delivered in a neonatal intensive care unit. This study aimed to examine the elemental content of precipitates isolated from infused BPN bags and determine the main physicochemical interactions occurring in these bags. MATERIALS AND METHODS: The infusion of BPN mixtures was simulated in vitro following hospital practices. Filter membranes were examined by scanning electron microscopy and energy dispersion spectroscopy (EDS). Amino acid (AA) profiles were obtained from BPN mixtures to determine the concentrations of each AA. RESULTS: Analyzed filter membranes revealed conglomerates of particles on filter surfaces. An EDS analysis generated spectra from isolated particles, identifying copper and sulfur as the major chemical elements. AA mean concentrations were relatively close to the expected value for each AA, except cysteine. Cysteine concentrations were very significantly lower than the expected values. CONCLUSION: A specific interaction was identified between 1 AA (cysteine) and a trace element (copper) in our BPN mixtures.

Resume Objectifs Verifier la conformite aux referentiels en vigueur et apprecier la facilite et le temps de mise melange des poches de nutrition parenterale compartimentees industrielles disponibles sur le marche francais en 2014. Materiels et methodes Trois tests in vitro ont ete effectues : mesure du volume extractible, tests de penetration et d’adhesion de la tubulure. Des manipulateurs evaluaient sur une echelle de Likert en 5 points les differentes etapes de remise en melange des poches. Les temps de lecture de la notice et de preparation de la poche etaient mesures. Resultats D’apres les tests in vitro, toutes les poches testees etaient conformes aux referentiels. Le test de manipulation a montre des disparites entre les gammes. Les deux gammes de poches bicompartimentees ont obtenu une appreciation generale similaire mais des temps de manipulation differents. Deux gammes de poches tricompartimentees (Olimel® et Kabiven®) pour administration par voie centrale presentaient une appreciation generale et un temps de manipulation differents. La gamme de poches tricompartimentees pour administration peripherique PeriOlimel® a recu de meilleures appreciations et un temps de manipulation inferieur aux deux autres elles-memes presentant des resultats similaires. Conclusion Les poches testees etaient conformes aux referentiels en termes de volume et de relation percuteur/cheminee. Le test de manipulation a objective des disparites de temps de manipulation et de facilite de remise en melange des poches.

Background Continuous compensation of dopamine represents an ideal symptomatic treatment for Parkinson's disease (PD). The feasibility in intracerebroventricular administration (i.c.v.) of dopamine previously failed because of unresolved dopamine oxidation. Objectives We aim to test the feasibility, safety margins and efficacy of continuous i.c.v. of anaerobic-dopamine (A-dopamine) with a pilot translational study in a non-human primate model of PD. Methods Continuous and circadian i.c.v. of A-dopamine was administered through a micro-pump connected to a subcutaneous catheter implanted into the right frontal horn of 8 non-human primates treated with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). A-dopamine was assessed at acute doses previously reported for dopamine as well as evaluating the long term therapeutic index of A-dopamine in comparison to anaerobically prepared L-dopa or methyl ester L-dopa. Results Over 60 days of a continuous circadian i.c.v. of A-dopamine improved motor symptoms (therapeutic index from 30 to 70 mg/day) without tachyphylaxia. No dyskinesia was observed even with very high doses. Death after 1 to 10 days (without neuronal alteration) was only observed with doses in excess of 160 mg whereas L-dopa i.c.v. was not effective at any dose. The technical feasibility of the administration regimen was confirmed for an anaerobic preparation of dopamine and for administration of a minimal infusion volume by micro-pump at a constant flow that prevented obstruction. Conclusion Continuous circadian i.c.v. of A-dopamine appears to be feasible and shows efficacy without dyskinesia with a safe therapeutic index.

Objective The aim of this review is to analyse the clinical consequences of intravenous drug incompatibilities in critically ill patients, especially the incidence of organ dysfunctions and mortality. Methods A review of literature was conducted according to the PRISMA statement in June 2017, using Medline, ISI Web of Science and Clinicaltrials.gov. Data extraction Eligible studies were case reports and randomised controlled trials (RCTs) that assessed the effects of drug incompatibilities in critically ill patients on morbidity or mortality as primary or secondary outcomes, or adverse events. Two investigators independently reviewed the eligibility of the study from abstracts or manuscript data. Data synthesis Twelve articles met the selection criteria. The six articles reporting RCTs concern only four RCTs. RCTs were single-centre studies comparing infusion with or without filter. One of them included adult patients. The others included paediatric and neonatal intensive care unit patients. Primary endpoints were SIRS, organ failure, overall complication rate, bacteraemia, sepsis, phlebitis and length of stay. The results are mixed with one RCT reporting a reduction in SIRS, organ failure and overall complication rate, two studies in disagreement over the occurrence of sepsis and one study reporting no impact on length of hospital stay. The six articles on case reports show different drug incompatibility situations. They report pulmonary toxicity. Conclusion Little data is available on this topic. Infused particles may induce organ failure, in particular pulmonary toxicity and SIRS. Further studies are needed to establish a link between the level of exposure to drug incompatibilities and clinical implication.

Background Evidence increases that a high or a standard dose of tranexamic acid (TA) reduces postpartum bleeding. The TRACES pharmacobiological substudy aims to establish a therapeutic strategy in hemorrhagic (H) Cesarean section (CS) with respect to the intensity of fibrinolysis by using innovative assays. Method/Design The TRACES trial is a multicenter, randomized, double-blind, placebo-controlled, TA dose-ranging study that measures simultaneously plasmatic and uterine and urine TA concentrations and the plasmin peak inhibition tested by a simultaneous thrombin plasmin generation assay described by Van Geffen (novel hemostasis assay [NHA]). Patients undergoing H CS (>800 mL) will receive blindly TA 0.5 g or 1 g or placebo. A non-hemorrhagic (NH) group will be recruited to establish plasmin generation profile. Venous blood will be sampled before, at the end, and then at 30, 60, 120, and 360 min after injection. Uterine bleeding will be sampled after injection. Urine will be sampled 2 h and 6 h after injection. The number of patients entered into the study will be 114 H + 48 NH out of the 390 patients of the TRACES clinical trial. Discussion To explore the two innovative assays, a preliminary pilot study was conducted. Blood samples were performed repeatedly in patients undergoing either a H (>800 mL) or NH (

Introduction La dermatite auto-immune a la progesterone (DAIP) est une pathologie rare liee a une reaction d’hypersensibilite a la progesterone endogene chez les femmes en âge de procreer. Elle survient parfois apres une phase de sensibilisation a la progesterone exogene (pilule ou sterilet). Observations Une femme de 27 ans consultait pour une eruption cutanee dorsale evoluant par poussees depuis 4 ans. Ses antecedents etaient marques par un syndrome des ovaires polykystiques traite par acetate de cryproterone et ethinylestradiol puis par chlormadinone (progestatif). Cette eruption mensuelle debutait en general 2 jours avant les menstruations et disparaissait quelques jours apres. Les lesions etaient invalidantes car douloureuses et recidivantes. Depuis l’introduction d’un traitement hormonal par dydrogesterone (progestatif de synthese) et clomifene (inducteur de l’ovulation) dans le cadre d’une procreation medicalement assistee, les poussees etaient de plus en plus etendues. L’examen clinique revelait des papules erythemateuses et des vesicules excoriees du dos. Le diagnostic de DAIP etait evoque. Les patch-tests et les intradermoreactions (IDR) a l’acetate de medroxyprogesterone (50 mg/mL, dilution 1/1000, 1/100, 1/10) realisees en phase folliculaire etaient negatifs. Mais les IDR declenchaient a 48 h une nouvelle poussee papulo-vesiculeuse dorsale plus etendue et prolongee ( Fig. 1 et 2 ). Discussion Le diagnostic de DAIP a ete retenu sur les deux criteres suivants : eruption cutanee cyclique, survenant en phase luteale s’aggravant sous dydrogesterone ; declenchement par l’intradermoreaction a l’acetate de medroxyprogesterone d’une poussee cutanee en phase folliculaire du cycle menstruel. Le troisieme critere diagnostique de la DAIP propose par Warin en 2001, a savoir l’amelioration apres blocage de l’ovulation, n’a pu etre evalue du fait du projet actuel de grossesse. Conclusion L’originalite de ce cas de DAIP reside dans le declenchement d’une poussee par l’intradermoreaction a l’acetate de medroxyprogesterone en phase folliculaire, alors que les patch-tests et les IDR etaient restees negatifs.

Injecting intracameral cefuroxime has been found beneficial in reducing the risk of postoperative endophthalmitis but its use has been limited through a lack of approved marketing and of ready-to-use single-units as well as the problem of aseptic compounding.Our aim was to assess a new automated primary packaging system which should ensure a higher level of sterility, thanks to its closed, sterile, ready-to-use polymer vial called "Crystal® vial". The chemical stability of a 10 mg/mL cefuroxime solution was compared in 1 mL Crystal® vials and 1 mL Luer-lock polypropylene syringes (actual reference) to eliminate any potential and specific interactions with its cyclic olefin copolymer (COC) body and elastomer stopper.Cefuroxime solution was introduced into vials and syringes and stored at -20 °C, +5 °C and +25°C/60% Relative Humidity. Cefuroxime concentration and the relative amount of the main degradation product (descarbamoyl-cefuroxime) were both determined by an HPLC/UV method indicating stability. Solutions were considered steady if the concentration remained at over 90% of the initial value. In the adapted storage conditions, the evolution of osmolality, pH and sterility was assessed.Stability profiles were identical between vials and syringes in all storage and temperature conditions. The solution was stable (cefuroxime concentration, pH and osmolality) and still sterile for 365 days at -20°C. The concentration fell below 90% after 21 days at +5 °C and after 16 h at +25°C/60%s relative humidity.The COC and thermoplastic elastomer of the vials had no impact on the degradation process confirming its possible use for a ready-to-use cefuroxime solution single-unit dose.

Background Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy. Methods/design The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non-haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level. Discussion TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section. Trial registration ClinicalTrials.gov, ID: NCT02797119. Registered on 13 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2420-7) contains supplementary material, which is available to authorized users.

Background As many drugs are unavailable for paediatric use, hospital pharmacies are often requested to develop suitable formulations. Clonidine is often used in paediatrics (in severe hypertension or in anaesthetic premedication) but no appropriate formulation is available. Purpose We developed an oral solution of clonidine dedicated to children and assessed its physicochemical and microbiological stability. Material and methods Formulation of an oral solution of clonidine hydrochloride was developed using the active pharmaceutical ingredient (API), with the least excipients as possible and suitable for neonates and children. The stability study was led according to the GERPAC-SFPC guidelines. At each time point (D0, D1, D7, D15, D29, D60 and D90), the visual aspect (limpidity) was checked. pH and osmolality were measured (using 2 vials). Clonidine concentration was determined using a stability indicating HPLC-UV-DAD method (a previous forced degradation study under acidic, basic and oxidative conditions allowed the detection of 6 degradation products). Microbiological stability was also tested according to the European Pharmacopoeia monograph after assessing that the culture conditions were adequate to inhibit the effect of the preservative agent, and with the most adapted method. Solutions were stored in brown glass bottles with an oral adapter for up to 3 months under two different conditions: at 2–8°C and at 25°C with 60% residual humidity. Results The formulated oral solution was composed of API at a concentration of 10 µg/mL and potassium sorbate (0.3%), citric acid, potassium citrate (pH 5) and sodium saccharine (0.025%). On day 29, the mean percentages of the initial clonidine concentrations (±SD) were 92.95±1.28% in the solution stored at 25°C and 97.44±1.21% when stored at 2–8°C. On day 90, the mean values were, respectively, 81.82±0.41% and 93.66±0.71%. The visual aspect did not change. Physical parameters remained stable during the study: pH varied from 4.94 to 5.09 and osmolality from 82 to 92 mOsm/kg under the two conditions tested. Whatever the storage conditions, E coli detected. Conclusion This formulation was stable for at least 3 months when stored at 2–8°C in brown glass bottles and for 1 month when stored at room temperature. The microbiological stability was proven in accordance with the European Pharmacopoeia. No conflict of interest

Background As part of the development of a double blind clinical trial using Ritalin LA (extended release) 10 mg containing methylphenidate hydrochloride (MH), over-encapsulated capsules have to be compounded and MH release studied. This release is bimodal (SODAS technology), with the first 50% of the dose released immediate at strong acidic pH, and the second 50% release at a pH >6. Capsules and backfilled excipient used for masking Ritalin LA capsules have a potential impact on MH release, compared with bare capsules. Purpose To study the potential impact of masking in over-encapsulated capsules with microcrystalline cellulose (MC), on in vitro biopharmaceutical parameters. Material and methods A dissolution study was carried out by comparing MH release from bare capsules (n=6) with over-encapsulated capsules (n=6) using MC as the backfilled excipient. The two release phases of MH were studied in a unique dissolution medium. A Britton–Robinson buffer, pH 2, was used for 2 hours at 37°C. Then, the same buffer was adjusted to pH 6.8 for a 5 hour dissolution time. The basket dissolution apparatus (European Pharmacopoeia (EurPh) 2.9.3) was used at 50 rotations/min. 15 samples of 2 mL were filtrated using cellulose acetate membrane filters. MH dosing was quantified by a stability indicating (HPLC-UV-diode array detector) method. The two dissolution profiles were compared with fit factors (difference factor f1 50% for similarity) and the Rescigno index (zeta1 and zeta2 with values close to 0 tending toward similarity). A disintegration test (EurPh 2.9.1) was led on 6 capsules. Statistical analysis was conducted using non-parametric tests (α Results On the whole dissolution, fit factors and Rescigno index were: f1=2.2% f2=96.0% zeta1=0.012 zeta2=0.025 A lag time of a few minutes at the beginning of dissolution was observed for over-encapsulated capsules. This can be explained in part by the delay in capsule disintegration (103 s and 170s (p Conclusion A similarity between over-encapsulated and bare capsules was demonstrated using MC. No conflict of interest

Background Voriconazole is an antifungal agent effective on most keratitis causative fungi with an excellent transcorneal penetration. Voriconazole eyedrops (VED) are unavailable in Europe and are usually compounded in hospital pharmacies. New eyedrop containers emerged on the hospital market (eg, high density polyethylene bottles available in trays (CAT)) for which few stability data are available, or Novelia bottles which innovative insert maintains sterility after opening (no stability data available). Purpose To collect data on VED stability in 3 different containers in order to switch if necessary: amber glass, HPDE bottles and Novelia bottles stored frozen (−20°C) and refrigerated once thawed. Material and methods 3 batches of 1% VED (10 mL) were aseptically compounded under a laminar flow hood from injectable Vfend (Pfizer) and sterile water for injection (Baxter), and stored at −20°C in amber glass (n=32; Gravis), HDPE (n=32; CAT) or Novelia (n=31; Nemera) bottles. The stability study was done according to the GERPAC-SFPC stability study guidelines. At each time point, the visual aspect was checked and voriconazole concentration (using a stability indicating HPLC-UV-diode array detector method), pH and osmolality were measured. Non-visible particle counts (by light obscuration particle count test), sterility and absence of racemisation (impurity D–(2S,3R)-voriconazole–detected by chiral HPLC) were assessed at the beginning and end of the study. Parameters were measured: when stored for 3 months at −20°C; then thawed, after 15 days at +2 to +8°C, with comparison of two thawing methods (+2 to +8°C for 6 hours or 25°C for 2 hours). Statistical analysis were performed using non-parametric tests (α Results During storage, the concentration was between 95.2±1.4% and 103.6±1.3% of the initial concentration (Co) (NS); 15 days after thawing, the concentration was between 97.1±1.6% and 98.6±0.8% of Co (NS). pH remained stable (NS). Osmolality was slightly higher in glass than in plastic containers (p=0.003). Sterility was preserved. Count of ≥ 10 µm particles remained Conclusion VED remained stable for up to 3 months at −20°C and for 15 days after thawing, with no notable difference between the three containers, allowing us to choose the most suitable. No conflict of interest

Background In the paediatric surgery unit, low doses of opioid analgesics are used daily for anaesthesia. Because dilutions in series are required, potential preparation errors may occur. Thus stock solution (SS) syringes are prepared each morning in the post anaesthesia care units, resulting from a 10-fold dilution of commercial products. SS syringes are then extemporaneously diluted all day long by a factor of 2, 2.5, 5 or 10 to obtain serial dilution (SD) syringes used in the operating ward. Purpose We quantified the concentration of ketamine (Ket), remifentanil (Rem) and sufentanil (Suf) in prepared syringes to evaluate the compounding accuracy of the anaesthetic staff before injection to children. Material and methods Over a 1 month period, Ket, Rem and Suf samples were collected from SS and SD syringes prepared in the care unit. Samples were quantified by a HPLC-UV-DAD method, previously validated according to the SFSTP-Pharma requirements. Results were expressed as bias (%) and were considered acceptable if included between acceptance limits of ±10% of the theoretical concentration (drugs with a narrow therapeutic margin). Results 150 syringes were collected on 31 days: 73 SS (25 Suf; 24 Rem; 24 Ket) and 77 SD (36 Suf; 24; Rem; 17 Ket). Biases were not within acceptance limits for 15 of the 31 days, representing 25 syringes (17%). Focusing on dilution modalities, the total error rate and extremes biases (min; max) obtained for the 17 SD syringes out of 77 were 28% (−17%; +12%), 21% (−10%; +15%) and 14% (−7%; +14%) for Suf, Rem and Ket, respectively. For the SS syringes, the total error rate and extremes biases (min; max) obtained were 20% (−25%; +22%), 4% (−23%; +2%) and 8% (−23%; +3%) for Suf, Rem and Ket, respectively, representing 8 syringes (11%). Whatever the drug, the error rate was higher with the SD syringes compared with the SS syringes. Conclusion We found that 22% of syringes administered to children were not within acceptance limits. In order to reduce the occurrence of compounding error in the ward, a preparation procedure will be defined. Its impact will be further assessed. No conflict of interest

Background Voriconazole is a triazole antifungal agent effective in most cases of keratitis caused by fungi. Off-label use of extemporaneously compounded intraocular (intrastromal, intracameral) voriconazole has shown promising results in deep fungal ophthalmic infections, and abscessed, recurrent or drug resistant eye infections. Stability data on voriconazole intraocular solutions (VIS) are lacking. Purpose To assess the stability of 50 and 100 µg/0.1mL VIS stocked at 2–8°C. Material and methods 2 batches of VIS (2 mL; 1 batch per concentration) were aseptically compounded from injectable Vfend (Pfizer) and Ringer’s lactate solution (Baxter), stored at 2–8°C in 3 part syringes (n=66) and analysed on day 13 (D13) and after 1 (D30) and 1.5 (D44) months. Stability study was led according to the GERPAC-SFPC stability studies guidelines. At each time point, visual aspect was checked, and voriconazole relative concentration (% of initial concentration, using a stability indicating HPLC-UV-diode-array-detector method), pH and osmolality were measured. Non-visible particle counts (using light obscuration particle count test) for particle size ≥ 10 µm and ≥25 µm (Eur Pharm 2.9.19 threshold: 6000 and 600/recipient, respectively) and sterility were assessed. Statistical analysis was carried out using non-parametric tests (α Results For every time point, CI relative concentrations were (0.993; +infinite (and) 0.951; +infinite (respectively, for 50 and 100 µg/0.1 mL), and remained superior to 95% (p Sterility was preserved to at least D13 with no change in visual aspect. Conclusion VIS remained stable for 13 days at 2–8°C. We advise a shelf-life of a maximum of 13 days for both VIS kept at 2–8°C. No conflict of interest

Purpose The aims of the study are to make an inventory of fixtures of aseptic compounding structures, to compare, using real examples, the design and operating costs of controlled atmosphere area (CAA) with isolators and CAA with laminar flow biological safety cabinets (BSCs) in order to determine the most economical scheme in hospitals and to give a final facilities cost calculated for one workstation. Methods Forty-three hospitals were interviewed (21 French and 22 from four European countries) over seven months. Hospital pharmacists completed a form with 390 items. Hospitals are compared according to their workstation type: BSCII or BSCIII (group B) and isolator (group I), using Mann and Whitney’s statistical test and Monte-Carlo modeling. Results Twenty-one hospitals responded (11 French and 10 from other European countries). All European compounding unit organizations are not significantly different. The study compared items such as infrastructure cost, equipment cost, staff cost, consumable cost, cleaning cost and control cost. A synthesis of all costs has been drafted to calculate an estimated preparation cost which seemed to be higher for group B than for group I when staff costs were included ($46 and $31, respectively, in study conditions). Conclusions The different costs studied have revealed little significant difference between group B and I. The preparation cost in group B appears higher than in group I. This pilot study has resulted in the calculation of an estimated manufactured preparation cost but this work should be completed to help optimize resources and save money.

Resume L’administration des medicaments oraux chez les patients sous nutrition enterale est une problematique frequente. La prescription doit etre revue par le medecin afin d’eviter d’eventuelles administrations non indispensables et de l’adapter a l’administration par sonde. La voie orale lorsqu’elle est possible est a privilegier. Le choix de la sonde devrait integrer la possibilite d’une administration medicamenteuse. Des precautions doivent etre respectees pour eviter l’obstruction de la sonde ; certaines manœuvres de desobstruction sont recommandees. En cas d’administration par sonde, les formes liquides doivent etre privilegiees, en tenant compte de certaines caracteristiques (viscosite, osmolarite) susceptibles d’entrainer un risque d’occlusion ou d’intolerance digestive. Les formes orales a liberation prolongee ou gastro-resistantes ne doivent pas etre ecrasees. L’administration de comprimes ecrases ou du contenu de gelules doit se faire en respectant des precautions permettant d’eviter les instabilites, interactions ou obstructions. Les medicaments comportant une substance toxique doivent faire l’objet de precautions particulieres.

Introduction Depuis 2013, le service de dermatologie du CHRU de Lille a mis en place un programme labellise d’education therapeutique du patient (ETP) atteint de psoriasis, impliquant des dermatologues, des infirmiers, des aide-soignants, un psychologue, un tabacologue, un dieteticien et une cadre de sante. Depuis septembre 2015, deux pharmaciens (hospitalier et officinal) ont rejoint l’equipe. L’objectif de notre travail etait de determiner la place et l’impact de leur participation a l’ETP. Materiel et methodes Les niveaux d’intervention du pharmacien ont ete decrits. Un questionnaire telephonique a ete propose aux patients apres les ateliers afin d’evaluer l’impact de la presence des pharmaciens sur l’action d’ETP. Les pharmaciens intervenaient au cours de l’atelier concernant la gestion d’un traitement systemique au quotidien. Quinze fiches-support a destination des animateurs des ateliers, ayant pour themes le bon usage des traitements systemiques, la conservation des biotherapies, la gestion des dechets d’activite de soins a risque infectieux, les biosimilaires ont ete realisees. Pour chaque traitement, une fiche synthetisait le mode d’administration, le mecanisme d’action, les contre-indications, les effets indesirables, les mesures concernant les populations particulieres, la surveillance et les conseils necessaires au bon usage. Le dossier pharmaceutique (DP) consistant a porter l’information de l’ensemble des traitements medicamenteux sur la carte vitale du patient, y compris les vaccins, etait promu. Consultable par tout pharmacien d’officine, il permettait la recherche des interactions medicamenteuses et le conseil officinal le plus adapte. Resultats Au total, 42 patients sur 51 [sex-ratio : 0,81 ; âge moyen (± ecart-type) : 47 ans (± 14)] ont participe a l’etude. Le PASI moyen etait de 13,8 (± 8,4) et le DLQI moyen de 10,4 (± 6,9). Parmi, 59,5 % des patients avaient souvenir que la question du DP avait ete abordee. Quatre patients possedaient deja un DP avant leur participation aux ateliers d’ETP. Au moment du recueil des reponses, 10 patients supplementaires declaraient avoir ouvert un DP a la suite du programme d’ETP. Parmi ceux qui n’avaient pas ouvert de DP, 25 % avaient l’intention de le faire, 11,1 % disaient ne pas avoir ete informes sur le DP, 5,6 % avaient fait face a un refus a l’officine et 2,8 % ne souhaitaient pas ouvrir de DP. Conclusion La presence d’un pharmacien au sein des ateliers d’ETP permet d’assurer un lien entre l’hopital et la ville ainsi qu’une sensibilisation au bon usage des traitements parfois peu aborde en ville. Cette action permet de repondre aux interrogations du patient (perspectives de nouveaux traitements, differences entre traitement de reference et biosimilaires, medicaments generiques). Enfin, la presence d’un pharmacien a sensibilise les patients au dossier pharmaceutique.

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 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.

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.

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 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.

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 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.

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%.