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(1) Background: Precarious patients are more difficult to care for due to low literacy rates and poor adherence to treatment and hospitalization. These difficulties have detrimental effects on general practitioners (GPs), deteriorating medical communication, advice, diagnoses, and drug prescriptions. To better understand how precariousness affects primary care, we tested whether, among GPs, exposure to high precariousness prevalence more severely impacts drug prescriptions to precarious and non-precarious populations compared to low precariousness prevalence. Materials and methods: This pharmaco-epidemiological study, using linear regression analyses, compared the defined daily dose of 20 drugs prescribed by GPs to precarious and non-precarious patients in four French regions with low and high precariousness prevalence in 2015. (2) Findings: Exposure to high precariousness prevalence significantly impacted the prescriptions of nine medications to precarious patients and two medications to non-precarious patients, and distributed into three interaction patterns. (3) Interpretation: The selective over-prescription of drugs with easy intake modalities to precarious patients probably reflects GPs’ attempts to compensate for poor patient compliance. In contrast, the under-prescription of drugs targeting fungal infections in precarious populations and diabetes and cardiovascular diseases in non-precarious populations was seemingly due to a breakdown of empathy and professional exhaustion, causing medical neglect.

Background The association between precariousness and lack of access to health care is well-documented. Prescribing drugs is one promising marker for this health care inequality. A recent study, carried out on the entire French population, has developed a new measurement model based on the 20 most prescribed molecules. It reports that drugs, targeting diseases known to more affect precarious populations, are under-prescribed by general practitioners (GP) to these populations. If these findings highlight unequal drugs prescriptions between populations despite epidemiological factors, it is still unknown whether a high and daily exposure to precariousness negatively impacts GPs prescriptions. Here, we investigated whether there are more inequalities in prescriptions of GPs who are highly and daily exposed to precariousness, compared to GPs who are less exposed to precariousness. Methods This retrospective pharmaco-epidemiological study compared the Defined Daily Dose relative to different reimbursed drugs prescribed by GPs to precarious and non-precarious patients in four French regions respectively with low and high precariousness prevalence in 2015. Data were analyzed using repeated-measures ANOVAs (Sphericity correction: Greenhouse-Geisser; Post-Hoc Tests, Bonferroni corrected). Results 2 out of 20 molecules were significantly over-prescribed (tamsulosine and timolol) and 7 were under-prescribed (amoxicillin, econazole, ciclopirox, prednisolone, paracetamol, cromolyn sodium, ibuprofen) to precarious populations in regions with high precariousness prevalence. Conclusions The over-reimbursement of tamsulosine and timolol did not reflect the negative impact of exposure to precariousness on the GPs prescriptions but a failure of the health system to compensate for inequalities in access to chirurgical treatments. In contrast, the under-reimbursement of amoxicillin, ciclopirox and econazole indicated an effect of the exposure to precariousness on GPs’ prescriptions, these molecules targeting acute diseases that affect more significantly precarious than non-precarious populations. The same explanation is probably suitable for the under-reimbursement of prednisolone, paracetamol, cromolyn sodium, and ibuprofen, although their various indications render difficult to delimitate the clinical purpose at the basis of their prescription. We assume that exhausting working conditions, repeated exposures to difficult living conditions, and repeated experiences of failure impairs empathic skills in GPs, leading to burnout which negatively impacts the quality of care and, thus, prescriptions.

International audience

BackgroundSafety of rechallenge of immune checkpoint inhibitor (ICI) after grade ≥2 immune-related adverse events (irAEs) leading to ICI discontinuation remains unclear.MethodsAll adverse drug reactions involving at least one ICI reported up to December 31, 2019 were extracted from the French pharmacovigilance database. Patients were included if they experienced at least one grade ≥2 irAE resulting in ICI discontinuation, with subsequent ICI rechallenge. The primary outcome was the recurrence of at least one grade ≥2 irAE in these patients after ICI rechallenge.ResultsWe included 180 patients: 61.1% were men (median age of 66 years), 43.9% had melanoma and 78.9% were receiving anti-programmed cell death 1. First ICI discontinuation was related to 191 irAEs. After ICI rechallenge, 38.9% of the patients experienced at least one grade ≥2 irAE. Among them, 70.0% experienced the same irAE, 25.7% a distinct irAE, and 4.3% both the same and a distinct irAE. Lower recurrence rates of irAEs were associated with rechallenge with the same ICI treatment (p=0.02) or first endocrine irAEs (p=0.003). Gastrointestinal irAEs were more likely to recur (p=0.007). The median duration from ICI discontinuation to rechallenge and the severity of the initial irAE did not predict recurrent irAEs after ICI rechallenge (p=0.53 and p=0.40, respectively).ConclusionsIn this study, 61.1% of the patients who discontinued ICI treatment for grade ≥2 irAEs experienced no recurrent grade ≥2 irAEs after ICI rechallenge. Although ICI rechallenge appears to be safe under close monitoring, it should always be discussed balancing usefulness of rechallenge, patient comorbidities and risk of recurrence of first irAE(s). Due to inherent bias associated with pharmacovigilance studies, further prospective studies are needed to assess risk factors that may influence patient outcomes after ICI rechallenge.

Aims To provide real-life data on patterns of use and safety of ibrutinib. Methods A cohort study including all patients initiating ibrutinib between 21 November 2014 and 21 November 2018, and followed for 1 year was conducted. Patient characteristics, ibrutinib use and adverse drug reactions (ADRs) were collected from medical records. Kaplan-Meier analysis estimated the probability of developing ibrutinib-associated serious ADRs (SADRs) with a 95% confidence interval (CI). A Cox proportional hazards model was used to investigate factors associated with SADR occurrence. Results In total, 102 patients were included in the study. The median age was 70.3 years (interquartile range 64.7-75.6), the male/female gender ratio was 2.9. Almost half the patients (47.1%) were prescribed ibrutinib for chronic lymphocytic leukaemia (CLL). Forty-three patients (42.1%) permanently discontinued ibrutinib in the first year, mostly for progression (51.2%) or ADRs (32.6%). Forty-eight patients (47.1%) experienced at least one ibrutinib-associated SADR. Haematological, infectious and vascular disorders were the most frequent SADRs. The probability of developing ibrutinib-associated SADR was 35.1% (95% CI 26.3-45.7%) at 3 months, 44.8% (35.2%; 55.8%) at 6 months and 54.3% (44.0%; 65.2%) at 12 months. Age ≥80 years (hazard ratio [HR] 2.03; 95% CI 1.02-4.05) and CLL (HR 1.81; 95% CI 1.01-3.25) were significantly associated with a higher risk of SADR occurrence. Conclusion This study found a high cumulative incidence of ibrutinib-associated SADRs within the first year of treatment. In view of the risk of SADR, patients aged ≥80 years or treated for CLL deserve special attention.

International audience; A recent pre-clinical study has shown that brain-penetrating statins can reduce risks of relapse to cocaine and nicotine addiction in rats. Based on this information, we conducted a randomized, double-blind, placebo-controlled, proof-of-concept trial to assess the efficacy of simvastatin in smoking cessation. After informed consent, 118 participants received behavioral cessation support and were randomly assigned to a 3-month treatment with simvastatin or placebo. The primary outcome was biochemically verified abstinence or smoking reduction at 3-month post-target quit date (TQD). Secondary outcomes were abstinence during weeks 9-12 post-TQD, prolonged abstinence or reduction at months 6 and 12 post-TQD, safety and craving assessed at each visit during the 3-month period of treatment. Simvastatin treatment was not associated with higher 3-month abstinence or smoking reduction compared to placebo. There was no significant difference in any of the secondary outcomes. Simvastatin was well tolerated. Over 3 and 9 months follow-up period, 78% simvastatin and 69% placebo participants were retained in the study. At 6 and 12 months, smoking remained significantly reduced from baseline in both groups. Our results demonstrate that a 3-month simvastatin treatment (40 mg/day), added to individual behavioral cessation support, does not improve significantly smoking cessation compared to placebo in humans. According to the World Health Organization, smoking is the largest preventable cause of disease and death in the world 1. Although the prevalence of everyday tobacco use has dropped in most nations since 1990, the total number of smokers has increased 2. In 2015, 6.4 million deaths worldwide were attributable to smoking, representing a 4.7% increase in smoking-attributable deaths since 2005. This number is likely to reach 8 to 10 millions a year by 2030 1,2. The benefits of smoking cessation have been clearly proven in terms of morbidity and mortality for different diseases related to tobacco, especially for lung cancer 3,4. Although over 70% of smokers want to quit, less than 5% of quit attempts are successful annually 5. Currently, there are only 3 first-line approved medications in the USA and Europe for smoking-cessation: nicotine replacement therapy (NRT), sustained release bupropion, and varenicline, which are widely recommended in many national guidelines. Nevertheless, the therapeutic effectiveness of NRT is relatively modest, bupropion is not widely used because of its safety profile and varenicline's use is limited because of fear of potential cardio-vascular or neuropsychiatric adverse effects 6,7. Therefore, the discovery of new medications that could facilitate abstinence and reduce relapse to cigarette use represents a pressing necessity to reduce risks associated with tobacco smoking. We recently reported in rats that brain-penetrating statins-simvastatin and atorvastatin-can reduce risks of relapse to addiction 8. In fact, chronic treatment with low doses of statins daily during a 21-day period of abstinence , significantly reduced cocaine or nicotine seeking compared with placebo without altering seeking for food. Based on this information, we hypothesized that simvastatin could have beneficial effects on smoking cessation in

International audience; INTRODUCTION: According to French guidelines on good pharmacovigilance practices, a pharmacovigilance survey is an assessment of the available drug safety data. It is requested by the French national agency for medicines and health products safety (ANSM). The objective is to validate a signal, to characterize it, or to provide strengthened monitoring of a drug. MATERIAL AND METHODS: All the available data were retrieved by ANSM/Regional Pharmacovigilance Centers (RPC) and assessed by a nominate RPC which provides a report for discussion during the monthly Committee between ANSM and the Regional Pharmacovigilance Network (RPN). A descriptive analysis of the minutes available on the ANSM website between 2016 and 2018 has been done: objective, data sources, duration of the survey, number of suspected adverse drug reactions, nature of the drugs and of the signals and recommendations for actions. RESULTS: Between 2016 and 2018, a total of 115 surveys were discussed concerning 135 drugs, mainly from the nervous system according to the anatomic therapeutic chemical classification (n=31, 27%). They involved a whole pharmacological class for 18 ones. The main objective of the 115 surveys was to provide a strenghtened monitoring for some drugs (72%) or to validate one or more than one signal (28%). Result from surveys allowed to detect one or several new potential safety signals in 63 ones (55%), an off-label-use in 12 (10%) or to characterize some others signals in all the studies. The Committee recommended one or several actions by survey: 67 prolongations (58%) of the survey and regulatory or investigatory actions which included 43 European actions (37%), 37 label changes (32%), 30 national communications (26%) and 29 additional monitoring (25%). DISCUSSION/CONCLUSION: The current process allows a collegiate, clinical and pharmacological discussion with integration of the regulatory framework. A significant number of new signals are detected and/or validated. This efficient tool which is unique in Europe and is allowed by the decentralized pharmacovigilance which leads to a great reactivity of decision-making. It has to be reassessed and to be adapted continuously to the new challenges of the growing multiplication of signals.

International audience

Summary Introduction Nalmefene, an opioid antagonist, causes withdrawal syndromes in patients exposed to an opioid agonist. Despite its contraindication, this illogical drug association persists, especially with opioid substitution drugs (ODS). We measured the benefits of the modification in the summary of product characteristics (SPC) in March 2015 and the package leaflet of Selincro® in September 2016 on this misuse. Material and method We analyzed the observations regarding a use of nalmefene with an opioid between September 2014 and August 2017 in the French pharmacovigilance database and the laboratory. Results The combination nalmefene and methadone was reported in about half of the cases (46/90). Observations were highest between October 2015 and March 2016 (29/90) and then decreased. Those with self-medication have increased. From October 2016, declarations become rarer. Conclusion The effect of modifications in the SPC and the package leaflet on the use of nalmefene with ODS was real and progressive.

Introduction En France, la codeine a longtemps ete disponible dans les officines sans ordonnance et utilisee pour ses proprietes antitussives ou antalgiques. Cette facilite d’acces etait la source de nombreuses derives notamment les usages detournes comme dans la fabrication du “purple drank” induisant des dependances a la suite de mesusages repetes. Ainsi, depuis le 12 juillet 2017, tous les produits codeines ainsi que le dextromethorphane, la noscapine et la codethyline ne sont desormais delivres que sur ordonnance [1] , [2] . Le panel de medicaments « conseils » delivrables en pharmacie s’est vu alors diminue. Methodes Une enquete a ete realisee aupres de pharmaciens d’officine, de preparateurs en pharmacies ainsi que d’etudiants en pharmacie afin d’estimer les impacts de cette nouvelle reglementation sur la pratique officinale et le ressenti des professionnels a l’officine. Resultats Les resultats de 116 reponses montrent que les pharmaciens utilisaient les produits codeines comme medicaments-conseils pour de nombreuses indications telles que des douleurs dentaires, des cephalees, de la toux seche ou encore des maux de dos. De plus, ils observent, depuis cette decision ministerielle, une augmentation des ordonnances falsifiees avec de la codeine. Par ailleurs, les professionnels de sante interroges sont majoritairement en desaccord avec cette nouvelle loi car ils constatent qu’ils n’ont plus de reels moyens ni d’alternatives efficaces pour soulager les douleurs aigues severes. Une autre etude realisee dans 8 officines a montre une tres nette diminution des ventes des 4 medicaments codeines (Prontalgine®, Codoliprane®, Euphon®, Neocodion®) qui etaient, avant la nouvelle reglementation, les plus delivres. Seulement une legere augmentation des prescriptions medicales de ces medicaments a ete observee, ce qui suggere que les patients se tournent vraisemblablement vers d’autres therapeutiques pour soulager leurs douleurs. Discussion Cette nouvelle loi sur la codeine a modifie la pratique officinale principalement pour le traitement de la douleur aigue. Neanmoins, il persiste le probleme des patients addicts a la codeine qui doivent soit trouver des therapeutiques de sevrage, soit se tourner vers d’autres substances psychoactives.

Introduction La France est le plus gros consommateur de medicaments au monde et se distingue de maniere plus importante avec la consommation de psychotropes [1] . Les intoxications medicamenteuses representent l’une des premieres causes de consultation aux urgences et d’admission en reanimation. L’incidence annuelle des intoxications medicamenteuses volontaires est estimee a environ 4 pour 1000 habitants [2] . Les medicaments psychotropes occupent le 2e rang derriere les produits analgesiques et sont a l’origine d’une letalite significative. Les intoxications se traduisent par des symptomes qui varient suivant les molecules en cause ; les symptomes peuvent etre neurologiques, cardiovasculaires, respiratoires, digestifs… Methodes Une enquete epidemiologique descriptive retrospective a ete realisee a partir de 107 dossiers medicaux issus de la base de donnees des urgences du CHU de Poitiers sur l’annee 2019. L’objectif etait de determiner le profil des patients concernes, de s’interesser aux differentes molecules incriminees et a la prise en charge des patients aux urgences. Resultats Les resultats nous ont permis de dresser un profil de patients : il s’agit majoritairement de femmes (63 %) âgees pour 78 % des cas de 10 a 59 ans. Dans 89 % des cas l’intoxication est d’origine volontaire chez des patients ayant des antecedents medicaux (73 %) dont des antecedents d’origine psychiatrique dans 68 % des cas. Concernant les medicaments en cause, sont majoritairement retrouves les benzodiazepines (76 %) sachant que ces traitements etaient prescrits dans seulement la moitie des cas. L’evolution de ces intoxications s’est averee favorable dans 90 % des cas avec une prise en charge tres souvent symptomatique. Discussion Ces conclusions peuvent amener a quelques interrogations a propos de la prescription et de la delivrance des medicaments psychotropes. La prevention et l’information aux professionnels de sante et aux patients devrait-elle etre encore une fois renforcee ? Les professionnels de sante ont aujourd’hui encore un grand role a jouer afin de lutter contre le mesusage et l’abus de consommation de cette classe therapeutique.

Introduction Les poppers sont des derives nitres aliphatiques qui sont detournes de leur usage d’origine pour un usage sexuel et recreatif. En plus de leurs proprietes vasodilatatrices, ces produits sont responsables de nombreux effets indesirables du plus benin (maux de tete, flush facial, nausees…) au plus grave (toxicite dermatologique, oculaire, cardiaque, hematologique) pouvant conduire a des convulsions, des comas voire des deces [1] . Methodes Une enquete a ete realisee aupres de consommateurs via un questionnaire informatique anonyme diffuse sur les reseaux sociaux. Les questions portaient sur l’etat des connaissances des personnes interrogees a propos des poppers, ainsi que sur leurs usages et leurs habitudes de consommation. Resultats Les resultats montrent que parmi les participants a l’enquete (261 personnes), la plupart sont des jeunes de 20 a 29 ans. Parmi eux, 2/3 en ont deja consomme et sont surtout des hommes. La totalite des etudiants ayant repondu au questionnaire ont consomme des poppers. La majorite des personnes interrogees ont une bonne connaissance du statut legal et de la dangerosite des « poppers », en revanche, seuls 13 % connaissent precisement son usage therapeutique d’origine, la vasodilatation cardiaque. En grande partie, les consommateurs utilisent les poppers a des fins recreatives (93 %) en association a d’autres substances, mais tres peu dans un contexte sexuel (8 %), ce qui traduit une inversion des tendances puisqu’a la base, les poppers etaient tres sollicites par la communaute homosexuelle pour faciliter et ameliorer les pratiques sexuelles. Les effets ressentis lors de l’inhalation des poppers correspondent a ceux attendus et decrits dans la litterature : euphorie, fous rires et bien-etre. De meme pour les effets secondaires tels que bouffees de chaleur et palpitations cardiaques. Discussion L’ensemble de ces resultats montre que les poppers sont des produits connus et pleinement ancres dans les moeurs des populations de moins de 30 ans. De plus, cette consommation est banalisee du fait du statut legal des poppers, des effets ephemeres qu’ils procurent mais aussi de sa facilite d’approvisionnement. Neanmoins, il faut rester vigilant quant aux risques toxiques de ces produits comme l’avait rappele en 2014 l’Agence Nationale de Securite des Medicaments [1] .

Retina is the part of the eye suffering most damage from pharmaceutical molecules. Drug-induced retinopathies have been described but data are scarce and sometimes conflicting especially concerning its potential seriousness. The aim of this study was to investigate potential associations between drugs and retinal disorders using the French Pharmacovigilance data. We used the case/non-case method in the French PharmacoVigilance Database (FPVD) to identify drugs able to induce retinopathies. Cases were reports of retinal disorders in the FPVD between January 2008 and December 2012. Non-cases were all other reports during the same period. To assess the association between retinopathy and drug intake, we calculated the odds-ratio (OR) [with their 95% confidence intervals] for all drugs associated with at least 3 cases of retinopathy. Among the 123 687 adverse drug reactions recorded during the studied period, we identified 164 cases of retinal disorders. Significant associations were found for 11 drugs. The main therapeutic classes were antirhumatismals (hydroxychloroquine, chloroquine and etanercept: 18 cases), anti-infective (ribavirine, PEG-interferon-alfa-2a and cefuroxime: 16 cases) and antineoplastic drugs (imatinib and letrozole: 8 cases. Three other drugs were also found: raloxifene (5 cases), erythropoietin beta (4 cases) and ranibizumab (3 cases). Taking into account the limits of the methodology, our study confirmed the association between retinopathy and some expected drugs such as aminoquinolines, interferons, imatinib or ranibizumab. Other drugs like erythropoietin beta, cefuroxime, letrozole and etanercept were significantly associated with retinal disorders although this was not or poorly described in the literature. Thus, further prospective studies are necessary to confirm such associations.

Summary Introduction Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3 to 6 months following MTX therapy. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP. Material/methods Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed. Results Data were obtained on 52 pregnant women. The median age of patients was 28 (18–38), and the median gestational age at inclusion was 7 weeks after last menstrual period (3–22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 to 210 mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3 spontaneous abortions (6.7%) occurring 63 to 94 days after MTX administration, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48 mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50 mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6–20.4). Discussion/conclusion Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However, the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings.

Therapies - In Press.Proof corrected by the author Available online since lundi 5 decembre 2016

International audience; PURPOSE:To assess the efficacy of acetylleucine to improve or stop an attack of vertigo and dizziness (vertigo/dizziness).METHODS:Systematic review by 2 independent reviewers. Consultation of the Medline, Cochrane and ClinicalTrials.gov databases until September 2018. Keywords used: Acetylleucine, Tanganil®, Acetyl-DL-leucine, Acetyl-leucine. Trial selection: randomised controlled trials (RCTs) comparing acetylleucine against placebo.RESULTS:Up until 2018, no RCTs have been published on the efficacy of acetylleucine in vertigo/dizziness.CONCLUSION:There is no solid evidence of the efficacy of acetylleucine in vertigo/dizziness. Given its frequent prescription and the cost generated for the French social security system, high-quality randomised trials should be carried out to assess its efficacy.

Therapies - In Press.Proof corrected by the author Available online since jeudi 7 fevrier 2019

The objectives of this study were to describe the characteristics and natural history of beta-lactam-induced severe neutropaenia and to evaluate the risk of recurrences after another beta-lactam readministration. Reports of pure agranulocytosis associated with a beta-lactam exposure within the 10 days preceding the neutropaenia were extracted from the French Pharmacovigilance Database over the year 2010. Cases with another evident cause or more likely attributable to another drug were excluded. Data were analyzed for demographics, clinical and biological features, prognosis factors, granulocyte colony stimulating factors administration and outcome. Sixty-two cases were included (median age: 65 years). The median duration of treatment before neutropaenia was 16 days. In 47% of cases, the diagnosis was made on a systematic blood cell count. The median neutrophil count at nadir was 0.125 × 109 /L, and bone marrow examination evidenced features of neutrophilic maturation arrest or aplasia in 21 patients, hyperplasia of granulopoietic cells in three and normal findings in five. Three patients developed severe sepsis. All but one recovered a normal blood cell count within 2-56 days after beta-lactam discontinuation. The last patient died from recurrent severe septic shock. No significant effect of granulocyte colony stimulating factor on the mean duration of haematological recovery was found. Among the 21 patients who later received another beta-lactam, two experienced recurrence of the neutropaenia after receiving a beta-lactam from another subfamily. Beta-lactam-induced agranulocytosis was usually observed after prolonged treatment, and severe complications are uncommon. In most patients, a subsequent treatment with another beta-lactam was well tolerated.

Kaolin eating is an ancestral and worldwide tradition, particularly in women in order to relieve nauseas and abdominal troubles. Nevertheless, damaging effects such as anemia and intestinal troubles are well documented. However, compulsive disorders associated with kaolin intake are less known. We reported in this paper a severe craving observed in a young woman consuming kaolin for several years, associated with a microcytic iron-deficiency non-regenerative anemia. This paper allows to draw attention among physicians who are rarely informed of this practice imported from abroad and have consequently a limited role in informing patients of the potential deleterious side effects of geophagia.

Resume L’importance du fardeau medico-social des maladies du systeme nerveux contraste avec les limites de l’arsenal therapeutique disponible et les difficultes pour le developpement de nouvelles approches therapeutiques. Ces echecs sont expliques par une conjonction de phenomenes lies aux limites des modeles animaux, une trop forte focalisation sur des mecanismes physiopathologiques precis, ou des defauts methodologiques des essais cliniques. C’est peut-etre aussi le paradigme meme de la maniere dont la recherche est menee qui pourrait etre responsable de l’incapacite a aboutir a des strategies efficaces. L’objectif de cet atelier etait de definir les grandes orientations a donner pour aboutir au developpement efficace de nouvelles solutions therapeutiques. La recherche s’est longtemps focalisee sur les maladies au lieu de se consacrer aux dimensions cognitivo-comportementales, dont on sait maintenant qu’elles peuvent etre communes a differentes pathologies. Leur expression est souvent partielle et variable, mais il est aujourd’hui possible de les caracteriser au plan neurophysiologique ou en imagerie. Cette approche dimensionnelle ou syndromique devrait permettre d’aborder la question de maniere transnosographique en decloisonnant la recherche pour proposer : des modeles translationnels explorant les memes fonctions chez l’animal ou chez l’homme ; l’identification de groupes homogenes de patients definis selon leurs dimensions cliniques, anatomofonctionnels et moleculaires ; des developpements precliniques et cliniques enrichis par l’utilisation de biomarqueurs cognitivo-comportementaux, biologiques, neurophysiologiques et d’imagerie. Pour que la mutation s’opere, elle devra etre accompagnee par une synchronisation des actions des Tutelles, et par les mesures ad hoc des agences regulatrices.

The present work reviews the case reports of drug-induced sleep apnea recorded in the French pharmacovigilance database. Notifications are very rare (around 1/100 000 notifications). This paper shows that sleep apnea can be aggravated or revealed by some drugs. Main drugs involved were psychotropics (benzodiazepines, neuroleptics) and opioids.

Introduction La cocaine, alcaloide et puissant psychostimulant, est consommee le plus souvent en situation recreationnelle par voie sniffee, inhalee ou injectee. Une majoration de sa consommation et de sa purete est observee en France ces dernieres annees. Sa toxicite sur le systeme nerveux central et cardiovasculaire est bien documentee. Methodes Nous rapportons ici un cas d’hepatite aigue toxique a la cocaine par voie inhalee. Resultats Il s’agit d’un homme âge de 31 ans, consommateur regulier de cocaine par voie inhalee, ancien heroinomane substitue par methadone, hospitalise pour l’exploration d’infiltrats pulmonaires radiologiques dans un contexte de dyspnee et de douleurs diffuses. Le bilan d’entree montre une legere cytolyse (transaminases : 1,5 N) sans insuffisance hepatocellulaire. Deux jours plus tard, les douleurs abdominales s’amplifient et sont associees a une asthenie. Le bilan biologique revele une cytolyse avec insuffisance hepatocellulaire (ASAT : 39 N ; ALAT : 40,6 N ; PAL : 1,3 N ; GGT : 1,4 N ; bilirubine : N ; TP : 42 % ; facteur V : 30 % ; CPK : N). Les serologies virales sont negatives, de meme que les antigenuries legionelle, pneumocoque, la recherche de leptospirose et le bilan auto-immun. La recherche urinaire de cocaine a J8 est negative (absence de screening). L’histologie hepatique objective une necrose hepatocellulaire centrolobulaire, plus rarement mediolobulaire epargnant les zones periportales ainsi que de rares images de steatose microvacuolaire. Il decede a J16 dans un contexte de choc cardiogenique refractaire. Discussion Les elements chronologiques et l’histologie hepatique sont en faveur du role de la cocaine, les autres causes ayant ete eliminees et la recherche urinaire de cocaine realisee trop tardivement. Les hepatites aigues toxiques a la cocaine sont rares, elles surviennent generalement dans les heures ou les jours suivant une overdose. Les transaminases sont elevees et les phosphatases alcalines legerement augmentees. Le TP chute rapidement et la bilirubine commence a croitre 2 a 3 jours plus tard. L’histologie hepatique montre le plus souvent une necrose centrolobulaire ainsi qu’une steatose. Les deces sont frequents dans un contexte de defaillance multiviscerale. Les cliniciens doivent garder a l’esprit que la cocaine peut induire des hepatites toxiques qui peuvent conduire au deces.

Purpose To assess the prevalence of adverse drug reactions (ADRs) occurring in patients with Alzheimer’s disease (AD) or other dementia in France. Methods A cross-sectional multicentre study was conducted by the French network of the 31 regional pharmacovigilance centres on a given day. The subjects were selected by random draw to be a representative sample of French patients with dementia: consultations of dementia clinics, nursing-homes, acute and long care geriatric units, rehabilitation care geriatric units. The staff of each medical structure together with that of the pharmacovigilance centre defined a day for including the patients. Socio-demographic data, history, ADR and drugs given were registered. Results There were 1332 subjects included, 51.1% living at home, 48.8% in institutions, aged 82.08.0years (46–108); 61.3% suffered from AD. Meannumber of drugs was 6.33.1. Anti-dementia drugs were given to66.4%subjects. ADR prevalence was 5.0%(95% CI: 3.9–6.2) without a significant difference between at home and institutionalized patients. ADR consisted of gastro-intestinal (23.2%), central nervous system (17.4%) and psychiatric disorders (8.7%). Of the ADR, 31.9% were serious, and 47.8% preventable. The drugs most often involved were anti-dementia (28.9%), cardio-vascular (28.9%) and psychotropic drugs (26.4%, anxiolytics, hypnotics, antidepressants, neuroleptics). Conclusion This national scale study showed that iatrogenesis in patients with AD and related dementia can at times be serious and preventable. Therefore, special attention is required when prescribing psychotropic and anti-dementia drugs, as they are frequently used and induce half of the ADR in this population. Copyright © 2013 John Wiley & Sons, Ltd. key words—Alzheimer’s disease; dementia; adverse drug reaction; pharmacovigilance; cross-sectional study; pharmacoepidemiology

Background In addiction care, urine drug screening tests are recommended to assess psychoactive substances use. While intrinsic diagnostic value of these tests is demonstrated, the consequences of carrying out these tests on opiate maintenance treatment (OMT) have not been established. The main objective will be to assess the impact of on-site urine drug screening tests (OS-UDS) in general practice compared to routine medical care on OMT retention at 6 months in opioid-dependent patients initiating buprenorphine. Methods/Design The ESUB-MG study uses a pragmatic, cluster randomized controlled trial design. General Practitioners (GPs) regularly managing patients treated with buprenorphine and consenting for participating will be invited to participate. GPs will be randomly assigned to one of two groups for 6 to 24 months: (a) control group (usual care: standard medical strategy for assessing drug use); (b) interventional group (including 1/ a training session on practice and interpretation of OS-UDS; 2/ the supply of OS-UDS at GPs’ medical offices; 3/ performing an OS-UDS before the first prescription of buprénorphine). GPs will have to include 1 to 10 patients aged 18 years-old or more, consulting for starting treatment by buprenorphine, not opposed to participate. The primary outcome will be OMT retention at 6 months. Discussion This randomized interventional trial should bring sufficient level of evidence to assess effectiveness of performing OS-UDS in general practice for patients treated by buprenorphine. Training GPs to drug tests and supplying them in their office should lead to an improvement of opioid-addicted patients’ care through helping decision. Trials registration NCT02345655 (first registration May 14, 2014)

Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system. As effective treatment is unavailable, identification of all drugs that could be associated with PML is essential. The objective of this study was to investigate the putative association of reports of PML and drugs. We used the case/noncase method in the French PharmacoVigilance database (FPVD). Cases were reports of PML in the FPVD between January 2008 and December 2015. Noncases were all other reports during the same period. To assess the association between PML and drug intake, we calculated an adverse drug report odds ratio (ROR) with its 95% confidence interval. We have studied the delay of onset of PML for each drug concerned. Among the 101 cases of PML, 39 drugs were mentioned as suspect. The main therapeutic classes suspected with significant ROR were antineoplastic agents (n = 85), immunosuppressants (n = 67), and corticosteroids. A latent interval from the time of drug initiation to the development of PML is established: the median time to onset was 365 days (123-1095 days). The onset of PML is highly variable and differs among drug classes [from 1 to 96 months (IQR: 39.0-126)]. An association between PML and some immunosuppressant drugs was found as expected, but also with antineoplastic agents and glucocorticoids. An important delay of PML onset after stopping treatment is suspected and should alert prescribers. Prescribers but also patients should be informed about the potential associations with all these drugs. Monitoring could be necessary for many drugs to early detect PML.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Iatrogenic amnesia is one of the main aetiologies of transient amnesia. • Benzodiazepines and anticholinergic drugs are considered to be the drugs most often responsible for iatrogenic amnesia. • The impact of drugs in memory disorders is particularly pronounced in elderly people, especially due to polymedication. WHAT THIS STUDY ADDS • An association between memory disorders and some drugs, such as benzodiazepines, antidepressants and older anticonvulsants, was found as expected. • A strong association was found with unexpected drugs, such as benzodiazepine-like hypnotics (zopiclone and zolpidem), serotonin reuptake inhibitor antidepressants and newer anticonvulsants. • Non-neurotropic drugs, such as isotretinoin and ciclosporin, were also associated with memory disorders. AIMS To investigate putative associations of reports of memory disorders and suspected drugs. METHODS We used the case/noncase method in the French PharmacoVigilance Database (FPVD). Cases were reports of memory loss in the FPVD between January 2000 and December 2009. Noncases were all other reports during the same period. To assess the association between memory impairment and drug intake, we calculated an odds ratio with its 95% confidence interval. RESULTS Among the 188 284 adverse drug reactions recorded, we identified 519 cases of memory loss. The sex ratio was 0.6 and the median age was 54 years (range 4–93). The maximal number of cases occurred between 40–49 and 50–59 years. Evolution was favourable in 63% of the cases. We found significant odds ratios for benzodiazepines (alprazolam, bromazepam, prazepam, clonazepam etc.), benzodiazepine-like hypnotics (zolpidem and zopiclone), antidepressants (fluoxetine, paroxetine and venlafaxine), analgesics (morphine, nefopam and tramadol), anticonvulsants (topiramate, pregabalin, levetiracetam etc.), antipsychotics (aripiprazole and lithium) and other drugs, such as trihexyphenidyl, ciclosporin and isotretinoin. CONCLUSIONS Our study confirmed an association between memory disorders and some drugs, such as benzodiazepines and anticonvulsants. However, other drugs, such as benzodiazepine-like hypnotics, newer anticonvulsants, serotonin reuptake inhibitor antidepressants, isotretinoin and ciclosporin were significantly associated with memory disorders, although this was not described or poorly described in the literature. Taking account of the limits of this study in the FPVD (under-reporting, notoriety bias etc.), the case/noncase method allows assessment and detection of associations between exposure to drugs and a specific adverse drug reaction, such as memory disorders, and could thus generate signals and orientate us to further prospective studies to confirm such associations.

Resume Objectif Cette etude a evalue les notifications spontanees d’effets indesirables (EI) medicamenteux collectees sur le territoire francais entre le 21 octobre 2009 et le 15 juin 2010 pour les vaccins antiviraux A (H1N1)v. Methodes Cette campagne s’est caracterisee par la declaration en ligne par les professionnels de sante sur le site de l’Agence francaise de securite sanitaire des produits de sante (Afssaps) ainsi que par la declaration directe par les patients. Resultats Un total de 4 183 EI sous Pandemrixr® (5 % d’EI « graves ») pour 4,1 millions de doses administrees et de 591 EI sous Panenzar® (16 % d’EI « graves ») pour 1,6 millions de doses ont ete notifies. Pour Pandemrixr®, les EI « graves » les plus frequents concernaient des EI neurologiques (38,9 %), representes majoritairement par des paresthesies isolees ascendantes sans autre anomalie neurologique ni complication ulterieure. Pour Panenzar®, les EI neurologiques (28,9 %) etaient les EI le plus frequemment rapportes avec en majorite des convulsions febriles chez l’enfant. Les 22 deces (17 avec Pandemrixr® et 5 avec Panenzar®) ont ete notifies chez des patients presentant de lourds antecedents pathologiques : un lien avec le vaccin n’a pas ete retenu. Treize cas de syndrome de Guillain-Barre et 15 cas d’affections demyelinisantes ont ete declares. Aucune association avec le vaccin n’a pu etre etablie. Aucun cas de narcolepsie n’a ete releve durant cette periode de surveillance. Conclusion Les EI les plus frequemment observes ont ete neurologiques (paresthesies avec Pandemrixr® et convulsions febriles avec Panenzar®). Aucun EI « grave » et « inattendu » n’a ete, a ce jour, identifie durant ce suivi de pharmacovigilance. Le suivi de ces EI et les etudes complementaires, notamment pharmaco-epidemiologiques, viendront completer ce bilan.

Stimulation of cholinergic muscarinic receptors has been shown to provide substantial protection from DNA damage, oxidative stress and mitochondrial impairment, insults that may be encountered by neurons in development, aging, or neurodegenerative diseases. A study recently indicated that the activation of muscarinic receptors in astrocytoma cells modified the expression of the kinase p70S6K involved in the translational control. The translational control is in part regulated by a cascade of phosphorylation affecting proteins of the anti-apoptotic way controlled by mTOR (mammalian target of rapamycin) and the pro-apoptotic way controlled by PKR. The aim of our study was to investigate the effect of cholinergic muscarinic stimulation by an agonist oxotremorine on the anti-apoptotic way of translational control, in human neuroblastoma cells and in mice brain. Our results showed that muscarinic receptor activation significantly increased the expression of phosphorylated p70S6K, eIF4E and ERK without modification of mTOR activity in neuroblastoma cells and in cerebral cortex and hippocampus of mice, suggesting a stimulation of protein synthesis. Our findings support the notion that synaptic activity, through activation of neurotransmitter receptors, can provide substantial support of cellular survival mechanisms and suggest that loss of such synaptic input increases vulnerability to insult-induced programmed cell death.

The important medical and social burden of nervous system diseases contrasts with the currently limited therapeutic armamentarium and with the difficulty encountered in developing new therapeutic options. These failures can be explained by the conjunction of various phenomena related to the limitations of animal models, the narrow focus of research on precise pathophysiological mechanisms, and methodological issues in clinical trials. It is perhaps the paradigm itself of the way research is conducted that may be the real reason for our incapacity to find effective strategies. The purpose of this workshop was to define overall lines of research that could lead to the development of effective novel therapeutic solutions. Research has long focused on diseases per se rather than on cognitive and behavioural dimensions common to several diseases. Their expression is often partial and variable, but can today be well-characterised using neurophysiological or imaging methods. This dimensional or syndromic vision should enable a new insight to the question, taking a transnosographic approach to re-position research and to propose: translational models exploring the same functions in animal models and in humans; identification of homogeneous groups of patients defined according to the clinical, anatomico-functional and molecular characteristics; and preclinical and clinical developments enriched by the use of cognitive-behavioural, biological neurological, and imaging biomarkers. For this mutation to be successful, it must be accompanied by synchronised action from the public authorities and by ad hoc measures from the regulatory agencies.

Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3 to 6 months following MTX therapy. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP.Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed.Data were obtained on 52 pregnant women. The median age of patients was 28 (18-38), and the median gestational age at inclusion was 7 weeks after last menstrual period (3-22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 to 210mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3 spontaneous abortions (6.7%) occurring 63 to 94 days after MTX administration, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6-20.4).Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However, the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings.

Resume Le but de notre enquete aupres de 50 volontaires sains d’une etude monocentrique etait d’evaluer, a partir d’un questionnaire rempli par les participants, la comprehension, l’appreciation de l’information orale et ecrite et du cadre legal des essais, ainsi que l’hesitation a participer en fonction de l’âge, du sexe et de la profession. Une satisfaction globale a ete recueillie sur la comprehension et l’information orale mais 42 % des participants ont trouve le consentement ecrit trop long et un quart d’entre eux ne l’ont pas lu entierement. La connaissance du cadre legal (20 %) n’influencait pas la comprehension ni l’hesitation. Les hesitants (26 %) ont plus souvent juge ce cadre rassurant que les non hesitants (77 % versus 38 % ; p = 0,015). C’etait le cas des femmes, des professions medicales ou paramedicales et des plus jeunes (≤ 35 ans). Il serait interessant d’etudier chez les personnes ne donnant pas leur consentement, les raisons du refus et l’impact du cadre legal et ethique des etudes cliniques, pour ameliorer le partenariat des patients dans un contexte de medecine factuelle.

Depression is a complex disorder with heterogeneous clinical anomalies whose neurobiological understanding still remains unclear. Medications have been implicated as potential causes of depression but for many of them, data are controversial. The present study aims to investigate association bet ween drugs and reports of depression. We used the case/non case method in the French pharmacovigilance database (FPVD) to identify drugs associated with depression. Cases were reports of depression in the FPVD between January 2007 and December 2011. Non cases were all other reports during the same period. Data were expressed as reporting odds ratio (ROR) with their 95% confidence interval. Of the 114,692 reports recorded in the FPVD during the studied period, we identified 474 cases of depression. For the majority of the patients, they were considered as "non serious" (56%) and evolution was favorable (64%). Significant RORs were found for antiepileptics (topiramate, levetiracetam), anti-infective and especially anti-retroviral drugs (efavirenz, emtricitabine, tenofovir, etravirine, raltegravir), interferons and other agents including isotretinoin, methylphenidate, sodium oxybate, varenicline, montelukast, flunarizine, adalimumab, anastrozole. Taking into account the limits of the methodology, the present study described associations with mainly expected drugs belonging to various therapeutic classes but it also found a signal with some anti-retrovirals. On the contrary, we did not find some assumed associations like cardiovascular medications, antimalarial. For most of the drugs, one or more mechanisms were found to explain these depressogenic effects on the basis of animal and human literature. Even if such associations need to be confirmed by further prospective studies, cautions are necessary for many drugs to early detect depressive symptoms.

National audience; We report a case of behavioural impairments with hallucinations in a twelve-year-old girl, after consumption of boldo leaf infusions. The main alkaloid of boldo, named boldine, is very likely responsible for temporary neuropsychiatric disturbances present in the patient. The emergence of behavioural problems and hallucinations without any obvious cause, should lead to search for consumption of boldo leaf infusion ("tisanes"). This consumption must be avoided in children.

Neonatal acute adrenal insufficiency (AAI) is a rare but severe condition. We report a case of AAI following maternal exposure to moderate doses of corticosteroids during pregnancy. The neonate, born at term, presented with hypoglycaemia complicated by seizures. The AAI was confirmed by endocrine tests and after exclusion of differential diagnoses. Early diagnosis and treatment led to full recovery.

Background: Available data concerning the contribution of patient adverse drug reaction (ADR) reporting in practice are scarce. Few studies have compared patients’ reports with reports from healthcare professionals (HCPs). During the 2009–10 mass immunization campaign with A (H1N1)v2009 pandemic influenza vaccines, a reinforced pharmacovigilance plan was introduced in France according to European Medicines Agency recommendations. For the first time, patients were offered the opportunity to report suspected ADRs to pandemic vaccines directly to regional pharmacovigilance centres. Objective: The aim of the study was to compare the characteristics of patient and HCP ADR reports in order to assess the qualitative and quantitative contribution of patient reporting to the French Pharmacovigilance System. Methods: All spontaneous ADRs registered into the French Pharmacovigilance Database from 21 October 2009 to 15 June 2010, in which either one of the most frequently administered pandemic vaccines (i.e. Panenza® or Pandemrix®) was involved, were analysed. ADRs were classified as ‘serious’, ‘medically serious’ and ‘non-serious’. This study focused on ‘serious’ and ‘medically serious’ ADRs. An ADR was ranked as ‘medically serious’ when it required medical intervention or hospitalization within less than 24 hours. In each level of seriousness, frequency of ‘unlabelled’ ADRs, ADRs of ‘special interest’, imputability scores and category of ADRs according to Medical Dictionary for Regulatory Activitives (MedDRA®) primary System Organ Class were compared between patient and professional reports. Results: Among the 4746 reports received during the study period, 1006 (21.2%) originated from patients. HCPs reported significantly more ‘medically serious’ or ‘serious’ ADRs than patients (15.1% [565/3740] vs 8.4% [85/1006], respectively; p < 0.001). No difference was found in ‘unlabelled, serious’ ADRs between patients and HCPs (56.5% [n= 13] vs 56.7% [n= 136], respectively). Conclusions: In this first French experience of formal patient participation to ADR reporting, patient contribution to the total number of ADRs reached 21.2%. This study revealed no major qualitative difference between patient and HCP reports. ADR profiles reported by patients appeared to be consistent with those from professionals. Further investigations are necessary to assess the intrinsic quality of notification forms coming from non-professional reporters. However, this study is of particular interest in the context of publication of the first governmental decree that will formally integrate patient participation to the current French ADR reporting scheme.