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Background: Drug prescribing errors are frequent in the hospital setting and pharmacists play an important role in detection of these errors. The objectives of this study are (1) to describe the drug prescribing errors rate during the patient’s stay, (2) to find which characteristics for a prescribing error are the most predictive of their reproduction the next day despite pharmacist’s alert (i.e. override the alert). Methods: We prospectively collected all medication order lines and prescribing errors during 18 days in 7 medical wards’ using computerized physician order entry. We described and modelled the errors rate according to the chronology of hospital stay. We performed a classification and regression tree analysis to find which characteristics of alerts were predictive of their overriding (i.e. prescribing error repeated). Results: 12 533 order lines were reviewed, 117 errors (errors rate 0.9%) were observed and 51% of these errors occurred on the first day of the hospital stay. The risk of a prescribing error decreased over time. 52% of the alerts were overridden (i.e error uncorrected by prescribers on the following day. Drug omissions were the most frequently taken into account by prescribers. The classification and regression tree analysis showed that overriding pharmacist’s alerts is first related to the ward of the prescriber and then to either Anatomical Therapeutic Chemical class of the drug or the type of error. Conclusions: Since 51% of prescribing errors occurred on the first day of stay, pharmacist should concentrate his analysis of drug prescriptions on this day. The difference of overriding behavior between wards and according drug Anatomical Therapeutic Chemical class or type of error could also guide the validation tasks and programming of electronic alerts. Background Drug prescribing errors are defined as a prescribing decision or prescription writing process that results in an unintentional, significant reduction in the probability of treatment being timely and effective or increase in the risk of harm, when compared with generally accepted practice. High rates of inpatient prescribing errors have been reported: 1.5-5.3 per 100 drug orders, or 1.4 errors per admission [1,2].

International audience; This article focuses on parameter estimation of multilevel nonlinear mixed-effects models (MNLMEMs). These models are used to analyze data presenting multiple hierarchical levels of grouping (cluster data, clinical trials with several observation periods, ...). The variability of the individual parameters of the regression function is thus decomposed as a between-subject variability and higher levels of variability (e.g. within-subject variability). We propose maximum likelihood estimates of parameters of those MNLMEMs with 2 levels of random effects, using an extension of the stochastic approximation version of expectation-maximization (SAEM)-Monte Carlo Markov chain algorithm. The extended SAEM algorithm is split into an explicit direct expectation-maximization (EM) algorithm and a stochastic EM part. Compared to the original algorithm, additional sufficient statistics have to be approximated by relying on the conditional distribution of the second level of random effects. This estimation method is evaluated on pharmacokinetic crossover simulated trials, mimicking theophylline concentration data. Results obtained on those data sets with either the SAEM algorithm or the first-order conditional estimates (FOCE) algorithm (implemented in the nlme function of R software) are compared: biases and root mean square errors of almost all the SAEM estimates are smaller than the FOCE ones. Finally, we apply the extended SAEM algorithm to analyze the pharmacokinetic interaction of tenofovir on atazanavir, a novel protease inhibitor, from the Agence Nationale de Recherche sur le Sida 107-Puzzle 2 study. A significant decrease of the area under the curve of atazanavir is found in patients receiving both treatments.

6 pages; International audience; The fate of organic herbicides applied to agricultural fields may be affected by other soil amendments, such as copper applied as a fungicide. The effect of copper on the leaching of diuron and glyphosate through a granitic and a calcareous soil was studied in the laboratory using sieved-soil columns. Each soil was enriched with copper sulfate to obtain soil copper concentrations of 125, 250, 500, and 1000 mg kg(-1). Glyphosate leaching was influenced by soil pH and copper concentration, whereas diuron leaching was not. In the calcareous soil, glyphosate leaching decreased as copper levels increased from 17 mg kg(-1) (background) to 500 mg kg(-1). In the granitic soil, glyphosate leaching increased as copper levels increased from 34 mg kg(-1) (background) to 500 mg kg(-1). The shapes of the copper elution curves in presence of glyphosate were similar to shapes of the glyphosate curves, suggesting the formation of Cu-glyphosate complexes that leach through the soil. Soil copper concentration does not influence diuron leaching. In contrast, increasing copper concentrations reduces glyphosate leaching through calcareous soils, and conversely, increases glyphosate leaching through granitic soils. Our findings suggest that the risk of groundwater contamination by glyphosate increases in granitic soils with elevated copper concentrations.

This study demonstrates that the Rho-kinase (ROCK) inhibitor, Y-27632, potentiates not only the effect of cobalt chloride (CoCl(2)) but also that of deferoxamine, another HIF-1 inducer, on mesenchymal stem cell (MSC) neuronal differentiation. HIF-1 is essential for CoCl(2)+/-Y-27632-induced MSC neuronal differentiation, since agents inhibiting HIF-1 abolish the changes of morphology and cell cycle arrest-related gene or protein expressions (p21, cyclin D1) and the increase of neuronal marker expressions (Tuj1, NSE). Y-27632 potentiates the CoCl(2)-induced decrease of cyclin D1 and nestin expressions, the increase of HIF-1 activation and EPO expression, and decreases pVHL expression. Interestingly, CoCl(2) decreases RhoA expression, an effect potentiated by Y-27632, revealing crosstalk between HIF-1 and RhoA/ROCK pathways. Moreover, we demonstrate a synergistic effect of CoCl(2) and Y-27632 on neurosphere differentiation into neurons and PC12 neurite outgrowth underlining that a co-treatment targeting both HIF-1 and ROCK pathways might be relevant to differentiate stem cells into neurons.

Twenty five derivatives of the drugs terfenadine and ebastine have been designed, synthesized and evaluated as inhibitors of recombinant human CYP2J2. Compound 14, which has an imidazole substituent, is a good non-competitive inhibitor of CYP2J2 (IC(50)=400nM). It is not selective towards CYP2J2 as it also efficiently inhibits the other main vascular CYPs, such as CYP2B6, 2C8, 2C9 and 3A4; however, it could be an interesting tool to inhibit all these vascular CYPs. Compounds 4, 5 and 13, which have a propyl, allyl and benzo-1,3-dioxole terminal group, respectively, are selective CYP2J2 inhibitors. Compound 4 is a high-affinity, competitive inhibitor and alternative substrate of CYP2J2 (K(i)=160+/-50nM). Compounds 5 and 13 are efficient mechanism-based inhibitors of CYP2J2 (k(inact)/K(i) values approximately 3000Lmol(-1)s(-1)). Inactivation of CYP2J2 by 13 is due to the formation of a stable iron-carbene bond which occurs upon CYP2J2-catalyzed oxidation of 13 with a partition ratio of 18+/-3. These new selective inhibitors should be interesting tools to study the biological roles of CYP2J2.

INTRODUCTION: In France, the access to treatment has become a priority and a right. Hence, the supply of care has been reorganised in order to improve the management of the health scourges for all the patients, whether they can pay for what they need or not. The free delivery of drugs (FDD) is part of the services offered by the public hospitals for the low income patients or those who do not yet benefit from social security coverage. As such, it is inscribed within the context of the right to treatment and is a corner stone to a new mission of the public hospital services and care networks. METHOD: The polyclinic of the Max Fourestier hospital is one of hospitals in the Paris area that supplies medical and surgical consultations to the population and provides drugs free of charge. From April 1, 1999 to the end of June 2000, all the FDD were studied for all the non-hospitalised outpatients who came to the consultations with a prescription for drugs, which could not be supplied in a pharmacy because of lack of revenues or social security coverage. RESULTS: The diseases encountered in the context of FDD were the same as those of the general population. No specificity was revealed in the prescriptions related to vulnerability. If it were necessary, this would confirm the fact that the management of persons in difficulty should be integrated in the provisions of common rights. The treatments concerned were essential, and for some persons life saving, and justifying the interest of FDD without which the health of these individuals would rapidly decline. Furthermore, this study shows the need for careful management of FDD in order to avoid the anarchical and uncontrolled delivery of several prescriptions, source of deleterious drug interactions and iatrogenia. This is the reason for the recommendation to all the staff delivering free drugs that they systematically ask the patients to meet a referring physician and contact the hospital pharmacist when necessary. COMMENTS: The FDD request is an ideal occasion for a physician to meet the patient and, because of the professional secrecy, to learn more of the patient's life style, and reveal, other than the diseases, the patients risk factors or elements of vulnerability that interact with the general state of health. The access to rights, on the occasion of FDD, is a fundamental public health strategy, since it provides the patient with access to preventive and primary care health measures. This is why we propose that FDD, other than the medical consultation, become systematically coupled with a consultation with a social care worker, to permit the rapid return of the patients to their common rights. CONCLUSION: Free drug delivery should not be conceived as a traditional pharmaceutical delivery, it should be the pretext for the reintegration of persons to their social rights and with a strategy of improved medical care. Organised in this manner, FDD is a precious tool for access to care and prevention, but also to the construction of a social relationship.

International audience; This study investigated the effect of seizure prophylaxis on busulfan (Bu) plasma exposure. Twenty-four adult patients received an intravenous Bu-cyclophoshamide conditioning regimen prior to bone marrow transplantation. Busilvex (0.8 mg/kg) was administered every six hours during four consecutive days. Clonazepam (0.025 to 0.03 mg/kg/day as a continuous 12-h i.v. infusion) was administered at least 12 hours prior to i.v. Bu dosing and continued until 24 hours after the last dose. Pharmacokinetic (PK) data were compared with those previously collected in patients (n=127) treated with phenytoin for seizure prophylaxis. Through population PK analysis, a 10% average increase (coefficient of variation, RSE=5.35%) in total clearance of Bu was quantified when Bu was associated with clonazepam as compared to phenytoin, which was considered as not being clinically relevant. The suspected induction on Bu metabolism by phenytoin should have resulted in the opposite effect. The patient efficacy and safety profiles were comparable between the two cohorts.