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Background: The French national drug regulatory authority stated, in 2017, that a secured prescription pad must be used for zolpidem prescriptions. This study aimed to evaluate the evolution of the problematic consumption of zolpidem at the individual level since the new regulation. Methods: Two nationwide populations of at-risk users of zolpidem were recruited: one in general practitioner (GP) offices and one in specialized care centers dedicated to drug dependence (SCDDs). Participants were asked about their zolpidem consumption before and after the regulation change. The primary outcome was the evolution of problematic zolpidem consumption, as defined by at least one of the following criteria: overconsumption, fraudulent ways of obtaining, effects sought other than hypnotic, and modes of administration other than oral. Results: A total of 243 participants were included: 125 from GP offices and 118 from SCDDs. In the GP population, the prevalence of patients who were identified as problematic consumers decreased from 24.8% to 20.8% (p = 0.593), whereas the prevalence decreased from 73.7% to 51.7% in the SCDD population (p < 0.001). The most prevalent criteria for problematic status were overconsumption and fraudulent ways. Conclusions: The new French regulation of zolpidem had different impacts among two different populations of at-risk zolpidem consumers.

Smoking cessation is underestimated in terms of drug interactions. Abrupt smoking cessation is common in cases of emergency hospitalization and restrictions of movement. Tobacco is a known cytochrome P450 1A2 (CYP1A2) inducer, its consumption and withdrawal can lead to major pharmacokinetic drug interactions. Nevertheless, references do exist, but may have different results between them. The objective of our work was to establish the broadest and most consensual list as possible of CYP1A2 substrates treatments and propose a pharmacological approach. We searched the widest possible list of CYP1A2 substrates based on various international references. We compared the references and defined probability and reliability scores of our results to sort the substances based on the scores. For the 245 substances identified as CYP1A2 substrates, we focused on the 63 CYP1A2 substrates with both probability and reliability scores >50%. Our work establishes adaptive pharmacological approaches for the management of patients initiating smoking cessation which must be integrated into the management of smoking cessation. Pharmacologists can now adopt adaptive pharmacological approaches to complement patient-specific clinical information about smoking cessation by considering pharmacokinetic risk. This work establishes an unprecedented list. It should guide in the care of patients initiating smoking cessation to prevent pharmacokinetic drug interactions.

In recent years, zolpidem has been the subject of numerous reports of misuse, abuse and dependence. In view of these risks, the French drug agency decreed the implementation of secure prescription pads in April, 2017. The objective of this study was to characterize the impact of this regulatory change on the patterns of zolpidem use.We included patients with at least one reimbursement for zolpidem before and/or after the regulatory change using a sample of the French health insurance database. For each period, we identified profiles of users using a latent class analysis (LCA).In total, 15,550 zolpidem users were identified before the measure and 8,301 after the measure. We identified the same three profiles of zolpidem users before and after the measure: non-problematic users (the most prevalent), users whose drug prescriptions suggest psychiatric disorder and potential problematic users. The profile of potential problematic users was similar after the regulatory change but represented a lower absolute number of patients.In conclusion, the regulatory change had a positive impact on the patterns of zolpidem use, but the impact should be reevaluated, because withdrawal can take a long time, especially in long-term users.The study was registered at www.clinicaltrials.gov under the reference number NCT03584542.

Background: To “limit the risk of abuse and misuse” and “encourage correct usage”, the French drug regulatory authority stated that—from April 2017—zolpidem prescription must be performed on a secured prescription pad. This national study aims to evaluate the perception of general practitioners (GPs) towards this new regulation and its link with prescription strategies. Methods: We conducted structured interviews of GPs. Data were collected about GPs’ perception of the measure and therapeutic strategies towards zolpidem. The primary outcome was the description of the GPs’ strategy of prescription, based on the perception towards the new regulation for zolpidem. Results: For 206 GPs, the new regulation was mainly perceived as helpful (61%) and as a difficulty (55%). Other perceptions were the awareness of the risks of zolpidem (18%), awareness of the risks of hypnotics (13%), and nothing changed (5%). Four clusters of GPs were identified. In the clusters with the perception as a difficulty (only or associated with helpful), the GPs who applied the strategy “no modification” for >50% of their patients were more frequently compared to awareness and helpful only clusters (60.8%; 42.9%; 20.4%; 26.7%) (p < 0.001). Conclusions: We highlighted an association between the perception of the new regulation of zolpidem prescription by GPs and a strategy of prescription.

AIMS Polypharmacy increase the risk of drug-drug interactions (DDIs) in the elderly population living with human immunodeficiency virus (HIV). Several expert databases can be used to evaluate DDIs. The aim of the study was to describe actual DDIs between antiretroviral drugs and comedications in an elderly population and to compare grading of the DDIs in 3 databases. METHODS All treatments of HIV-infected subjects aged 65 years and older were collected in 6 French HIV centres. Summary of Product Characteristic (SPC), French DDI Thesaurus (THES), and Liverpool HIV DDI website (LIV) were used to define each DDI and specific grade. DDIs were classified in yellow flag interaction (undefined grade in SPC and THES or potential weak interaction in LIV), amber flag interaction (to be considered/precaution of use in SPC and THES and potential interaction in LIV) and red flag interaction (not recommended/contraindication in SPC and THES and do not administer/contraindication in LIV). RESULTS Among 239 subjects included, 60 (25.1%) had at least 1 DDI for a total of 126 DDIs: 23/126 red flag DDIs were identified in 17 patients. All these 23 DDIs were identified in LIV. THES and SPC missed 6 and 1 red flag DDIs, respectively. Seven of 23 red flag DDIs were identified in the 3 databases concomitantly. CONCLUSION Polypharmacy is frequent in this elderly HIV population leading to DDI in a quarter of the subjects. The discrepancies between databases can be explained by differences in analysis methods. A consensus between databases would be helpful for clinicians.

BackgroundAmoxicillin is the first-line treatment for streptococcal or enterococcal infective endocarditis (IE) with a dose regimen adapted to weight.ObjectivesCovariates influencing pharmacokinetics (PK) of amoxicillin were identified in order to develop a dosing nomogram based on identified covariates for individual adaptation.Patients and methodsPatients treated with amoxicillin administered by continuous infusion for IE were included retrospectively. The population PK analysis was performed using the Pmetrics package for R (NPAG algorithm). Influence of weight, ideal weight, height, BMI, body surface area, glomerular filtration rate adapted to the body surface area and calculated by the CKD-EPI method (mL/min), additional ceftriaxone treatment and serum protein level on amoxicillin PK was tested. A nomogram was then developed to determine the daily dose needed to achieve a steady-state free plasma concentration above 4× MIC, 100% of the time, without exceeding a total plasma concentration of 80 mg/L.ResultsA total of 160 patients were included. Population PK analysis was performed on 540 amoxicillin plasma concentrations. A two-compartment model best described amoxicillin PK and the glomerular filtration rate covariate significantly improved the model when included in the calculation of the elimination constant Ke.ConclusionsThis work allowed the development of a dosing nomogram that can help to increase achievement of the PK/pharmacodynamic targets in IE treated with amoxicillin.

International audience; OBJECTIVES: Benzodiazepines and non-benzodiazepine hypnotics (or Z-drugs) (BZD/Z) are widely prescribed for older patients despite major side effects and risks when chronically used. The patient's understanding of the treatment is one of the keys to good adherence. The purpose of the study was to assess the knowledge of BZD/Z treatment among older people who were taking BZD/Z for the long term by studying the concordance between the declared reason for taking BZD/Z and its indication. METHODS: This was a cross-sectional, pharmacoepidemiologic ancillary of a national study. Data were collected through a semi-structured interview. All patients from the main study were included. "Good knowledge" was considered when patients gave an indication for each BZD/Z that was similar to its marketing authorization. Univariate and multivariate analyses were carried out to adequately determine profiles and characterize associations. RESULTS: More than half of the patients (61.6%) had a good knowledge regarding their treatment. The presence of a psychiatric disorder, a mean duration of BZD/Z use of less than 120\,months, a desire to stop treatment, educational status, and number and type of BZD/Z used were significantly associated (P\

The risk for drug-drug interactions (DDIs) associated with antiseizure drugs (ASDs) used to manage status epilepticus (SE) patients in the intensive care unit (ICU) has been poorly investigated. We aimed to quantify and describe those potential DDIs and determine SE patient risk profiles.We conducted an observational bi-centric cohort study including all SE patients admitted to the ICU in the period 2016-2020.Overall, 431 SE patients were included and 5504 potential DDIs were identified including 1772 DDIs (33%) between ASDs, 2610 DDIs (47%) between ASDs and previous usual treatments (PUTs), and 1067 DDIs (20%) between ASDs and ICU treatments (ICUTs). DDIs were moderate (n = 4871), major (n = 562) or severe (n = 16). All patients exhibited potential DDIs, which were major-to-severe DDIs in 47% of the cases. DDIs were pharmacokinetic (n = 1972, 36%), mostly involving cytochrome P450 modulators, and pharmacodynamic (n = 3477, 64%), mainly leading to increased sedation. ASD/PUT DDIs were the most frequent and severe. Age, PUT and ASD drug numbers and length of ICU stay were significantly associated with increased DDI number. We identified four SE patient profiles with different DDI risks and outcomes including (1) epileptic or brain trauma patients, (2) withdrawal syndrome patients, (3) older patients with comorbidities and (4) self-poisoned patients with psychiatric disorders and/or past epilepsy.SE patients are subject to potential DDIs between ASDs, ASD/PUT and ASD/ICUT. Major-to-severe DDIs mostly occur between ASDs and PUTs. Physicians should pay attention to SE patient characteristics and history to limit DDI numbers and prevent their consequences.

International audience

The inherent risk of agranulocytosis associated with clozapine requires the realization of weekly white blood cell monitoring (WBCM) during the 18 first weeks of treatment. The aim of this study was to assess the compliance with WBCM during clozapine initiation for schizophrenia and Parkinson's disease (PD) subjects.The analysis was conducted using SNDS data on a cohort of new users of clozapine in 2018. We analyzed all reimbursements for WBCM from 2 weeks before the index date to 18 weeks after (optimal monitoring during hospitalization was assumed). The primary outcome was the proportion of good realization of WBCM according to different thresholds of completion (70%; 80%; 90%). Descriptive and comparative analyses with chi-squared test or Student's t-test were performed.Two hundred and ninety-six subjects were included. Rates of patients with WBCM realization over 70%, 80%, and 90% of WBCM expected were, respectively, 78.1%, 70.0%, and 56.9% for subjects with schizophrenia and 71.3%, 63.2%, and 47.8% for PD subjects. Only hospitalization during the follow-up period for schizophrenia subjects was significantly associated with good WBCM realization.We observed rather good results for compliance with clozapine initial monitoring. Other studies are needed to confirm our results.

Depression as well as a treatment by antidepressant are factors that may interfere with sexuality. Due to this complex relationship between depression, antidepressant and sexuality, it is difficult to incontestably establish the exclusive accountability of a treatment or of a psychiatric disorder on sexual dysfunctions. The main purpose of the SADD (for Sexuality, Anti-Depressant and Depression) study is to evaluate sexual dysfunctions in depressed men treated with antidepressant or not.Participants of this transversal, observational study were men aged over 18 years old, suffering from unipolar major depressive disorder and treated by a psychiatrist, with or without antidepressant. Assessment of sexual functioning through three times: euthymia (before depression), untreated depression and treated depression if applicable was performed based on the ASEX scale.Seventy patients were included. Eight percent of euthymic patients presented a sexual dysfunction (average score on the ASEX=12.4) whereas 56% of untreated patients presented a sexual dysfunction (average total score on the ASEX=17.7) and 62% (34/55) of patients treated with antidepressant (average total score on ASEX=18.5) (P0.001). Sexual functioning of men receiving treatment is not significantly different to that among men not receiving any antidepressant, even if patients treated with antidepressant reported that they had a better mood than those untreated.Our results reveal a high prevalence of sexual dysfunction within the framework of major depressive disorder and its treatment and underlines the complex relationship between major depressive disorder, antidepressant and sexuality.

Paliperidone palmitate (PP), a long-acting intramuscular formulation of paliperidone, has been marketed in Europe within the last 10 years and provides an important treatment option for patients with schizophrenia.Our aim was to describe PP-related adverse drug reactions (ADRs) leading to death or life-threatening events, specifying their main clinical and pharmacological characteristics.This observational study was a retrospective review of PP-related ADRs in the French pharmacovigilance database between January 1, 2013, and December 31, 2019.Out of 473 PP-related ADRs, we identified 13 deaths and 14 life-threatening events. ADRs were primarily cardiorespiratory (In this study, PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms and tended to occur in the first 6 months after the initiation of treatment and within postadministration periods aligned with peak plasma PP concentrations. The hypothesis of supratherapeutic drug concentrations following intramuscular PP injection must be raised.PP-related ADRs leading to death or life-threatening events mainly presented with cardiorespiratory symptoms. Cardiac arrests and sudden unexpected deaths following initiation of PP treatment could be due to supratherapeutic drug concentrations. This study highlights the need to monitor blood concentrations of PP.Key pointsAdverse reactions to paliperidone palmitate can lead to death or life-threatening events.It is hypothesized that cardiac arrests and sudden unexpected deaths following initiation of paliperidone palmitate treatment could be due to supratherapeutic drug concentrations.This paper proposes the need to monitor blood concentrations of paliperidone palmitate in future studies.

Benzodiazepines (BZDs) and related drugs (Z-drugs) are mainly taken chronically, and older people are much more likely to take them on a chronic basis despite recommendations. Withdrawal symptoms could be an obstacle to stopping BZD/Z-drug administration. The main objective of this study is to estimate the prevalence of withdrawal symptoms in patients aged 65 years and older who have experience a stop of BZD/Z-drug. The secondary objectives are to describe the withdrawal symptoms and identify factors associated. This ancillary study was based on a national observational study in patients with chronic BZD/Z-drug consumption. Patients who made at least one BZD/Z-drug stop experience were selected. Withdrawal symptoms are described, and a logistic regression was carried out to identify the variables most associated with withdrawal symptoms. In total, 697 patients were selected: 78% experienced at least one withdrawal symptom after a stop administering BZDs or Z-drugs; most of the withdrawal symptoms were psychological disorders. Our study identifies a specific population experiencing withdrawal symptoms and who cannot stop administering BZD/Z-drug. We assume that withdrawal symptoms in patients with chronic use play an essential role in the nonstop use of BZD/Z-drugs.

AIMS In recent years, zolpidem has been the subject of numerous reports of misuse, abuse and dependence. In view of these risks, the French drug agency (ANSM) decreed in April 2017 the implementation of secure prescription pads. The objective of this study was to evaluate the impact of this regulatory measure on the prescription of zolpidem and other sedative medications (zopiclone, benzodiazepines and antihistamines) in long-term users of zolpidem and associated factors. METHODS We performed a historical cohort study using data from the Generalist Sample of Beneficiaries (EGB). All patients aged over 18 years old who were long-term users (at least 3 months) before the measure were enacted. We analysed the reimbursement trajectories of zolpidem, zopiclone, benzodiazepines and antihistamines (hydroxyzine and alimemazine) up to 2 years after the measure using a state sequence analysis. RESULTS Overall, 2502 patients were analysed. A four-cluster typology was identified: continuation of zolpidem (n = 1044, 42%), discontinuation of sedative medications (n = 766, 31%), change to zopiclone (n = 537, 21%) and change to hypnotic benzodiazepines (n = 155, 6%). The most frequently prescribed hypnotic benzodiazepine was lormetazepam. We identified age, sex, treatment for psychiatric or addictive disorder and volume of zolpidem use before the measure as factors associated with different reimbursement trajectories after the regulatory change. CONCLUSION The regulatory change for zolpidem prescriptions reduced exposure to zolpidem among long-term users and also had a broad impact on prescriptions of other sedative medications. Switching to other medications that also present a potential risk of abuse or dependence should be carefully monitored.

Introduction Ces dernieres annees, le zolpidem a ete le medicament hypnotique le plus prescrit en France et a egalement fait l’objet de multiples rapports de mesusage, d’abus et de dependance. Devant ces risques, les medecins ont ete informes en janvier 2017 qu’a partir d’avril 2017 la prescription du zolpidem devait obligatoirement etre realisee sur ordonnance securisee. L’etude ZORRO (ZOlpidem et Renforcement de la Reglementation des Ordonnances) a ete mise en place pour evaluer l’impact global du changement reglementaire a partir d’une analyse de donnees de l’Assurance maladie et a partir d’une etude de terrain. L’objectif de l’etude presentee ici etait d’evaluer l’impact de la mesure sur le type de consommation du zolpidem a partir de donnees de remboursement de soins. Materiel et methodes Nous avons inclus tous les patients ayant au moins un remboursement de zolpidem avant et/ou apres le changement reglementaire a partir de l’Echantillon generaliste de beneficiaires (EGB). A partir des donnees de remboursement de soins, nous avons construit differents indicateurs afin de caracteriser le type de consommation tels que : la duree de traitement, le nomadisme medical, le nomadisme pharmaceutique, la surconsommation, la coprescription d’autres medicaments hypnotiques ou anxiolytiques, la prescription par un psychiatre, la presence d’une comorbidite psychiatrique. Une analyse en classes latentes a ete realisee chez les consommateurs reguliers de zolpidem (au moins deux delivrances dans chaque periode d’etude) avant et apres la reglementation pour identifier des profils de consommation. Resultats Au total, 15 550 consommateurs de zolpidem ont ete analyses avant la mise en place de la mesure et 8301 apres. Globalement, les habitudes de prescription ont evolue apres la reforme : moins de prescriptions par patient (nombre de patients avec au moins deux delivrances quasiment divise par deux) et moins de prescriptions concomitantes d’autres medicaments hypnotiques ou anxiolytiques. Chez les patients qui consommaient sur les deux periodes, nous avons egalement observe une diminution de la frequence de nomadisme pharmaceutique (2,1 % a 1,6 %), nomadisme medical (1,1 a 0,7 %) et surconsommation (24,2 % a 20,1 %). Parmi les patients ayant au moins deux delivrances de zolpidem, nous avons identifie les 3 memes profils de consommateurs de zolpidem avant et apres la reforme : – les consommateurs non problematiques (70–73 %), – les consommateurs avec une comorbidite psychiatrique associee (25–28 %), – les consommateurs potentiellement problematiques (2 %) (frequence elevee de nomadisme pharmaceutique, nomadisme medical et surconsommation). Le profil de consommateurs potentiellement problematiques, bien que toujours present apres la reforme, representait un nombre absolu de patients moins important apres la reforme. Conclusion En conclusion, le renforcement de la reglementation de prescription du zolpidem a eu un impact positif sur la consommation du zolpidem. Cet impact devra neanmoins etre reevalue avec plus de recul car l’arret ou la diminution de la consommation de zolpidem peuvent etre longs, specifiquement chez les utilisateurs chroniques.

Introduction La clozapine est le traitement de reference des schizophrenies (SZ) resistantes et le seul antipsychotique autorise dans la maladie de parkinson (MP) [1] , [2] . Le risque d’agranulocytose medicamenteuse auquel la prescription de clozapine est associee [3] impose la realisation hebdomadaire de numeration formule sanguine (NFS) pendant les 18 premieres semaines puis de facon mensuelle pendant la duree du traitement [2] . La mention de cette surveillance obligatoire dans les Resumes Caracteristiques Produits de la clozapine n’est toutefois pas une garantie de sa realisation. L’objectif de cette etude est d’evaluer la compliance de la realisation des NFS hebdomadaires a l’initiation de clozapine chez des patients SZ et MP. Materiel et methodes Il s’agit d’une cohorte historique, retrospective de pharmaco-epidemiologie. L’analyse a ete menee a l’aide des donnees du Systeme National des Donnees de Sante (SNDS) sur la region Pays de La Loire sur une cohorte de nouveaux utilisateurs de clozapine en 2018. Un nouvel usager de clozapine etait defini par un individu : – ayant eu au moins deux remboursements ambulatoires de clozapine ou un remboursement et une hospitalisation dans les 7 jours precedant le premier remboursement ambulatoire ; – n’ayant pas eu de remboursement ambulatoire de clozapine dans les 12 mois precedant le premier remboursement ambulatoire de clozapine. Les patients SZ et MP ont ete selectionnes par les codes F.20, F.25 et G.20 dans la liste d’Affection Longue Duree ou en code diagnostic d’une hospitalisation en 2017–2018. Nous avons evalue les NFS realisees en ambulatoire sur la periode de –2 a + 18 semaines apres l’initiation de clozapine ajustees sur la duree de traitement. Les NFS etaient considerees comme correctement realisees en cas d’hospitalisation sur la periode de suivi. Le critere de jugement principal etait la proportion de patient ayant une bonne realisation des NFS (NFS realisees/NFS attendues) a differents seuils : ≥ 70 % ; ≥ 80 % ; ≥ 90 %. Resultats 296 sujets ont ete inclus (160 sujets SZ et 136 sujets MP). Les taux de compliance de realisation des NFS ≥ a 70 %, 80 %, 90 % etaient respectivement de 78,1 %, 70,0 % et 56,9 % pour les sujets SZ et 71,3 %, 63,2 % et 47,8 % pour les sujets MP. L’hospitalisation (p = .001) a l’initiation ou pendant la periode de suivi pour les sujets SZ etait significativement associee a une bonne realisation au seuil de ≥ 90 % des NFS. Conclusion Dans notre etude, nous avons utilise le SNDS pour evaluer la bonne realisation ambulatoire des NFS pour les nouveaux utilisateurs de clozapine en conditions reelles. Nous avons observe une relativement bonne compliance pour les sujets SZ et MP et souligne l’importance de l’hospitalisation dans l’encadrement de la surveillance lors d’une initiation de clozapine.

Benzodiazepines and Z-drugs, zolpidem and zopiclone, (BZD/Z) are used longer than recommended in the elderly population. However, to date, very few attempts have been made to evaluate dependence on BDZ/Z among the elderly population. We conducted a national multicentric observational prospective study aimed at evaluating the prevalence of and risk factors for dependence among elderly adults. Patients aged 65 or older who were treated with BZD/Z for at least 3 months were evaluated through clinical interviews that conformed to official Diagnostic and Statistical Manual of Mental Disorders (DSM) dependence criteria. Among the 1,024 patients included in the survey, 442 of 976 (45.3%) met the dependence criteria. In the multivariate logistic regression model, dependent patients were categorized as follows: younger (odds ratio (OR) = 0.97), living mostly alone (OR = 1.45), showing psychiatric problems (OR = 2.22), having additional treatments (other than BZD/Z; OR = 1.37), having long-lasting treatment (OR = 1.04), exhibiting significant relationship difficulties (OR = 1.96), committing transgressional behaviors to procure BZD/Z (OR = 2.70), and wanting to stop their consumption of BZD/Z (OR = 7.60). A latent class analysis, which was applied to sort out subgroups within dependent patients, identified two profiles according to the prevalence of dependence items: profile 1 (73%), "withdrawal syndrome when BZD/Z is stopped" (100%) and "previous unsuccessful attempts to stop consumption" (82%); and profile 2 (27%), "tolerance" (76%) and "intake in larger amounts or over a longer period than intended" (86%). BZD/Z dependence is frequent in the elderly population, and among dependent patients, we found two profiles corresponding to positive and negative conditioning of the psychoactive effects of BZD/Z. This study is registered as NCT01920581.

International audience; Our objective was to quantify the impact on the use of zolpidem of the obligation implemented in France in 2017 to use secure prescription pads to prescribe it. We conducted a cohort study within the French SNDS healthcare database. Patients aged over 18 years of age were considered for inclusion. The number of prevalent users and incident episodes of zolpidem use were compared before the change in law (July 1, 2016 to January 1, 2017) and after (July 1, 2017 to January 1, 2018). A prevalent user was a patient who has been reimbursed for zolpidem at least once. An incident episode of zolpidem use was defined by a first administration of zolpidem without any prior administration within the previous six months. Regarding prevalence of zolpidem users, we observed a decrease from 2.79% (CI95%:2.75-2.83) to 1.48% (1.44-1.51), with a number of patients who stopped taking it after the change in law being approximately 4.3 times higher than the number of patients who started. We observed a negative association between the post-law change period (OR = 0.52 (0.51-0.53)) and the probability of receiving zolpidem, adjusting for sex, aging, low income and chronic disease. We observed a decrease from 183 treatment episodes per 100,000 insured months on average to 79 episodes per 100,000 insured months, with an incidence rate ratio (IRR) equal to 0.43 (0.38-0.49). The use of secure prescription pads seems to have reduced the exposure of the French population to zolpidem.

International audience; Therapeutic drug monitoring of β-lactam antibiotics is increasingly used for dose optimization in the individual patient to increase efficacy and reduce the risk of toxicity. The objective of this work is to develop and validate a fast and reliable method using liquid chromatography coupled to tandem mass spectrometric detection to quantify simultaneously amoxicillin, cloxacillin, cefazolin, cefotaxime, ceftazidime, cefepime, meropenem and piperacillin in plasma and cerebrospinal fluid (CSF). Sample clean-up included protein precipitation with acetonitrile followed by evaporation of the supernatant and reconstitution of the residue with mobile phase solvents. Eight deuterated β-lactam antibiotics were used as internal standards. Chromatographic separation was performed on a C18 column (50 mm x 2.1 mm) using a binary gradient elution of water and acetonitrile both containing 0.1% (v/v) formic acid. The total run time was 8 min. The method was then used to perform therapeutic drug monitoring on 2221 patient plasma samples. 32 CSF samples were also analyzed. This method, with its simple sample preparation provides sensitive, accurate and precise quantification of the plasma and cerebrospinal fluid concentration of β-lactam antibiotics and can be used for therapeutic drug monitoring.

Background: Proton pump inhibitors (PPIs) can trigger immediate-type hypersensitivity reactions (HSRs). Three main patterns of cross-reactivity have been identified: reactions to a single PPI, selective cross-reactions, and cross-reactions with all PPIs. Several hypotheses have been advanced, but no consensus has been reached. Objective: We sought to identify immediate-type hypersensitivity cross-reactions to PPIs using real-world data about hypersensitivity testing from French pharmacovigilance cases. Methods: Potentially relevant immediate-type HSRs reported from January 1985 to February 2015 were extracted from the French pharmacovigilance database using a standardized MedDRA query (SMQ). Cases describing skin tests or oral provocation tests (OPTs) performed with several PPIs that yielded at least one positive result were included. Results: The SMQ extracted 2,119 cases, 38 of which were included in our study. Data collected from skin tests and OPTs indicated cross-reactions with all PPIs (n = 1), reactions to a single PPI (n = 14), or selective cross-reactions (n = 23). Esomeprazole, omeprazole, and pantoprazole concerned 78% of all selective cross-reactions. In more than half of the cases (55.3%), only 2 PPIs were tested. Conclusion: To the best of our knowledge, this PPI cross-reactivity study is the largest to date in terms of population size, describing 38 immediate-type HSRs to PPIs explored by skin tests or OPTs. This paucity of data belies the lack of standardized procedures for PPI hypersensitivity testing. It is likely that PPI HSR workups in everyday clinical practice are often incomplete. Further research to gain insight into selective cross-reactions between PPIs is needed. In the meantime, thorough workups should be completed when a PPI is suspected to have triggered an HSR, instead of routine contraindication to all PPIs.

Aims To evaluate the risk of pleural disorders (PD) associated with 33 protein kinase (PK) inhibitors (PKIs) through a disproportionality analysis and to identify which PKs and pathways are involved in PKI-induced PD. Methods To evaluate the risk of PD, reporting odds ratios (RORs) were calculated for 33 PKIs through data registered in the World Health Organization safety report database (VigiBase). We undertook a literature review to identify PKs that were possibly involved in PD caused by PKIs. Pearson correlation coefficients (r) between RORs and affinity data of 19 PKIs were calculated to identify the cellular target most likely to be involved in PKI-induced PD. Results A total of 235 110 individual case safety reports were extracted from the database for 33 available PKIs. Among these reports, 5001 concerned PD (2.1%). Significant and positive disproportionality for PD was found for 29 of 33 PKI included in our study with top values for dasatinib [ROR = 115.3; 95% confidence interval (CI): 110.1-120.8], bosutinib (ROR = 20.4; 95% CI: 15.8-26.4) and ponatinib (ROR = 12; 95% CI: 9.2-15.6). Correlation analyses between the product of dissociation constant and ROR highlighted possibly Lyn involvement in PD with PKI (r = 0.73, P = 0.0004). Conclusions Our study showed that 28 of the 33 tested PKIs were associated with PD. Besides, the study highlighted the role of Lyn in PD caused by PKIs through an immune-mediated process.

Resume Introduction Le MEOPA (melange equimolaire d’oxygene et de protoxyde d’azote) est utilise pour ses proprietes analgesiques et anxiolytiques dans le but d’obtenir une sedation consciente du patient lors de la realisation de soins douloureux. Il fait l’objet d’un suivi renforce de pharmacovigilance et d’addictovigilance. Dans ce contexte, il est important de disposer de donnees d’utilisation en milieu hospitalier. Ce travail a pour objectif d’evaluer la conformite de l’utilisation du MEOPA par rapport aux recommandations du resume des caracteristiques du produit, dans un CHU francais (Nantes) et d’envisager des pistes d’amelioration. Materiel et methodes Etude descriptive, transversale type audit clinique menee fin 2014 aupres de tous les professionnels de sante des services utilisant le MEOPA. Resultats Deux cent trente-quatre professionnels de sante ont repondu au questionnaire ; les durees d’administration sont globalement conformes et les locaux sont globalement adaptes, mais presque 60 % des professionnels ont le sentiment d’inhaler le medicament. La systematisation de la prescription (toujours ou presque toujours prescrit pour 67 % des professionnels) et la tracabilite de l’utilisation (toujours ou presque toujours dans le dossier du patient pour 71 % des professionnels) constituent des pistes d’amelioration, ce d’autant que 18 % des professionnels de sante ont l’impression de « demandes abusives » de la part des patients. Conclusion La formation et l’information des professionnels de sante representent des enjeux majeurs de bon usage du MEOPA.

Objectifs SINTES est un dispositif national francais axe sur les drogues. Son objectif est d’analyser les substances collectees aupres des usagers principalement lorsque la consommation a provoque un effet inattendu. Notre etude s’est interessee aux resultats des echantillons preleves ces 7 dernieres annees en region Pays de la Loire afin d’identifier les situations ou il y a une discordance entre le produit souhaite et celui obtenu. Methode De 2012 a 2019, en region Pays de la Loire, tous les echantillons collectes ayant entraine des effets inattendus ont ete analyses. Les analyses sont effectuees par les laboratoires partenaires du dispositif SINTES ( https://www.ofdt.fr/enquetes-et-dispositifs/sintes/ ). Nous avons classe les resultats en trois types de discordances : l’arnaque totale (la substance obtenue est differente de celle supposee lors de l’achat par l’usager), l’arnaque partielle « dosage » (la substance obtenue est celle supposee au moment de l’achat par l’usager, mais en concentration inhabituelle) et l’arnaque partielle « composition » (la substance obtenue est celle supposee lors de l’achat par l’usager mais avec en plus differents produits de nature ou de quantite inattendue). Resultats Au total, 124 echantillons ont ete collectes, 60 (48,4 %) echantillons comprenaient au moins une discordance correspondant a 63 situations d’arnaques differentes. Parmi les 63 situations d’arnaque, 38 (60,3 %) etaient des arnaques totales (26 : remplacement par un produit d’une autre famille chimique, 6 : meme famille chimique et 6 : substance inerte), 14 (22,2 %) etaient des arnaques partielles « dosage » (10 sous-dosees et sur-dosees) et 11 (17,5 %) etaient des arnaques partielles « composition » (7 : au moins une autre substance psychoactive et 4 : quantite ou qualite anormale de produit d’adulteration). Notons que parmi les arnaques totales nous retrouvons des sedatifs vendus comme etant des stimulants et inversement. Parmi les arnaques « dosage », nous avons enregistre des echantillons particulierement concentres d’heroine (jusqu’a 41 %) et de cocaine (jusqu’a 93 %). La categorie des produits achetes comme « stimulants » etait la plus largement representee parmi les echantillons analyses (68 echantillons) avec 33 arnaques differentes identifiees (21 arnaques totales, 6 arnaques partielles « dosage » et 6 arnaques partielles « composition »). Parmi les produits analyses retrouves en plus grand nombre (NPS, MDMA, cocaine et heroine), l’heroine est le produit presentant le ratio « arnaque/nombre d’echantillon » le plus eleve : sur 20 echantillons, 14 arnaques ont ete identifiees. En ce qui concerne les complications somatiques, les arnaques totales representaient plus de la moitie des interventions medicales et environ la moitie des hospitalisations. Conclusion Dans notre travail, grâce aux analyses toxicologiques realisees, la moitie des echantillons ont ete identifies comme des arnaques. Ces situations peuvent entrainer des complications chez l’usager. Les produits consommes dans les situations d’arnaques totales ou d’arnaques partielles « dosage » peuvent conduire a une overdose ou a une nouvelle dependance chimique. Concernant les arnaques partielles « composition », differentes concentrations chimiques ou durees d’effets peuvent induire des complications a partir d’agents adulterants ou d’autres substances psychoactives presentes dans le produit.

International audience; INTRODUCTION: In France, an addictovigilance network is responsible for evaluating drug dependence, by drawing on pharmacoepidemiological studies, clinical studies and by assessing healthcare professionals' reports on problematic consumption. METHODS: The aim of this study was to determine whether zolpidem and zopiclone have different dependence profiles, based on healthcare professionals' reports, and to identify various consumer dependence profiles among zolpidem users and among zopiclone users. Dependence in reports was assessed using the EGAP scale; a scale developed using the DSM diagnostic dependence criteria. RESULTS: The comparison of dependence profiles for zolpidem and zopiclone showed differences both in total EGAP score and EGAP item positivity. The descriptive analysis showed that EGAP scores were higher for zolpidem than for zopiclone, suggesting more severe problematic consumption with zolpidem. For zolpidem 2 subpopulations of consumers were identified, with one subpopulation's consumption being more severe than the other, with a significantly higher total EGAP score and more harmful consequences. No subpopulation was highlighted for zopiclone. CONCLUSION: These results were in favour of a higher prevalence of physical and compulsive signs of dependence and of harmful consequences of dependence, with zolpidem than with zopiclone.

Optimal dosing of continuous-infusion cefazolin can be challenging in patients being treated for bacteremia or infective endocarditis. The aim of this work is to describe and analyze the pharmacokinetics of cefazolin in those patients using a population pharmacokinetics modeling approach and to establish a nomogram to determine the optimal daily dose. Population pharmacokinetics were modeled using the Pmetrics package for R. Plasma concentrations were collected retrospectively from patients treated with continuous-infusion cefazolin for bacteremia or infective endocarditis. The influence of multiple parameters, including renal function, total body weight, body mass index, body surface area (BSA), ideal weight, lean body weight, height, and age, was tested. The probabilities of target attainment for selected target concentrations (40, 60, and 80 mg/liter) were calculated. A dosing nomogram was then developed, using the absolute value of the glomerular filtration rate (aGFR), to determine the optimal daily dose required to achieve the target concentrations in at least 90% of patients. In total, 346 cefazolin plasma concentrations from 162 patients were collected. A one-compartment model best described the data set. The only covariate was aGFR, calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the patient’s body surface area, for the rate of elimination. Using the nomogram, achieving a cefazolin concentration target of 40 mg/liter with a success rate of at least 90% and with an aGFR of 30, 60, 90, and 120 ml/min requires a daily dose of 2.6, 4.3, 6.1, and 8.0 g/day, respectively. These results confirm the interest of posology adaptation of cefazolin according to aGFR.

Background: Nitrous oxide (N2O) is used worldwide for analgesia and anesthesia. It is also used for recreational purposes by some people. N2O can have major side effects (myeloneuropathy, delusions, emphysema) when used to excess. In France, N2O is available as an equimolar mixture of oxygen and nitrous oxide (EMONO). Its substance use disorder potential is monitored by the French Monitoring Centre for Addiction (CEIP-A) network. Our objective is to provide an overview of the substance use disorder potential of N2O in general, and of EMONO in particular. Methods: This paper is based on a systematic review of the literature for case reports involving N2O use disorder and on CEIP-A network cases involving EMONO use disorder. We characterized use disorder in accordance with DSM-5 ( Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria. Furthermore, we considered data relating to medical history, age, gender, and N2O consumption habits. Results: We identified 59 cases of N2O use disorder in the literature and 17 cases of EMONO use disorder from the CEIP-A network. More than 90% of the cases used N2O in larger quantities and for longer than intended. Conversely, more negative as opposed to positive cases have been documented regarding tolerance and failed attempts to reduce usage. Conclusions: A specific profile of substance use disorder starts to emerge from all the cases studied here. Furthermore, we identified another way N2O use disorder can appear: through exposure for medical purposes.

Introduction La consommation de substances psychoactives est tres frequente dans les festivals de musique avec une apparition recente de nombreuses nouvelles substances. Cependant, la consommation de substances chez les participants a des festivals de musique est encore peu connue car ces derniers ne consultent que rarement les structures de soins. L’observatoire OCTOPUS a ete mis en place afin d’ameliorer les connaissances sur la consommation des substances psychoactives dans les festivals de musique. L’objectif de l’etude presentee ici etait de decrire et caracteriser les profils de consommation de substances psychoactives en festival. Methodes Les sujets ont ete inclus parmi 13 festivals de musique (electronique, dub et eclectique) en Loire-Atlantique de juillet 2017 a juillet 2018. De nombreuses donnees ont ete recueillies par questionnaire : sociodemographiques, consommation de tabac, alcool et substances psychoactives et sur la reduction des risques. Nous avons analyse dans cette etude la consommation de drogues illicites dans les 12 derniers mois afin de decrire la prevalence de consommateurs et de caracteriser les profils de consommation par une analyse en classes latentes. Resultats Au total, 383 festivaliers ont ete inclus en festival (47 % en electronique, 18 % en dub et 35 % en eclectique). Les participants aux festivals etaient jeunes (28 ans en moyenne) et majoritairement des hommes (65 %). De nombreux participants (82 %) ont rapporte avoir consomme des drogues illicites au moins une fois dans les 12 derniers mois, avec une majorite de consommation de cannabis (77 %). Nous avons identifie differents profils de consommation de drogues illicites (a l’exception du cannabis) : « pas ou peu de polyconsommation » (frequence faible ou moderee de consommateurs de substances courantes : ecstasy/MDMA, cocaine, LSD and champignons hallucinogenes) et « polyconsommation importante » (frequence importante de consommateurs de substances courantes et frequence faible ou moderee de consommateurs d’autres substances telles que le speed, la ketamine, les nouveaux produits de synthese et les sedatifs). Discussion Nous avons mis en evidence une prevalence de consommation de drogues illicites elevee au sein de participants a des festivals de musique electronique, dub et eclectique. Certaines consommations de substances etaient uniquement rapportees dans le profil « polyconsommation importante ».

Introduction Ces dernieres annees, le zolpidem a ete le medicament hypnotique le plus prescrit en France et a egalement fait l’objet de multiples rapports de mesusage, d’abus et de dependance. Devant ces risques, les medecins ont ete informes en janvier 2017 qu’a partir d’avril 2017 la prescription du zolpidem devait obligatoirement etre realisee sur ordonnance securisee. L’etude ZORRO (ZOlpidem et Renforcement de la Reglementation des Ordonnances) a ete mise en place pour evaluer l’impact global du changement reglementaire a partir d’une analyse de donnees de l’Assurance maladie et a partir d’une etude de terrain. L’objectif de l’etude presentee ici etait d’evaluer l’impact de la mesure sur la prescription des medicaments sedatifs par l’analyse de trajectoires de traitement et d’etudier les facteurs associes a ces trajectoires a partir de donnees de l’Assurance maladie. Methodes Nous avons realise une etude de cohorte historique a partir des donnees de l’echantillon generaliste de beneficiaires (EGB, echantillon permanent du systeme national des donnees de sante [SNDS]). Tous les patients consideres comme consommateurs chroniques de zolpidem avant la mesure (au moins un remboursement pour du zolpidem dans les 3 mois consecutifs : octobre, novembre et decembre 2016) ont ete inclus dans l’etude. Nous avons etudie les remboursements de zolpidem, zopiclone, benzodiazepines et antihistaminiques jusqu’a 2 ans apres la mesure (de janvier 2017 a decembre 2018). Une analyse de sequences a ete realisee a partir du package R TraMineR et les clusters de sequences ont ete identifies a partir d’une classification ascendante hierarchique. Resultats Au total, 2502 trajectoires de traitement ont ete analysees. Quatre clusters de trajectoires de traitement ont ete mis en evidence : poursuite du zolpidem (42 %), arret des traitements hypnotiques/sedatifs (31 %), remplacement par de la zopiclone (21 %) et remplacement par des benzodiazepines hypnotiques (6 %). La benzodiazepine hypnotique la plus frequemment prescrite etait le lormetazepam. Des facteurs individuels ont ete identifies comme associes a ces clusters (âge et sexe). Discussion Le changement reglementaire a eu un impact important sur la prescription du zolpidem mais aussi plus largement sur la prescription des medicaments hypnotiques/sedatifs en general.

Introduction Les Centres Gratuits d’Information de Depistage et de Diagnostic des infections sexuellement transmissibles, du VIH et des hepatites (CEGIDD) sont egalement en charge de la prevention des risques en lien avec la sexualite. Ces dernieres annees, les equipes ont ete de plus en plus souvent confrontees a des patients avec un usage de substances psychoactives (SPA) variees. Une evaluation de ces consommations a ete realisee a Nantes. Ce travail presente un focus sur deux populations particulierement a risque : – les sujets utilisant des SPA pour faciliter un acte sexuel ; – les consommateurs solitaires et reguliers. Methodes Les donnees ont ete collectees pendant 4 semaines en 2019, a partir d’un auto-questionnaire anonyme propose a tous les sujets se presentant au CEGIDD de Nantes pendant cette periode. Resultats Les donnees de 442 patients ont ete analysees, majoritairement des hommes (62 %, n = 275). La moyenne d’âge etait de 28,8 ans mais la moitie des patients avaient moins de 25 ans. Un tiers des patients (n = 150) utilisait des SPA (tabac non comptabilise). Pres de 15 % des patients (n = 64, 14,5 %), dont les 3/4 sont des hommes, rapportent l’utilisation d’une ou plusieurs SPA pour avoir ou ameliorer un rapport sexuel. Leur moyenne d’âge est de 34,9 ans ; les 3 SPA les plus consommees avec le partenaire sexuel sont l’alcool, le cannabis et les poppers. Les consommateurs solitaires representent 21,9 % des patients inclus (n = 97), les 3/4 sont des hommes, leur moyenne d’âge est de 30,5 ans et les substances consommees rapportees par ces patients sont tres variees. Discussion Dans ces deux populations le risque pharmacologique est present : la consommation de multiples SPA peut potentialiser les effets de chacune, interagir avec des medicaments pris ou etre contre-indiquee en fonction de comorbidites. Pour les professionnels de sante des CEGIDD, prendre en compte les consommations de ces patients permettrait d’optimiser la reduction des risques pharmacologiques, et d’identifier des sujets vulnerables sur le plan addictologique et de les orienter pour une prise en charge adaptee.

Introduction Les antihistaminiques (antiH1) de premiere generation disponibles sans prescription sont approuves dans de nombreuses indications telles que l’insomnie, la toux, l’ecoulement nasal, la cinetose. Leurs proprietes pharmacologiques antihistaminiques et atropiniques en font des substances susceptibles d’etre mesusees, c’est-a-dire avec une utilisation non conforme au resume des caracteristiques du produit (RCP). L’objectif principal de l’etude ECHO etait de caracteriser ce mesusage. Methodes Il s’agissait d’une etude transversale menee en 2019, en pharmacies d’officine, dans la region des Pays de la Loire. Un questionnaire, a ete propose a chaque patient majeur se presentant a l’officine avec une demande spontanee d’un antiH1 de premiere generation disponible en vente libre. Les donnees recueillies concernaient notamment les effets recherches, la dose, la duree de prise et la voie d’administration, Resultats Au total, 433 patients ont ete inclus. Aucun detournement de la voie d’administration n’a ete rapporte. Les deux antiH1 de premiere generation les plus demandes etaient la doxylamine (n = 238) et l’oxomemazine (n = 99) et, pour chacun d’eux, plus de 40 % des patients avait une consommation non conforme au RCP par rapport a la dose, la duree de prise ou les effets recherches. La doxylamine etait souvent consommee sur une longue duree et/ou a dose elevee chez des sujets âges. Pour l’oxomemazine, une recherche d’effet sedatif etait rapportee par 25 % des patients. Parmi les autres antiH1, la cyproheptadine etait toujours prise par des femmes et mesusee avec une recherche d’effet orexigene (n = 6). Pour la promethazine, malgre un faible nombre de repondants (n = 4), la recherche d’effet hallucinogene etait rapportee. Discussion Notre etude a permis de mettre en evidence un taux de mesusage important des antiH1 de premiere generation disponibles en vente libre demandes en officine. Questionner les patients en officine sur les effets ressentis lors de la prise des antiH1 de premiere generation, pourrait permettre de prevenir d’eventuels risques de mesusages ulterieurs.

Objectif La paliperidone palmitate (PP) est une formulation intramusculaire (IM) a action prolongee de la paliperidone, un metabolite actif de la risperidone. Elle est indiquee dans le traitement d’entretien de la schizophrenie chez l’adulte et autorisee en France depuis 2013 pour la forme mensuelle PP1M (Xeplion®) et 2016 pour la forme trimestrielle PP3M (Trevicta®). L’objectif de cette etude etait de decrire et caracteriser la survenue des effets indesirables graves (EIG) associes au deces et a la mise en jeu du pronostic vital chez les patients traites par PP. Methode Etude retrospective descriptive des cas de la Base nationale de pharmacovigilance (BNPV) de deces et mise en jeu du pronostic vital chez les patients traites par PP entre le 01/01/2013 et le 01/01/2020. Resultats Vingt-sept cas, 13 deces et 14 mises en jeu du pronostic vital, ont ete recenses chez des patients traites par PP dont 23 cas (11 deces) concernaient PP1M et 4 cas (2 deces) un switch de PP1M par PP3M. Les EIG etaient majoritairement des symptomes cardiorespiratoires (15 patients) : morts subites (n = 6) ; arrets cardiaques sur torsades de pointe (n = 2) ; arret cardiorespiratoire sur crises convulsives (n = 1) ; embolies pulmonaires (n = 6). Les autres symptomes observes etaient principalement metaboliques (acidocetoses diabetiques n = 3 ; hyponatremie severe n = 1) digestifs (enterocolite necrosante n = 2 ; necrose hepatique n = 1) et neurologiques (parkinsonisme n = 2 ; convulsions n = 1). La date d’instauration du traitement etait connue dans 23 cas : les symptomes cardiorespiratoires etaient observes precocement apres instauration du traitement (11 cas dans les 6 premiers mois) contrairement aux troubles metaboliques (4 cas entre 12 et 21 mois). Les arrets cardiaques et mort subites survenaient entre j10–14 de la derniere injection pour PP1M et j11–24 pour PP3M. Ils concernaient dans la majorite des cas des patients sans antecedent cardio-vasculaire. Discussion Dans cette serie, les EIG de la PP sont semblables a ceux de la paliperidone orale, de la risperidone orale et injectable a action prolongee. Une serie japonaise rapporte 32 cas de deces, apres administration mensuelle de PP1M dont 12 morts subites inexpliquees [1] . Les concentrations toxiques a la PP sont decrites des 120 μg/L [2] . Ravenstijn et al. ont montre une grande variabilite pharmacocinetique interindividuelle des formes IM trimestrielles concernant le Tmax, la Cmax, et la demi-vie d’elimination pouvant etre a l’origine de concentrations elevees toxiques (jusqu’a 416 μg/L) [3] . Les arrets cardiaques et morts subites semblent survenir precocement apres l’instauration du traitement et dans un delai post-administration compatible avec le pic plasmatique de PP. Conclusion Il apparait necessaire d’etre particulierement attentif lors l’instauration de PP. D’autres etudes de suivi therapeutique des concentrations de paliperidone semblent necessaires et la documentation des deces par un dosage permettrait de verifier l’hypothese d’un possible surdosage en paliperidone dans ces cas.

ObjectivesAssess the stability of several antibiotics in peritoneal dialysis (PD) solutions under common conditions of use in pediatrics, particularly in automated PD.MethodsAmoxicillin, cefazolin, cefepime, ceftazidime, imipenem, cotrimoxazole, tobramycin, vancomycin, and the association of ceftazidime + vancomycin and ceftazidime + tobramycin, were tested in 3 different PD solutions: bicarbonate/lactate solution with 2 glucose concentrations (Physioneal 1.36 and 3.86%; Baxter Healthcare Corporation, Deerfield, IL, USA) and an icodextrin-containing solution (Extraneal; Baxter Healthcare Corporation, Deerfield, IL, USA). Concentrations were those recommended in guidelines for the treatment of peritonitis in pediatrics. Physioneal bags were incubated at 37°C for 24 hours, whereas Extraneal bags were stored 12 hours at room temperature (22 ± 2°C) and then 12 hours at 37°C. Drug concentrations were determined using high performance liquid chromatography (HPLC). Each measure was taken in triplicate. Stability of antibiotics was defined as less than 10% degradation of the drug over time.ResultsCefazolin, cotrimoxazole, tobramycin, and vancomycin were stable under studied conditions. Ceftazidime was stable 24 hours in icodextrin, 12 hours in Physioneal 1.36% and 6 hours in Physioneal 3.86%. The association of tobramycin or vancomycin did not influence the stability of ceftazidime. Cefepime and amoxicillin were stable 6 h, 4 h, and 8 h in Physioneal 1.36%, 3.86% and Extraneal, respectively. The stability of imipenem was very low: 2 h in Physioneal and 6 h in Extraneal. Moreover, an increasingly yellow coloration was observed with the use of imipenem, whereas no color change or precipitation occurred in other bags.ConclusionCefazolin, tobramycin, cotrimoxazole, and vancomycin are stable in PD solutions up to 24 hours and can be administered in the PD bag for the treatment of peritonitis, even in automated PD under studied conditions. However, amoxicillin, cefepime, ceftazidime, and imipenem must be used with caution due to their lack of stability.

Background The whole blood extraction for liquid chromatography tandem mass spectrometry (LC-MS/MS) of simultaneous quantification of cyclosporine A (Cys A), tacrolimus (Tacrs), sirolimus (Siros), and everolimus (Evers) is still performed manually in many laboratories. The analytical results obtained with an automated method using a liquid handler versus a classical manual preparation were compared. Methods Cys A (n = 36), Tacrs (n = 50), Siros (n = 34), Evers (n = 38) whole blood samples of patients were analyzed by LC-MS/MS assay after manual preparation and automated process using a liquid handling platform including a centrifugation step. Results The comparison between manual and automated extraction investigated by a linear regression showed a high correlation between results [(Tacrs “automated”) = 1.0927 × (Tacrs “manual”) − 0.36; (Cys A “automated”) = 1.0284 × (Cys A “manual”) + 0.0312; (Siros “automated”) = 0.9923 × (Siros “manual”) + 0.4001; (Evers “automated”) = 1.0000 × (Evers “manual”) − 0.0600]. Conclusion The results obtained by the automated and manual preparation are consistent. The automated method is applied for high-throughput therapeutic drug monitoring of immunosuppressive drugs in routine practice, leading to an increase in quality.

Resume Dans un essai clinique randomise, lorsque le resultat sur le critere de jugement principal montre un benefice significatif, les criteres secondaires sont scrutes a la recherche d’effets additionnels du traitement. Cette demarche entraine cependant une augmentation du risque de conclure a un benefice sur un de ces criteres alors que le benefice n’existe pas (inflation du risque alpha). Pour controler le risque de conclure a tort sur les criteres secondaires, il existe deux methodes. La premiere consiste a repartir le risque sur plusieurs co-criteres primaires, afin de conserver un risque global de 5 %. La seconde est l’approche sequentielle hierarchique, qui consiste a hierarchiser les criteres de jugement a priori et de conclure successivement sur ces criteres tant que le test statistique est significatif. Cette methode simple permet de demontrer les avantages supplementaires des traitements et ainsi d’identifier leurs facteurs de differenciation.

In a randomised clinical trial, when the result of the primary endpoint shows a significant benefit, the secondary endpoints are scrutinised to identify additional effects of the treatment. However, this approach entails a risk of concluding that there is a benefit for one of these endpoints when such benefit does not exist (inflation of type I error risk). There are mainly two methods used to control the risk of drawing erroneous conclusions for secondary endpoints. The first method consists of distributing the risk over several co-primary endpoints, so as to maintain an overall risk of 5%. The second is the hierarchical test procedure, which consists of first establishing a hierarchy of the endpoints, then evaluating each endpoint in succession according to this hierarchy while the endpoints continue to show statistical significance. This simple method makes it possible to show the additional advantages of treatments and to identify the factors that differentiate them.

International audience; BACKGROUND: In the last 10 years, dopamine replacement therapy (DRT) has become a well-known risk factor for developing an impulse control disorder, such as gambling disorder (GD). Another medication, aripiprazole (ARI), has been more recently identified as another risk factor. Dopamine replacement therapy and ARI share a dopamine agonist action. Our work aimed at comparing patients with PG according to their treatment with DRT or ARI. METHODS: Two methods were combined-a systematic review concentrated on case reports and the analysis of a French disordered gamblers cohort focused on patients using ARI or DRT at inclusion. RESULTS: We reported 48 cases of GD possibly due to DRT and 17 cases of GD possibly due to ARI. Because of their standardized assessment, only the EVALJEU patients could be compared. Two clinical patterns emerged. Patients in the ARI group were young, impulsive, and high novelty seekers and had a history of substance misuse. Their first gambling experience occurred during adolescence. Conversely, patients in the DRT group were old, and they began gambling late in life. They showed low levels of gambling-related cognition. CONCLUSIONS: Patients in the ARI group seemed to be more severe pathological gamblers than patients in the DRT group. Aripiprazole is a partial D2 receptor agonist, whereas DRT includes full D2 receptor agonist. The trigger mechanism of PG development is complex and cannot only be attributed only to the pharmacodynamic effects of dopaminergic drugs. Indeed, individual vulnerability factors and environmental factors need to be considered.

Introduction In recent years, zolpidem has been the most prescribed hypnotic drug in France and has been the subject of numerous reports of misuse, abuse and dependence. In view of these risks, the French drug agency (ANSM) decreed in April, 2017 the implementation of secure prescription pads. The objective of this study was to evaluate the impact of the measure on the prescription of hypnotic/sedative and anxiolytic molecules by examining the treatment trajectories and the factors associated with these trajectories. Material and methods We conducted an observational prospective study usizng the Generalist Sample of Beneficiaries (EGB) (a permanent sample of the French healthcare system database (SNDS)). Our study consisted of all patients aged over 18 years old who started zolpidem treatment in 2016 and who were long-term users before the measure (at least one reimbursement for zolpidem in the three consecutive months: October, November and December, 2016). We studied reimbursement trajectories for the psychoactive drugs most likely to be prescribed after zolpidem was stopped up to two years after the measure (from January 2017 to December 2018). We performed a state sequence analysis using the TraMineR R library. We computed pairwise distances using optimal matching method and performed agglomerative hierarchical clustering to identify clusters of treatment trajectories. We set the number of clusters using the fall in inertia and evaluated the clustering quality using the average silhouette width (ASW) and the Hubert's C index (HC) implemented in the WeightedCluster R library. We then assessed the association between individual characteristics and the patterns of treatment trajectories using univariate and multivariate analyses. Results Overall, we analysed 2503 treatment trajectories of long-term users before the measure. A four-cluster typology was found with a good quality (ASW = 0.45 and HC = 0.08). The four patterns of treatment trajectories were: continuation of zolpidem (46.3%), discontinuation of hypnotic/sedative and anxiolytic molecules (33.3%), changed to zopiclone (14.5%) or hypnotic benzodiazepines (5.9%). We identified individual characteristics such as age and sex that were associated with the different patterns of treatment trajectories. Discussion To our knowledge, this is the first study using state sequence analysis to identify clusters of drugs reimbursement trajectories in the French national health insurance database. State sequence analysis is a promising method in pharmacoepidemiology to study different patterns of drug use in the general population.

International audience; The principal outcome was to identify which hypnotics substances, medicated (benzodiazepines, antihistamine, antidepressant\ldots ) or not medicated (herbal medicine, homeopathy, melatonin\ldots ), were consumed by community pharmacy patients who reported taking something for sleep disorder, and which factors can influence the consumption of medicated substance rather than nonmedicated substance. Data were collected via a network of 73 partner pharmacies around Nantes, France. Patients who reported taking a substance to sleep completed a questionnaire that collected data relative to the different substances consumed by that person for sleep, and the desired effect. Substances were classified in Hypnotic Drug Substances and nonmedicated hypnotic substances. A logistical regression was done in order to highlight the factors associated with the consumption of Hypnotic Drug Substance rather than nonmedicated hypnotic substances. Six hundred and forty-seven patients were included, with an average age of 58 years and 74% female. The principal strategy employed to combat sleep disorder was the consumption of Hypnotic Drug Substance (54%), followed by herbal medicine (32%) and homeopathy (19%). The factors positively associated with the consumption of a Hypnotic Drug Substance are age, living alone, being out of work, or in the process of looking for a job and being a parent. In our survey, the use of Hypnotic Drug Substance to help patients with sleep is far from systematic. On the other hand, among patients who consume HDS, misuse is still significant, particularly in terms of the duration of consumption.

International audience; INTRODUCTION: Co-occurring pain impairs depression's prognosis. Selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) are first-line pharmacotherapies for depression and inhibit many cytochrome 2D6 enzymes. Codeine is a first-line treatment for pain and needs to be metabolized into morphine by cytochrome 2D6 to exert its analgesic effect. Concomitant prescription of both pharmacotherapies leads to inadequate analgesia. Areas covered: We performed a systematic review of the literature to amalgamate the current knowledge regarding the clinical effect of this association and quantified its prevalence in clinical practice in the French Pays de la Loire area using a retrospective observational cohort study design. Expert opinion: The literature review highlighted that antidepressants with moderate-to-strong inhibition of CYP2D6 should be avoided in patients receiving codeine. However, 0.44% of the 12,296 sampled patients received concomitant codeine and CYP2D6 inhibitor between January 2015 and June 2015. Switching drugs in both painful and depressive patients depends on the pain and depression subtypes. Promising drugs that both show an effect on pain and depression are currently being studied but are not usable in clinical practice. Until then, tailored communication reinforcement toward health-care professionals is needed to prevent these problematic occurrences of concomitant prescription administration.