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Introduction: Because patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012. Objectives: Describe and study determinants and evolution of patient reporting activity in France to assess patient involvement in pharmacovigilance.Method: Using the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare characteristics of patients and healthcare professionals (HCP) adverse drug reaction (ADR) report from 2011 to 2020. Then, we analyzed ADR report activities from patients according to regional demographics and economics characteristics.Results: We observed a significant and higher increase in ADR report over time from patient (r=0.89, pConclusion: Our results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance.

Introduction Because patients and patient organizations want to strengthen their role in the care pathway and drug evaluation and in order to improve pharmacovigilance activities, European competent authorities implemented regulations to allow direct reporting of adverse drug reactions related to medicinal products by patients in 2012. Objectives To describe evolution and analyze determinants of patient reporting activity in France in order to assess patient involvement in pharmacovigilance. Method Using the French national pharmacovigilance database, univariate and multivariate analyses were performed to compare the characteristics of adverse drug reaction (ADR) reports from patients and healthcare professionals (HCP) between 2011 and 2020. The relationship between regional patient ADR report activity and regional care provision and socio-professional characteristics was analyzed using the principal component analysis. Results A significant and higher increase in ADR reports over time from patients (r = 0.89, p r = 0.27, p = 0.002) has been observed. Patient ADR report activities compared to HCP concerned more women (80% vs. 55%, p p p p Conclusion Our results confirm an increasing involvement of patients in ADR report activities. The determinants of patient reporting activities are not only related to drug and medical factors but also to social factors. Digital tools may also play a role in health democracy in pharmacovigilance.

International audience; Dupilumab is an IgG4 antibody directed toward IL-4 and IL-13, two major effectors of the Th2 immunity response. It was originally developed for severe and/or refractory atopic dermatitis, nevertheless its use has secondarily been broadened to severe asthma . We report herein the case a 28-year-old, non-smoker male who presented to the emergency department with confusion, headaches, emesis and photophobia. His medical history included only a severe atopic dermatitis leading to dupilumab initation 4 months earlier. Physical examination revealed a meningoencephalitis syndrome, and a bilateral parotidomegaly.

Resume Objectifs Les Inhibiteurs Selectifs de la Recapture de la Serotonine (ISRS) et les Inhibiteurs de la Recapture de la Serotonine et de la Noradrenaline (IRSNA) peuvent induire des hyponatremies par le syndrome SIADH. Les objectifs de cette etude etaient de comparer le taux d’incidence des notifications d’hyponatremie en fonction des differents ISRS/IRSNA de maniere a identifier l'existence de molecules plus a risque, et de caracteriser un profil de patient a risque. Methode Les cas d’hyponatremie ont ete extraits de la Base Nationale de Pharmacovigilance (BNPV) et rapportes a l’exposition aux differents ISRS/IRSNA dans la population francaise. L’estimation de l’exposition a ete calculee a partir des donnees de delivrance extraites de l’Echantillon Generaliste des Beneficiaires (EGB), rassemblant les donnees du Systeme National d’Information Inter-regimes de l’Assurance Maladie (SNIIRAM). L’etude a porte sur la periode du 01/01/2011 au 31/12/2013. Resultats Le nombre de cas d’hyponatremie inclus dans l’etude etait de 169 pour 3 749 800 sujets majeurs ayant initie un traitement (taux d'incidence de cas notifies de 1,64/100 000 patients annee). La comparaison des taux d’incidence standardises ne montre pas de difference entre les molecules sauf pour la duloxetine qui preente un taux d'incidence significativement plus eleve (2,79/100 000 PA p > 0,03). Les facteurs de risque identifies sont l'âge avec un taux 12,5 fois plus important apres 75 ans, et le sexe feminin avec un taux d'incidence 2,4 fois plus eleve. Conclusions La comparaison des taux d’incidence a partir de la notification spontanee indique un risque d’hyponatremie plus important pour la duloxetine pour la periode 2011-2013. Ce resultat necessite d'etre confirme par d’autres etudes. L’âge eleve et le sexe feminin sont des facteurs de risque quelle que soit la molecule.

Aspirin (acetylsalicylic acid) has been used ever since the Antiquity for its painkilling and anti-inflammatory effects. Its antiplatelet properties have then extended its indications to the field of coronaropathy and vascular cerebral disease, and finally to vascular placental disease. Aspirin has been widely prescribed since the 1980's to prevent pre-eclampsia, intra-uterine growth retardation and fetal death of vascular origin. It has also been proposed to prevent unexplained recurrent miscarriages. Its use during pregnancy is considered as safe, provided the daily doses do not exceed 100mg. Aspirin has been proven efficient to prevent pre-eclampsia and fetal growth restriction in high-risk patients. The benefits of prescribing aspirin have been demonstrated neither for vascular placental disease prevention in low risk patients, nor in cases of unexplained recurrent miscarriages.

Objective We aimed to describe the effectiveness and safety of the moxifloxacin–rifampicin combination in non-staphylococcal Gram-positive orthopedic implant-related infections. Methods Patients treated with the moxifloxacin–rifampicin combination for an implant-related infection from November 2014 to November 2016 were retrospectively identified from the database of the referral centers for bone and joint infections in Western France. Results Twenty-three cases of infection due to Streptococcus spp. (n = 12), Cutibacterium acnes (n = 6), and Enterococcus faecalis (n = 5) were included. Ten patients with hip prosthesis were included. Infection was polymicrobial in 11 cases. According to the MIC, moxifloxacin was 1.5 to 11.7 times as active as levofloxacin against non-staphylococcal Gram-positive bacteria. We reported an 81.8% success rate, and no severe adverse effect. Conclusion The moxifloxacin–rifampicin combination is a valuable alternative for the treatment of non-staphylococcal Gram-positive implant-related infections because of the good activity of moxifloxacin against these bacteria and the potential activity on the biofilm.

Introduction Les patients immunodeprimes (ID) sont exposes a un risque accru d’infections severes responsables d’une morbi-mortalite importante, dont la grippe, qui peut etre prevenue par la vaccination. Malgre les recommandations du Haut Conseil de Sante Publique, la couverture vaccinale (CV) semble insuffisante chez les patients ID, mais les donnees sont limitees a l’echelon national. L’objectif de cette etude est d’estimer la CV anti-grippale au sein des differentes categories de patients ID en France. Materiels et methodes Les patients ont ete inclus a partir de l’echantillon generaliste beneficiaire (EGB), correspondant au 1/97e de l’ensemble de la population couverte par la Caisse Nationale d’Assurance Maladie, soit 805 000 personnes. Notre etude a porte sur les categories d’ID suivantes : personnes vivant avec le VIH (PVVIH), transplantes d’organe solide (TOS), chimiotherapie pour un cancer solide ou une hemopathie maligne, traitement immunosuppresseur (IS) et/ou biotherapie pour une maladie inflammatoire ou auto-immune (MI/AI) et splenectomises. Les patients ont ete identifies via leur affection de longue duree et/ou le PMSI et/ou un medicament immunosuppresseur prescrit. La delivrance de la vaccination anti-grippale par les pharmacies de ville a ete recherchee de 2011 a 2017. La vaccination a ete consideree complete si le patient avait eu une delivrance de vaccin une fois par an pendant toute cette periode et incomplete s’il avait eu au moins une delivrance de vaccin et au moins une annee sans delivrance. Resultats Au total, 3830 patients ont ete inclus : 1846 hommes et 1984 femmes, avec un âge moyen de 47,8 ans. La proportion de patients avec une vaccination complete de 2011 a 2017 etait de 9,6 % (119/1234) chez les PVVIH, 20,0 % (44/220) chez les TOS, 12,8 % (182/1420) chez les patients sous IS pour une MI/AI, 16,3 % (147/903) chez les patients sous chimiotherapie et 18,9 % (10/53) chez les splenectomises. La proportion de vaccinations incompletes etait, respectivement, de 29,5 %, 38,3 %, 26,1 %, 26,7 % et 18,9 % dans ces memes categories d’ID. La proportion de patients jamais vaccines contre la grippe sur cette periode etait de 60,9 %, 41,8 %, 61 %, 57 %, et 62,3 %. L’âge est un determinant majeur de la couverture vaccinale dans toutes les categories d’ID, avec une proportion de vaccinations completes, incompletes, et absentes, de 33,7 %, 36,9 % et 29,4 % chez les plus de 63 ans, versus 5,8 %, 24,7 % et 69,5 % chez les moins de 63 ans. Conclusion Cette etude confirme la faible couverture vaccinale contre la grippe au sein de differentes populations de patients immunodeprimes en France, particulierement chez les plus jeunes. Une meilleure sensibilisation des patients et des medecins est necessaire pour ameliorer cette couverture vaccinale.

International audience; OBJECTIVE: We aimed to explore whether the prevalence of manic switch was underestimated in randomized controlled trials (RCTs) compared to observational studies (OSs). METHOD: Meta-analyses and simple and systematic reviews were identified by two reviewers in a blinded, standardized manner. All relevant references were extracted to include RCTs and OSs that provided data about manic switch prevalence after antidepressant treatment for a major depressive episode. The primary outcome was manic switch prevalence in the different arms of each study. A meta-regression was conducted to quantify the impact of certain variables on manic switch prevalence. RESULTS: A total of 57 papers (35 RCTs and 22 OSs) were included in the main analysis. RCTs underestimated the rate of manic switch [0.53 (0.32-0.87)]. Overestimated prevalence was related to imipraminics [1.85 (1.22-2.79)]; to serotonin-norepinephrine reuptake inhibitors [1.74 (1.06-2.86)]; and to other classes of drugs [1.58 (1.08-2.31)], compared to placebo treatment. The prevalence of manic switch was lower among adults than among children [0.2 (0.07-0.59)]; and higher [20.58 (8.41-50.31)] in case of bipolar disorder. CONCLUSION: Our results highlight an underestimation of the rates of manic switch under antidepressants in RCTs compared to the rates observed in observational studies.

International audience; The oral antifibrotic agent, pirfenidone (PFD), 5-methyl-l-phenyl-[1H]-pyridine, is used to treat idiopathic pulmonary fibrosis (IPF), a chronic and fatal lung disease. In trials, PFD reduces disease progression and decreases mortality. The most common adverse events of PFD are skin manifestations (25%), described as photosensitivity or rash, but they are not well characterized. The objective of the present real-life study was to address the question of skin manifestations in patients treated with PFD for IPF.

Introduction Le demarrage de la dialyse en urgence est deletere et reste frequent en France (31 % en 2015). Aucune etude n’a explore l’association entre la consommation de medicaments potentiellement responsables d’atteinte renale aigue (Anti-Inflammatoires Non Steroidiens (AINS), Produits de Contraste Iode (PCI), Inhibiteurs Pompes a Protons (IPP)) et le demarrage de la dialyse en urgence chez les patients atteints d’Insuffisance Renale Chronique (IRC). Cependant, ces medicaments sont tres couramment prescris. Methodes Pour les patients ≥ 18 ans ayant demarre la dialyse en France en 2015, les donnees du registre REIN ont ete appariees indirectement a celles du Systeme National des Donnees de Sante (SNDS). Les patients ont ete categorises en 4 classes (utilisateur nouveau, actuel, ancien, non expose) en fonction des periodes d’exposition (1–30 jours, 31–90j, 91–365j) precedant le demarrage en dialyse, pour les AINS et IPP. Pour les PCI, leur exposition dans les 72 h et 7j precedant le demarrage a ete analysee. L’association entre l’exposition aux produits nephrotoxiques et le demarrage en urgence a ete etudiee apres ajustement sur les caracteristiques individuelles. Resultats obtenus ou attendus Parmi les 10 667 patients incidents 2015, 8805 ont ete apparies et 30,2 % ont demarre leur dialyse en urgence. Dans le modele multivarie, les nouveaux utilisateurs d’AINS avaient plus de probabilites de demarrer en urgence (OR : 1,95 ; IC95 % [1,1–3,4]). Le meme constat etait retrouve pour ceux ayant eu des actes avec PCI dans les 7 jours precedant le demarrage (OR : 1,44 ; IC95 %[1,2–1,7]). Aucune association significative n’a ete retrouvee entre l’exposition aux IPP et le demarrage en urgence. Conclusion Cette etude sur donnees appariees REIN/SNDS montre que le demarrage en urgence est independamment associe a une exposition recente aux AINS et PCI. L’utilisation de ces medicaments est surprenante car depuis longtemps non recommandee chez les patients atteints d’IRC a risque eleve de decompensation aigue. Une information renforcee doit etre donnee aux professionnels et aux patients.

Introduction Nous presentons le cas d’une patiente de 72 ans ayant presente une exceptionnelle toxidermie a l’Acupan. Methodes La patiente a beneficie d’un bilan en consultation d’allergologie suite a deux reactions de toxidermie, au decours d’anesthesies generales pour des ligatures de varices œsophagiennes. Resultats Le bilan allergologique retrouve une allergie au Nefopam avec des patch-tests positifs a 72 heures et une IDR positive en lecture retardee. Discussion La revue de la litterature ne retrouve pas de cas de toxidermie au Nefopam. Le Nefopam a ete contre-indique chez notre patiente, qui a par la suite ete reendormie pour de nouvelles ligatures de varices, sans recidive de la toxidermie. Conclusion A notre connaissance, il s’agit du premier cas de toxidermie au Nefopam, avec un bilan allergologique positif. Ainsi, en cas de reaction retardee apres une anesthesie, un bilan retarde pour le Nefopam doit etre effectue si celui-ci a ete utilise.

Introduction La pirfenidone (PFD), traitement oral antifibrotique de la fibrose pulmonaire idiopathique (FPI), est connue pour induire une photosensibilisation dans environ 25 % des cas. Au niveau des essais cliniques, ces reactions cutanees sont mal documentees. Nous rapportons les resultats d’une etude monocentrique menee chez des patients traites par PFD pour FPI. Materiel et methodes Entre avril 2014 et janvier 2017, tous les patients atteints de FPI sous PFD ont eu un examen dermatologique systematique dans leur suivi. Le but de notre etude etait d’analyser les cas de photosensibilisation a la PFD sur les plans clinique et photobiologique. Resultats Tous les patients (54 au total) recevaient des conseils de photoprotection avant mise sous PFD. Parmi les 12 malades ayant eu une photosensibilite sous PFD, huit (âge moyen de 71 ans) ont pu beneficier d’exploration photobiologiques : tous ont presente une reaction phototoxique (erytheme bien limite aux zones decouvertes siegeant sur le visage et dos de mains principalement, avec sensation de brulure suivi d’une pigmentation). Le temps d’exposition moyen a la PFD etait de 5,5 mois. La dose quotidienne de PFD au moment de l’eruption etait de 2403 mg pour tous les malades. A l’interrogatoire, les episodes de photosensibilite etaient lies a l’oubli d’application de creme solaire pour des expositions solaire minimes. L’atteinte cutanee etait evaluee comme peu severe (grade 2). Aucune hospitalisation n’etait necessaire. Une regression des lesions etait notee sous dermocorticoide. La PFD etait stoppee dans 3 cas et diminuee a 1602 mg/jour dans 1 cas. Les tests photobiologiques realises dans 6 cas au moment de l’eruption montraient une normalite de la dose erythemateuse minimale (DEM) polychromatique (spectre solaire : 95 % UVA et 5 % UVB) et une diminution de la DEM UVA, qui etait normale pour tous les patients testes (3 cas) avant mise sous PFD. Cinq malades ont beneficie de photopatch-test UVA a la PFD, avec 4 cas positifs et un temoin negatif ( Fig. 1 et 2 ). Discussion A notre connaissance, notre etude est la premiere mise au point documentee sur une serie de cas de photosensiblisation a la PFD « dans la vraie vie ». Les reactions etaient peu severes, ce qui peut etre explique par des mesures de prevention solaire assez bien respectees. Le potentiel phototoxique de la PFD etait confirme par le tableau clinique presente par nos malades. Les tests photobiologiques ont montre l’implication des UVA seuls comme responsables de la photosensibilite, ce qui est retrouve le plus souvent dans les photosensibilisations medicamenteuses. Conclusion Une prise en charge optimale des malades atteints de FPI sous PFD necessite une bonne collaboration entre pneumologues, dermatologues et medecins generalistes afin de prevenir les reactions cutanees de ce medicament.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) are frequently prescribed. These antidepressants can potentially induce serious hyponatremia through the SIADH syndrome. That seems to concern all molecules of these classes but the individual risk of each molecule is not well known. The aims of the study were to compare the incidence rate of each molecule in order to identify the existence of molecules more at risk of inducing hyponatremia and to characterize a profile of patients at risk for hyponatremia during a treatment with a SSRI or a SNRI.The cases of hyponatremia under SSRI/SNRI were extracted from the French pharmacovigilance database (BPNV). The exposition to the different SSRIs/SNRIs in the French population was estimated from the French National Health Insurance database (SNIIRAM) using a sampled database (Echantillon Généralistes des Bénéficiaires). The study ran from 01/01/2011 to 31/12/2013. The primary study endpoint was the incidence rate of notifications of the hyponatremia cases in patients treated by SSRI/SNRI and recorded into the BNPV database, related to the average annual number of corresponding treatments initiated during the same period.The number of cases of hyponatremia included in the study was 169 for 3 749 800 adult patients initiating treatment. The incidence rate of cases was 1.64 for 100 000 persons per year (PY). The standardized incidence rates between the different molecules showed no difference except for duloxetine (2.79/100 000 PY p 0.03). Identified risk factors were age, with a large increase of incidence rate from 75 years old (incidence 12.5 higher) and female gender.Comparison of the incidence rates from spontaneous reports indicates a greater risk of hyponatremia for duloxetine for 2011-2013. This result needs to be confirmed by other studies. The advanced age and female sex are risk factors, irrespective of the molecule.

Low-molecular-weight heparins are widely used for the prophylaxis and treatment of venous thromboembolism. However, they can induce adverse skin reactions. The most common reactions are delayed-type hypersensitivity reactions at injection sites. Rare systemic reactions have been reported. We report, to our knowledge, the first case of a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS) due to enoxaparin which belongs to the low-molecular-weight heparins class.

Aims. – To evaluate the incidence of the corticoid regulation in sports medicine. Topics. – Corticosteroids injections are a frequently applied therapy in sports medicine, for tendinitis, articular sprains and overuse syndromes. However, there is no updated agreement about effectiveness, and clinical guidelines are poor .Optimal timing, dosage and injection volume, remain answered. Comparison of efficacity with other treatments are not well established. At the present time, we cannot characterize the type of application (injection, pommade, iontophoresis…) in urine. Regarding anti-doping controls in France, during 2002, triamcinolone is the first corticosteroid discovered ( 81 cases), but bethametasone (26 cases) and prednisolone are also widely precribed. Perspectives. – Further researches are needed about type of prescription, effectiveness of therapy, time of elimination in reference with exercise, adverse effects. In our opinion, prescription of corticosteroids at present time cannot be widely justified.

Introduction Les recommandations actuelles sont en faveur de l’utilisation de fortes doses de cloxacilline pour le traitement des endocardites et infections osteoarticulaires a staphylocoques sensibles a la methicilline. Il existe peu de donnees sur la tolerance de cette utilisation. Nous decrivons une serie de 23 patients ayant presente une insuffisance renale aigue (IRA) au cours d’un traitement par fortes doses de cloxacilline. Patients et methodes Tous les cas d’IRA survenus chez les patients traites par cloxacilline et declares aupres du service de pharmacovigilance de notre CHU ont ete recenses retrospectivement. Les donnees des dossiers medicaux ont ete recueillies selon un questionnaire standardise. Resultats Parmi 23 patients inclus (16 hommes, 7 femmes), l’âge median etait 75 ans (66–80). L’IRA survenait apres un delai median de 4 jours avec une dose mediane de cloxacilline de 12 g par jour (10–12), pour des infections osteoarticulaires (n = 8) ou des endocardites (n = 7), a Staphylococcus aureus sensible a la methicilline (n = 17). Selon les criteres RIFLE, pour 20 patients, l’IRA etait au stade failure et la creatinine plasmatique mediane a 339 μmol/L (249–503). L’analyse urinaire suggerait une atteinte tubulaire pour 7 patients, 3 presentaient une hypereosinophilie et 8 des perturbations du bilan hepatique. Une seule ponction-biopsie renale a ete realisee retenant le diagnostic de nephropathie immuno-allergique aigue. Tous les patients presentaient au moins un facteur de risque d’IRA, dont l’administration de traitements nephrotoxiques : gentamicine (n = 19), diuretiques (n = 15), inhibiteur de l’enzyme de conversion de l’angiotensine (n = 8), antagonistes des recepteurs de l’angiotensine (n = 6). Treize patients (57 %) ont presente un surdosage en cloxacilline. A 3 mois, 12 patients ont recupere totalement et 10 partiellement, 1 est decede. Discussion La surveillance rapprochee du traitement par cloxacilline, de la fonction renale et l’eviction des facteurs de risque en particulier medicamenteux, pourrait reduire le risque d’IRA au cours du traitement par fortes doses de cloxacilline, en objectivant precocement le surdosage et en permettant l’adaptation de la posologie. Conclusion Dans notre etude, tous les patients ayant developpe une IRA au cours d’une antibiotherapie par cloxacilline presentaient d’autres facteurs de risque d’IRA ou un surdosage. L’evolution est le plus souvent favorable apres l’arret de la cloxacilline.

Resume Introduction La Disulonel (dapsone + oxalate de fer) est une sulfone utilisee dans le traitement de nombreuses dermatoses. Nous rapportons deux cas d’hepatosideroses secondaires a la prise au long cours de Disulonel. Observations Cas n° 1. Un homme de 51 ans etait traite par Disulonel pour une dermatose neutrophilique. Apres 17 ans de traitement, une hyperferritinemie, une augmentation du fer serique associees a une hemolyse etaient trouvees. La biopsie hepatique confirmait l’hepatosiderose. Une hemochromatose genetique etait ecartee par l’absence de la mutation C282Y du gene HFE. Cas n° 2. Un homme de 52 ans recevait un traitement par Disulonel depuis 25 ans pour une dermatite herpetiforme lorsqu’une hyperferritinemie, une augmentation du fer serique ainsi qu’une hemolyse etaient trouvees. La surcharge hepatique en fer etait confirmee par la biopsie hepatique. La recherche de la mutation C282Y du gene HFE etait negative. Commentaires Dans nos observations, une hepatosiderose etait decouverte apres l’utilisation prolongee de Disulonel. Cette complication est exceptionnellement rapportee. Chez les souris une relation entre utilisation de dapsone et surcharge en fer splenique et hepatique a ete trouvee par le biais de l’hemolyse chronique. Bien qu’il soit difficile d’extrapoler a l’homme, une hemolyse chronique avec une surcharge martiale etait egalement presente dans nos cas. De plus, en France, la dapsone est commercialisee sous la forme associee a de l’oxalate de fer, potentialisant la surcharge en fer. Nos cas posent donc la question d’une surveillance du fer serique et de la ferritinemie au cours d’un traitement par Disulonel.

Background Several case reports suggested that tumour necrosis factor-α (TNF) inhibitors might increase the incidence and/or alter the natural course of melanoma towards a more aggressive behaviour. Objective Our objective was to point if history of melanoma in patients exposed to TNF inhibitors could present with a particular pattern at diagnosis or during follow-up. Methods We performed a retrospective multicentre study settled in the West part of France to collect and analyse all cases of patients with melanoma who received anti-TNF therapy. Results Fifteen cases were included. First, 10 patients (mean age: 55.6 years; sex ratio: 1) had a melanoma diagnosed after TNF inhibitors initiation. The mean duration between initiation of treatment and melanoma was 48.7 months. Two patients died of metastatic disease. Second, four patients had a past history of melanoma before anti-TNF therapy (mean duration of treatment: 10.8 months). None experienced a progression of melanoma disease. Last, one woman had a past history of melanoma before and then developed a second melanoma when exposed to biotherapy. Conclusion Our case series does not reveal a distinct profile of melanoma in the patients exposed to TNF inhibitors. Additional prospective trials including larger number of patient are needed to demonstrate the possible link between biological therapy with TNF inhibitors and development of melanoma.

Introduction Les allergies a la chlorhexidine sont bien connues, mais restent rares chez l’enfant. Methodes Un garcon de 3 ans, ayant comme antecedent une probable maladie serique a l’amoxicilline consulte pour le bilan d’une reaction survenue a 2 ans, 15 minutes apres application sur une plaie du menton de Biseptine® que ses parents avaient longtemps utilisee pour les soins du cordon. Un œdeme labial et une toux seche sont survenus, traites aux urgences par corticoides et antihistaminiques oraux. Resultats Le prick-test a la chlorhexidine aqueuse (2 mg/mL) est tres positif et entraine en 30 min un œdeme labial et une toux seche resolutifs apres Polaramine® et Celestene® oraux. Il s’agit d’une allergie a la chlorhexidine avec une probable sensibilisation lors des soins au cordon. Discussion La chlorhexidine entraine des dermatites de contact et des reactions systemiques, rares chez l’enfant. Le diagnostic est pose par les PT, IDR et eventuellement des IgE specifiques. L’analyse de la litterature n’a pas retrouve d’autre cas de reaction systemique lors des tests cutanes, ni de reaction si jeune. L’usage de la chlorhexidine est frequent, dans des bains de bouche, des cosmetiques… elle est largement recommandee pour l’antisepsie, mais aussi les soins au cordon, ce qui a pu etre une voie de sensibilisation pour notre cas. Dans des etudes recentes, elle est imputee dans 5 a 9,6 % des anaphylaxies perioperatoires lorsqu’elle est recherchee systematiquement. Certains auteurs recommandent donc des tests a la chlorhexidine pour tout bilan de reaction perioperatoire, comme le latex, puisqu’elle n’est pas notee sur les feuilles d’anesthesie. Conclusion L’anaphylaxie a la chlorhexidine peut survenir chez l’enfant, en dehors de reactions perioperatoires. De plus, il est necessaire de confirmer l’augmentation de sa prevalence en la recherchant plus souvent dans les bilans d’allergo-anesthesie.

Disulone (dapsone + iron oxalate) is a sulfone used in the treatment of numerous skin diseases. We report two cases of hepatosiderosis secondary to long-term administration of Disulone.Case n degrees 1. A 51-year-old man was treated with Disulone for a neutrophilic skin disease. After 17 years of treatment, elevated serum ferritin and free iron with hemolysis were found. Liver biopsy confirmed hepatosiderosis. A diagnosis of genetic hemochromatosis was ruled out by the absence of C282Y mutation of the HFE gene. Case n degrees 2. A 52-year-old man receiving Disulone for dermatitis herpetiformis for 25 years presented elevated serum ferritin and free iron with hemolysis. Hepatic iron overload was confirmed by liver biopsy. The absence of C282Y mutation (HFE gene) ruled out a diagnosis of genetic hemochromatosis.In our two cases, hepatosiderosis was noted after long-term administration of Disulone. This complication has been reported only rarely. In murine models, a relationship was found between prolonged administration of dapsone and hepatic iron overload as revealed by hemolysis. Although it is difficult to extrapolate this relationship to humans with any certainty, our patients had also chronic hemolysis and iron overload secondary to administration of Disulone. Moreover in France, dapsone is marketed in combination with iron oxalate, with the attendant risk of iron overload. These cases raise the question of the need for serum ferritin analysis during Disulone therapy.

In some situations such as post-virus or post whooping cough, a non productive subacute cough may occur without apparent local inflammation, epithelium abnormalities or bronchoconstriction. This subacute or chronic cough represents a real syndrome (cough disease) due to the central nervous system (CNS) and its ortho and parasympathic outputs. At the CNS level, functional disturbancies and neosynaptogenesis can be described, with the intervention of the NMDA-type glutamatergic receptors.The neurons located in the expiratory area of the breathing center (Pre-Boetzinger complex of the lower brainstem) present exagerated responses to stimuli, due to the repetitive stimulation of the NMDA receptors; this phenomenon is similar to long-term-potentiation (LTP), the molecular basis of learning, memory and neosynaptogenesis. The cough reflex is thus amplified and rapidly chronic and would justify any pharmacological intervention at the NMDA-receptors level.More recently 5TH4 receptors have been implied in the control of respiration; an overexpression of these receptors in the Pre-Boetzinger area could contribute to an increase of the cough reflex.The present review aims at summarizing the main rationale target to pharmacologically block the chronic cough.

Two men (66 and 73 Years) with a cardiovascular history were hospitalized for rapid onset encephalopathy associated with myoclonia and an extrapyramidal syndrome. On the basis of the French Pharmacovigilance system, this symptomatology has been attributed to the coadministration of a proton pump inhibitor, lansoprazole (15mg/day) with levodopa. Lansoprazole withdrawal led to a normalisation of the situation.

The last decade was very fruitful in neuropharmacology and notably in the therapeutic strategies of dementia and Alzheimer's disease (AD). The amount of data, information and breakthroughs is nevertheless difficult to apply in direct relationship with patients. The present review aims at classifying information according to their origins: epidemiology, clinical trials, neurosciences. A guide for drug prescription in Alzheimer's disease is thus warranted and becomes clearer, sure that, in the next future modifications and new strategies will appear. The main goal of the present review is to summarize the state-of-the-art for a non specialist in AD.

Leflunomide is a new oral drug licensed for the treatment of rheumatoid arthritis and psoriatic arthritis. Common adverse events reported include gastrointestinal symptoms, reversible alopecia, hypertension and transient alteration in liver function tests. Severe cutaneous drug reactions have been reported recently with its increased clinical used such as vasculitis, erythema multiforme, toxic epidermal necrolysis (1) and drug hypersensitivity syndrome (2). We report a case of photodistributed eruption with rhabdomyolysis due to leflunomide. This patient was a 60-year-old woman, with a 19-year history of rheumatoid arthritis and Sjogren’s syndrome. She was previously treated with gold salts, hydroxychloroquine and salazopyrine. Leflunomide (10 mg/day) and prednisone (18 mg/day) were started in December 2008 after a methotrexate-induced leucopenia. Other laboratory findings revealed positive rheumatoid factor and a high titre (1/2560) of antinuclear antibodies. Anti-DNA and antiextractable nuclear antigen (ENA; anti-SSA and anti-SSB) antibodies were positive. On 11, May 2009, she developed skin lesions on her face. The administration of leflunomide was stopped and the patient received cholestyramine 8 mg/day. Fifteen days later, she presented to our department, with extensive eruption. Examination revealed erythematous plaques particularly on the face, sparing the eyelids and the area under the nose (physiological shade’s areas), on the neck and the upper back with cut-off in the area covered by the bra (Fig. 1). Some lesions were found on the limbs, abdomen and buttocks. There was neither fever nor mucosal involvement. Abnormal routine laboratory findings were as follows: AST, 54 IU/l (normal o 30); ALT, 59 IU/l (normal o 30); serum creatine kinase (CK), 1480 IU/l (normal o 145). Antinuclear antibodies’ titre was increased (1/2560), with the detection of anti-DNA and anti-ENA (anti-SSA and anti-SSB) antibodies. Complement C3 and C4 levels were normal. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies were elevated to 419 IU/ml (normal o 20) and 649 IU/ml (normal o 25), respectively. The results of hepatitis B, hepatitis C virus, cytomegalovirus, parvovirus, Epstein–Barr virus, human herpesvirus-6 and immunodeficiency virus analyses were negative. A skin biopsy showed numerous necrotic keratinocytes, vacuolization of the epidermal basal cell layer and lymphocytic perivascular infiltrate. Direct immunofluorescence performed in the skin lesion was negative. The evolution was marked by a normalization of aminotransferases and CK values within 1 month after stopping the drug. Treatment with topical desonide led to the disappearance of the lesions in 2 months without recurrence after a 1-year follow-up. The patient declined photobiological investigations. The clinical presentation of skin lesions was compatible with photosensitivity supported by occurrence of the rash in spring. The photodistributed eruption, the skin biopsy result and the liver involvement were consistent with drug reaction. Despite a long delay, the temporal relationship between the commencement of leflunomide in winter and the onset of the photodistributed eruption suggests a causative link in this patient.

In humans, some psychotropic agents (alcohol, drugs, illicit substances) have been suggested to play a role in the occurrence of major behavioural disorders, mainly due to the suppression of psychomotor inhibition. Behavioural disinhibition is a physiological mechanism which allows humans to behave appropriately according to a given environmental situation. The behavioural disinhibition induced by either therapeutic dosage or misuse involves the loss of restraint over certain types of social behaviour and may increase the risk of auto or hetero-aggression and acting out. The increased use of psychotropic agents in recent years and the occurrence of unwanted effects are worrying and must be detected and evaluated. The objective of the present study was to establish a causal relationship between psychoactive substance use and occurrence of major behavioural disorders, such as paradoxical rage reactions and suicidal behaviour, based on a literature analysis. It consisted of reviewing reports of drug-induced violent reactions in healthy volunteers and demonstrating, where possible, a cause-effect relationship. Patients with schizophrenia and psychopathic personalities were not included in our study since psychiatric comorbidity could influence behavioural responses. Psychotropic agents included drugs, licit and illicit substances already associated with violence in the past. Many reports used the "Go/No Go test" to evaluate the disinhibiting effect of psychotropic substances; this allows the "cognitive mapping" of drugs. The results suggest that only alcohol, antidepressants, benzodiazepines and cocaïne are related to aggressive behaviour. The best known precipitant of behavioural disinhibition is alcohol, which induces aggressive behaviour. However, there are large differences between individuals, and attentional mechanisms are now recognised as being important in mediating the effects of alcohol. Suicidal tendency as an adverse antidepressant reaction is rare, especially with atypical antidepressants. However, the risk of acting out exists and the responsibility of antidepressant agents in the genesis of suicidal tendencies is now established. The disinhibiting effects of benzodiazepines are well-known and proven by clinical trials. It's a "model" of acting out, and the causal relationship is undeniable. That cocaïne is related to violent behaviour is demonstrated by its pharmacological actions on CNS. The chronic use of cocaïne induces "a limbic dyscontrol syndrome" based on the altered activity of limbic structures. On the contrary, we could not demonstrate a causal relationship between aggression and either cannabis, ecstasy or phencyclidine. Cannabis abusers look particularly for euphoria and relaxing effects. Aggression as an adverse cannabis reaction is very rare and occurs in most cases in association with other drugs and in predisposed individuals. Ecstasy use may lead to long-term alterations of neuronal function in the human CNS and cause psychiatric disorders. However, there is insufficient information about long-term use of ecstasy to estimate its role in the occurrence of behavioural disorders. Clinical and forensic assumptions about phencyclidine and violence were not warranted. However, the substance-effect relationships can be criticized in the case of alcohol, antidepressants, benzodiazepines and cocaïne. In fact, individual, social and psychiatric factors exert an influence on behaviour that is superior to the pharmacological effect of psychotropic agents. The most important parameter in drug-induced behavioural disinhibition is dosage, but mode of administration is also important. In addition, polysubstance abuse is very common. Substances may be taken simultaneously and alcohol is frequently combined with drugs. The combinations of substances result in multiple interactions, and very little is known about the effects of these interactions on violence in humans. Co-occurrence of substance abuse and other mental disorders is also very frequent. Multiple substance abuse should be avoided, because potential interactions between two or more drugs are more likely to cause violent behaviour. In the future, a specific treatment of these deleterious phenomena will have to be considered in order to reduce drug-induced iatrogenic behavioural disorders.

Introduction et objectifs Le vaccin 17D est un vaccin vivant attenue utilise depuis 1936 pour la prevention de la fievre jaune. Trois types d’evenements indesirables graves (EIG) neurologiques ont ete rapportes, avec une incidence estimee a 0,5/100 000 vaccins : i) meningite/meningo-encephalite ; ii) syndrome de Guillain Barre ; iii) encephalomyelite demyelinisante. Materiels et methodes Etude retrospective des EIG neurologiques rapportes au centre de pharmacovigilance de Rennes entre 2000 et 2008 et classes comme certainement ou probablement lies au vaccin anti-amarile selon les criteres du Yellow Fever Safety Working Group . Resultats Deux meningoencephalites et 2 meningites ont ete signalees. Il s’agit de 3 hommes et 1 femme, âges de 21 a 55 ans. Les premiers symptomes, apparus 19 a 23 jours apres une premiere administration de vaccin 17D, sont fievre ( n = 4), syndrome meninge ( n = 2) et confusion ( n = 2). L’analyse du LCR revele une meningite (10-84 elements/mm 3 ), de predominance lymphocytaire (64-84 %), peu hyperproteinorachique (0,4-0,68 g/l). Le lien avec la vaccination est certain dans un cas (IgM anti-amarile dans le LCR) et probable pour les 3 autres. Trois patients ont gueri sans sequelle, tandis qu’un patient a conserve un deficit de l’attention et un syndrome cerebelleux. Rapportes aux 18 000 doses de vaccin anti-amarile administrees au centre de vaccinations sur cette meme periode, ces 4 observations suggerent une incidence d’EIG neurologiques a 9,9/100 000 vaccins. Conclusion Cette serie confirme les donnees anterieures concernant les EIG neurologiques du vaccin 17D, uniquement decrits chez des primo-vaccines, sans predilection pour les personnes âgees et de bon pronostic. L’incidence estimee a travers cette etude, 20 fois plus elevee que les estimations anterieures, est proche du risque de contracter la fievre jaune en Amerique du Sud ou en Afrique (respectivement estime a 10 et 100/100 000 voyageurs/mois).

Molecules currently available or in late phases of development for the treatment of Alzheimer's disease have modest and apparently equivalent efficacies. Thus, the choice will depend on the safety profile of these drugs and on the patient characteristics. The aim of this review is to undertake an inventory of adverse effects and interactions reported in the literature for anticholinesterasics (the only ones approved by authorities). As most of the molecules described in this article are still in early phases of development, data reported here mainly issued from clinical trials carried out on specific populations. Most of these reported adverse effects have not been attributed according to the rules of pharmacovigilance. Nevertheless, we believe that the data presented in this review will be of great interest to clinicians and pharmacovigilance specialists as the compounds concerned become available on the market.

International audience; BACKGROUND: The European Medicines Agency (EMA) has developed risk minimization measures (RMMs) to reduce the use of the teratogenic drug, sodium valproate (VPA). The objective was to assess the impact of these RMMs among females with epilepsy in France. METHODS: We used data from the French National Health Insurance Database (SNDS), including 114,936 females aged under 50, with a reimbursement claim for an antiepileptic drug from January 2011 to December 2017, and identified as people with epilepsy. We used a controlled interrupted time series stratifying on age: girls (0-14 years old) and women of childbearing age (15-49 years), and with 129,917 males as controls. RESULTS: VPA prevalent use among girls and women of childbearing age with epilepsy decreased significantly after the issue of the RMMs (trend changes of, respectively, -5 and -4 users per 1000 females at-risk per quarter in comparison to the control group). We did not detect any significant change in VPA incident use. CONCLUSIONS: VPA use decreased over the study period among females with epilepsy but there were still 317 women and 206 girls started on VPA therapy VPA in 2017 (8 per 1000 at-risk and 18 per 1000, respectively). This suggests that either the measures should be strengthened or that the lowest level of VPA use has been reached. In this context, the introduction of a new RMM (in 2018) needs to be evaluated.